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`Merck Exhibit 2141, Page 126
`Mylan v. Merck, lPR2020-00040
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`Merck Exhibit 2141, Page 126
`Mylan v. Merck, IPR2020-00040
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`Mylan v. Merck, lPR2020-00040
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`Merck Exhibit 2141, Page 127
`Mylan v. Merck, IPR2020-00040
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`Mylan v. Merck, lPR2020-00040
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`Merck Exhibit 2141, Page 128
`Mylan v. Merck, IPR2020-00040
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`Mylan v. Merck, lPR2020-00040
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`Merck Exhibit 2141, Page 129
`Mylan v. Merck, IPR2020-00040
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`Mylan v. Merck, lPR2020-00040
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`Merck Exhibit 2141, Page 130
`Mylan v. Merck, IPR2020-00040
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`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 131
`Mylan v. Merck, IPR2020-00040
`
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`Merck Exhibit 2141, Page 132
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 132
`Mylan v. Merck, IPR2020-00040
`
`

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`Mylan v. Merck, lPR2020-00040
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`Merck Exhibit 2141, Page 133
`Mylan v. Merck, IPR2020-00040
`
`

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`Merck Exhibit 2141, Page 134
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 134
`Mylan v. Merck, IPR2020-00040
`
`

`

`e MERCK
`
`R. Leigh Shultz
`26 Feb 2002
`
`k
`
`300k10060659 Pagp: 9E7
`
`v"
`
`Subject: Solubility of L-221869 tartrate, L-224715 phosphate in Isopar G
`
`In order to determine the solubility of L-221869 tartrate hemi-hydrate and L-224715 phosphate in Isopar G
`(used on the Microtrac for particle sizing), samples of each salt were weighed into tared centrifuge tubes.
`An additional sample of L—221869 tartrate hemi-hydrate was weighed into a tube to more closely estimate
`the water solubility of this salt (initial water pH = 6.15). Aliquots of the appropriate solvent were then
`added to the tubes according to the table below:
`
`
`Salt
`L-224715 phophate
`
`NB Reference Mass (mg)
`70316-35
`5.08
`
`Solvent
`Isopar G
`
`Vol Solvent (mL)
`0.20 x 5
`0.50 x 2
`1.00 x 5
`
`L-22l869 tartrate hemi-hydrate
`
`31683-261
`
`0.20 x 5
`0.50 x 2
`1.00 x 5
`0.50 x 3
`Water
`51.85
`31683-261
`L-221869 tartrate hemi-h drate
`
`
`6.59
`
`Isopar G
`
`None of the samples dissolved completely. The L-224715 phosphate sample seemed to have much less
`solid remaining than the two tartrate salt samples of L—221869. The Isopar G samples were spun down in
`the centrifuge to see exactly how much solid was left; both still had appreciable solid. They were shaken to
`mix, and all three tubes were placed in the rotator to equilibrate at 11:25 am. The Isopar G samples will
`have to be calibrated by UV—Vis or some other method, as Isopar G is immiscible with 0.1% phosphoric
`acid and acetonitrile (HPLC mobile phase).
`
`Qwegé SM? 0! W4 200.17%
`
`28 Feb 2002
`
`Sub'ect: Stabilit of L-224715 hos hate with mannitol
`
`The one-week samples of L-224715 phosphate with mannitol (60659-164) were removed from the stability
`stations at 3:00 pm. They were placed in the freezer until they could be analyzed.
`
`//""g§3 v
`
`/
`
`% pg/ng «ZS/”70¢2cm
`
`RSIGNATURE
`
`DATE
`
`”III"III""III III"""I"IIIIII""milII"II
`
`”III""ill"III"I""II""II'll
`
`BSF 12312 99
`
`Merck Exhibit 141, Page 135
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 135
`Mylan v. Merck, IPR2020-00040
`
`

