`
`BDR021089§
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`"MMMMMMMMH
`
`Merck Exhibit 2141, Page 1
`Mylan v. Merck, IPR2020-00040
`
`

`

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`Merck Exhibit 2141, Page 2
`Mylan v. Merck, IPR2020-00040
`
`

`

`fl
`
`'
`Information
`CARE OF MERCK NOTEBOOK
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`Merck Exhibit 2141, Page 3
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 3
`Mylan v. Merck, IPR2020-00040
`
`

`

`GENERAL (can't)
`9 Use unambiguous date format: (e.g., 12 Dec
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`Merck Exhibit 2141, Page 4
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 4
`Mylan v. Merck, IPR2020-00040
`
`

`

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`W0oqJ:5b'0nwhoa.005:2>>U02mC_.EVAJ:3c0HE8032.go5:2>>”#25.
`
`-' k Exhibit 2141, Page 5
`Mylan v. Merck, lPR2020-00040
`
`
`
`
`
`mxoommhczEmotions”5@2552..=n=>_
`
`
`
`Merck Exhibit 2141, Page 5
`Mylan v. Merck, IPR2020-00040
`
`
`

`

`Q MERCK
`
`Merck & Co., Inc.
`
`Cover Sheet
`
`.
`
`LABORATORY NOTEBOOK No. 0060659
`
`Notebook Type Code:
`
`IC
`
` Investigator:
`
`sign
`
`.
`
`E6bécca Let-g; 14/ 81/: W42.
`print
`
`Date Assigned: 0| \5} Lent Zr. 0 1
`
`Date Completed:
`
`iZJw/IG 2002.
`
`Please return completed index to the nearest Research Information site:
`
`RIWP (WPI-I)
`
`RIPH (WP78-100)
`
`RI-BPP (WP17-201)
`
`RIR (RY86E—250)
`
`Merck Exhibit 2141, Page 6
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 6
`Mylan v. Merck, IPR2020-00040
`
`

`

`Rankin!“
`
`R 6 ConiieontialWm:
`
`The data contained within this binder are considered
`
`restricted confidential.
`
`.
`
`Distribution should be on a need to know basis.
`
`Rubia!“
`
`R 9 Confidential
`limited access
`
`Merck Exhibit 2141, Page 7
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 7
`Mylan v. Merck, IPR2020-00040
`
`

