`437
`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 1 of 36 PageID #:5473
`
`IN THE UNITED STATES DISTRICT COURT
`NORTHERN DISTRICT OF ILLINOIS
`EASTERN DIVISION
`
`Docket Nos. 16 C 651
` 17 C 7903
`
`Chicago, Illinois
`July 18, 2018
`10:10 a.m.
`
`)))))))))
`
`HOSPIRA, INC.,
`
`Plaintiff,
`
`vs.
`
`FRESENIUS KABI USA, LLC,
`
`Defendant.
`
`VOLUME 3A
`TRANSCRIPT OF PROCEEDINGS - Bench Trial
`BEFORE THE HONORABLE REBECCA R. PALLMEYER
`
`APPEARANCES:
`
`For the Plaintiff:
`
`For the Defendant:
`
`Also Present:
`
`JENNER & BLOCK LLP
`BY: MR. BRADFORD P. LYERLA
`MR. YUSUF ESAT
`MR. AARON A. BARLOW
`MR. REN-HOW H. HARN
`MS. SARA T. HORTON
`353 North Clark Street
`Chicago, Illinois 60654
`
`SCHIFF HARDIN LLP
`BY: MR. IMRON T. ALY
`MR. JOEL M. WALLACE
`MS. TARA L. KURTIS
`MR. KEVIN M. NELSON
`233 South Wacker Drive, Suite 6600
`Chicago, Illinois 60606
`
`SCHIFF HARDIN LLP
`BY: MR. AHMED M.T. RIAZ
`666 Fifth Avenue, 17th Floor
`New York, New York 10103
`
`Mr. Michael P. Bauer, Hospira
`Mr. Ryan Daniel, Fresenius Kabi
`Mr. Ali Ahmed, Fresenius Kabi
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`438
`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 2 of 36 PageID #:5474
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`Court Reporter:
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`FRANCES WARD, CSR, RPR, RMR, FCRR
`Official Court Reporter
`219 S. Dearborn Street, Suite 2144D
`Chicago, Illinois 60604
`(312) 435-5561
`frances_ward@ilnd.uscourts.gov
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`Kipp - cross by Horton
`439
`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 3 of 36 PageID #:5475
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`THE COURT: All right. We are prepared, I think,
`
`to hear continued cross-examination.
`
`MS. HORTON: Yes, your Honor.
`
`THE COURT: I want to remind you, sir, that you are
`
`under oath.
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`You may proceed, counsel.
`
`JAMES KIPP, DEFENDANT'S WITNESS, PREVIOUSLY SWORN
`
`CROSS-EXAMINATION - Resumed
`
`BY MS. HORTON:
`
`Q.
`
`A.
`
`Q.
`
`Good morning, Dr. Kipp.
`
`Good morning.
`
`I just have a few more things to ask you about.
`
`You mentioned Remington's in your testimony
`
`yesterday; is that right?
`
`A.
`
`Q.
`
`A.
`
`Yes.
`
`What is Remington's?
`
`It's a general guidance book that formulators would
`
`consult, basically a bible that any formulator would consult.
`
`Q.
`
`Okay. Let's look at JTX20.1, please.
`
`This is Remington's?
`
`It's also in the binder in front of you, if you
`
`would like to look at the --
`
`A.
`
`Q.
`
`A.
`
`I can see it on the screen.
`
`Okay. So yes, this is Remington's?
`
`Yes.
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`Kipp - cross by Horton
`440
`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 4 of 36 PageID #:5476
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`Q.
`
`Okay. If we could look at Page JTX20.5, please, there
`
`is a heading entitled "Product Stability."
`
`Do you see that?
`
`Yes.
`
`And that says, "Many factors affect the stability of a
`
`A.
`
`Q.