`

`eMERCK
`
`R. Leigh Shultz
`04 Mar 2002
`
`..>Z~
`
`300k10060659 Pagezo1 8
`iJ»I l.
`
`a.»5
`f
`
`Is:
`
`Sub'ect: Stabilit of L-224715 hos hate with mannitol
`
`The one—week samples of L—224715 phosphate in mannitol (60659-167) were removed from the freezer at
`9:00 am. Each sample was dissolved in 0.1% phosphoric acid to make 20 0 mL of solution; the samples
`dissolved immediately with no sonication. An aliquot of each solution was placed in an HPLC vial for
`analysis. Two sets of L-224715 standards were also placed in LC vials to be analyzed before and after the
`mannitol samples for calibration. Due to an LC problem, however, the vials had to be placed in the
`refrigerator overnight.
`
` flaw \
`
`05 Mar 2002
`
`Sub'ect: Solubilit of L-221869 tartrate in water
`
`The solubility sample of L-221869 tartrate was removed from the rotator (60659-167) after several days.
`All of the solid had dissolved. In order to check if degradation had occurred, 0.075 mL of the solution were
`placed in an LC vial and diluted with 0.925 mL of 0.1% phosphoric acid. The sample was analyzed in the
`sample set 60659.168.seq using the method L221869_method1.
`
`Sub'ect: Bulk and solution stabilit of L-224715 hos hate 4-week time oint
`
`The four-week samples of L-224715 phosphate were removed from the stability stations at 1:00 pm. The
`bulk samples appeared unchanged from the original samples. They were each dissolved in 19.0 mL of
`0.1% phosphoric acid, and an aliquot of each of these solutions was placed in an LC vial for analysis. The
`bulk samples were analyzed with the solution samples in the sample set 60659.168.seq using the method
`L22 1 869_method1 .
`
`
`
`\
`
`/4 gag ZSflfor 2021
`
`cou E SIGNATURE
`
`DATE
`
`||||||||||||||||||||||||||||||||||||||||||||||||||
`
`||||||||||||||||||||||||||||||||||| w
`
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 136
`Mylan v. Merck, IPR2020-00040
`
`

`

`9mm
`
`R. Leigh Shultz
`06 Mar 2002
`
`Book:0060659 pagegfie
`”‘2'a
`.r
`' 3h
`1
`
`Subject: Stoichiometry of L-224715 phosphate batch 70316-43
`
`A solution of the phosphate salt of L—224715 (NB 70316-43) was made by dissolving 3.78 mg in 3.78 mL
`of 0.1% phosphoric acid. Two HPLC samples were made from this 1.0 mg/mL solution by twice placing
`an aliquot of the solution (0.10 mL) in an HPLC vial and diluting with 0.90 mL of 0.1% phosphoric acid.
`Each of these samples was analyzed in the sample set 60659.169.seq using the method L221869_method1.
`Three standard solutions of L—224715 free base were analyzed in the set to calibrate the phosphate salt
`solutions.
`
`Subject: Preliminary attempts to create amogphous L-224715 phosphate salt
`
`A solution of the phosphate salt of L-224715 in wet methanol was created by dissolving ca. 2 mg of
`L-224715 phosphate (NB 70316-35) in ca. 3 mL methanol with 2—3 drops of water added. The solution
`was placed in the refrigerator overnight.
`
`Subject: Comparative solubility of L-224715 phosphate batches
`
`To ensure that four different batches of the phosphate salt of L-224715 are all the same polymorph, a
`sample of each was weighed into a tared 4-mL vial according to the table below. An aliquot (1.00 mL) of
`absolute ethanol was added to each vial, and the vials were placed on the vortexer and shaken for 2 hours.
`The supernatants were then isolated by centrifuge filtration and analyzed by HPLC in the sample set
`60659.169.seq.
`
`Sample NB reference Mass (mg)
`70316-25
`6.29
`70316-31
`4.62
`70316-35
`4.41
`70316-43
`7.27
`
`Subject: Physical stability of L-224715 phosphate salt
`
`The physical stability samples for L-224715 phosphate were removed from the stability stations at 9:00 am.
`Samples were removed from each of the vials and were analyzed by DSC and TGA (traces appear as
`supplemental data behind this notebook page). These samples (60659-160) have been on stability for 20
`days. No changes have taken place in the material under any of the storage conditions (25/60, 40/amb, or
`40/75). In each of the DSC traces, the onset of melting and the peak of the endotherm are within 0.5 °C of
`the original material, and no additional water is gained by TGA. The degree of crystallinity of the material
`cannot be ascertained due to the immediate decomposition seen upon melting.
`'Wtc samples Ware plmcd back rn-H/ie cuppvopncute 2;ij l:
`Siam MS aP+ar m DSC/T6] Y—t expanwmots were ccvalei’ed
`((30. 110(9me .
`
`07 Mom £00}
`
`[In 25 ”2/ 252»)
`cou TERSIGNATURE
`DATE
`
`“III" III""HI“I""I“III““I“I'm"II"II
`
`“III""III"III"I""II"III"II
`
`BSF12312 99
`
`Merck Exhibit 141, Page 137
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 137
`Mylan v. Merck, IPR2020-00040
`
`