`

`Index to Notebook 60659
`Index to Notebook 60659
`
`Investigator: Rebecca Leigh Shultz (WEIN 10127262)
`Pages filed sequentially in binder 60659
`
`Mafia-d
`
`R econrid-mial
`
`-
`
`Page 1 of4 4;
`‘‘3
`‘
`
`
`
`O0COOOOOOOCO0000L1]WNt—h
`
`0004
`
`0007
`0008
`
`oooooo»->—o--c>\o
`
`OO ,_i N
`
`00OOb—‘D—iAm
`0O ._. Ur
`
`OOOOOOOOb—ID—It—‘b—I
`
`\OOONO
`
`OONO
`
`COCONMNr—I
`0023
`
`0025
`
`0027
`
`OOL»U1
`0OD.) O\
`
`
`
`Sub'ect of Ex | eriment
`
`05 Jun 2001
`06 Jun 2001
`
`DSC of JR_B186_B_VTI (L-031942-ar_inine salt)
`Pre-aration of L-031942-ar_inine salt
`Isolation of L-031942-ar inine salt
`07 Jun 2001
`Attemted conversion of L-031942—ar_inine salt to form A
`08 Jun 2001
`H ,nroscoicit of form A and behavior of form B in acetone (L-03l942)
`11 Jun 2001
`Isolation of L-031942-arinine salt from acetone
`14 Jun 2001
`Pol mo hs of L-031942—arinine salt in ethanol
`15 Jun 2001
`Isolation of L-031942-arinine salt from ethanol
`18 Jun 2001
`P01 mo nhs of L-031942-ar_inine salt in 2—o-roanol
`19 Jun 2001
`Pol mo nhs of L-031942-arinine salt in 2---roanol, ethanol, ethanol/methanol
`20 Jun 2001
`Cr stallization of L-031942-ar_inine salt from ethanol, ethanol/methanol
`21 Jun 2001
`DSC heat/cool/reheat 0f L-031942-arinine salt
`27 Jun 2001
`DSC heat/cool/reheat of L-031942—ar_inine salt
`28 Jun 2001
`Recr stallization of form B (L-031942) from methanol solution
`29 Jun 2001
`DSC anal sis of form B (L-031942) cr stallized from methanol
`02 Jul 2001
`Determination of CMC for L-031942—ar_inine salt in water
`10 Jul 2001
`Determination of CMC for L-031942-ar_inine salt in water
`12 Jul 2001
`13 Jul 2001-Ka determination for L-031942 free acid (raw data)
`13 Jul 2001
`Ka determination for L-031942 free acid
`
`16 Jul 2001iKa determination for L-031942 free acid (raw data)
`16 Jul 2001
`Ka determination for L-031942 free acid (raw data)
`17 Jul 2001-Ka determination for L-03l942 free acid
`
`17 Jul 2001-Ka determination for L-031942 free acid (raw data)
`17 Jul 2001
`Ka determination for L-03l942 free acid (raw data)
`17 Jul 2001
`Ka determination for L-031942 free acid
`
`25 Jul 2001
`26 Jul 2001
`26 Jul 2001
`
`Thermal anal sis of L-031942~ar_inine salt batch 31773-221
`Determination of molar abso utivit
`for L-031942—arinine salt in water
`Determination of molar abso ntivit
`for L-031942—ar_inine salt in water
`
`for L-031942—ar_inine salt in water
`Determination of molar abso utivit
`Solubilit estimate for L-179764 free base and salt forms
`01 Au_ 2001
`Solubilit estimate for L-179764 free base and salt forms
`02 Au 2001
`Solubilit estimate for L-l79764 free base and salt forms
`02 Au; 2001
`02 Au; 2001 Native nH values for a ueous solutions of L-179764 and salts
`08 Au; 2001
`Cr stallinit of L-179764 free base and salt forms
`10 Au; 2001
`Initial Characterization of L-114902-001D002
`13 Au_ 2001
`Initial HPLC method develoment for L-114902-001D002
`15 Au; 2001
`Initial HPLC method develoment for L-114902-001D002
`21 Au_ 2001 H values of L-114902—sodium salt solutions
`22 Au 2001
`Effect of water on L-114902 sodium salt rin; oenin_; Microsco of free acid
`23 Au; 2001
`Pre-aration of bulk and solution stabilit sam-les for L-114902 sodium salt
`24 Au_ 2001
`Prearation of solution stabilit samles for amo hous L-114902 sodium salt
`27 Au 2001
`Initial thermal characterization of L-114902-001D004 and L-114902-000B003
`27 Au_ 2001
`Photostabilit
`(1 week) of L-114902-001D004
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`08088888bah-PAUJLQUJwNv—‘OOOON
`
`
`O
`
`AA
`
`CO
`OO0AAam
`0047
`
`Last printed 06/13/02 3:59 PM
`
`\\crwp0f04\shulleig\60659\Index to Notebook 60659.doc
`
`Merck Exhibit 2141, Page 8
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 8
`Mylan v. Merck, IPR2020-00040
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`Rollfictod
`
`R econvidmtiat
`
`:
`
` 28 Au ; 2001
`
`
`
`Index to Notebook 60659
`m Sub'ect of Ex teriment
`Investi ation of rin-
`'
`of the free acid in the nresence of water (L-114902)
`29 Au_ 2001 H _roscoicit of L-114902-001D004 (sodium salt, amo IhOUS)
`30 Au ”001 HPLC anal sis of L 114902 behavior in buffers, water, methanol, and H202
`31 Au 2001 One-week solid state and solution stabilit samles for L 114902 001D004
`04 Set 2001 H _rosco-icit of L-ll4902-001D004 (amo ohous sodium salt)
`04 Set 2001
`Solution stabilit of L-114902-001D004
`
`Page 2 of 4 '~§
`m
`0049
`0050
`0051
`52
`053
`
`_rosco icit of L-114902-000B003; ”rearation of bulk samles for free acid
`
`O U! G
`0
`
`
`OOOOOO0mo:Lit-b
`
`0000GOODOWL/1L]!0000\1
`
`05 Oct 2001
`1
`05 Oct 2001
`—
`08 Oct 2001
`11 Oct 2001
`
`Anal sis of Dru- Metabolism dosin- vehicles for L-114902 — otical microsco
`
`
`
`
`Pre-aration of buffered saline solubilit of L-114902-0003 in oil vehicles
`L-114902 bulk stablllt
`results — anal sis of HPLC data
`
`11 Oct 2001
`11 Oct 2001
`
`(solution hase) of L-114902 001D
`Thermal stablllt
`Solution hotostablllt of L-114902; thermal de_redatlon of L 114902 (anal sis)
`
`12 Oct2001
`
`_ H74, 37 °C b HPLC; 60659-81 data anal sis
`'
`Rate of L-114902 tin,
`Rate of rin
`'
`ofL-114902-001D; 60659-83 data anal sis
`Rate of rin
`‘
`'
`H7.4, saline); 60659—83 data anal sis
`Rate of rin
`‘
`in L-114902( H74, saline, 37 °C); 60659-84 data anal sis
`
`
`
`Rate of rin;
`in L-114902 (H74, saline, 37 °C); 60659-84 data anal sis
`
`
`
`
`
`
`Rate of rin_
`'
`H7.4, saline, 37 °C); 60659—86 data anal sis
`
`
`
`-
`Rate of rin
`'
`H7.4, saline, 37 °C); 60659-87 data anal sis
`60659—88 data anal sis; Behavior of L-114902 under astric conditions
`
`
`
`
`
`
`OOOOOOOOOOOO000000000000flow-5393B)
`
`
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`Rate of rin_o-oenin of L-114902 under h si0101cal condltlons: Summar
`Solubilit of L-778902 in oil exci ients; microsco. of L-778902-000J008
`
`Initiation of solution stabilit
`
`studies for L-221869-000R
`
`HPLC anal sis of L-221869 stressed samles and nossible de,radates
`HPLC of ossible de_radates (L-221869) rovided b Basic Chemistr
`L-221869-000R one week bulk stabilit
`
`12 Nov 2001
`
`Solution stabilit of L-221869-000R (1 wk); Vehicle for SC dosin_ of L-778902
`13 Nov 2001
`Ph sical stabilit of L-778902 formulations
`16 Nov 2001
`16 Nov 2001 DSC anal sis of L-778902
`
`Last printed 06/ 13/02 3:59 PM
`
`\\crwp0f04\shulleig\60659\Index to Notebook 60559.doc
`
`Merck Exhibit 2141, Page 9
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 9
`Mylan v. Merck, IPR2020-00040
`
`