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`pharmaceutical product and include the stability of the
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`active ingredients; the potential interaction between active
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`and inactive ingredients; the manufacturing process; the
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`dosage form; the container, liner, closure system; and the
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`environmental conditions encountered during shipment,
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`storage, and handling; and the length of time between
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`manufacture and usage."
`
`Is that right?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`Yes.
`
`Do you agree with that as a general statement?
`
`Yes, I do.
`
`Okay. Let's talk a little bit more about this, as it
`
`says, container system.
`
`We talked yesterday about sealed glass vials.
`
`A.
`
`Q.
`
`Yes.
`
`And those have to have stoppers to make sure it's
`
`closed?
`
`A.
`
`Q.
`
`Yes.
`
`Okay. And the drug could have some interaction or some
`
`sorption issues with a stopper, right?
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`Kipp - cross by Horton
`441
`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 5 of 36 PageID #:5477
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`A.
`
`Q.
`
`It could, yes.
`
`Okay. And one of the ways to deal with that would be to
`
`use a coated stopper?
`
`A.
`
`Q.
`
`Yes.
`
`And there are many coated stoppers that you could use on
`
`the market?
`
`A.
`
`It's not unlimited. There are a few select stoppers
`
`that could be used, yes. They have to be approved and,
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`obviously, acceptable in pharmaceutical products, especially
`
`in injectables.
`
`Q.
`
`A.
`
`Q.
`
`Are there more than ten on the market?
`
`I don't know the exact number.
`
`Okay. So there is something -- because of this
`
`potential sorption issue, that's why the FDA requires testing
`
`in both the upright and inverted configuration; is that
`
`right?
`
`A.
`
`Q.
`
`A.
`
`Yes.
`
`And what's the reason for the inverted testing, I guess?
`
`Well, you want to look at the worst case. The FDA
`
`always wants you to look at the worst possible case. So the
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`stopper material would be in constant contact with the fluid
`
`inside the bottle.
`
`Q.
`
`Okay. And that could be something that happens, for
`
`example, in shipping or handling or something?
`
`A.
`
`Yes.
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`Kipp - cross by Horton
`442
`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 6 of 36 PageID #:5478
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`Q.
`
`Now, if there is sorption on the stopper, the amount of
`
`sorption could depend -- or would depend on the size of the
`
`stopper and the amount of contact it has with the drug,
`
`right?
`
`A.
`
`Q.
`
`It might.
`
`Well, if there is a bigger surface area for the stopper,
`
`there is a bigger surface area for the molecule to react with
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`the stopper, right?
`
`A.
`
`Yes. But it's relative to the size of the glass
`
`container that it's contained in, too.
`
`Q.
`
`Okay. And for ready-to-use formulations, those are
`
`typically stored in larger volumes than the concentrated
`
`formulations, right?
`
`A.
`
`Q.
`
`Yes.
`
`We talked a little bit yesterday about accelerated
`
`stability studies and accelerated testing.
`
`A.
`
`Q.
`
`Do you remember that?
`
`Yes.
`
`And you told me a little bit about stress conditions.
`
`I want to ask you now about -- you differentiated
`
`between stress and accelerated studies?
`
`A.
`
`Q.
`
`A.
`
`Yes.
`
`What are accelerated studies?
`
`Accelerated studies are studies with the intended
`
`formulation but stored at a higher temperature in order to
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`Kipp - cross by Horton
`443
`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 7 of 36 PageID #:5479
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`accelerate degradation that would normally happen at room
`
`temperature, because you don't want to wait a long period of
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`time to see any change.
`
`Q.
`
`A.
`
`Q.
`
`So you are just raising the temperature?
`
`Well, yes.
`
`Okay. Does that tell you anything about what happens at
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`longer-term conditions?
`
`A.
`
`Q.
`
`It may, yes. Yes, it may.
`
`And there is actually an equation you can use to use the
`
`accelerated conditions to convert to what would happen in
`
`room temperature conditions, right?
`
`A.
`
`Well, you have to be very careful about how you apply
`
`your extrapolation.
