throbber

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`29.01.2015
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` טנטפ תשקבל תודגנתה
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`רחסמה ינמיסו םימגדמה ,םיטנטפה םשר
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`הכרב ןילק'ז 'בג :םשרה תינגס 'בכ ינפב
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` 'סמ טנטפל תודגנתה
`29.01.2015 םוימ ןויד
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`172563
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`Merck Sharp & Dohme CORP
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` :טנטפה תשקבמ
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` מ"עב תויטבצמרפ תוישעת עבט
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`
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`:תדגנתמ
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` תשקבמה:
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`
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` דצמ
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`םי
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`חכונ
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`ןייטשטו דעיל
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` ד"וע
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`ןוטרק ידע
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` ד"ו
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`עלס יתיא
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` ד"וע
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` תדגנתמה:
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` דצמ
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`םי
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`חכונ
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`דנב לט
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`וע" ד
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`יי
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`לב םעונ
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` ד"וע
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`ויז ריאי
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`ד"וע
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`ץיבומוקואל היטק
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`ד"וע
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` דיעמ
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`23
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` : ןוידב םויה
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`)תדגנתמה םעטמ דע(
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`ליי'צ דרנואל ר"ד
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`24
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`L/80044/5480/3855628/1
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`Merck Exhibit 2227, Page 1
`Mylan v. Merck, IPR2020-00040
`
`

`

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`29.01.2015
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` םוי
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`מ ןויד
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`2
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`לוקוטורפ
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`172563
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` טנטפ תשקבל תודגנתה
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` תא לומתא קודבנ ונחנא
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`ש השקיב יתרבג ,תחא היינש החילס קר
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`
`
`:דנב ד
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`וע"
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`
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`.השקבב ןכ ,בוט רקוב
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`
`
`:םשרה תינגס 'בכ
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` לכ תאו
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`
`
`reference
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`-
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`ה תאו ,
`
`HPLC
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`-
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`ה ינותנ תא בויחב קודבל
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`
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`:דנב ד
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`וע"
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`
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`,ה תא ריבעהל תורשפאה
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`
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`
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` .בויחב קודבל
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`:םשרה תינגס 'בכ
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` תישאר
`
`-
`
` הזל רשקב םירבד ינש רמול יתיצרו ונקדב זא ,םירמוחה
`
` תובתכתהה תא שיגהל ךירצ אלו ונמצע תא וא ימצע תא יתקדבו יתרזח
`
` ירבח
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` ש
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`
`
`בותכש המל רשקב םיקולח אל ונחנא יכםושמ םג אלא ,
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` קר אל
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` ,לבא .דווטא ריהצתל חפסנכ תיטנוולרה תובתכתהה לכ תא שיגה רבכ
`
` םינוש םיניינעב היינשה ירחא תחא תויונמדזה שולשב הנפ ירבח
`
` והשמ לע רבדמ ינא ,ול םירסח ויהי ותעדלש םירמוחל םירושקש
`
` בוש הז תא ריכזה ךכ רחאו םעפ
`
`
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`2011
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` ראונימ
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` תא םירמוחה תאו תוסחייתה שקיב אוה
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`ה ינותנ יבגלש םעפ
`
`שקיבו ,רבד לש ופוסבו ,
`HPLC
`-
`
` רחא ,
`
`םרפסמב
`
`
`
`ודי לע ובקננש תויפיצפס תואמגוד לש תוקידבה תואצות
`
` ךיא טרפל םישקבתמ םג ונחנא הלאה םירמוחל ףסונבש שקיבו רזח ךכ
`
`-
`
`רע תא בשיח אוה ךיאו תוסיסמה תמוקע תא בשיח ליי'צ ר"דה ך
`
`
`pHmax
`friction
`
` ה תא
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`
`
`,ה יפוליח תא יתרבגל ךוסחא ינא רבד לש ופוסב .
`
` ראורבפב
`
`-24
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`ב רבד לש ופוסב לבא ,םידדצה ינש לש ,םיבתכמ
`
` ב
`
` לכ ופרוצ וילאש םידומע השיש לש בתכמ ,ןאכ הז תא ףריצ
`

`
` ,לביק אוה
`
` ומכ ןכא שקיב אוהש םירבסהה יבגל ,ופרוציש שקיב אוהש םיצבקה
`
` שקבמ אוהש הרהבה תולאשהש ונבתכ ונחנא
`
`
`
`לומתא רמא ירבחש
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` ונחנא
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`,
`
`םייוסינ לש םלג ירמוחל וא םייוסינ לש דועיתל השקבמ תוגרוח
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` עיגמ אוהש ינפל דעמ הרהבה תולאש לש הרודצורפ םיריכמ
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` אל
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` ,הזב החכ
`