`

`Page 3 of 4
`Index to Notebook 60659
`m;
`M“
`Euilibriumsolubilit ofL-221869 -TSA salt
`
`Rosiictud
`R emnfidmtial
`
`g
`~
`
`0103
`O H OA
`O ,_. OU:
`
`iir—tt—IOO\10
`
`O ._. 0 oo
`
`
`Photostabilit ofL-221869,h _roscoicit ,bulkstabilit
`for L-224715-000T001
`
`0113
`1
`p...L114}.
`.— O’\
`
`COr—‘p—n
`._.
`0
`
` Stabilit of L-221869 HCl, tos late (4 wk); h --roscoicit of L-tartaric acid
`
`Stabilit of L-224715; cr stallization c~f L-221869; L-383548 initial assessment
`
`
`
`0119
`
`2
`O p— NJ;
`
`H.—
`
`b—lj—IO U.)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`20 Nov 2001
`26 Nov 2001
`29 Nov 2001
`30 Nov 2001
`03 Dec 2001
`04 Dec 2001
`04 Dec 2001
`
`06 Dec 2001
`06 Dec 2001
`07 Dec 2001
`07 Dec 2001
`07Dec2001
`llDec2001
`
`12 Dec2001
`13Dec2001
`13Dec2001
`14 Dec 2001
`14De02001
`15Dec2001
`17 Dec 2001
`20Dec 2001
`28 Dec 2001
`02 Jan 2002
`03Jan2002
`
`04 Jan 2002
`07Jan2002
`08Jan2002
`08Jan2002
`09Jan2002
`09Jan2002
`09Jan2002
`15Jan2002
`151an2002
`15Jan2002
`151an2002
`151an2002
`15Jan2002
`15Jan2002
`
`22 Jan 2002
`22 Jan 2002
`23Jan2002
`24Jan2002
`
`COCOOO._.._.._.._.j—tfi—ANNNt—tv—IMNfi—‘OOO\I
`
`
`OOOOOOD—‘)—‘>—‘wNNNNNO\OOO\IONKJI
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`
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`MNt—‘OO
`
`151an2002_‘
`18121112002
`2lJanZOO2
`
`144
`145
`
`24 Jan 2002 Microsco ne ima _es of L-221869 tartrate, L-224715 besylate and tartrate
`25 Jan 2002
`01 Feb 2002
`01 Feb 2002
`
`O ._. A 00
`0149
`
`04 Feb 2002
`
`Stabilit of L-221869 tartrate; L-221369 tartrate, bes late with _e]atin, HPMC
`
`
`
`Last printed 06/13/02 3:59 PM
`
`\\crwp0f04\shulleig\60659\1ndex to Notebook 60659.doc
`
`Merck Exhibit 2141, Page 10
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 10
`Mylan v. Merck, IPR2020-00040
`
`

`

`
`
` OOOOOOOOO
`HP—‘P—‘r—‘D—‘h—IHH
` ’—r—-._ir—IO\OO’\0\lO\LIIJ;
`
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`
`
`O ._i 71
`
`
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`oooooooomhwwv—‘O
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`
`L-224715 hos-hate with _elatin, HPMC; L-224715 tartrate, bes late H
`
`L-224715 bes
`
`'
`
`'
`
`'
`
`;mixtures with elatin, HPMC
`
`L-224715 hoshatestabilit with elatin, bulk
`
`'
`
`"
`
`Stoichiometr ,solubilit of L-224715 uohoshate; uh sical stabilit
`
`,amo hous
`
`L ohilization ofL-221869tartrate/L-224715 unhoshate; Bioharm solubilit
`
`Stabilit of L-224715 u-hoshate salt with various _rades of mannitol
`
`DSC, LC anal sis of L-224715 hoshate and blends; bulk stabilit data
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
`O ,_. ob.)
`
`
`
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`
`173
`
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`
`19
`
`Page 4 of 4
`Index to Notebook 60659
`m—-— 1
`0153
`154
`
`Rustic!“
`R enema-nun:
`
`1
`
`
`
`
`
`
`
`Stabilit of L-224715 hoshate salt with _elatin oowder
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`10 Jun 2002
`
`11 Jun 2002
`
`Anal sis of L-224715-006F006 8wk stabilit
`
`
`
`, amorhous uhotostabilit samtles
`
`
`
`0200
`
`
`
`Last printed 06/13/02 3:59 PM
`
`\\crwp0f04\shullei g\60659\1ndex to Notebook 60659.doc
`
`Merck Exhibit 2141, Page 11
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 11
`Mylan v. Merck, IPR2020-00040
`
`

