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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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`)תדגנתמה םעטמ דע(
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`L/80044/5480/3855628/1
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`Merck Sharp & Dohme Corp. Exhibit 2030
`Dr. Reddy’s Laboratories Inc. v. Merck Sharp and Dohme Corp.
`IPR2020-01060
`Page 1
`
`

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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
`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
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`:דעה
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`L/80044/5480/3855628/1
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`Merck Sharp & Dohme Corp. Exhibit 2030
`Dr. Reddy’s Laboratories Inc. v. Merck Sharp and Dohme Corp.
`IPR2020-01060
`Page 2
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`No. they weren't. because even on your summary, even
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`on your representation to me, as to what I did, you say
`4031-27-01 diluted 200. Oh wait a minute, I'm sorry,
`0.5 ml of it. 0.5 ml of it.
`
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`you're right, you're right, sorry.
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`0.5 ml of it.
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`sorry.
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`so it's the same dilution parameters.
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` OK.
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`it's the same scale, right?
`yes.
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`OK, so our rule of 3, the solubility value of 60 mg per ml
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`you want to say anything about it? do you agree with it?
`simple arithmetic.
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`Let me just burrow a calculator. I can be sure, I am sure I
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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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`doesn't matter. I am sure that if we had your standards,
`we could have had the exact values.
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`I make it to be around 58, just by using another
`calibration standard,
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`OK, fine, that's fine, we won't argue about 2 mg per ml
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`Dr. Chyall. thank you. So, we have a solubility. We have
`a sample at pH 5.9, which is below the pH max, namely it
`should be a salt, right?
`yes.
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`fine. With a solubility which is 58 or 60. And this is the
`XRPD of the sample that was,
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`/במ
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`L/80044/5480/3855628/1
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`Merck Sharp & Dohme Corp. Exhibit 2030
`Dr. Reddy’s Laboratories Inc. v. Merck Sharp and Dohme Corp.
`IPR2020-01060
`Page 3
`
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` of the sample, of the
` And this is the XRPD
`117
`/במ
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`sample of the solids from the measurement in pH 5.9.
`yes, I remember, this is the co-crystal, this is the sample.
` yes, that's fine. Now, ok, let's,
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` תא םינמסמ ךיא יתרבג
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`קר ,
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`ןכ
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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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`.
`118
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`Let's, let's see what we have here. We'll start,
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`
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`:םשרה ת
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`ינגס 'בכ
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`:ןייטשטו ד
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`וע"
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` ליחתנ ונחנא
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`.ןורחאה דומעהמ יתרבג
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`?הז
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`The last page is again the XRPD of the sample which
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`you obtain, of the solids which you obtain at pH 5.9,
`right? It's the same XRPD which we saw before.
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`yes.
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`thank you. The second page is Professor Atwood's
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`sample 1.2, the 2:1 salt. I know you don't agree so we
`will call it the Atwood solids, which he prepared in
`isopropanol and water.
`yes.
`
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`fine. And the cover page is an overlay of Dr. Atwood's 2:1
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`solids prepared in isopropanol and water, and of the
`solids which you prepared at pH 5.9. and I see here, Dr.
`Chyall, a perfect match. So essentially when you ran
`your pH adjusted solubility tests, you obtained Professor
`Atwood's salts, or solids, whatever you want to call them,
`and you concealed this important, this dramatic piece of
`evidence, from the patent commissioner, for years and
`years. You have Professor Atwood's solids in your lab,
`after you ran your first experiments. and you did not tell
`that not in your second declaration, not after you saw Dr.
`AtwoodAtwood's declaration, not in your third declaration.
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`L/80044/5480/3855628/1
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`Merck Sharp & Dohme Corp. Exhibit 2030
`Dr. Reddy’s Laboratories Inc. v. Merck Sharp and Dohme Corp.
`IPR2020-01060
`Page 4
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`How dare you conceal such piece of information? You
`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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`solids and this, the crystal material from this pH adjusted
`experiment, these are the same solid form. these are
`both, the, the lines of diffraction pattern match up. I did
`not recognize Professor Atwood's sample while doing
`this work because I didn't have his declaration at the
`time. When I first saw this difragotram from the material, I
`assumed that it was a decomposition product, because
`of all the difficulties that we had with respect to getting
`the pH stable, and in the case where we had a stable pH
`this clearly was not Sitagliptin base or the phosphoric
`acid salt. so I didn't know what to make of this at the
`time, and I assumed it was a decomposition product.
`When Professor Atwood put in his report, I then
`recognized his crystalline phase as the same phase as
`this material here. but in my rebuttal reports I was
`primarily addressing Professor Atwood's criticisms of my
`work and I didn't, didn't include this in my second report
`because that was my understanding that I was to rebut
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`his work.
`Dr Chyall,
`
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`with respect to the identity of this sample we did have
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`ample time to characterize it in my third declaration, and I
`understand this material to be the co-crystal.
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`Dr. Chyall, you submitted your second declaration after
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`Dr. Atwood submitted his experiments. In Dr. Atwood's
`declaration he submits this, these solids, with this
`identical X-ray powder diffraction of the 2:1 solids. In your
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`Merck Sharp & Dohme Corp. Exhibit 2030
`Dr. Reddy’s Laboratories Inc. v. Merck Sharp and Dohme Corp.
`IPR2020-01060
`Page 5
`
`