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`נ וישכע ילוא יתרבגש חמש ינא
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`
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`,בושחל רשפא
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` ,רקחיהל
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` שי םימעפל יכ
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`
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`הז תא רמוא ינא ,בוט אל הזש
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`,
`
`בוט הזש
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` בושחל רשפא
`
` ייוליגב ךרוצה לע םירחא םיקיתב וא םירחא תומוקמב םיחוכיו ונל
`
` לכ תא לביק
`
`,
`
`ןפוא לכב ,בצמה הז לבא ,דעומ דועבמ ,לשמל םיכמסמ
`Having said all that
`
` לש הצלמהה ,השקבה רואל
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` ,
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` .ינממ רמוחה
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`2
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`L/80044/5480/3855628/1
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`17
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`18
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`19
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`20
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`21
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`25
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`26
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`27
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`28
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`29
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`30
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`Merck Exhibit 2227, Page 2
`Mylan v. Merck, IPR2020-00040
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`

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`29.01.2015
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` םוי
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`מ ןויד
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`3
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`172563
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` טנטפ תשקבל תודגנתה
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` לכ ,ליימב טרדנטסה תא ברעב ששב לומתא ונרבעה ונחנא ,יתרבג
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` יירבחל ונבתכ ןכלו ליימב ןתוא ריבעהלמ תודבכ ויה תו
`
`רחאה תואצותה
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` תא ונאבה
`

`
` ,קסיד לע הז תא
`
` םהל
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` רוסמל םינכומ ונחנאש ששב לומתא
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` חילש איצוהל םינכומ ונחנאש ונבתכ םג
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`,
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`איצוהל םינכומ ונייה
`

`
` ,קסידה
`
` רתוי םירבדב םיקוסע ויה םהש חוטב ינא תונעט םוש ונל ןיא לומתא
`HPLC
`-
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` ויה וליאש הזה
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`
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`ה תואצות אלו
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`
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`תמאב םהל םיצוחנש םיבושח
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`1
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` קר אלו םינש יצחו שולש ינפלמ הז לע םיעמוש ונייה תמאב תוצוחנ
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`
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`,רדסב הזש הבושת ונלביק הלילב יצחו םייתש
`

`
` ,וישכע
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`
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`.הלילב תחא ,תחא
`
`
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`:ןייטשטו ד
`
`וע"
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`
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` .תחאב םתחלש םתא ילוא ,ונלביק ונחנא ,אל
`
`
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`:דנב ד
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`וע"
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`10
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`
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`?ביבא לתל םילשורי
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` ןיב תועש
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` לש
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`
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` לדבה שי
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`:םשרה תינגס 'בכ
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`11
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`
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`,ה תא ריבסמ הזש תויהל לוכי
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`
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`:ןייטשטו ד
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`וע"
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`12
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` םא עבש שולש םייתש ןמוסמ הז ,השק ךכ לכ ודבעש ונמשרתה םתס
`
`
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`:דנב ד
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`וע"
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`13
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` אל זא םינפ לומ םינפ םתוא םיאור ונחנאש הז תא ונלביק .העוט אל ינא
`
`
`
`.השקבב ,זא ,קסידה םע חילש איצוהל ךירצ
`
`
`
`.קסידה הנה
`
`14
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`15
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`16
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`.הזה ןיינעב דרוקרה תא רשייל יל בושח היה טושפ ,קסידה הנה
`
`
`
`:דנב ד
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`וע"
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`17
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` ינא ,דרוקרה תא רשייש ירבחל הדומ ינא ,ותוא רשייא ינא ,ינא זא
`
`
`
`:ןייטשטו ד
`
`וע"
`
`18
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`
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`:םשרה תינגס 'בכ
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`
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` ,זא .ףוסה דע ותוא רשייא
`
`19
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`
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`,וישכע ,םוקע תצק היה תמאב אוה
`
`
`
`:םשרה תינגס 'בכ
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`20
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`חל הדומ ינא לכ םדוק זא ,קוידב ,ןכ
`
`
`
`:ןייטשטו ד
`
`וע"
`
`21
`
`ה םע קסידה לע ירב
`
`data
`-
`
`
`
` ,ףסונה
`data
`
` לש תומוצע תויומכ ם
`
` ע
`
`קסיד לבקל םיבהוא דואמ ונחנאש ןבומכ
`
`
`
`,הפ הרוקש המ ,הפוס תארקל תמאה ןעמל ,תידגנה הריקחה ךלהמב
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`22
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`23
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`
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`.הווקמ ינא .הפוס תארקל ונחנאש עומשל החמש ינא
`
`
`
`:םשרה תינגס 'בכ
`
`24
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`
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`.שקבל היה רשפא םינש עברא
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`
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`:דנב ד
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`וע"
`
`25
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`
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`,יתוא עמשת התאש ענכושמ ינא ,תונלבסב ךתוא יתעמש ,ךתוא יתעמש
`
`
`
`:ןייטשטו ד
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`וע"
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`26
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`
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`
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` ,קדוצ
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`:דנב ד
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`וע"
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`27
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`
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`.תוחפ אל הבר תונלבסב
`
`
`
`:ןייטשטו ד
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`וע"
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`28
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`
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` .לומתא ךל ויהש תויגרנאה תא יל שי רקובב
`
`
`
`:דנב ד
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`וע"
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`29
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`
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`.תידדה הירפה לש ךילהת ןאכ שיש יתרבג חמש ינא ,ןאכ שיש חמש ינא
`
`
`
`:ןייטשטו ד
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`וע"
`
`30
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`3
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`
`
`L/80044/5480/3855628/1
`
`Merck Exhibit 2227, Page 3
`Mylan v. Merck, IPR2020-00040
`
`