`

`emancx
`
`R. Leigh Shultz
`30 Nov 2001
`
`Book20060659 Pag§:0_1g6
`
`i:
`"i
`
`Subject: Initiation of Bulk and Solution Stability Studies for L—221869 Tartrate and Besylate Salts
`
`A stock solution of the L-tartaric acid salt (NB7206l-16) was made by dissolving 7.64 mg of the salt in
`7.64 mL water (note water solubility greater than 1 mg/mL). Similarly, a stock solution of the besylate salt
`(NB72061-22) was made by dissolving 7.23 mg of the salt in 7.23 mL of water (note water solubility
`greater than 1 mg/mL). Aliquots of each of these stock solutions were used to make HPLC samples of the
`two salts in water (0.1 mg/mL) to check the salts by HPLC. The salts were run in the sample set
`60659.106.seq using the original L—221869 method L221869_method1.mth.
`
`The stock solutions prepared above were used to make stability samples for the two salts. For each salt, 54
`samples were prepared. One set of vials was made for each of three time points (1, 2, and 4 weeks).
`Within each time point, a set of vials was placed in each of 3 stability stations: —20 °C (samples R), 40 °C
`(samples C), and 80 °C (samples F). In each station at each time point, samples were prepared at pH 2, 4,
`6, 8, 10, and in water (concentration of salt ca. 0.1 mg/mL). The vials were crimped with Teflon-lined
`caps, labeled as 60659-106 Tar or 60659-1‘91'33, and placed in the stability stations at 12:00 pm. Bulk — / oé BS
`stability was also initiated for both salts. Nine vials were prepared for each salt according to the table
`below. The vials were placed in the appropriate stability stations at 12:00 pm.
`MPG R563
`
`
`Sam 1e (Tar)
`Conditions
`Mass salt (
`)
`Sam le (Bs)
`Conditions
`Mass salt (
`)
`
`60659-106R1
`—20 °C 1 wk
`1.07
`60659-1061R1 —20 °C 1 wk
`2.00
`60659-106 R2
`—20 °C 2 wks
`1.69
`60659-106 R2
`—20 °C 2 wks
`1.18
`60659-106 R4
`—20 °C 4 wks
`1.36
`60659-106 R4
`—20 °C 4 wks
`1.56
`60659-106 D1
`40/75 lwk
`1.15
`60659-106 D1
`40/75 lwk
`1.49
`60659-106 D2
`40/75 2 wk
`1.42
`60659-106 D2
`40/75 2 wk
`1.14
`60659-106 D4
`40/75 4 wk
`1.28
`60659-106 D4
`40/75 4 wk
`1.01
`60659-106 F1
`80 °C 1 wk
`1.22
`60659-106 Fl
`80 °C 1 wk
`1.82
`60659-106 F2
`80 °C 2 wks
`1.42
`60659-106 F2
`80 °C 2 wks
`2.66
`
`60659-106 F4 1.60 80 °C 4 wks 1.44 60659-106 F4 80 °C 4 wks
`
`
`
`
`
`The remaining Tar and Bs stock solutions were frozen to prevent decomposition.
`
`AW / a
`
`50 Nov 2601
`
`[3% [25,251 2,17... 2cm
`
`COUN RSIGNATURE
`
`DATE
`
`“ll""lllllllllIII""I“IllllllllllllllllIlllll
`
`”IIIHIIIIIHIIIIIIIIlmlllllllll
`
`391231?
`
`Merck Exhlbi I341, Page 12
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 12
`Mylan v. Merck, IPR2020-00040
`
`

`

`9mm
`
`R. Leigh Shultz
`03 Dec 2001
`
`Bookzooeoe59 Page:0107
`
`
`
`,u
`a
`
`...;::::4.
`r“-)
`
`Subject: Bulk stability of L-221869 free base {4—week time point)
`
`Samples 60659-93 A4-R4 (7 samples) were removed from the stability stations at 10:30 am. All of the
`samples appeared unchanged (white powder) except for sample F4, which had turned yellow. Each of the
`samples was dissolved in 3.0 mL of 0.1% phosphoric acid; this solution was in turn diluted with 16 mL of
`0.1% phosphoric acid (total volume = 19mL, approximate concentration of free base = 0.1 mg/mL). An
`aliquot of each solution was placed in an HPLC vial and assayed in the sample set 60659.107.seq using the
`method L221869_method1.mth. Each sample was assayed twice.
`
`Sub'ect: Bulk and solution stabilit of L-221869 tos late and HCl salts 2—week time oint
`
`The bulk and solution stability samples (labeled R2, C2 (solution) or D2 (bulk), and F2) for the tosylate and
`the HCl salts of L—221869 were removed from the stability stations (—20 °C, 40 °C (40/75 for bulk), and 80
`°C) at 10:30 am and allowed to come to ambient temperature. The caps of the solution samples were
`removed and replaced with PP/Al caps. The bulk samples, which did not appear to have changed over the
`2-week time period (except for HCl F2, which had yellowed), were dissolved in 3.0 mL of O. 1%
`phosphoric acid; these solutions were then further diluted with 16 mL of 0.1% phosphoric acid. Aliquots of
`each of these solutions were transferred to HPLC vials for analysis along with solution stability samples.
`They were assayed in the sample set 60659.107.seq using the method L221869_method1.mth. Each
`sample was analyzed once.
`
`
`
`,/
`
`/4? @071}; Z} Jom ’Zrb L
`
`OUNTERSIGNATURE
`
`DATE
`
`I“II""I""“IIll“"IIIIII“III"“III“II II"
`
`”Ill" "I"”I""I"III“II"II"
`
`BSF12312/99
`
`Merck Exhibit 2141, Page 13
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 13
`Mylan v. Merck, IPR2020-00040
`
`