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`second declaration you very forcefully challenge Dr.
`Atwood's experiments. you have dozens and dozens of
`paragraphs, dozens of pages in which you criticize what
`Professor Atwood did, and you argue that he actually did
`not obtain 2:1 solids, and yet, at the very same time,
`when you submit your second declaration, you have this
`XRPD, you yourself prepared Dr. Atwood's solids when
`you ran your pH adjustment experiments, and you don't
`bother to report that to the patent office? I am not asking
`you now to characterize these solids, you made the very
`same solids, and you knew that, you knew that in the
`moment, you probably knew that before, but let's keep
`that aside for a second. the moment Dr. Atwood
`submitted his first declaration years ago, years ago, you
`knew that you prepared the same solids, and you
`conceal that from the patent office?
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`I certainly wasn't hiding anything, and the data I
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`submitted to Goodwin Procter, and you had the data, and
`it was all in my notebooks as to what was done. so I,
`again, I didn't recognize that I had the same crystalline
`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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`That was years ago. You had ample opportunities - you
`had you second your declaration, you had your third
`declaration,
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`it was my understanding that my role was to rebut
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`Professor Atwood's assertion that he had a 2:1 salt, and I
`believe that his experiments couldn't be relied upon to
`demonstrate that.
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`L/80044/5480/3855628/1
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`Merck Sharp & Dohme Corp. Exhibit 2030
`Dr. Reddy’s Laboratories Inc. v. Merck Sharp and Dohme Corp.
`IPR2020-01060
`Page 6
`
`

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`your role is primarily to provide a frank and candid
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`description of
`the experiments which you have
`conducted, and in your experiments, at your own lab,
`four years ago, you made Dr. Atwood's solids and you
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`never discovered that to the patent office Dr. Chyall.
`The, the work that I did for the rebuttal report didn't
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`involve recasting data that I collected earlier. The third
`declaration I addressed this protocol in great detail, and
`as a consequence of that I had the opportunity to, to
`characterize this material. So the fact that I found it
`earlier versus what I know about it today - it doesn't
`change the reality that this is a co-crystal of the DHP salt.
`Dr. Chyall you have in your first declaration a very clear
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`and strong statement, which you also reiterate today. We
`have a universe of pH values. We have a borderline,
`that's the pHmax. You calculated the pHmax to be 6.6.
`Above 6.6 it's a base. Below 6.6 it's a salt. You crystallize
`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.
`It's still a DHP salt. It was, it was collected at pH 6,
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`but it's a salt.
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`it's, it's a DHP salt, it's co-crystallized with a free base,
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`and the low solubility explains why we have different
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`values,
`Low solubility? 60 Mg per ML is low solubility? 60 mg per
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`ml is a typical solubility of the phosphate salts of
`sitagliptin. That's reported in the Merck Patent. That's not
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`low solubility.
`the low solubility in this context is with respect to the
`DHP salts which is about double. It was about a hundred.
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`L/80044/5480/3855628/1
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`Merck Sharp & Dohme Corp. Exhibit 2030
`Dr. Reddy’s Laboratories Inc. v. Merck Sharp and Dohme Corp.
`IPR2020-01060
`Page 7
`
`