`

`
`
`29.01.2015
`
` םוי
`
`מ ןויד
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`
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`4
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`172563
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` טנטפ תשקבל תודגנתה
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` םייוסינב יאדווב ,ולש םייוסינב ליי'צ ר"ד ךמתסה םהילע םירמוחה לכ
`
`
`
`:ןייטש
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`וע"טו ד
`
`
`
` .ןכ
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`:דנב ד
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`וע"
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` םתוא ףרצל םירומא ויה ,התאר יתרבגש יפכ םיבכרומ ךכ לכ םהש
`
` רחאל .הז תא וניאר ,ללכב ופרוצ אל הדבעמה תורבחמ .הליחתכלמ
`
` תוסנל ונלחתה זאו םירמוחה לש יקלח טס ונלביק ונשקיב ונחנאש
`
` הגרדהבו ,הדבעמ תורבחמ לש הזה םוצעה ךובמה
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` תא םימרוגל קרפל
`
` ונינפ .םירסחש םייוסינ לש ףסונ דועיתו םירסחש םיפסונ םיטרפ וניליג
`
`
`
`,םייפיצפס םיטנמלא תוברל רמוחה לכ תא ונשקיבו
`
`
`
`
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` ,אל
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`:דנב ד
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`וע"
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`1
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`2
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`3
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`4
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`5
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`6
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`7
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`8
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`9
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`,זאו ,הליחתכלמ רמוחה לכ תא ףרצל םירומא םתייה םתא ,החילס
`
`
`
`:ןייטשטו ד
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`וע"
`
`10
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`
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`?ךישמהל רשפא .יל ועירפת אל םתא ,יל ועירפת אל םתא ,אל
`
`
`
`:ןי
`
`יטשטו ד
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`וע"
`
`12
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`
`
`13
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`
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`)דחי םירבדמ(
`
`11
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` הז יכ
`
`
`
`HPLC
`
`-
`
`ה לש םיבושיחה לש יפיצפס דועית ונשקיב דועית .הדות
`
`
`
`:ןייטשטו ד
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`וע"
`
`14
`
`
`
` .ןכ ,ןכ
`
`:םשרה תינגס 'בכ
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` ונשקיבו .הדבעמ תורבחמהמ ותוא חנעפל רשפא יאש רורב היהש והשמ
`
` דועית שקבל ונלוכי א
`
`לש יאדווב .תויפיצפס תואמגוד יבגל דועית םג
`
` תעדל ונלוכי אלו םיטרדנטסה לע ונעדי אל ,תועיפומ אלש תואמגוד יבגל
`
` יפיצפס ןפואב שקבל רשפא יא יכ ,ונל ורפיס אל יכ םיטרדנטסה לע
`
` לע רתסנה ןאכ ברש ונבהש רחאמו ומויק לע םיעדוי אל ונחנאש והשמ
`
` אל יכ ,בוש
`
`יחה עצוב דציכ וריהביש ,דציכ ונל וריבסיש ונשקיב ,הלגנה
`
` םאש התאר יתרבגש תקמחתמה הבושתה תא ונל ונע זאו ,םינותנה ויה
`
` ?קסידה הפיא ,הבושתב ךירצ היה .דעה תא לאשנ זא תולאש ונל שי
`
` ךשמב לבא ,קסידה תא ונל חולשל ךירצ היה ונלש הלאשל הבושתב
`
` המ לומתא דעהמ ןיבנש דע וניתמהו הז תא ושע אל םינש עברא שולש
`
` הממ רבד םוש
`
`-
`
` דחא רבד יתרבגל רמול הצור ינא ו
`
`ישכע .ןאכ הרק
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` ןאכ ןיא ,דעהמ תעמוש יתרבגש המו ,הדבעמה תורבחמב האור יתרבגש
`
` ,םלגה רמוח תא ,סיסבה תא ונל ונתנ אל
`
`-
`
` הרקמ אוהש רבד םוש
`
` תא קודבל לכונו עדנ ונחנאש וצר אל יכ ,תוסיסמה תואצות תקידבל
`
` הדבעמה תורבחמב םיעי
`
`פומש םיפסונ םייוסינ לש תוסיסמה תואצות
`
` הלילב לומתא ונחנא הרקמ לכב
`
`.
`
`ירקמ אל רבד םוש ,םהב ןודנ דימו
`
`15
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`16
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`17
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`18
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`19
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`20
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`21
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`L/80044/5480/3855628/1
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`Merck Exhibit 2227, Page 4
`Mylan v. Merck, IPR2020-00040
`
`

