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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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`:תדגנתמ
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` תשקבמה:
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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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`סולגנמ הרימא
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`ןוטרק ידע
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` ד"ו
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`ע
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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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`ויז ריאי
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`ד"וע
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`ץיבומוקואל היטק
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`ד"וע
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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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`29.01.2015
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` טנטפ תשקבל תודגנתה
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` רחאל ונינע ,הרשע םיתשב ךרעב ירבח לש ליימה תא יתיאר ינא ,ונלביק
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` ליי'צ ר"ד לש ותעד תווחמו וריהצתמ קלח לכש איה ונתדמע ,ןכמ
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` ,הקיחמ
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` וניד
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`-
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` דעומב ונל ורסמנ אלש םייוסינ וא םלג ירמוח לע ךמסנש
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`.םימוכיסב הזה ןיינעל ןעטנ ונחנאו
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` .ךישמהל רשפא .הריקחב ליחתנ ואוב ,ןכ .הטלחהב הזל סחייתנ ,רדסב
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`:םשרה תינגס 'בכ
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`.ןכ
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`:ןייטשטו ד"ועל תידגנ הריקח ךשמהב בישמ ,קוחכ רהזוהש רחאל ,ליי
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`'
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`צ ר"ד
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`OK, good morning Dr. Chyall, welcome back.
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`:ןייטשטו ד
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`וע"
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`I appreciate you have some more questions for me. Your
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`:דעה
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`honor, before we begin I just wanted to respond to some
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`requests that were made of me to look at some things on
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`the breaks. so I can confirm sir that the calculations with
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`respect to the percentage theoretical values of carbon,
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`those, those are correct. For the samples you asked if I
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`had added the phosphoric acid drop wise for all my
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`experiments and I did. There was one thing that I needed
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`to clear up though - the concentrations of phosphoric
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`acid were different depending on the experiment, and I
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`checked in my declarations so when I write out what I did
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`in my declaration I say what the concentrations of
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`phosphoric acid are. those are correct, I believe that's
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`everything that,
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` OK.
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`:ןייטשטו ד
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`וע"
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`you have done your homework
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`thank you.
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`thank you Dr. Chyall. We will go back to your pH-
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`:דנב ד"וע
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`:דעה
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`:ןייטשטו ד
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`וע"
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`solubility experiments, and now we'll focus on table 5 of
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`C1 which is page 24 of your first declaration. In this table
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`actually what you attempt to do is to obtain additional
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`No. they weren't. because even on your summary, even
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`:דעה
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`on your representation to me, as to what I did, you say
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`4031-27-01 diluted 200. Oh wait a minute, I'm sorry,
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`0.5 ml of it. 0.5 ml of it.
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`:ןייטשטו ד
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`וע"
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`you're right, you're right, sorry.
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`:דעה
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`0.5 ml of it.
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`:ןייטשטו ד
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`וע"
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`sorry.
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`:דעה
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`so it's the same dilution parameters.
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`:ןייטשטו ד
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`וע"
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` OK.
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`:דעה
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`it's the same scale, right?
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`:ןייטשטו ד
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`וע"
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`yes.
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`:דעה
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`OK, so our rule of 3, the solubility value of 60 mg per ml
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`:ןייטשטו ד
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`וע"
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`you want to say anything about it? do you agree with it?
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`simple arithmetic.
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`Let me just burrow a calculator. I can be sure, I am sure I
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`:דעה
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`can find the exact value,
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`rough value is also fine, you know, 1 mg up or down
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`:ןייטשטו ד
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`וע"
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`doesn't matter. I am sure that if we had your standards,
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`we could have had the exact values.
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`I make it to be around 58, just by using another
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`OK, fine, that's fine, we won't argue about 2 mg per ml
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`calibration standard,
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`Dr. Chyall. thank you. So, we have a solubility. We have
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`a sample at pH 5.9, which is below the pH max, namely it
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`should be a salt, right?
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`:דעה
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`וע"
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`yes.