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` טנטפ תשקבל תודגנתה
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`The Merck DHP salt, the solubility of the Merck DHP salt
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`is around 60 or 70 mg per ml, and you are in the region
`where salts are supposed to be made, that's the essence
`of your first declaration. You determine a demarcation
`line. Below 6.6 it's a salt. You make a salt according to
`your own theory. Your salt, the finger print of your salt is
`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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`unreacted free base in it, and there is actually two DHP
`salt molecules, and one molecule of unreacted free base.
`This is the new, the new crystalline form of sitagliptin
`DHP.
`
`that's what you say in C3 and we discussed C3. I am not
`
`even interested now to hear your views about the
`characterization of the Atwood's solids. Because we are
`dealing now with something which is much more severe,
`and must be explained before you conclude your
`testimony here.
`
`
`you asked him six times and he answered
`
`, you prepare Dr.
` You prepare,
`השקבב יל עירפת לא
`
`Atwood's solids in 2010. May 20, 2010. You measure the
`pH. That’s a measurement at a pH of 5.9 which is
`critically relevant to your pH solubility curve. You do not
`report that measurements. You do not disclose this
`experiment
`in your declaration. Then Dr. Atwood
`prepares his 2:1 salts. One of the 2:1 salts which he
`prepares in the isopropanol and water solvent system
`has the exact finger print of the salt which you prepared.
`We are now in 2011. You have this data in front of you.
`You have Dr. Atwood's experiments in front of you. You
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`:ןייטשטו ד
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`וע"
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`:דעה
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`:דנב ד"וע
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`L/80044/5480/3855628/1
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`Merck Sharp & Dohme Corp. Exhibit 2030
`Dr. Reddy’s Laboratories Inc. v. Merck Sharp and Dohme Corp.
`IPR2020-01060
`Page 8
`
`

`

`
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`29.01.2015
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`
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`40
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`172563
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` טנטפ תשקבל תודגנתה
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`submit the declaration in which you try to rebut Dr.
`Atwood's experiments. You tried to argue that the salts
`which he prepared are not the 2:1 salts, and you do not
`show this XRPD to the commissioner? You do not share
`
`this piece of information with the patent office?
`the fact that I obtained this material out of water doesn't
`
`change any opinion concerning what the salt is. The
`scientific reality is that this is a DHP salt. It has an
`unreacted molecule that co-crystallizes with it.
`
`the scientific reality is that you prepared solids which are
`
`identical to Dr. Atwood's solids. If you had wanted, if you
`had considered that this helps your case, or that this
`promotes your argument, you would have disclosed it in
`your second declaration. But you kept this behind closed
`curtains, you didn't want the patent office to know that
`you, in your pH-solubility experiments made Atwood's 2:1
`solids.
`
`I couldn't,
`
`below the pHmax. At pH of 5.9 which is the region where
`
`salts are made, according to your theory and your
`contentions.
`
`I couldn't disagree with you more. First of all this is not
`
`my case. I am an independent expert in this field. It was
`my duty to provide a pHmax curve, it was my role to
`make that curve, I did my best effort and that was the
`focus of that work - to make a pHmax curve. We did the
`best possible effort we could with the system in front of
`us. Now, as it turned out at retrospect, we identified a
`new solid form in this process. This is something
`characteristic as sitagliptin DHP. There
`is many
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`וע"
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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 Sharp & Dohme Corp. Exhibit 2030
`Dr. Reddy’s Laboratories Inc. v. Merck Sharp and Dohme Corp.
`IPR2020-01060
`Page 9
`
`