`

`
`
`29.01.2015
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` םוי
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`מ ןויד
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`
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`5
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`172563
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` טנטפ תשקבל תודגנתה
`
` רחאל ונינע ,הרשע םיתשב ךרעב ירבח לש ליימה תא יתיאר ינא ,ונלביק
`
` ליי'צ ר"ד לש ותעד תווחמו וריהצתמ קלח לכש איה ונתדמע ,ןכמ
`
` ,הקיחמ
`
` וניד
`
`-
`
` דעומב ונל ורסמנ אלש םייוסינ וא םלג ירמוח לע ךמסנש
`
`
`
`.םימוכיסב הזה ןיינעל ןעטנ ונחנאו
`
` .ךישמהל רשפא .הריקחב ליחתנ ואוב ,ןכ .הטלחהב הזל סחייתנ ,רדסב
`
`
`
`:םשרה תינגס 'בכ
`
`.ןכ
`
`
`
`
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`'
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`צ ר"ד
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`:ןייטשטו ד
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`וע"
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`:ןייטשטו ד"ועל תידגנ הריקח ךשמהב בישמ ,קוחכ רהזוהש רחאל ,ליי
`OK, good morning Dr. Chyall, welcome back.
`
`
`I appreciate you have some more questions for me. Your
`
`honor, before we begin I just wanted to respond to some
`requests that were made of me to look at some things on
`the breaks. so I can confirm sir that the calculations with
`respect to the percentage theoretical values of carbon,
`those, those are correct. For the samples you asked if I
`had added the phosphoric acid drop wise for all my
`experiments and I did. There was one thing that I needed
`to clear up though - the concentrations of phosphoric
`acid were different depending on the experiment, and I
`checked in my declarations so when I write out what I did
`in my declaration I say what the concentrations of
`phosphoric acid are. those are correct, I believe that's
`everything that,
` OK.
`
`you have done your homework
`thank you.
`
`thank you Dr. Chyall. We will go back to your pH-
`
`solubility experiments, and now we'll focus on table 5 of
`C1 which is page 24 of your first declaration. In this table
`actually what you attempt to do is to obtain additional
`
`:דעה
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`L/80044/5480/3855628/1
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`Merck Exhibit 2227, Page 5
`Mylan v. Merck, IPR2020-00040
`
`

`

`
`
`29.01.2015
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` םוי
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`מ ןויד
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`
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` טנטפ תשקבל תודגנתה
`
`solubility data points in different pH values. That's
`correct?
`
`Yes that's correct.
`
`thank you. And essentially for this objective what you do
`
`experimentally is to adjust the pH of solutions of either
`Sitagliptin free base, or Sitagliptin DHP and then to
`measure by HPLC the solubility values.
`
`The additional thing is the solutions have to have
`
`undisssolved solids present so we establish equilibrium.
`so it's a solution that is saturated with the material, and
`then there's particles of solids they're always present in
`the sample. so we filter and analyze the filtrate which Is
`the liquid by HPLC, and then we collect the solids, and if
`we have enough solids - we run powder diffraction, and
`as I mentioned yesterday there was one sample where
`we had solids but not enough for powder diffraction.
`
`OK, that was in table 4, you mentioned it yesterday with
`
`regards to a sample in table 4, you mentioned it was in
`regard to table 4 sample 4031-27-05.
`yes sir.
`
`
`OK. So here, and that was actually my next question, you
`
`have excess, I call it excess solids, you call it particles
`flowing in the solutions, doesn't matter, but you have
`those excess solids, you actually dicant the solution and
`then you compare the X-ray of your starting solids and of
`the recovered solids after slurry, as you mentioned in the
`right hand columns of the table 5.
`yes.
`
` ok.
`
`
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`:דעה
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`L/80044/5480/3855628/1
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`Merck Exhibit 2227, Page 6
`Mylan v. Merck, IPR2020-00040
`
`