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`:דעה
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`fine. With a solubility which is 58 or 60. And this is the
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`:ןייטשטו ד
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`וע"
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`XRPD of the sample that was,
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`.ןכ ,
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`/במ
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` םכתושרב ןמסנ קר
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`:םשרה תינגס 'בכ
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` טנטפ תשקבל תודגנתה
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` of the sample, of the
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`117
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`/במ
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` And this is the XRPD
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`sample of the solids from the measurement in pH 5.9.
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`yes, I remember, this is the co-crystal, this is the sample.
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` תא םינמסמ ךיא יתרבג
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`קר ,
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`ןכ
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` yes, that's fine. Now, ok, let's,
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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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`?הז
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`.
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` /במ
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`:םשרה ת
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`ינגס 'בכ
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` ליחתנ ונחנא
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`Let's, let's see what we have here. We'll start,
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`:ןייטשטו ד
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`וע"
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`.ןורחאה דומעהמ יתרבג
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` .ןכ
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`:םשרה תינגס 'בכ
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`The last page is again the XRPD of the sample which
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`:ןייטשטו ד
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`וע"
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`you obtain, of the solids which you obtain at pH 5.9,
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`right? It's the same XRPD which we saw before.
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`yes.
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`:דעה
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`thank you. The second page is Professor Atwood's
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`:ןייטשטו ד
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`וע"
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`sample 1.2, the 2:1 salt. I know you don't agree so we
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`will call it the Atwood solids, which he prepared in
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`isopropanol and water.
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`fine. And the cover page is an overlay of Dr. Atwood's 2:1
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`:ןייטשטו ד
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`וע"
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`yes.
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`:דעה
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`solids prepared in isopropanol and water, and of the
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`solids which you prepared at pH 5.9. and I see here, Dr.
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`Chyall, a perfect match. So essentially when you ran
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`your pH adjusted solubility tests, you obtained Professor
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`Atwood's salts, or solids, whatever you want to call them,
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`and you concealed this important, this dramatic piece of
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`evidence, from the patent commissioner, for years and
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`years. You have Professor Atwood's solids in your lab,
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`after you ran your first experiments. and you did not tell
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`that not in your second declaration, not after you saw Dr.
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`AtwoodAtwood's declaration, not in your third declaration.
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` טנטפ תשקבל תודגנתה
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`How dare you conceal such piece of information? You
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`prepared Atwood's solids.
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`When, I, let me say that first of all I agree that the Atwood
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`:דעה
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`solids and this, the crystal material from this pH adjusted
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`experiment, these are the same solid form. these are
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`both, the, the lines of diffraction pattern match up. I did
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`not recognize Professor Atwood's sample while doing
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`this work because I didn't have his declaration at the
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`time. When I first saw this difragotram from the material, I
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`assumed that it was a decomposition product, because
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`of all the difficulties that we had with respect to getting
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`the pH stable, and in the case where we had a stable pH
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`this clearly was not Sitagliptin base or the phosphoric
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`acid salt. so I didn't know what to make of this at the
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`time, and I assumed it was a decomposition product.
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`When Professor Atwood put in his report, I then
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`recognized his crystalline phase as the same phase as
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`this material here. but in my rebuttal reports I was
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`primarily addressing Professor Atwood's criticisms of my
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`work and I didn't, didn't include this in my second report
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`because that was my understanding that I was to rebut
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`his work.
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`Dr Chyall,
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`:ןייטשטו ד
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`וע"
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`with respect to the identity of this sample we did have
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`:דעה
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`ample time to characterize it in my third declaration, and I
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`understand this material to be the co-crystal.
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`Dr. Chyall, you submitted your second declaration after
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`:ןייטשטו ד
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`עו"
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`Dr. Atwood submitted his experiments. In Dr. Atwood's
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`declaration he submits this, these solids, with this
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`identical X-ray powder diffraction of the 2:1 solids. In your
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`second declaration you very forcefully challenge Dr.