`
`Generally you run a study at different temperatures
`
`to show that an extrapolation from higher temperatures is
`
`valid.
`
`Q.
`
`Okay. So the accelerated studies is just a way to have
`
`stability testing done in a shorter amount of time to tell
`
`you what could happen at the longer amount of time?
`
`A.
`
`It may tell you something about the longer storage
`
`period, generally speaking. It's meant to catch any failure
`
`modes early on, before you store samples for a longer period
`
`of time.
`
`Q.
`
`So the accelerated studies are typically at
`
`40 degrees C, right?
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`Kipp - cross by Horton
`444
`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 8 of 36 PageID #:5480
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`A.
`
`Q.
`
`A.
`
`Q.
`
`Yes.
`
`Is that about 100 degrees Fahrenheit?
`
`Roughly.
`
`So that could also tell you something about how the drug
`
`reacts if it's, for example, stored in hot conditions?
`
`A.
`
`Yes, if it's stored in the desert or something like
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`that.
`
`Q.
`
`Okay. Yesterday you mentioned that dexmedetomidine is
`
`rock stable.
`
`Do you remember that?
`
`Yes.
`
`And you said there is no way at normal conditions over
`
`A.
`
`Q.
`
`any period of time that dex would react significantly, right?
`
`Chemically speaking, the drug is stable.
`
`Okay.
`
`MS. HORTON: So let's look at JTX51, please, at
`
`A.
`
`Q.
`
`.33.
`
`BY MS. HORTON:
`
`Q.
`
`And, Dr. Kipp, this is the development report from
`
`Hospira on its 4 microgram-per-ml product, right?
`
`A.
`
`Q.
`
`Yes.
`
`You saw Dr. Roychowdhury be asked questions about this,
`
`correct?
`
`A.
`
`Q.
`
`Yes.
`
`Okay. So under the table there, it says, "The total
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`Kipp - cross by Horton
`445
`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 9 of 36 PageID #:5481
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`percent drop in potency over five months was 2.3 percent and
`
`4.5 percent when stored at 25 C and 40 C, respectively."
`
`Do you see that?
`
`Yes.
`
`And that 4.5 percent is showing some loss, right?
`
`I don't know if that's real loss or whether that's just
`
`A.
`
`Q.
`
`A.
`
`that one point that shows that it could be due to statistical
`
`variation as well.
`
`Q.
`
`A.
`
`Q.
`
`Okay.
`
`You have to analyze all the data points collectively.
`
`But what it says here is, that's 4.5 percent loss,
`
`right?
`
`A.
`
`Q.
`
`That's what it says, yes.
`
`Okay. Do you stand by your statement that there is no
`
`way this would degrade over any period of time?
`
`A.
`
`Well, some of this could be due to sorption of the drug.
`
`I don't know.
`
`But again, you have to analyze the data
`
`collectively, look for the trend, and see whether that
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`deviation is a significant deviation or not.
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`MS. HORTON: Dr. Kipp, I have no more questions at
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`this time. Thank you.
`
`THE COURT: Redirect examination.
`
`MR. ALY: Yes, your Honor.
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`Kipp - redirect by Aly
`446
`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 10 of 36 PageID #:5482
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`REDIRECT EXAMINATION
`
`BY MR. ALY:
`
`Q.
`
`A.
`
`Q.
`
`Good morning, Dr. Kipp.
`
`Good morning.
`
`Dr. Kipp, counsel just asked this morning about stress
`
`tests and accelerated aging testing?
`
`A.
`
`Q.
`
`Yes.
`
`What are the conditions that were shown in the patent
`
`for stress tests to show any amount of oxidation?
`
`A.
`
`The stress test that was used, I believe, was 60 degrees
`
`for eight hours -- 60 degrees Celsius, which is 140 degrees
`
`Fahrenheit, for eight hours.
`
`Q.