`

`
`
`29.01.2015
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` םוי
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`מ ןויד
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`
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`172563
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` טנטפ תשקבל תודגנתה
`
`the X-rays have to match the starting material, the base
`or the acid depending on the experiment.
`
`OK, very good, so just so that we understand in more
`
`depth how this process is being carried out, let's review
`one sample which you ran,
`
`
`
`
`:דעה
`
`:ןייטשטו ד
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`וע"
`
`
`:םשרה תינגס 'בכ
`?דחיב לוכה הז
`
`
`
`
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`,יתרבג ןושארה דומעה ליגרכ זא
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`
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`:ןייטשטו ד
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`וע"
`
` הז .הז תא םתקליח יכ טושפ דרפנב ותוא השענ ,ןושארה דומעה ,היינש
`
`
`
`:םשרה תינגס 'בכ
`
`.
`
`112
`
`/במ
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`,רתוי ונל היהיש ידכ 'ב
`
`-
`
`ו 'א הז תא השענ ילוא
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`
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`:ןייטשטו ד
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`וע"
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`10
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`.'ב
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`112
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`/במ ,'א
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`
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`112
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`/במ
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`
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` :ם .רומג רדסב
`
`שרה תינגס 'בכ
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`11
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`,'א
`
`
`
`112
`
`/במ ןושארה דומעה ליגרכ זא
`
`
`
`:ןייטשטו ד
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`וע"
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`12
`
`
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` .ןכ
`
`:םשרה תינגס 'בכ
`
`13
`
` לע תצק לקמ הזש הווקתב ,לקהל ידכ ונכה ונחנאש המירז םישרת הז
`
`
`
`:ןייטשטו ד
`
`וע"
`
`14
`
`
`
`.ייקוא .םירחא
`
`:םשרה תינגס 'בכ
`
`
` .ןכ
`So let's take a look at mem bet 112bet that's a collection
`
`of pages from your lab notebook. and you start actually
`we have these red rectangles which are supposed to
`assist us in going over, you actually start with a free base
`
`sample 4031-21-09,
`
`:ןייטשטו ד
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`וע"
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`:םשרה תינגס 'בכ
`
`20-08
`
`הז ןמוסמה
`
` That doesn't matter, I see I have too many LIMS
`
`numbers, essentially we are discussing the marked
`rectangle is 4031-20-08, which is a pH adjusted sample,
`you adjust the pH to 7.02. right?
`
`yes and it looks like sample 4031-21-01 was added to
`that sample and,
` ok.
`
`it's probably a starting material.
`
`:ןיי
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`טשטו ד
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`וע"
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`23
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`24
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`וע"
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`L/80044/5480/3855628/1
`
`Merck Exhibit 2227, Page 7
`Mylan v. Merck, IPR2020-00040
`
`

`

`
`
`29.01.2015
`
` םוי
`
`מ ןויד
`
`
`
`8
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`172563
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` טנטפ תשקבל תודגנתה
`
`
`yes, that's the free base, right.
`the free base. Well I am not sure about that. 4031-21-01
`
`is ground 229438, which is the LIMS number for either
`the free base or the phosphoric acid salt, we could look
`that up and,
`
`it's for the free base, take a look. You can look at page
`
`21, you can see that they define it, that you defined it.
`Ground 229438
`
`229438. I was just trying to confirm in the patent if it
`corresponds to the free base.
`
`it is. you also mentioned it in your declaration. you
`
`mentioned that your starting solids, you can see entry
`4031-24-08 in table 5, your starting solids are sitagliptin
`base and your recovered solids are sitagliptin base.
`yes.
`
`
`so you actually you take the free base, you adjust the pH
`
`to 7.02, and number of the sample of the pH adjusted
`sample is 20-08 and then we move on to page 22, and
`after 22 hours, sorry, after 18 hours, you measured the
`pH, which is now 7.35, right?
`that's correct.
`
`and you adjust it, again, to your desired pH values, it's
`again adjusted to 7.03. right?
`roughly yes.
`
` ok.
`
`7.03 looks like, yes.
`
`ok. Then on the next page, page 23, after 24 hours you
`
`again measure the pH of that sample, and it remains
`7.04.
`
`
`
`
`
`
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`:ןייטשטו ד
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`וע"
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`:דעה
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`:ןייטשטו ד
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`וע"
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`:דעה
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`L/80044/5480/3855628/1
`
`Merck Exhibit 2227, Page 8
`Mylan v. Merck, IPR2020-00040
`
`

`

`
`
`29.01.2015
`
` םוי
`
`מ ןויד
`
`
`
`9
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` טנטפ תשקבל תודגנתה
`
`yes and this is an important criteria for the experiments
`
`that is the pH remains constant, you see, we went from
`7.03 to 7.04 so we assume that equilibration of pH has
`been maintained.
`
`yes but initially it changed from 7.02 to 7.35.
`yes.
`
`ok thank you, and now you take 1 milliliter sample and
`filter it, that's on page 23, you can see on the top line,
`yes.
`
`you take 1 ml, you remove 1 ml from the sample and you
`filter it, correct?
`
`filtered and then the pH was taken yes, and then the
`
`remaining material was filtered too, there is another
`filtration to collect solids.
`
`OK. Please move on to the next page, page 24, what you
`
`do now is to take 0.5 ml of the sample, and you dilute it in
`15 ml of water, and this is sample 4031-24-08, which we
`have recorded in your table 5.
`
`diluted 500 micro liters of source sample in designated
`value of water.
`
`which is 15 ml because that’s the quantity which you use
`
`for your HPLC studies, and you can also see that at the
`bottom,
`
`it says volume, yes, 15 ml.
`
`15 ml. OK. So, to cut a long story short, you adjust the
`
`pH of the free base to 7, about 7, by adding phosphoric
`acid, you dilute 0.5 ml of the solution in water and you
`send it to HPLC, that's a fair presentation of what is being
`done here?
`
`there is a probably further dilution prior to HPLC work.
`
`
`
`
`
`
`
`:דעה
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`:ןייטשטו ד
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`וע"
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`:דעה
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`:ןייטשטו ד
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`וע"
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`:דעה
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`L/80044/5480/3855628/1
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`Merck Exhibit 2227, Page 9
`Mylan v. Merck, IPR2020-00040
`
`