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`Atwood's experiments. you have dozens and dozens of
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`paragraphs, dozens of pages in which you criticize what
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`Professor Atwood did, and you argue that he actually did
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`not obtain 2:1 solids, and yet, at the very same time,
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`when you submit your second declaration, you have this
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`XRPD, you yourself prepared Dr. Atwood's solids when
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`you ran your pH adjustment experiments, and you don't
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`bother to report that to the patent office? I am not asking
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`you now to characterize these solids, you made the very
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`same solids, and you knew that, you knew that in the
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`moment, you probably knew that before, but let's keep
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`that aside for a second. the moment Dr. Atwood
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`submitted his first declaration years ago, years ago, you
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`knew that you prepared the same solids, and you
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`conceal that from the patent office?
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`I certainly wasn't hiding anything, and the data I
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`:דעה
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`submitted to Goodwin Procter, and you had the data, and
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`it was all in my notebooks as to what was done. so I,
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`again, I didn't recognize that I had the same crystalline
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`phase until I saw Professor Atwood's declaration.
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`and even then you do not report that to the patent office.
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`:ןייטשטו ד
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`וע"
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`That was years ago. You had ample opportunities - you
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`had you second your declaration, you had your third
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`declaration,
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`it was my understanding that my role was to rebut
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`:דעה
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`Professor Atwood's assertion that he had a 2:1 salt, and I
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`believe that his experiments couldn't be relied upon to
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`demonstrate that.
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` טנטפ תשקבל תודגנתה
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`your role is primarily to provide a frank and candid
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`:ןייטשטו ד
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`וע"
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`description of
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`the experiments which you have
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`conducted, and in your experiments, at your own lab,
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`four years ago, you made Dr. Atwood's solids and you
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`never discovered that to the patent office Dr. Chyall.
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`The, the work that I did for the rebuttal report didn't
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`:דעה
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`involve recasting data that I collected earlier. The third
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`declaration I addressed this protocol in great detail, and
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`as a consequence of that I had the opportunity to, to
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`characterize this material. So the fact that I found it
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`earlier versus what I know about it today - it doesn't
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`change the reality that this is a co-crystal of the DHP salt.
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`Dr. Chyall you have in your first declaration a very clear
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`:ןייטשטו ד
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`וע"
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`and strong statement, which you also reiterate today. We
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`have a universe of pH values. We have a borderline,
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`that's the pHmax. You calculated the pHmax to be 6.6.
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`Above 6.6 it's a base. Below 6.6 it's a salt. You crystallize
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`a salt at pH below 6.6 well below 6.6. It's 5.9. You obtain
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`Dr. Atwood's solids, and you do not disclose that.
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`It's still a DHP salt. It was, it was collected at pH 6,
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`:דעה
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`it's, it's a DHP salt, it's co-crystallized with a free base,
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`but it's a salt.
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`:ןייטשטו ד
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`וע"
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`:דעה
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`and the low solubility explains why we have different
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`values,
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`Low solubility? 60 Mg per ML is low solubility? 60 mg per
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`:ןייטשטו ד
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`וע"
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`ml is a typical solubility of the phosphate salts of
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`sitagliptin. That's reported in the Merck Patent. That's not
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`low solubility.
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`the low solubility in this context is with respect to the
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`:דעה
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`DHP salts which is about double. It was about a hundred.
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`The Merck DHP salt, the solubility of the Merck DHP salt
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`:ןייטשטו ד
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`וע"
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`is around 60 or 70 mg per ml, and you are in the region
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`where salts are supposed to be made, that's the essence
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`of your first declaration. You determine a demarcation
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`line. Below 6.6 it's a salt. You make a salt according to
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`your own theory. Your salt, the finger print of your salt is
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`Dr. Atwood's solids, and you never show it.
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`this, this salt is a salt that has an additional molecule of
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`:דעה
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`unreacted free base in it, and there is actually two DHP
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`salt molecules, and one molecule of unreacted free base.
