I 1111111111111111 11111 111111111111111 IIIII IIIII 1111111111 111111111111111111
`US008329696B2
`
`c12) United States Patent
`Pilarski et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,329,696 B2
`Dec. 11, 2012
`
`(54) SOLID STATE FORMS OF SITAGLIPTIN
`SALTS
`
`(75)
`
`Inventors: Gideon Pilarski, Holan (IL); Nurit
`Perlman, Kfar Saba (IL); Ariel
`Mittelman, Elad (IL); Nada Kosutic
`Hulita, Zagreb (HR); Marina Kalujny,
`Ariel (IL); Revital Ramaty,
`Ramat-Hasharon (IL)
`
`(73) Assignee: Teva Pharmaceuticals Industries Ltd.,
`Petach-Tikva (IL)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 144 days.
`
`(21) Appl. No.: 12/749,486
`
`(22) Filed:
`
`Mar. 29, 2010
`
`(65)
`
`Prior Publication Data
`
`US 2010/0249140Al
`
`Sep. 30, 2010
`
`Related U.S. Application Data
`
`(60) Provisional application No. 61/164,563, filed on Mar.
`30, 2009, provisional application No. 61/170,697,
`filed on Apr. 20, 2009, provisional application No.
`61/174,073, filed on Apr. 30, 2009, provisional
`application No. 61/182,772, filed on Jun. 1, 2009,
`provisional application No. 61/186,031, filed on Jun.
`11, 2009, provisional application No. 61/302,626,
`filed on Feb. 9, 2010, provisional application No.
`61/304,615, filed on Feb. 15, 2010, provisional
`application No. 61/309,024, filed on Mar. 1, 2010,
`provisional application No. 61/312,376, filed on Mar.
`10, 2010, provisional application No. 61/315,149,
`filed on Mar. 18, 2010.
`
`(51)
`
`Int. Cl.
`(2006.01)
`A61K 311495
`(52) U.S. Cl. ........................................ 514/249; 544/350
`(58) Field of Classification Search .................. 514/249;
`544/350
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`FOREIGN PATENT DOCUMENTS
`10/2004
`WO 2004/085378
`10/2004
`WO 2004/085661
`10/2004
`WO 2004/087650
`1/2005
`WO 2005/003135
`3/2005
`WO 2005/020920
`4/2005
`WO 2005/030127
`8/2005
`WO 2005/072530
`3/2006
`WO 2006/033848
`3/2007
`WO 2007 /035198
`6/2009
`WO 2009/070314
`7/2009
`W02009/085990
`1/2010
`W02010/000469
`W02010/012781
`2/2010
`
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`Primary Examiner - Douglas M Willis
`(74) Attorney, Agent, or Firm -Arent Fox LLP
`
`(57)
`
`ABSTRACT
`
`Solid state forms of Sitagliptin salts ( e.g. Sitagliptin sulfate,
`Formula I), processes for preparing the solid state forms, and
`pharmaceutical compositions thereof, are provided. These
`compounds are of a class of dipeptidyl peptidase IV enzyme
`inhibitors which are useful, for example, for the manufacture
`ofa medicament for the treatment of type 2 diabetes mellitus.
`
`Formula!
`
`0
`II
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`0
`
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`
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`
`10 Claims, 70 Drawing Sheets
`
`Merck Exhibit 2043, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
`
`Sheet 1 of 70
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`US 8,329,696 B2
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`Merck Exhibit 2043, Page 2
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
`
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
`
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`Merck Exhibit 2043, Page 4
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

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`U.S. Patent
`
`Dec. 11, 2012
`
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`Merck Exhibit 2043, Page 5
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

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`U.S. Patent
`
`Dec. 11, 2012
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

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`U.S. Patent
`
`Dec. 11, 2012
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`Merck Exhibit 2043, Page 8
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
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`Merck Exhibit 2043, Page 9
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

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`U.S. Patent
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`Dec. 11, 2012
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
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`Merck Exhibit 2043, Page 13
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

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`Dec. 11, 2012
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

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`Dec. 11, 2012
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