`

`
`
`29.01.2015
`
` םוי
`
`מ ןויד
`
`
`
`10
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`172563
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` טנטפ תשקבל תודגנתה
`
`
`
`
`
`Which is not recorded in here?
`
`it was probably recorded in the HPLC notebook, which
`would be notebook 4060.
`
`OK, so it's there, so, go on to the next page, you see we
`
`attach 4060 page 28?
`yes.
`
`do you see any additional dilution? I don't see any
`
`additional dilution here, because that's the sample that
`was transferred, you see "4031-24-08 (pH 7)", and that's
`the sample which is being transferred to HPLC.
`
`The summary sheet I want to refer to that as well as the
`
`notebook, because this is the pH, this is table entry, table
`entry 6, 4060-28-08 was the HPLC sample.
`
`that's right, you can see it in the lab notebook, we
`
`marked it for you. The sample number 4031-24-08 in
`table 5 is being transferred to HPLC, put in an HPLC vial,
`it is stated at the top of page 28,
`yes.
`
`in lab notebook 4060, and it is assigned the LIMS
`number 4060-28-08.
`
`yes, and there is a dilution factor of 31, yes, ok.
`
`ok? We are
`in agreement,
`fine, so
`the HPLC
`
`measurement if you just move on to the last page in mem
`bet 112B the last page of this is the HPLC measurement
`which is recorded in your table 5, whose outcome is
`recorded in your table 5.
`yes.
`
`OK. Now just to make sure we are all in agreement here,
`
`in the absence of your standards calibrations, whatever
`name we want to attach to it - there is no way that we
`
`
`
`
`
`
`
`
`
`
`
`
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`:ןייטשטו ד
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`וע"
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`:דעה
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`וע"
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`וע"
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`L/80044/5480/3855628/1
`
`Merck Exhibit 2227, Page 10
`Mylan v. Merck, IPR2020-00040
`
`

`

`
`
`29.01.2015
`
` םוי
`
`מ ןויד
`
`
`
`11
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`172563
`
` טנטפ תשקבל תודגנתה
`
`could have checked whether the solubility value, which
`you record in table 5, indeed corresponds to the HPLC
`result, which is the last page of this bundle.
`
`The HPLC trace, the Chromatogram as we call it, should
`
`have had a method file and a sequence file that would
`have had the calibration standards, because we run, this
`calibration standards before, and then we run the
`sample, and
`then we run a calibration standard
`afterwards. That information would have been in the
`data, I appreciate it would have been.
`
`I am not blaming you for anything Dr. Chyall, I just want
`
`to make sure that we agree that in the absence of this
`data we could not have checked whether your solubility
`measurement as indicated in table 5 is indeed correct.
`We just have to take your word for it, which is also an
`option.
`
`This is presuming that you didn't have,
`yes.
`
`calibration files that are listed on the front page, so,
`
`yes, so assuming we didn't have that, we just have to
`take your word for it.
`
`
`
`
`
`
`
`
`
`
`
`
`
`I guess, I mean I don’t' know what precisely you got and
`when you got it.
`
`assuming we didn't have it we just have to take your
`word for it, right?
`yes,
`
` OK.
`
`but certainly you could have asked for it,
`
`let's leave that for the lawyers, that's not your part. Now,
`
`in this assay which you are conducting in this pH
`
`
`
`
`
`
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`
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`
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`:דעה
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`L/80044/5480/3855628/1
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`Merck Exhibit 2227, Page 11
`Mylan v. Merck, IPR2020-00040
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`solubility measurement, actually you are, you have a
`starting base in solution and you add acid so it's actually
`an acid base reaction, so you must as you indicated
`previously, and also in your declaration - you must
`evaluate when you do it by XRPD, that the solids which
`were recovered were indeed as the starting solids, that
`you started with a base, and ended with a base, although
`you added phosphoric acid and lowered the pH of the
`solution, right?
`
`in theory you could start with a base and bring it over to
`
`the acidic side and end up with an acid, and as long as
`that acid was the same acid that you were starting with
`for the other data points, then that was all would have
`been valid. In practice I believe that we found it much
`better to work just in two halves of the curves. so that if
`we were equilibrating a base - we didn't want to add so
`much to convert it over to the acid and then vice versa,
`although the theory would be equally applicable if we had
`done it that way.
`
`Well, I'll reiterate my question - you told us it's indicated
`
`clearly in your declaration, and you also told us this
`morning that in order to verify that your starting solids,
`that the recovered solids are the same as your starting
`solids, you ran X-ray powder diffraction of the excess
`solids, to make sure that this is indeed the case, you
`highlighted that in table 4 in one entry this was not
`conducted.
`right.
`
`
`right, but definitely this should have been conducted
`
`when you react a base with an acid at pH 7 which is very
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`L/80044/5480/3855628/1
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`Merck Exhibit 2227, Page 12
`Mylan v. Merck, IPR2020-00040
`
`