`
`And did they only just heat the drug for the stress
`
`test, or did they do something more?
`
`A.
`
`No, they didn't just heat the solution. They also used
`
`an oxidizing agent to deliberately induce oxidation of the
`
`molecule. That is hydrogen peroxide.
`
`Q.
`
`Another issue that came up this morning was about
`
`Remington's.
`
`Let's please take a look at that, JTX20.
`
`Okay.
`
`And counsel asked you about the different items that can
`
`A.
`
`Q.
`
`interact with the drug, right?
`
`A.
`
`Q.
`
`Yes.
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`And one of those -- then she, right after that, asked
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`Kipp - redirect by Aly
`447
`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 11 of 36 PageID #:5483
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`about the closures, the stoppers that could be used?
`
`A.
`
`Q.
`
`Yes.
`
`But doesn't Remington's address the closures that can be
`
`used, also?
`
`A.
`
`Q.
`
`Yes.
`
`Let's look at Page 14, lower left.
`
`Do you see that "Closures" section?
`
`In terms of the closures -- and the section goes
`
`off to the top of the right page -- what does Remington's
`
`teach about closures that can be used to avoid interaction
`
`with drugs?
`
`A.
`
`You can see at the bottom, from that excerpt, that
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`Teflon-coated rubber stoppers will basically nip the matter
`
`in the bud and prevent sorption -- it may prevent sorption
`
`and leaching.
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`In fact, as I pointed out earlier, that's what we
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`used at Baxter as a control sample in Type 1 glass, using a
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`Teflon-coated rubber closure.
`
`Q.
`
`Now, Teflon is a trade name. I want to just be clear.
`
`Does that mean only Teflon-coated can be used for this
`
`purpose?
`
`A.
`
`Well, it's the trade name originally by DuPont for
`
`perfluorinated hydrocarbon or rubber -- or coating,
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`basically.
`
`Q.
`
`That's a name that's kind of used generically in the
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`Kipp - redirect by Aly
`448
`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 12 of 36 PageID #:5484
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`field?
`
`A.
`
`Q.
`
`Yes.
`
`And, by the way, in the real world, do people hold or
`
`store vials upside down?
`
`A.
`
`No, they don't, obviously. In fact, we would -- when we
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`stored our controls, they were constantly upright. We
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`didn't -- as a control sample, we would use -- they would be
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`stored upright. I mean -- yeah.
`
`So yeah. Inverted storage is not the usual way you
`
`would store a bottle.
`
`Q.
`
`Let's now talk about some of the issues from yesterday's
`
`portion of the cross-examination.
`
`I would like to start with your expert report. A
`
`lot of time was spent on two pages -- three pages of that.
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`MR. ALY: DTX457 at 141.
`
`BY MR. ALY:
`
`Q.
`
`On the bottom of Page 141 and going on to Page 142 and
`
`going on to Page 143, what have you explained in your expert
`
`report?
`
`A.
`
`Okay. These are estimated shelf life. Well, actually,
`
`the period required for 2 percent loss in months.
`
`And this was brought up earlier, I believe, by the
`
`plaintiff's attorneys.
`
`Q.
`
`We can't fit all of the data from the three pages on the
`
`screen at the same time, but of the data, counsel only asked
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`Kipp - redirect by Aly
`449
`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 13 of 36 PageID #:5485
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`you about one of those rows, right?
`
`A.
`
`Q.
`
`Yes, that's correct.
`
`Let's start with that row. That's for the second row,
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`and it's showing -- what concentration was counsel asking
`
`about?
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`A.
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`Well, she was comparing the 200
`
`micrograms-per-milliliter estimate for percent -- for
`
`2 percent loss, which was calculated to be 60.1 months.
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`And then she was comparing that with Lot 21-261-DK
`
`for upright storage. And that shows a loss of 23 point -- a
`
`2 percent loss after 23.2 months.
`
`Q.
`
`A.