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`Dec. 11, 2012
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
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`
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`11
`i
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`Sample After 12 days at 100% RH -form S1
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`j
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`1.
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`6.0
`
`10.0
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`14.0
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`18.0
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`26.0
`22.0
`degrees 2 theta
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`30.0
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`34.0
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`38.0
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`42
`
`~
`00
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`
`Merck Exhibit 2043, Page 18
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`FIG. 1 r
`
`~
`00
`•
`~
`~
`~
`
`~ = ~
`
`:,.::-Y-"_;,_;,n7.,-_;,_;,,._,._,._,.,,h~;..,:,:,:,.h~.,,,.~.~'.~;_,,
`
`Method: 25-250C 10C/min 40ml/minN2150µI Alumina
`di 1.00 s
`25.0-250.0°C 10.00°C/min, N2 40.0 ml/min
`Synchronization enabled
`
`-;~=·-0',:~ ..•.
`
`.,.,,,,.,,,,,,,,,,,✓//✓/✓//✓/✓/✓''"''''''' .... ,,,,,,""',/.;,"''''''""'
`W/t/.•'/.;;;;;;;;;;;;;,•'~f////✓//✓//✓/l✓/.1
`i
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`1 / / . ,Y / / / / / / / / / / / / /~% t
`
`1///////////✓✓•✓✓/////////////,,
`
`*
`..
`
`2
`mgl Step
`
`-0.9317%
`-0.1189 mg
`32.86 °C
`Left Limit
`Right Limit 97.20°C
`
`•
`
`:
`\
`~_(//✓/✓>(//////////////////-4'✓✓-
`::
`"w;;;,,;,\~"'''w,Mq;"'+-w,,,-,,,,,,,,hv,-,,
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`
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`
`0.01
`O A
`mg C -1
`
`!
`
`1
`
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`
`Step
`
`-2.2059 %
`-0.2816 mg
`Left Limit 97.43 °C
`Right Limit 165.38 °C
`
`if/-t////////jffe~_.. .... .,..,..,...,..,..,...,..,..,...,.f'"., • .,.,,..,..,..,...,..,..,...,.4-,..,....,,.,....,.,,..,,.,,,,.,4,,
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`r
`
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`Step
`
`-3.0889 %
`-0.3943 mg
`Left Limit 165.63 °C
`Right Limit 202.20 °C
`
`c ('D
`~ ....
`.... .
`0 ....
`
`N
`
`N
`
`('D
`('D
`
`QO
`
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`.....
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`
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`1
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`l
`40
`
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`60
`
`1
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`
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`1
`240 °C
`
`d r.,;_
`00 w
`N
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`\0
`
`0--, = N
`
`Merck Exhibit 2043, Page 19
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`FIG. 1s
`
`Sitagliptin SAL60-b
`Sitagliptin SAL60,
`
`~
`00
`•
`~
`~
`~
`
`~ = ~
`
`Method: 25-250C 10C/min 40ml/minN2 150µ1 Al203
`di 1.00 s
`25.0-250.0°C 10.00°C/min, N2 40.0 ml/min
`Synchronization enabled
`
`-~·:;r'.::::: ·.. --~~-...... ::;~l
`
`MinMax
`Min -3.76e-03 mg°CA-1
`at 153.20°G
`o A
`Max -99.68e-06 mg C -1
`at
`168.93°G
`
`0.01
`o A
`mg C -1
`
`. ., ____ _
`
`, .. ,
`
`-~.,~-
`
`0.5
`mg
`
`MinMax
`Min -2.25e-03 mg°CA-1
`at 67.62°C
`o A
`Max -753.39e-06 mg C -1
`at
`90.28°G
`
`Step
`
`-1.9474 %
`-0.1513 mg
`Left Limit 33.80°G
`Right Limit 90.35°G
`
`~
`
`.
`
`\,J
`
`'~,,
`
`'\
`
`·(•;.,
`
`':}
`
`J......._.,.,_········--····=·····•·····
`
`'·.,._.,,
`
`Step
`
`-2.6481 %
`-0.2058 mg
`Left Limit 90.11 °C
`Right Limit 168.95 °C
`
`'
`-r----- -----r-----------y-----------f ·------ --f----- ----:-:-----------; --------- t ----------:------- -- ; --- ---- ; ---------~---------- r------- -- :------ ---- ::----------/2 ----------; ----------r ------ ---1---- -----:: --------- ~ ---------·:: ~ ---- - 1
`220 240 ...... tsC
`40
`60
`80
`100
`120
`140
`160
`180
`200
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`
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`
`0--, = N
`
`Merck Exhibit 2043, Page 20
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
`
`Sheet 20 of 70
`
`US 8,329,696 B2
`
`0
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`Merck Exhibit 2043, Page 21
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
`
`Sheet 21 of 70
`
`US 8,329,696 B2
`
`0
`00
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`Merck Exhibit 2043, Page 22
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
`
`Sheet 22 of 70
`
`US 8,329,696 B2
`
`ro
`+-'
`(])
`..c
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`
`Merck Exhibit 2043, Page 23
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
`
`Sheet 23 of 70
`
`US 8,329,696 B2
`
`0
`00
`M
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`
`0 -
`
`0
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`
`0
`
`Merck Exhibit 2043, Page 24
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
`
`Sheet 24 of 70
`
`US 8,329,696 B2
`
`ro
`+-'
`(l)
`..c
`+-'
`N
`Cl)
`(l)
`~
`0)
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`"O
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`(cid:127) -LL
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`0
`0
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`
`Merck Exhibit 2043, Page 25
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
`
`Sheet 25 of 70
`
`US 8,329,696 B2
`
`0
`··co
`M
`
`0
`0
`M
`
`0
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`(cid:127) -LL
`
`Merck Exhibit 2043, Page 26
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
`
`Sheet 26 of 70
`
`US 8,329,696 B2
`
`ro --(])
`..c --N
`
`Cl)
`(])
`~
`0)
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`(cid:127)
`
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`
`Merck Exhibit 2043, Page 27
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
`
`Sheet 27 of 70
`
`US 8,329,696 B2
`
`0
`-~
`M
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`0
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`0
`
`Merck Exhibit 2043, Page 28
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
`
`Sheet 28 of 70
`
`US 8,329,696 B2
`
`0
`00
`M
`
`0
`0
`M
`
`0
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`
`'
`0
`0
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`
`Merck Exhibit 2043, Page 29
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
`
`Sheet 29 of 70
`
`US 8,329,696 B2
`
`(cid:127) -LL
`
`Merck Exhibit 2043, Page 30
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
`
`Sheet 30 of 70
`
`US 8,329,696 B2
`
`., .. :::·
`
`::::::::::::,
`
`···················~,¥.;-;
`
`(cid:127)
`
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`
`8
`
`9
`
`z
`
`0
`
`Merck Exhibit 2043, Page 31
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
`
`Sheet 31 of 70
`
`US 8,329,696 B2
`
`0
`00
`M
`
`0
`-···"lit
`M
`
`0
`0
`M
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`0
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`
`Merck Exhibit 2043, Page 32
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
`
`Sheet 32 of 70
`
`US 8,329,696 B2
`
`······························································································································································· ..............
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`
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`
`Merck Exhibit 2043, Page 33
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
`
`Sheet 33 of 70
`
`US 8,329,696 B2
`
`_J
`
`......
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`
`Merck Exhibit 2043, Page 34
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
`
`Sheet 34 of 70
`
`US 8,329,696 B2
`
`ro
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`
`Merck Exhibit 2043, Page 35
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
`
`Sheet 35 of 70
`
`US 8,329,696 B2
`
`:·o
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`