`

`0 MERCK
`
`R. Leigh Shultz
`04 Dec 2001
`
`Book:0060659 Pagp: 0_1_0_8
`2.5.
`
`Subject: Solution stability of L-221869-000R (4-week data)
`
`The four-week solution stability samples (60659—93) were removed from the stability stations at 10:00 am
`and were allowed to come to ambient temperature. Seven samples were removed from each of five stations
`(—20, 5, 25, 40, and 80 °C). Upon examination, sample 60659-93 R4 pH=W was observed to be in a
`cracked vial (discovered before the sample melted completely). In order to salvage the sample, the solution
`was transferred to a new vial as the sample melted. The samples were assayed in the sample set
`60659.108.seq using the method L221869_method1.mth. Each sample was assayed twice.
`
`5.
`
`Subject: Evaluation of thermal effects on vials and HPLC caps
`
`The blank vials which had been placed in the stability stations on 05 Nov 2001 (60659-93) were removed
`after 4 weeks and weighed to determine if the mass of the vials had changed on storage. The conditions,
`intial weights, and final weights are shown in the table below.
`
`Vial label
`Blank vial A
`Blank vial C
`Blank vial D
`Blank vial E
`Blank vial F
`Blank vial G
`Blank vial R
`
`Conditions
`5 °C
`40 °C
`40 °C/75%RH
`60 °C
`80 °C
`25 °C/60%RH
`~20 °C
`
`Mass (initial) (g) Mass (final) (g)
`6.25932
`6.25912
`6.20152
`6.17624
`6.26689
`6.28318
`6.21773
`6.17478
`6.21650
`6.16892
`6.26962
`6.28055
`6.20560
`6.20658
`
`Change (g)
`+0.00020
`—0.02528
`+0.01629
`—0.04295
`—0.04758
`+0.01093
`+0.00098
`
`These results indicate that vials kept in a humid environment (—20 °C, 5 °C, 25 °C/60% RH, or 40 °C/75%
`RH) gain weight, most likely due to absorption of water by the cap liner or the label. Vials kept at elevated
`temperatures (40, 60, 80 °C) at ambient RH show weight loss, probably due to evaporation of plasticizers
`in the vial caps and labels. These results suggest that total vial weights (including sample) should not be
`used to assess weight changes of samples on stability.
`
`HPLC vials capped with the Al/PP crimp caps were also removed from the stability stations (7) after 4
`weeks. Each vial had initially contained 1 mL of water, and the liquid level had been marked on the
`outside of the vial. The loss of liquid over the four-week period was evaluated visually, as shown in the
`table below.
`
`
`
`Vial label
`Conditions (t = 4 wks) Liguid level
`Blank vial A
`5 °C
`No change
`Blank vial C
`40 °C
`~ 40 % loss
`Blank vial D
`< 5 % loss
`40 °C/75%RH
`Blank vial E
`100 % loss
`60 °C
`Blank vial F
`80 °C
`100 % loss
`Blank vial G
`< 5 % loss
`25 °C/60%RH
`Blank vial R
`—20 °C
`No chan e
`
`
`These results indicate that the Al/PP caps are not sufficient for stability studies due to sample loss via
`evaporation.
`
`am 6% w a
`
`(:34 DC C Zoo|
`
`/% %fl(
`
`CO
`
`ERSIGNATURE
`
`2F];n 26122
`
`DATE
`
`ii
`2
`F I
`MercESExhiibit/29f41, Page 14
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 14
`Mylan v. Merck, IPR2020-00040
`
`