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`Merck Exhibit 2141, Page 138
`Mylan v. Merck, lPR2020-00040
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`Merck Exhibit 2141, Page 138
`Mylan v. Merck, IPR2020-00040
`
`

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`Merck Exhibit 2141, Page 139
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 139
`Mylan v. Merck, IPR2020-00040
`
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`Merck Exhibit 2141, Page 140
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 140
`Mylan v. Merck, IPR2020-00040
`
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`Merck Exhibit 2141, Page 141
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 141
`Mylan v. Merck, IPR2020-00040
`
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`Merck Exhibit 2141, Page 142
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 142
`Mylan v. Merck, IPR2020-00040
`
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`Merck Exhibit 2141, Page 143
`Mylan v. Merck, lPR2020-00040
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`Merck Exhibit 2141, Page 143
`Mylan v. Merck, IPR2020-00040
`
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`Mylan v. Merck, lPR2020-00040
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`Merck Exhibit 2141, Page 144
`Mylan v. Merck, IPR2020-00040
`
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`Merck Exhibit 2141, Page 145
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 145
`Mylan v. Merck, IPR2020-00040
`
`
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`Mylan v. Merck, lPR2020-00040
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`Merck Exhibit 2141, Page 146
`Mylan v. Merck, IPR2020-00040
`
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`Merck Exhibit 2141, Page 147
`Mylan v. Merck, lPR2020-00040
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`Merck Exhibit 2141, Page 147
`Mylan v. Merck, IPR2020-00040
`
`

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`Merck Exhibit 2141, Page 148
`Mylan v. Merck, lPR2020-00040
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`2:
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`Merck Exhibit 2141, Page 148
`Mylan v. Merck, IPR2020-00040
`
`

`

`éoeW— /é9—/z
`
`
`
`
`
`EcoEswaS.0n.m>_mw5>_:3AOovQLDHWLmQEQI—n
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`
`Merck Exhibit 2141, Page 149
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 149
`Mylan v. Merck, IPR2020-00040
`
`

`

`9mm
`
`R. Leigh Shultz
`07 Mar 2002
`
`Book20060659 pag§;()1_70
`
`iii
`
`Subject: Stability of L-224715 phosphate with HPMC and gelatin
`
`The four-week stability samples of L-224715 phosphate with gelatin and HPMC (60659-155) were
`removed from the stability stations at 9:00 am. The gelatin samples were placed in the freezer until they
`could be analyzed. The HPMC samples were each extracted with 0.1% phosphoric acid (3 x 3.0 mL); and
`aliquot (1 mL) of the resulting mixture was syringe-filtered at 0.2 microns into an HPLC vial for analysis.
`The samples were analyzed in the sample set 60659.170.seq using the method L221869_method1.
`
`Subject: Stability of L-224715 phosphate with mannitol g2 grades)
`
`The two—week stability samples of L-224715 phosphate with Pearlitol 2OOSD and SP1 mannitol (60659-
`164) were removed from the stability stations at 9:00 am. Each sample was dissolved in 20.0 mL of 0.1%
`phosphoric acid (graduated cylinder), and a 1.0-mL aliquot of each solution was placed in an HPLC vial for
`analysis. A single standard of L-224715 free base was run in the sample set with the stability samples
`(60659.170.seq).
`
`Subject: Physical stability of HPMC/gelatin mixtures with L—224715 phosphate and L-221869 tartrate
`
`The samples of L-221869 tartrate with gelatin and HPMC (60659-144a) L—224715 phosphate with gelatin
`and HPMC (60659—155) were removed from the stability stations (40/amb and 40/75) after 31 and 20 days,
`respectively. The samples were taken to Bob Wenslow for solid—state NMR analysis.
`
`Sub'ect: Attem ted creation of amo hous material for L-224715 hos hate salt
`
`The solution of the‘ phosphate salt in methanol (60659-169) was removed from the refrigerator. A drop of
`the solution was placed on a microscope slide, and the solvent was allowed to evaporate. The sample was
`monitored by optical microscopy during this process. Small, birefringent crystals began to appear within
`one minute. A solution of the salt in wet methanol likely cannot be used to generate amorphous material.
`Other solvents will have to be tried for this.
`
`07th 81002;
`
`COUN RSIGNATURE
`
`DATE
`
`Merck Exhibit 2121, Page 150
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 150
`Mylan v. Merck, IPR2020-00040
`
`