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`This is the new, the new crystalline form of sitagliptin
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`
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`DHP.
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`that's what you say in C3 and we discussed C3. I am not
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`וע"
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`13
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`even interested now to hear your views about the
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`characterization of the Atwood's solids. Because we are
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`dealing now with something which is much more severe,
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`and must be explained before you conclude your
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`testimony here.
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`you asked him six times and he answered
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`:דנב ד"וע
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`, you prepare Dr.
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`השקבב יל עירפת לא
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` You prepare,
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`:ןייטשטו ד"וע
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`20
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`Atwood's solids in 2010. May 20, 2010. You measure the
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`pH. That’s a measurement at a pH of 5.9 which is
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`critically relevant to your pH solubility curve. You do not
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`report that measurements. You do not disclose this
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`experiment
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`in your declaration. Then Dr. Atwood
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`prepares his 2:1 salts. One of the 2:1 salts which he
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`prepares in the isopropanol and water solvent system
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`has the exact finger print of the salt which you prepared.
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`We are now in 2011. You have this data in front of you.
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`You have Dr. Atwood's experiments in front of you. You
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` טנטפ תשקבל תודגנתה
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`submit the declaration in which you try to rebut Dr.
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`Atwood's experiments. You tried to argue that the salts
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`which he prepared are not the 2:1 salts, and you do not
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`show this XRPD to the commissioner? You do not share
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`this piece of information with the patent office?
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`the fact that I obtained this material out of water doesn't
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`:דעה
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`change any opinion concerning what the salt is. The
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`scientific reality is that this is a DHP salt. It has an
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`unreacted molecule that co-crystallizes with it.
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`the scientific reality is that you prepared solids which are
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`וע"
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`10
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`identical to Dr. Atwood's solids. If you had wanted, if you
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`had considered that this helps your case, or that this
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`promotes your argument, you would have disclosed it in
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`your second declaration. But you kept this behind closed
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`curtains, you didn't want the patent office to know that
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`you, in your pH-solubility experiments made Atwood's 2:1
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`below the pHmax. At pH of 5.9 which is the region where
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`
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`solids.
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`I couldn't,
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`:דעה
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`:ןייטשטו ד
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`וע"
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`salts are made, according to your theory and your
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`contentions.
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`I couldn't disagree with you more. First of all this is not
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`:דעה
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`my case. I am an independent expert in this field. It was
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`my duty to provide a pHmax curve, it was my role to
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`make that curve, I did my best effort and that was the
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`focus of that work - to make a pHmax curve. We did the
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`best possible effort we could with the system in front of
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`us. Now, as it turned out at retrospect, we identified a
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`new solid form in this process. This is something
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`characteristic as sitagliptin DHP. There
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`is many
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` טנטפ תשקבל תודגנתה
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`crystalline
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`forms known of
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`this salt, and we, we
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`accidentally discovered one back in this, in this first work.
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`I admit - I did not recognize this at the time as a new
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`solid form of DHP. Now, it came about that Professor
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`Atwood also identified this, this new solid form. I believe
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`he mischaracterized that form. But there was certainly no
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`intention to ever withhold anything relevant to the patent
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`office. It was my judgment at the time that this was not a
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`relevant experiment, which is why I didn't include it. With
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`respect
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`to
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`the second declaration
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`it was my
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`understanding that I was to rebut what Professor Atwood
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`did, not to introduce any new data, which is why I didn't
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`include it.