`

`QMERCK
`
`R. Leigh Shultz
`04 Dec 2001
`
`Bookz0060659 Page 0109
`ripar
`u.is”3;in;
`
`Sub'ect: Initial h sical characterization of L-224715-000T001
`
`The DP-IV antagonist L-224715 was received from Basic Chemistry (D. Kim) as the free base. This
`material is a white powder. I: was analyzed by microscopy to determine particle size and morphology and
`to assess crystallinity. Two images at 200K magnification are shown below. In each image, the large bar
`is 75 microns in length. In the second image, the smaller bar is 7.5 microns in length.
`
`
`
`L-224715-000T001: free base (image 1)
`
`L—224715-000T001: free base (image 2)
`
`The particles are birefringent under polarized light. Most are between 50-100 microns in length, though
`there are smaller particles observed. The aspect ratio of the particles is ca. 10:1 (needles). The
`birefringence suggests crystallinity, which will have to be confirmed by XRPD.
`
`The thermal properties of the material were probed using DSC and TGA. The data are shown in the two
`figures below.
`
`Slnple. L22471$_lraebaee_dac
`Size
`1.3200 nu
`Method standard
`
`DSC
`
`File 6'. \L224715_lb_DSC 000
`Opemtor LS
`Run Data wee-01 1531
`
`Sarl'ple L224715_1b_lp
`slze
`3 6000 no
`Method standard metttod
`110
`
`TGA
`
`File C . \TGA\LZZA715_1b_lga
`Operator LS
`Run Dale 4-Deo-01 “'45
`
`0 3858% Loss before 150 deg C
`(0 01389mg)
`
`8 8
`
`
`
`Weight(‘70)
`
`11801°C -9
`
`
`
`HeatFlow(W/g)
`
`20
`
`"'"’
`
`70
`
`170
`120
`Temperature (“0)
`
`220
`
`270
`“WWW"
`
`0
`
`50
`
`100
`
`150
`Temperature (°C)
`
`200
`
`250
`
`300
`“an...“
`
`DSC of L-224715-000T001 (25-300 °C, 10 °C/min)
`
`TGA of L-224715-OOOT001 (25—300 °C)
`
`DSC results suggest a crystalline material (single polymorph) with a melting point of 118.01 °C (102.7 J/g).
`The endotherm above 223 °C is most likely due to decomposition of the sample. This is consistent with the
`TGA results, which show weight loss of ca. 30% beginning around 225 °C. TGA also indicates that the
`solid contains 0.39% volatiles (Basic Chemistry indicated that the sample contained WWW——
`gm X g& Stw/é '
`COUNTE SI NATURE
`DATE
`m 1””
`“if
`41% P
`w T
`‘M‘?
`""
`0496c: 2001
`
`.
`
`,
`
`4
`
`<14
`
`7,15") 2
`
`.
`
`1
`
`Merck Exhibit 2141, Page 15
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 15
`Mylan v. Merck, IPR2020-00040
`
`

`

`e MERCK
`
`R. Leigh Shultz
`06 Dec 2001
`
`LL
`
`Book:0060659 Fag)... 9_1_1_0
`
`1«I
`
`~"13'.,2";
`
`Subject: Hygroscopicity of L-224715-000T001 at 25 °C
`
`A small sample of L-224715-000T001 (ca. 7-8 mg) was placed in the clean, tared microbalance pan of the
`VTI to measure the hygroscopicity of the solid at 25 °C from 5-95 %RH. The method std25A.mth was
`used, which incorporates a drying step at 40 °C. The sample was left to run overnight.
`
`Subject: Photostability of L-221869—000R (crystalline free base)
`
`The photostability samples for L-221869-000R (60659-94, 12 samples) were removed from the freezer and
`allowed to thaw. The dark samples were wrapped with aluminum foil to prevent exposure, and all 12
`samples were placed in the Rayonet irradiator for 17 hours (fluorescent light).
`
`Subject: Initiation of bulk stability for L-224715-000T001 (free base)
`
`Samples of L-224715-000T001 (Basic Chemistry) were weighed into tared scintillation vials to initiate
`bulk stability studies of the free base according to the table below.
`
`Conditions
`5 °C, 1 week
`5 °C, 2 weeks
`5 °C, 4 weeks
`40 °C, 1 week
`40 °C, 2 weeks
`40 °C, 4 weeks
`
`Mass L224715 (mg) Cap
`1.17
`closed
`1.11
`closed
`1.81
`closed
`1.58
`closed
`1.50
`closed
`1.28
`closed
`
`Sample
`60659-1 10 A1
`60659-1 10 A2
`60659-1 10 A4
`60659-110 C 1
`60659-1 10 C2
`60659-1 10 C4
`60659-1 10 D1
`60659-1 10 D2
`60659-1 10 D4
`60659-1 10 E1
`60659-1 10 E2
`60659-1 10 E4
`60659-1 10 F1
`60659-1 10 F2
`60659-1 10 F4
`60659-1 10 G1
`open
`1.47
`25 °C/60%RH, 1 week
`60659-1 10 G2
`open
`1.24
`25 °C/60%RH, 2 weeks
`60659-1 10 G4
`open
`1.45
`25 °C/60%RH, 4 weeks
`60659-1 10 R1
`closed
`1.17
`—20 °C, 1 week
`60659—1 10 R2
`—20 °C, 2 weeks
`1.68
`closed
`60659-1 10 R4
`-20 °C, 4 weeks
`1.40
`closed
`
`40 °C/75%RH, 1 week
`40 °C/75%RH, 2 weeks
`40 °C/75%RH, 4 weeks
`60 °C, 1 week
`60 °C, 2 weeks
`60 °C, 4 weeks
`80 °C, 1 week
`80 °C, 2 weeks
`80 °C, 4 weeks
`
`1.14
`1.15
`1.76
`1.06
`1.15
`1.60
`1.10
`1.21
`1.02
`
`open
`open
`open
`closed
`closed
`closed
`closed
`closed
`closed
`
`The vials were placed in the stability stations at 3:00 pm (each set of vials was placed in a 50-mL beaker
`with a green tape label).
`
`0C2 Dec: 2/51)!
`
`/ ,
`
`co TERSIGNATURE
`
`in, 2/13» Zcrb‘l
`
`DATE
`
`MerckSEigiblll/fin Page 16
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 16
`Mylan v. Merck, IPR2020-00040
`
`