`

`9mm
`
`R. Leigh Shultz
`11 Mar 2002
`
`t ,+
`
`4.;
`
`Book20060659 pag§201
`
`113:“:1‘31‘tint;1"
`
`1
`
`Subject: Stability of L—224715 phosphate salt with gelatin
`
`The 4-week stability samples of L-224715 phosphate salt in gelatin (60659-155) were removed from the
`freezer at 9:00 am. Each sample was extracted with 0.1% phosphoric acid (3 x 3.0 mL). An aliquot (1 mL)
`of each of the resulting solutions was syringe-filtered at 0.2 microns into an HPLC vial for analysis. The
`three samples were analyzed in the sample set 60659.171.seq using the methods L221869_method1 and
`L221869_meth0d1_270 (210 and 270 nm detection, respectively).
`
`
`
`/%/%(w 23/4,, 2m)
`
`CO TERSIGNATURE
`
`DATE
`
`||||||||||||||||||||||||||||||||||||||||||||||||||
`
`|||||||||||||||||||||||||||||||||||
`
`6am
`
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 151
`Mylan v. Merck, IPR2020-00040
`
`

`

`emacx
`
`R. Leigh Shultz
`12 Mar 2002
`
`Book20060659 pag§o1_72
`
`«Gristif:......
`
`y
`
`Subject: Lyophilization of L—224715 phosphate and L-221869 tartrate
`
`A solution of L-224715 phosphate in water was prepared by dissolving the salt (batch 70316-35, 142.16
`mg) in 4.2 mL of deionized water in a 20-mL scintillation vial. Likewise, a sample of the tartrate salt of
`L-221869 (NB 31683-261, 205.08 mg) was dissolved in 10 mL of deionized water. The samples were
`sonicated to break up any large chunks of material. Both samples were transferred to labeled conical vials
`with holes burned into their tops. The tubes were placed in liquid nitrogen for ca. 4 minutes to freeze them,
`and they were then taken to Analytical Research and placed in the lyophilizer for freeze-drying. The
`samples will be checked in the morning to see if the drying is complete; they will then be checked by
`XRPD to determine if they are amorphous or crystalline. Sample preparation and use of the lyophilizer
`were aided by Russ Ferlita, Physical Measurements.
`
`Subject: Solubility of L-221869 tartrate in water for Biopharm dosing
`
`In order to determine if solutions in water can be used to dose L—221869 to rats for Biopharm dose ranging
`studies, a sample of L-221869 tartrate hemihydrate (60.24 mg) was weighed into a tared 20-mL vial. An
`aliquot (1.00 mL) of deionized water was added to the salt, forming a milky suspension. The suspension
`did not dissolve to a solution after 5 minutes of sonication, so sonication was continued for 25 minutes
`
`(total time). The salt was completely in solution after this time. The sample had warmed during
`sonication, so it was allowed to cool to ambient temperature on the bench, and no crystallization was noted.
`Thus, using sonication, concentrations of 60.2 mg/mL L-221869 tartrate salt in water (42.7 mg/mL free
`base) can be achieved; this concentration is higher than the one needed for the high dose in rats for dose
`ranging, so DI water solutions can be used for these dosings. The pH of the final solution was 3.44, in the
`stable range for L-221869. Added acid should not be needed for the SA formulation for L-221869.
`
`Subject: Physical stability of L—2247 15 and L—221869 salts in binary mixtures
`
`Binary mixtures of L-221869 tartrate herni-hydrate and L-224715 phosphate with gelatin, HPMC, and
`mannitol were received back from Bob Wenslow after solid-state NMR analysis. The gelatin and HPMC
`samples were placed back in the appropriate stability ovens at 5:00 pm (see 60659-161). The mannitol
`samples (60659-164) were separated into two samples per type of mannitol according to the following table
`and placed in the stability ovens at 5:00 pm.
`
`
`Conditions
`Mass
`Drug
`Excipient
`Compound
`Sample ID
`(
`)
`Load (%)
`
`10.2
`46.33
`60659-164 physl/Pearl
`L—224715 phosphate
`Pearlitol ZOOSD
`40 °C/amb RH
`60659-164 physZ/Pearl
`L-224715 phosphate
`Pearlitol 200SD
`10.2
`62.48
`40 °C/75% RH
`60659-164 phys 1/SPI
`L—224715 phosphate
`SPI mannitol
`10.3
`43.42
`40 °C/amb RH
`60659-164 h sZ/SPI
`L-224715 hos hate
`SPI mannitol
`10.3
`46.84
`40 °C/75% RH
`
`
`The samples will be removed in 1-2 weeks and taken back to Bob Wenslow for NMR analysis.
`
`WW fig sway
`
`
`/Z 77’] (M QOOA
`
`/%égflj g1 75/479/ 2612)}:
`
`CO TERSIGNATURE
`
`DATE
`
`Merck ithlzbaiiyfzt Page 152
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 152
`Mylan v. Merck, IPR2020-00040
`
`