`
`And what is your response to that comparison, Dr. Kipp?
`
`Well, she was claiming that, indeed, the lower
`
`concentration shows a lower shelf life in accord with their
`
`proposed sort of mechanism of absorption to the stopper.
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`Do you agree with that?
`
`No, I don't agree at all.
`
`Why not?
`
`Well, if you look further down the table, in fact, there
`
`are other instances where there are also other lots that are
`
`stored, in fact, inverted, which would be worst case, at the
`
`lower concentration.
`
`For example, 21-263-DK inverted, which again, we
`
`have said is worst case. And that predicts almost a six-year
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`period for 2 percent loss, 71 months.
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`Kipp - redirect by Aly
`450
`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 14 of 36 PageID #:5486
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`Q.
`
`Dr. Kipp, did any of the data -- when we are looking at
`
`the 2 percent threshold for five months, did any of the data
`
`approach 2 percent loss?
`
`A.
`
`No.
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`In fact, if you want to look at this even further,
`
`you can see that 21-265-DK, for the upright storage, you are
`
`seeing a predicted shelf life for 2 percent loss -- or
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`actually, the period required for 2 percent loss, based on
`
`ordinary regression, is almost 630 months.
`
`And for inverted, which we would expect, again, to
`
`be worst case, it's actually a negative value, in which you
`
`are actually seeing an increase.
`
`Q.
`
`A.
`
`What does that tell you?
`
`That means that there is no change whatsoever, because
`
`you obviously can't generate drug from nothing.
`
`Q.
`
`Now, these are concentrations, and I can understand why
`
`it's helpful to look at 200 micrograms-per-ml and
`
`100 micrograms-per-ml, but in this very same table, did you
`
`also look at 4 micrograms-per-ml?
`
`A.
`
`I also looked at 4 micrograms-per-ml.
`
`MR. ALY: Let's look at Page 143 -- 142 on the
`
`bottom, going to 143 of DTX457. I'm sorry. You have got
`
`the -- okay.
`
`Maybe we should just scroll through. I
`
`understand -- okay. That's --
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`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 15 of 36 PageID #:5487
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`BY MR. ALY:
`
`Q.
`
`What Mr. Haw is showing on the screen here, Dr. Kipp, on
`
`the left we have got the kind of heading over there.
`
`And on the right, can you just explain to us which
`
`are the batches with the 4 micrograms-per-milliliter
`
`concentration.
`
`A.
`
`Okay. Yes. The batches starting with PD. So PD 2-049
`
`to, I believe, PD 2-054. Well, this slide is showing the
`
`first four. But you can see that, if you look at the second
`
`column from the right, the predicted length of time for
`
`2 percent loss is 79 months.
`
`So there is quite a bit of variability. But in
`
`general, it's consistent with no change at all.
`
`Q.
`
`Now, for the analysis here that you did, for how long,
`
`if you were to just extend the lines further, would a
`
`compound lose 2 percent?
`
`What's the smallest, shortest amount of time that
`
`you saw that you might hit the 2 percent number?
`
`A.
`
`Q.
`
`A.
`
`Well, based on this data?
`
`That's right.
`
`Okay. Well, based on this data, the shortest period of
`
`time would be the Lot PD 2-051, inverted.
`
`THE COURT: And 052 inverted.
`
`THE WITNESS: And 052 inverted.
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`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 16 of 36 PageID #:5488
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`BY MR. ALY:
`
`Q.
`
`And as far as the claim limitation here, the five-month
`
`time point, do either of those lots reach 2 percent?
`
`A.
`
`No, no. Obviously this is over one year before it even
`
`approaches 2 percent.
`
`Q.
`
`And in the right column of your table, have you also
`
`provided the value for what the loss actually was measured at
`
`for five months based on your analysis?
`
`A.
`
`Q.
`
`Yes. And it's saying it's well less than 1 percent.