`

`9mm
`
`R. Leigh Shultz
`06 Dec 2001
`
`L
`
`Book20060659 Pagfi:01_11
`
`‘1
`
`rm?"1,”;
`
`Subject: Initiation of solution stability for L-224715—000T001 (free base)
`
`A sample (12.91 mg) of L-224715-000T001was weighed into a tared 20-mL scintillation vial. Water
`(HPLC grade, 12.91 mL) was added via pipet to make a 1.0 mg/mL stock solution of L-224715. This stock
`solution was used to prepare all solution stability and photostability samples discussed below. The buffers
`used were 20mM sodium acetate (pH = 4.02), 20 mM sodium phosphate (2 buffers, pH = 6.04 and pH =
`7.97), and 20 mM sodium carbonate (pH = 9.95). For stability at pH 2, 0.01N HCl was used.
`
`Four sets of samples were prepared: a photostability set, labeled 60659-110 L (light-exposed samples, pH
`2, 4, 6, 8, 10, and water) and 60659-110 D (dark control samples, pH 2, 4, 6, 8, 10, and water). An aliquot
`of the stock solution (0.10 mL) was added to each HPLC vial, followed by 0.90 mL of the appropriate
`buffer or water. The vials (12 total) were crimp-capped with Teflon-lined caps and placed in the freezer (—
`20 °C).
`
`Three additional sets of samples were prepared. The sets were identical to each other and are intended to
`represent three different stability timepoints (1, 2, and 4 weeks). Each set contains vials to be put in each of
`five stability stations: —20 °C freezer (R), 5 °C refrigerator (A), 25 °C/60%RH oven (G), 40 °C/75%RH
`oven (C), and 80 °C/ambient RH oven (F). The set in each stability station contains six vials: pH’s 2, 4, 6,
`8, 10, and plain water. All of these samples were prepared in a fashion analogous to the photostability
`samples described above using the 1 mg/mL stock solution of L-224715 (90 vials total). The vials were
`labeled with the notebook page 60659-110, a letter indicating the stability station, a number indicating the
`timepoint (1, 2, or 4), and the pH buffer used. They were crimp-capped with Teflon-lined caps to prevent
`evaporation and placed in the stability stations at 3:00 pm.
`
`Additional samples were prepared, again using the stock solution of L—224715 (0.1 mL) and an appropriate
`diluent (0.9 mL). Two of the samples were diluted with 0.1 N HCl, while two others were diluted with 0.1
`N NaOH. The other two vials were diluted with 3% w/v H202. The two peroxide samples were placed in
`the 25 °C/60%RH oven. The remaining vials (HCl and NaOH) were placed in the 80 °C oven. These vials
`will be left overnight and will be used to evaluate the applicability of the HPLC method for L-221869 to
`L-2247 15.
`
`A fresh sample of L-224715-000T in water (0.1 mg/mL) was prepared from the stock solution and was
`assayed immediately by HPLC along with a sample of the cyclic amine fragment of the molecule
`(NB32073-11). These two samples were assayed in the set 60659.110.seq using the current method for
`L-221869, L221869_methodl .mth.
`
`The stock solution of L—224715 was frozen for future use. Note that preparation of these samples showed
`that the solubility of L-224715 in water is greater than 1 mg/rnL; the solubility across the pH range 2-10 is
`greater than 0.1 mg/mL.
`
`Qmfigz Show}
`
`0&2 (2ch 4203/
`
`/% [M Z
`
`ERSIGNATUR
`
`CO
`
`—/
`
`.
`
`21 J an 2‘”?
`
`DATE
`
`Merck Exhibit 2141, Page 17
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 17
`Mylan v. Merck, IPR2020-00040
`
`

`

`ma
`Page 1 of 1
`
`:33?
`
`: 6.2.0.0.0:B27
`Software Version
`Reprocess Number : ry80m-108-pelc: 136
`Sample Name
`: cyclic amine fragment
`nstrument Name
`: PELC
`Rack/Vial
`: 1/2
`Sample Amount
`: 1.000000
`Cycle
`: 2
`
`Result File : D:\Projects\L224715\FlawData\60659._1.10.002.rst
`Sequence File : D:\Sequences\L224715\60659.110.idx
`
`Date
`
`: 12/6/01 5:03:03 PM
`
`Data Acquisition Time : 12/6/01 4:20:38 PM
`Channel
`: A
`Operator
`:
`lhshultz
`Dilution Factor
`: 1.000000
`
`:5
`’3
`2;;
`"
`
`;
`E
`
`
`
`12...“. 2.....-
`
`22.22,,
`
`~
`
`
`
`THU—ll'lTITIT1-111111"l[Tm—11111—mlWITil—I‘ll"Hm-11[Tl—mTlTWfll—H‘Ilfl-ll—lWWWUWTWllnllmTHTlflTWlWWWFWWWHWl-ll1]
`1
`2
`3
`4
`5
`6
`7
`a
`9
`1o
`11
`12
`1a
`Time[min]
`
`Single Injection Report
`
`Rebecca Leigh Shultz
`NB 60659
`
`’eak Component
`#
`Name
`
`Time RRT
`[min]
`
`Area
`[uV'sec]
`
`Height
`[uV]
`
`1
`3
`4
`
`1.598 0.18
`10.742 1.22
`13.247 1.50
`
`825677.27 121102.50
`14212.82
`1036.09
`205624.04
`1221.29
`
`Area
`[°/o]
`
`78.97
`1.36
`19.67
`
`1045514.13 123359.89
`
`100.00
`
`Merck Exhibit 2141, Page 18
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 18
`Mylan v. Merck, IPR2020-00040
`
`