`

`Q MERCK
`
`R. Leigh Shultz
`13 Mar 2002
`
`Book: 0060659 Paggaz 0_1_Z_3
`
`uI
`
`
`
`-.“”51”
`
`Subject: SA formulation for L-224715 phosphate salt
`
`The solubility of the phosphate salt of L-224715 (>81 mg/mL free base) will permit all SA dosing to be
`done in solution. However, the pH of solutions of the phosphate salt made in plain deionized water will be
`above 5 and may result in reduced stability for the solutions. As a result, I suggested to SA (G. Lankas)
`that the phosphate salt be dosed as a solution in 5 mM HCl to lower the pH and increase stability.
`
`A 5 mM HCl solution was prepared by dilution of 0.410 mL concentrated HCl (12.18 M) to 1.00 L with
`deionized water (volumetric flask). After mixing, the solution was transferred to a glass bottle for storage.
`The pH of the solution was 2.38 (theoretical pH = 2.30).
`
`The following solutions are needed for dosing in SA and will be made to evaluate solubility, physical
`stability, and pH stability:
`
`0.4 mg/mL
`2 mg/mL
`4 mg/mL
`10 mg/mL
`12 mg/mL
`36 ngmL
`
`(0.5 mg/mL phophate salt)
`(2.5 mgmL salt)
`(5.0 mg/mL salt)
`(12.4 mg/mL salt)
`(14.9 mg/mL salt)
`(44.7 mg/‘mL salt)
`
`Sub'ect: L o h lization of L-224715 hos hate and L-221869 tartrate salts
`
`The progress of the lyophylization of the salts (60659-172) was checked at 10:30 am. The L-224715
`sample appeared dry and was removed from the lyophylizer. The L-221869 sample had residual solvent in
`it; it was redissolved in 6.5 mL of deionized water, frozen with liquid nitrogen, and placed back on the
`lyophylizer overnight. The L-224715 sample was checked by XRPD to determine if it was amorphous (R.
`Ferlita, Physical Measurements). The XRPD pattern showed only a broad halo, indicating that amorphous
`material was formed. The XRPD pattern follows this page as supplemental information.
`
`
`
`
`Lou (ZS/”r 7612)),
`RSIGNATURE
`
`
`”III"III“"IIIIII""III"IIIIII“lllllllII"II
`
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`
`BSF12312/99
`
`Merck Exhibit 2141, Page 153
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 153
`Mylan v. Merck, IPR2020-00040
`
`

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`Merck Exhibit 2141, Page 154
`Mylan v. Merck, lPR2020-00040
`
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`
`Merck Exhibit 2141, Page 154
`Mylan v. Merck, IPR2020-00040
`
`