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`.הז תא קוחמל יזוחמל ץר תייה ,והשמ םיפיסומ ויהש ונל רסח קר
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`:דנב ד
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`וע"
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` המ רואל םוקמב וזה הרעהה ןיינעה תוביסנבש בשוח אל ינא .לט
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`:ןייטשטו ד
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`וע"
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`.תוקד שמח
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` םיכירצ ונחנאש תבשוח ינא םגו הקספה שקבמ דעה
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`:םשרה תינגס 'בכ
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`.עגרכ
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` וניארש
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` .ןכ
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`וע"
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`.תוקד רשע זא ?רוצעל רשפא
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`:םשרה תינגס 'בכ
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`)הקספה(
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` דרשממ ןיד ךרוע םלואב שי ,דרוקרל ,יתרבג שקבמ קר ינא .הדות
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`וע"
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` היעב םוש ןבומכ ונל ןיא ,עבט לש יאקירמאה דרשמה רטקורפ
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` ןיוודוג
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` חווד
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`,
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`שקיב לי
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`'י
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`צ ר"דש הקספהב .הדוקנה וז אל ,םלוא
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`ב
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` אוהש ךכ םע
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` ןידה ךרוע ןכמ רחאלו ,וחחוש ליי'צ ר"דו יאקירמאה ןידה ךרועש יל
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`.דרוקר ןוא היהי הזש שקבמ קר ינא ,יירבח םע חחוש יאקירמאה
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`.רוסיא ןיא ?המ זא ,ןמזה לכ םיחחושמ ונחנא
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`דנב:
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`וע" ד
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`.רוסיא םוש ןיא
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`ןייטשטו:
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`וע" ד
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` אל ונחנאש ןוויכ .החישה םצע אל ,ה
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`חישה אשונ קר הז היעבה ,אל ,אל
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`:םשרה תינגס 'בכ
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`,זא םכל םיתתוצמ
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`:דנב ד
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`וע"
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` טנטפ תשקבל תודגנתה
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` ול יתרמא ינא
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`ו דרטומ אוהש יתיאר
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` זא
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`,
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`רקובב דרטומ היה ירבח
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`:דנב ד
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`וע"
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`,םייסמ אוהש ירחא לייטל ךלוה אוה ןאל תולאשב ונקסעש
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` .ןיידע
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`:םשרה תינגס 'בכ
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`.רקובב היה הז
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`:ןייטשטו ד
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`וע"
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` .ןוכנ
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`:דנב ד
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`וע"
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` חינמ ינא הלאה תוקד שמחב וישכע שקיב ליי'צ ר"דש הקספהב לבא
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`:ןייט
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`שטו ד
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`וע"
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` ר"ד הייסנכ וזיא לע התייה אל רטקורפ
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` ןיוודוגמ
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`ה ןיד
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` ךרוע םע החישהש
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`.תוארל ךלוה ליי'צ
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`.ןיוודוגמ ןיד ךרועה תא יתלאש אל ינא
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`:דנב ד"וע
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` .בוט
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`:םשרה תינגס 'בכ
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`.הפ רוצעל ףידע ,רמאנש המ רמאנ
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`:ןייטשטו ד
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`וע"
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` .טלקוה ,רמאנ
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`:םשרה תינגס 'בכ
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` .ןכ
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`:ןייטשטו ד
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`וע"
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` .בוט
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`:םשרה תינגס 'בכ
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`Dr. Chyall, one quick question and then we move on to
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`:ןייטשטו ד
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`וע"
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`another example. At a pH of 5.9 the ionization of the free
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`base is about 95 percent right?
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`assuming the pKa 7.7, that's probably about right. It could
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`:דעה
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`18
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`be more.
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`could be even more? How much more? 97 percent? I
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`:ןייטשטו ד
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`וע"
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`think it's 97 but,
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`yes.
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`:דעה
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` ok.
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`:ןייטשטו ד
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`וע"
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`there, but clearly there is free base present in the
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`solution as well, some free base.
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`but we have 97 percent ionization, ok, thank you, now
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`:דעה
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`:ןיי
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`טשטו ד
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`וע"
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`let's move on, let's move on to another example.
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`.'ב
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`/במ119
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` תשקבמה לש ףדה
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`.'א
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`119
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`/במ
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` ןושארה ףדה
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`:םשרה תינגס 'בכ
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` Let's take a look what was done here, it is sample
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` .הדות
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`:ןייטשטו ד
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`וע"
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`4031, we are looking at mem bet 119, sample 4031-29-
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