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`close to the pHmax which you determined. And indeed
`you say so, you say in your table that your starting solids
`are similar, are the same as the solids recovered after,
`
`right. and the X-ray analysis is in the notebooks but it
`
`was also summarized on the sheet that I provided
`yesterday.
`
`OK so take a look, take a look Dr. Chyall at the bundle of
`
`lab notebook pages which I gave you and according to
`your lab notebooks, this particular sample – 4031-24-08
`was not sent to XRPD.
`
`The solids at the filtration step would have been given
`
`another sample number, and if I could point you to, I'll
`point you to the notebook page, but it would be easier if
`we refer to this, this summary table, this is called "pHmax
`XRPD studies", it's a one page summary of samples, this
`is table entry 5.6 I believe, 4031-23-08, should have
`been the solids, 4031-23-08 I believe is the sample
`number for the solids, and you can see the LIMS number
`in the XRPD file associated with that test.
`
`can you show it in the lab notebook pages? Where was
`this sample? Sample 4031-24-08 where was it sent to X-
`ray?
`
`Hmm, it says remaining,
`
`what page are you reading from?
`
`I am reading from page 4031, I'm sorry, notebook 4031
`page 23, we were looking at it earlier.
`yes.
`
`so there is two, there is two samples perhaps here, first
`
`there is the filtration to prepare the solution that we
`analyze by HPLC, and then there is another step to
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`L/80044/5480/3855628/1
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`Merck Exhibit 2227, Page 13
`Mylan v. Merck, IPR2020-00040
`
`

`

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`collect the solids, that we want to analyze, and that is the
`second, the second part of the notebook, so, and again I
`apologize for this gentleman's writing, it is difficult to
`read, but it says the remaining value of each sample V.F
`that means vacuum filter,
`
`no, no it's not value, excuse me. It's "the remaining
`
`volume".
`
`oh yes sorry.
`
`it relates to solvents, it does not relate to solids.
`
`"remaining volume". This is not, it has nothing to do with
`solids.
`
`oh I assure you it does. If you just let me read this
`
`sentence I would be able to explain – "remaining volume
`of each sample vacuum filtered into clean vile, assigned
`new sample number", so this, this sample number here is
`the sample number that we use for the solids, and that is
`the, the 40, from my sheets,
`yes?
`
`sorry but I just had, the solids I.D is 4031-23-08, and you
`
`can see the LIMS number 234258 and then the X-ray
`task to leave that final number.
`
`no, I need to see it on the lab notebook, because sample
`
`number 4031-23-08 that's the sample number we are
`discussing, right?
`
`It's 24-08.
`
`24-08.
`
`Dr. Chyall is referring us to 23-08.
`Oh, I'm sorry.
`
`It's not the same.
`24-08.
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`L/80044/5480/3855628/1
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`Merck Exhibit 2227, Page 14
`Mylan v. Merck, IPR2020-00040
`
`

`

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`
`29.01.2015
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`:דעה
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`וע"
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`on the page 23 it says sample number 4031-23-08, and
`
`:םשרה תינגס 'בכ
`in the table at the affidavit it's 24-08. so it might be
`
`different samples, it must be different samples.
`See, the, the question is very simple - where did you
`send sample 4031-24-08 recorded in table 5 to X-ray?
`
`OK let me check. I'm not sure, I'll have to check.
`
`I can tell you, that, you of course arguably more familiar
`
`with this maze of lab notebooks than we are, but we were
`very carefully looking for X-ray powder diffraction for that
`particular sample, and couldn’t find any.
`
`the sample has a LIMS number and an XRPD file, so I
`can check,
`
`it's not, it's not in your lab notebook. In your lab notebook
`
`when we have sample 4031-24-08 - there is nothing in
`these lab notebooks that indicates that it was sent for X-
`ray. When you sent a sample to X-ray you have those,
`
`
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`:דעה
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`,הלאה םידוקרבה תא האור יתרבג
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`:םשרה תינגס 'בכ
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`You have those barcodes like we see on page 28, there
`
`is no barcode anywhere which we could find which
`indicates that this particular, any barcode by the way
`contains, can you take a look at page 28?
`
`yes.
`
`you see, you see that every barcode which you issue for
`
`a sample which is sent for analysis, it contains the
`barcode, the LIMS number and the sample ID which for
`instance 4060-28-08, which is the lab notebook page
`which identifies the sample. so we could see no
`indication in the lab notebooks that this particular sample
`was sent for X-ray.
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`L/80044/5480/3855628/1
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`Merck Exhibit 2227, Page 15
`Mylan v. Merck, IPR2020-00040
`
`