`

`9mm
`
`R. Leigh Shultz
`14 Mar 2002
`
`Book20060659 pag§o1_74
`
`"hf
`
`,..
`. w.
`’,
`
`3
`
`Subject: L—224715 phosphate lyophylized material
`
`The lyophylized material (60659—173) was left on the lab bench overnight; when checked at 8:30 am, it had
`reduced significantly in volume. The sample was weighed into a vial (126.47 mg) and examined by optical
`microscopy, which indicated some birefringence and an undefined particle morphology. A DSC sample
`was prepared and analyzed. The trace follows this page as supplemental material. The material is mostly
`crystalline and of the same polymorph as before lyophylization; however, the lower onset of melting (203
`°C as opposed to 207 °C) suggests some amorphous character. The sample was taken to Bob Wenslow for
`NMR analysis.
`
`Subject: L-221869 tartrate lyophylized material
`
`The L-221869 tartrate sample was removed from the lyophylizer at 8:30 am. It appeared totally dry upon
`initial inspection. An XRPD sample was prepared; during the sample preparation, it was noted that some
`water remained in the bottom of the tube. The fluffy, dry material was removed from the vial and
`transferred to a clean 20-mL scintillation vial. The XRPD was obtained in Physical Measurements with the
`help of Russ Ferlita and was saved in the project L-221869 with the filename 60659-174. XRPD indicated
`that the material was amorphous with no crystalline component. The scintillation vial was given to Bob
`Wenslow for immediate 19F SSNMR analysis.
`
`02/066184 X% é/Mjf) A
`
`/L/ ”ma/L 900%
`
`/ 9‘
`
`/4%Zlg, Qfi/fii m1
`
`COU TERSIGNATURE
`
`DATE
`
`Merck th it‘a/fiLPagMSS
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 155
`Mylan v. Merck, IPR2020-00040
`
`

`

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`Merck Exhibit 2141, Page 156
`Mylan v. Merck, lPR2020-00040
`
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`Merck Exhibit 2141, Page 156
`Mylan v. Merck, IPR2020-00040
`
`

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`Merck Exhibit 2141, Page 157
`Mylan v. Merck, lPR2020-00040
`
`
`
`
`
`Merck Exhibit 2141, Page 157
`Mylan v. Merck, IPR2020-00040
`
`
`
`

`

`6 MERCK
`
`R. Leigh Shultz
`20 Mar 2002
`
`Book20060659 pagé: o1_75
`
`V5
`.“l
`
`j.’
`
`Subject: Bulk and solution stability of L—224715 phosphate salt
`
`The bulk stability data for the phosphoric acid salt of L-224715 (60659-153) are shown in the table below.
`Data are reported in area % relative to samples stored at —20 °C.
`
`Bulk thermal stability of L-224715 phosphate salt
`Conditions
`Rel Area % L-224715
`1 wk
`2 wk
`4 wk
`102.2
`100.4
`98.9
`99.8
`99.6
`99.9
`
`40 °C/75% RH
`80 °C/amb RH
`
`Minimal loss of parent is observed over 4 weeks at 40 °C/75% RH; the loss is not statistically significant,
`and no degradates are observed by HPLC.
`
`The solution stability data for the phosphate salt of L-224715 (60659-153) are shown in the table below.
`Data are reported in area % relative to samples stored at —20 °C.
`
`Conditions
`
`water
`
`pH 2
`pH 4
`pH 6
`pH 8
`RH 10
`
`Solution thermal stability of L-224715 phosphate salt
`Rel Area % L-224715, 40 °C
`Rel Area % L-224715, 80 °C
`lwk
`2wk
`4wk
`lwk
`2wk
`4wk
`93.9
`89.8
`75.9
`0.0
`0.0
`0.0
`
`99.9
`101.8
`99.0
`88.2
`83.1
`
`98.1
`93.2
`101.6
`81.6
`62.9
`
`100.6
`94.1
`98.5
`60.2
`36.5
`
`99.0
`100.9
`24.9
`0.0
`0.0
`
`100.3
`93.6
`5.0
`0.0
`0.0
`
`95.4
`90.9
`0.4
`0.0
`0.0
`
`The phosphate salt is most stable between pH 2 and 4, similar to other saltsof L-224715. Although the
`stability of the salt in water at 80 °C is poor, the stability of the salt at 40 °C in water shows a marked
`improvement over the other salts of this compound. This is likely a pH effect, as the phosphate salt
`solutions have a lower pH after storage at 40 °C than do solutions of other salts of L-224715. Based on this
`data, the phosphoric acid salt has a distinct advantage over the benzenesulfonate salt for development. The
`table below compares the degradation (both hydrolysis and de-amination) of L-224715 in the
`benzenesulfonate, phosphate, and tartrate salt forms at 0.1 mg/mL salt in water at 40 °C.
`
`Com arison of de adation in salts of L-224715
`
`Rel Area %
`Rel Area %
`
`Salt of L-224715
`
`Free Base
`
`Hydrolysis
`2wk
`20.4
`
`lwk
`8.9
`
`4wk
`47.7
`
`De-amination
`lwk
`2wk
`4wk
`3.8
`11.8
`28.8
`
`5.1
`2.3
`7.8
`3.8
`Phosphate
`7.4
`3.6
`18.2
`8.3
`Benzenesulfonate
`6.1
`4.2
`13.7
`6.3
`L—Tartrate Hemih drate
`
`Conditions: 0.1 mg/mL salt, 40 °C, unbuffered water
`
`19.5
`41.3
`
`9.1
`25.3
`
`The data clearly indicate that the phosphate salt is much more stable in unbuffered water. This is an
`advantage for the phosphate salt should some of the salt dissolve in a formulation.
`
`wa59669 SW
`
`’20 Mar Zocz.
`
`flu? [% ?S(ch.r2fl?>?
`
`COUN RSIGNATURE
`
`DATE
`
`BSF12312/99
`Merck Exhibit 2141, Page 158
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 158
`Mylan v. Merck, IPR2020-00040
`
`