`

`
`
`29.01.2015
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`this salt, and we, we
`forms known of
`crystalline
`accidentally discovered one back in this, in this first work.
`I admit - I did not recognize this at the time as a new
`solid form of DHP. Now, it came about that Professor
`Atwood also identified this, this new solid form. I believe
`he mischaracterized that form. But there was certainly no
`intention to ever withhold anything relevant to the patent
`office. It was my judgment at the time that this was not a
`relevant experiment, which is why I didn't include it. With
`respect
`to
`the second declaration
`it was my
`understanding that I was to rebut what Professor Atwood
`did, not to introduce any new data, which is why I didn't
`include it.
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`.הז תא קוחמל יזוחמל ץר תייה ,והשמ םיפיסומ ויהש ונל רסח קר
`
`
`
`:דנב ד
`
`וע"
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`14
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` המ רואל םוקמב וזה הרעהה ןיינעה תוביסנבש בשוח אל ינא .לט
`
`
`
`:ןייטשטו ד
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`וע"
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`15
`
`
`
`.תוקד שמח
`
` םיכירצ ונחנאש תבשוח ינא םגו הקספה שקבמ דעה
`
`
`
`:םשרה תינגס 'בכ
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`17
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`
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`.עגרכ
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` וניארש
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` .ןכ
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`:ןייטשטו ד
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`וע"
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`.תוקד רשע זא ?רוצעל רשפא
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`
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`:םשרה תינגס 'בכ
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`19
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`
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`)הקספה(
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`20
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` דרשממ ןיד ךרוע םלואב שי ,דרוקרל ,יתרבג שקבמ קר ינא .הדות
`
`
`
`:ןייטשטו ד
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`וע"
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`21
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` היעב םוש ןבומכ ונל ןיא ,עבט לש יאקירמאה דרשמה רטקורפ
`
` ןיוודוג
`
` חווד
`
`,
`
`שקיב לי
`
`'י
`
`צ ר"דש הקספהב .הדוקנה וז אל ,םלוא
`
`ב
`
` אוהש ךכ םע
`
` ןידה ךרוע ןכמ רחאלו ,וחחוש ליי'צ ר"דו יאקירמאה ןידה ךרועש יל
`
`
`
`.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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`26
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`.רוסיא םוש ןיא
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`
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`ןייטשטו:
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`וע" ד
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`27
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` אל ונחנאש ןוויכ .החישה םצע אל ,ה
`
`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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` .רורב
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`:דנב ד
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`וע"
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`L/80044/5480/3855628/1
`
`Merck Sharp & Dohme Corp. Exhibit 2030
`Dr. Reddy’s Laboratories Inc. v. Merck Sharp and Dohme Corp.
`IPR2020-01060
`Page 10
`
`

`

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`29.01.2015
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`42
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`172563
`
` טנטפ תשקבל תודגנתה
`
` ול יתרמא ינא
`
`ו דרטומ אוהש יתיאר
`
` זא
`
`,
`
`רקובב דרטומ היה ירבח
`
`
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`:דנב ד
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`וע"
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`
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`,םייסמ אוהש ירחא לייטל ךלוה אוה ןאל תולאשב ונקסעש
`
`
`
`
`
` .ןיידע
`
`:םשרה תינגס 'בכ
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`
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`.רקובב היה הז
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`
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`:ןייטשטו ד
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`וע"
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`
`
`
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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
`
`
`
`:ןייט
`
`שטו ד
`
`וע"
`
` ר"ד הייסנכ וזיא לע התייה אל רטקורפ
`
` ןיוודוגמ
`
`ה ןיד
`
` ךרוע םע החישהש
`
`
`
`.תוארל ךלוה ליי'צ
`
`
`
`.ןיוודוגמ ןיד ךרועה תא יתלאש אל ינא
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`
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`:דנב ד"וע
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` .בוט
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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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`11
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`:םשרה תינגס 'בכ
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` .טלקוה ,רמאנ
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`:םשרה תינגס 'בכ
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`12
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`
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` .ןכ
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`:ןייטשטו ד
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`וע"
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`:םשרה תינגס 'בכ
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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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`:ןייטשטו ד
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`וע"
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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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` .בוט
`
`
`Dr. Chyall, one quick question and then we move on to
`
`another example. At a pH of 5.9 the ionization of the free
`
`base is about 95 percent right?
`assuming the pKa 7.7, that's probably about right. It could
`
`be more.
`
`could be even more? How much more? 97 percent? I
`think it's 97 but,
`yes.
`
` ok.
`
`there, but clearly there is free base present in the
`solution as well, some free base.
`
`but we have 97 percent ionization, ok, thank you, now
`
`let's move on, let's move on to another example.
`
`.'ב
`/במ119
`
`
` תשקבמה לש ףדה
`.'א
`119
`
`/במ
` ןושארה ףדה
` Let's take a look what was done here, it is sample
` .הדות
`
`4031, we are looking at mem bet 119, sample 4031-29-
`
`
`:םשרה תינגס 'בכ
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`27
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`:ןייטשטו ד
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`וע"
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`29
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`L/80044/5480/3855628/1
`
`Merck Sharp & Dohme Corp. Exhibit 2030
`Dr. Reddy’s Laboratories Inc. v. Merck Sharp and Dohme Corp.
`IPR2020-01060
`Page 11
`
`