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`U.S. Patent
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`Dec. 11, 2012
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`Sheet 36 of 70
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
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`Dec. 11, 2012
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`

`U.S. Patent
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`Dec. 11, 2012
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`U.S. Patent
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`Dec. 11, 2012
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
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`U.S. Patent
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`Dec. 11, 2012
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`U.S. Patent
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`Dec. 11, 2012
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`

`

`U.S. Patent
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`Dec. 11, 2012
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`Sheet 43 of 70
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`US 8,329,696 B2
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`

`

`U.S. Patent
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`Dec. 11, 2012
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`Sheet 44 of 70
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`US 8,329,696 B2
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`

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`U.S. Patent
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`Dec. 11, 2012
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`Sheet 45 of 70
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`US 8,329,696 B2
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`

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`U.S. Patent
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`Dec. 11, 2012
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`Sheet 46 of 70
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`US 8,329,696 B2
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`U.S. Patent
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`Dec. 11, 2012
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`Sheet 47 of 70
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`U.S. Patent
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`Dec. 11, 2012
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`Sheet 48 of 70
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`US 8,329,696 B2
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`U.S. Patent
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`Dec. 11, 2012
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`Sheet 49 of 70
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`US 8,329,696 B2
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`U.S. Patent
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`Dec. 11, 2012
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`Sheet 50 of 70
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`U.S. Patent
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`Dec. 11, 2012
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`Sheet 51 of 70
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`US 8,329,696 B2
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`U.S. Patent
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`Dec. 11, 2012
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`Sheet 52 of 70
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
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`Sheet 53 of 70
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`US 8,329,696 B2
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`Merck Exhibit 2043, Page 54
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
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`Sheet 54 of 70
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`US 8,329,696 B2
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`Merck Exhibit 2043, Page 55
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`

`U.S. Patent
`
`Dec. 11, 2012
`
`Sheet 55 of 70
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`US 8,329,696 B2
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`

`

`U.S. Patent
`
`Dec. 11, 2012
`
`Sheet 56 of 70
`
`US 8,329,696 B2
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`

`

`U.S. Patent
`
`Dec. 11, 2012
`
`Sheet 57 of 70
`
`US 8,329,696 B2
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`Merck Exhibit 2043, Page 58
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Dec. 11, 2012
`
`Sheet 58 of 70
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`US 8,329,696 B2
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`Merck Exhibit 2043, Page 59
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`

`U.S. Patent
`
`Dec. 11, 2012
`
`Sheet 59 of 70
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`US 8,329,696 B2
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`Merck Exhibit 2043, Page 60
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`

`

`U.S. Patent
`
`Dec. 11, 2012
`
`Sheet 60 of 70
`
`US 8,329,696 B2
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`Merck Exhibit 2043, Page 61
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`U.S. Patent
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`Dec. 11, 2012
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`Sheet 61 of 70
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`US 8,329,696 B2
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`Merck Exhibit 2043, Page 62
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

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