`

`
`
`29.01.2015
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`:דעה
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`עו"
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`וע"
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`:דעה
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`there was certainly a sample that we sent,
`
`no, no, no there is no such thing as "certainly a sample
`
`that was sent", everything is either recorded in the lab
`notebook, definitely in such level of detail or simply was
`not done.
`
`a sample, a sample definitely exists because we have a
`difragtogram and we have a LIMS number of a sample,
`
`where is the difragtogram? We have never seen any
`difragogram of this particular sample.
`
`I, I don't know what you received from Teva's counsel. I
`
`have the data, I made it available to Teva's counsel, I
`definitely reviewed the difragtogram that I believed to be
`associated with this sample. With respect to why it's not
`documented, it could have just been on oversight from
`the technician who forgot to document what he was
`doing.
`
`you see,
`
`but I believe that if I can have some time on a break or
`
`something,
` OK.
`
`:םשרה תינגס 'בכ
`I can look through the sample log and see if there is an
`
`explanation.
`You see, Dr. Chyall, this particular sample we didn't
`
`arbitrarily select it. This particular sample was measured
`probably at the most critical pH range because it is a pH
`of seven, very in the vicinity, very close to your pHmax,
`the pHmax which you, that you determined. and this is
`very important data point, and we were simply surprised
`that from all this huge quantities, almost unmanageable
`quantities of data, the only XRPD that was not indicated
`
`
`
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`L/80044/5480/3855628/1
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`Merck Exhibit 2227, Page 16
`Mylan v. Merck, IPR2020-00040
`
`

`

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`in the lab notebook, and the only XRPD that we did not
`receive was for that particular sensitive point.
`
`I'll see if I can find the documentation for you, in the
`
`event that we forgot to document it, I believe that was
`just an innocent mistake, we had no expectation going
`into this experiment as to what we were going to get so I
`didn't, I never considered seven to be any more or less
`critical than any other data point.
`
`We will take a look at the data points. I have one more
`
`question for you, just so that we understand the rules of
`the game - when you utilize the pHmax, and I think you
`used similar terminology a few minutes ago, you actually
`divide the pH universe into two regions - above the
`pHmax you're supposed to get, to obtain a base, and
`below the pHmax you're supposed to obtain a salt, that's
`the logic of the pHmax, right?
`
`we had information at that time we had already
`
`measured solubilities of the base and the acid and we
`knew the pKa, so just for those 3 data points we can
`assemble the pHmax curve, and these additional data
`points were really just for confirmation that the samples
`would be on that curve.
`
`Let me ask you the same question again - when you, you
`
`determined the pHmax. it doesn't really matter now
`whether you did
`it with your calculations or
`experimentally, we'll discuss that. but assuming you have
`a pHmax which is accurate, this means that we have a
`universe of pH values, and we divided it, we have a
`borderline above the pHmax, the base below the pHmax
`salt. Generally, not with relation to sitagliptin necessarily.
`
`
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`L/80044/5480/3855628/1
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`Merck Exhibit 2227, Page 17
`Mylan v. Merck, IPR2020-00040
`
`

`

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`29.01.2015
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`that's what the theory dictates, yes.,
`
`
`Ok, very good, thank you, so now let's look at this sample
`
`again, the missing, the missing sample. In your table 5.
`we know, Dr. Chyall, that the solubility, the solubility of
`the salt is quite high, it's normally around 70 mg per ml, it
`can reach 100 mg per ml, on the other hand we know
`that the solubility of the base is low, it's about 7 mg per
`ml. when we look.
`
`just to say, we measured a different solubility value than
`
`you quoted, we had for the solubility of the acid this is in
`table 4, we had, we had values, it depends on whether
`you counted per acid or per base equivalent, but we are
`measuring values that were around a 100 mg per ml of
`sitagliptin phosphate.
`
`for the particular crystalline form which you were using
`
`the Merck form is about 70 mg per ml, right? According
`to the patent.
`
`I am aware of the mono hydrate form,
`
`yeah.
`
`
`which, which could have,
`
` OK,
`
`could have a different solubility.
`
`And then the base, the solubility of the base which you
`measured in table 4, is around 7, 6.5, 7. Right?
`I'm sorry but what was the question?
`
`The solubility of the free base.
`Oh, around 6,
`six, seven,
`mg per ml.
`
`
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`L/80044/5480/3855628/1
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`Merck Exhibit 2227, Page 18
`Mylan v. Merck, IPR2020-00040
`
`

`

`
`
`29.01.2015
`
` םוי
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`מ ןויד
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`

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