`

`9 MERCK
`
`R. Leigh Shultz
`20 Mar 2002
`
`it
`
`Book: 0060659 Pag—
`::01 6
`sum
`'.13.»...
`
`Subject: Bulk and solution stability of L-224715 besylate salt
`
`The bulk stability data for the besylate salt of L—224715 (60659-142) are shown in the table below. Data
`are reported in area % relative to samples stored at —20 °C.
`
`Bulk thermal stability of L-224715 besylate salt
`Conditions
`Rel Area % L-224715
`1 wk
`2 wk
`4 wk
`100.3
`100.3
`99.7
`100.8
`99.5
`100.3
`
`40 °C/75% RH
`80 °C/amb RH
`
`Minimal loss of parent is observed after 4 weeks at 40 °C/75% RH, but no degradates are observed by
`HPLC. There is no trend in the 80 °C data indicating that degradation is taking place.
`
`The solution stability data for the besylate salt of L-224715 (60659-142) are shown in the table below.
`Data are reported in area % relative to samples stored at ~20 °C.
`
`Solution thermal stabilit of L-224715 bes late salt
`
`Conditions
`Rel Area % L-224715, 40 °C
`Rel Area % L-224715, 80 °C
`lwk
`2wk
`4wk
`lwk
`2wk
`4wk
`85.8
`73.2
`51.9
`0.0
`0.0
`0.0
`
`water
`
`95.9
`92.3
`97.4
`104.5
`94.9
`99.3
`pH 2
`93.2
`90.9
`97.5
`98.3
`94.7
`101.8
`pH 4
`0.0
`4.3
`23.9
`99.5
`93.9
`102.6
`pH 6
`0.0
`0.0
`0.0
`50.0
`69.1
`85.1
`pH 8
`0.0
`0.0
`0.0
`28.9
`53.4
`74.0
`H 10
`
`
`The besylate salt is most stable between pH 2 and 4, similar to other salts of L-224715. However, the loss
`of parent drug in solution over time is only slightly less than for the free base (60659—140) in unbuffered
`
`GQW 60239 snub
`
`20 Max 2002.
`
`,/
`
`7/ @964 113/7119?"
`co TERSIGNATURE
`DATE
`
`“III""I""I"III"""I"III"I"“III"II"II
`
`“III""III"I""I“I'll"I"“ll
`
`BSF12312 99
`
`Merck Exhibit {141, Page 159
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 159
`Mylan v. Merck, IPR2020-00040
`
`