`

`€Page1of1
`
`: 6.2.0.0.02827
`Software Version
`Reprocess Number : ry80m-108-pelc: 137
`Sample Name
`: L224715-000T
`nstrument Name
`: PELC
`Rack/Vial
`: 1/3
`Sample Amount
`: 1.000000
`Cycle
`: 3
`
`Result File : D:\Projects\L224715\RawData\60659.110.003.rst
`Sequence File : D:\Sequences\L224715\60659.110.idx
`
`Date
`
`: 12/6/01 5:03:03 PM
`
`Data Acquisition Time : 12/6/01 4:40:11 PM
`Channel
`: A
`Operator
`:
`lhshultz
`Dilution Factor
`: 1.000000
`
`:5
`3;
`::_
`'“'
`
`n4: 2.
`__._J\J~\,:L-._,_-_~__________*___
`l
`
`_
`E
`
`%
`
`__
`
`g //j>fl\
`1 ~. ”r/“l V
`
`
`
`W'llllllll‘l’lllll‘llllWlTlllllllTlllTlll'WTHTllllTlTllTl‘lTlTWfifimmfifllll'lllm‘q’mm‘mllflllflwmflllfl‘flm
`1
`2
`3
`4
`5
`6
`7
`a
`9
`1o
`11
`12
`13
`Time [min]
`
`Single Injection Report
`
`Rebecca Leigh Shultz
`NB 60659
`
`’eak Component
`#
`Name
`
`Time RRT
`[min]
`
`Area
`[uV’sec]
`
`Height
`[W]
`
`1
`2
`4
`
`1452.92
`23607.54
`1.794 0.20
`9.274 1.05 432751838 827594.00
`13.238 1.50
`145182.76
`1043.54
`
`Area
`[‘70]
`
`0.53
`96.25
`3.23
`
`449630868 830090.46
`
`100.00
`
`Merck Exhibit 2141, Page 19
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 19
`Mylan v. Merck, IPR2020-00040
`
`

`

`4..r-
`
`a.
`
`'0Q)(D(D _L o_.
`_L
`
`.4.1
`
`Software Version
`Reprocess Number
`Sample Name
`nstrument Name
`Rack/Vial
`Sample Amount
`Cycle
`
`: 6.2.0.0.0:B27
`: ry80m-108-pelc: 135
`: water
`: PELC
`: 1/1
`: 1.000000
`:
`1
`
`Result File : D:\Projects\L224715\RawData\60659.110.001.rst
`Sequence File : D:\Sequences\L224715\60659.110.idx
`
`Date
`
`: 12/6/01 5:03:02 PM
`
`12/6/01 4:01 :07 PM
`Data Acquisition Time :
`: A
`Channel
`:
`lhshultz
`Operator
`: 1.000000
`Dilution Factor
`
`
`
`...;;...4,,,7"r‘:"'Z-‘'
`
`co
`“l,.
`r.-,
`
`13.27
`Ex
`
`
`
`
`
`Response[mV]
`
`
`
`’lmlTWPWlWlWllml'WllmlWWWWTWWWWIWWWWWWWWW"!
`Time [min]
`
`Single Injection Report
`
`Rebecca Leigh Shultz
`NB 60659
`
`’eak Component
`#
`Name
`
`Time RRT
`[min]
`
`Area
`[uV'sec]
`
`Height
`[uV]
`
`8.429 0.96
`9.465 1.07
`10.540 1.20
`11.276 1.28
`13.272 1.50
`
`113397.75
`89365.33
`62106.22
`112238.05
`142622.36
`
`2681.96
`2009.54
`1737.39
`9168.55
`4324.58
`
`519729.70 19922.02
`
`
`
`Merck Exhibit 2141, Page 20
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 20
`Mylan v. Merck, IPR2020-00040
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`

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`QMERCK
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`R. Leigh Shultz
`07 Dec 2001
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`s»;
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`BOOK 0060659 Page: 0 12
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`Subject: Hygroscopicity of L-224715-000T001
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`The VTI run on the free base of L-224715 was finished by 8:00 am, so the solid was removed from the pan
`and saved for analysis. The data are shown below and appear after this page as supplementary material.
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`Adsorption/Desorption
`lsotherm
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` Weight(%change)
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`Adsorption/Desorption
`lsotherm
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`E E
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` (moles)
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`H20Isample
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`2. Moles H20 versus %RH for L-224715-000T
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`The free base L-224715-000T is non—hygroscopic, gaining only 0.125% water over the entire RH range.
`See NB60659-113 for physical characterization of the solid remaining after the VTI run was complete.
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`Subject: HPLC analysis of stressed samples of L—224715
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`The fresh sample of L-224715 in water was analyzed by HPLC using th