`

`9mm
`
`R. Leigh Shultz
`20 Mar 2002
`
`Book:0060659 pagézo1_77
`
`z“;
`
`f:
`‘
`
`Subject: Bulk and solution stability of L-224715 tartrate salt
`
`The bulk stability data for the tartrate salt of L-224715 (60659-143) are shown in the table below. Data are
`reported in area % relative to samples stored at —20 °C.
`
`Bulk thermal stability of L-224715 tartrate salt
`Conditions
`Rel Area % L-224715
`1 wk
`2 wk
`4 wk
`100.1
`97.0
`no data
`100.7
`101.7
`no data
`
`40 °C/75% RH
`80 °C/amb RH
`
`The four—week samples for this salt were not analyzed due to the amount of degradation seen at 2 weeks.
`Minimal loss of parent is observed after 2 weeks at 40 °C/75% RH, but no degradates are observed by
`HPLC. There is no trend in the 80 °C data indicating that degradation is taking place.
`
`The solution stability data for the tartrate salt of L-224715 (60659-143) are shown in the table below. Data
`are reported in area % relative to samples stored at —20 °C.
`
`Solution thermal stabilit of L-224715 tartrate salt
`
`Conditions
`Rel Area % L-224715, 40 °C
`Rel Area % L-224715, 80 °C
`lwk
`2wk
`4wk
`lwk
`2wk
`4wk
`89.2
`81.8
`no data
`0.0
`0.0
`no data
`
`water
`
`no data
`97.6
`99.7
`no data
`99.1
`99.4
`pH 2
`no data
`93.0
`100.7
`no data
`94.5
`100.5
`pH 4
`no data
`5.9
`26.0
`no data
`97.4
`99.3
`pH 6
`no data
`0.0
`0.0
`no data
`78.1
`88.0
`pH 8
`no data
`0.0
`0.0
`no data
`61.6
`78.3
`H 10
`
`
`The tartrate salt is most stable between pH 2 and 4, similar to other salts of L-224715. However, the loss
`of parent drug in solution over time is only slightly less than for the free base (60659-140) in unbuffered
`water due to the increase in the pH of L-224715 tartrate salt solutions upon storage at elevated temperatures
`(60659-154).
`.
`\
`
`082W 3% §%
`
`20 MW 2002
`
`90 “a”
`
`M“
`
`950
`
`,g’
`
`.///Q:%/5
`
`/
`
`{(12 fig” any 2am.
`
`cou ERSIGNATURE
`
`DATE
`
`l|||||||||||||||||||||||||||||||||||||||||||||||||
`
`|||||||||||||||||||||||||||||||||||
`
`....a:tg.gyzz.,p.....
`
`Mylan v. Merck, lPR2020-00040
`
`Merck Exhibit 2141, Page 160
`Mylan v. Merck, IPR2020-00040
`
`

`

`9mm
`
`R. Leigh Shultz
`20 Mar 2002
`
`Book20060659 Page; o_12_8
`
`ml.7
`
`235.;“L131
`
`Subject: Stoichiometry of L-224715 phosphate salt
`
`Two samples of L-224715 phosphate (NB 70316-43) in water were analyzed by HPLC against standard
`solution of L-224715 to determine the stoichiometry of this batch (60659-169). The data were analyzed in
`the Excel spreadsheet U:\L224715\60659-169.xls. The average salt factor calculated from the data was
`0.804; the theoretical salt factor for a monobasic phosphate salt of L-224715 is 0.806. These values are in
`excellent agreement; this batch of phosphate is therefore a monobasic phosphate salt.
`
`Subject: Comparison of L-224715 phosphate salt batches gsolubility, SSNMR)
`
`The solubilities of 4 different batches of L-224715 phosphate salt in ethanol were determined (60659-169)
`and are reported in the table below.
`
`Batch
`
`70316-25
`70316-31
`70316-35
`70316-43
`
`Solubility in EtOH
`(mgmL L-224715)
`0.187
`0.187
`0.181
`0.196
`
`The solubilties of the 4 batches of phosphate salt are very close, indicating that they are the same
`polymorphic form.
`
`Several batches of the phosphate salt were also analyzed by 15lF solid-state NMR. The overlaid —CF3 region
`of the spectra is shown in the graph below and can be found in the file U:\Igor Files\DP-IV\
`L-224715 physical stability.pxp.
`
`
`
`
`
`
`M— Iot4