`
`Now, has anyone else in this case, Dr. Kipp, seen as
`
`much data as you have?
`
`A.
`
`Well, I have seen quite a bit of data. I have looked at
`
`30 lots altogether, batch configuration combinations.
`
`Q.
`
`And for the 4 micrograms-per-milliliter claimed
`
`concentration, you looked at the Hospira batches.
`
`That's what you are showing here?
`
`A.
`
`Q.
`
`Correct.
`
`And you also plotted those, and I just want to confirm
`
`from looking at this data and comparing it to the plot.
`
`DDX224. We will look at one of those.
`
`I know you explained this slide yesterday, so today
`
`I am going to ask you, based on the data we just looked at,
`
`did you detect any noticeable change at five months for any
`
`Hospira batch with 4 micrograms per milliliter?
`
`A.
`
`No, I did not. And this illustrates that all the
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`Kipp - redirect by Aly
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`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 17 of 36 PageID #:5489
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`regression lines are completely flat.
`
`Q.
`
`I did have a question about that.
`
`When you are referring to the regression lines, do
`
`you see how they sort of have different starting points?
`
`A.
`
`Q.
`
`That's correct.
`
`So for a regression analysis, what do you consider as
`
`the starting point?
`
`A.
`
`Well, one would consider the predicted intercept; that
`
`is, the point where the line crosses the Y axis. And that is
`
`taken as the initial value. That's the best estimate from
`
`your analysis of what the actual initial value was.
`
`Q.
`
`Is that the analysis that you did for all of your
`
`regression lines?
`
`A.
`
`Q.
`
`That's correct.
`
`Keeping an eye on this particular slide, I would like to
`
`talk about another issue that was discussed yesterday, and
`
`that is zero or first order of kinetics.
`
`What are first order and zero order kinetics,
`
`Dr. Kipp?
`
`A.
`
`Okay. First order kinetics means the loss of a
`
`substance in solution is -- the rate of loss is proportional
`
`to the amount of -- the concentration of that substance in
`
`solution.
`
`Q.
`
`A.
`
`And the other?
`
`Zero means that it's independent of the concentration in
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`Kipp - redirect by Aly
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`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 18 of 36 PageID #:5490
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`solution. In other words, the rate is constant irregardless
`
`of what the concentration is.
`
`Q.
`
`Now, to see if there is a 2 percent loss at 5 months,
`
`does it matter what kind of kinetics there are?
`
`A.
`
`No, because a zero sloped line is a zero sloped line,
`
`and if you are not losing anything, you can't really assign a
`
`model to that data. There is no loss, period.
`
`Q.
`
`And if you saw no noticeable change in this time window
`
`of five months, how could you differentiate between zero
`
`order and first order?
`
`A.
`
`Well, you just can't. Again, a zero sloped line is a
`
`flat line, and a flat line is the same as any other flat
`
`line. So you can't discern model -- the model order or the
`
`type of model.
`
`Q.
`
`By the way, does the patent-in-suit, do they explain the
`
`reaction kinetics?
`
`A.
`
`Q.
`
`No, they don't.
`
`Now let's look at the new article that counsel put in
`
`front of you. This is your article, PTX68.
`
`Do you remember discussing this one?
`
`A.
`
`Q.
`
`Yes.
`
`The discussion yesterday was on Page 5 at the end, the
`
`last column.
`
`A.
`
`Q.
`
`Correct, yes.
`
`I know counsel pointed to part of the summary.
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`Kipp - redirect by Aly
`455
`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 19 of 36 PageID #:5491
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`What I want you to consider is the last two
`
`sentences about the work that you did in this article.
`
`A.
`
`Okay. Yes. I say, "These results validate those from
`
`earlier work indicating that apparent reaction order may be
`
`very difficult to ascertain in cases in which drug
`
`concentration is not followed to nearly complete degradation.
`
`In such cases, additional studies are imperative for
`
`determining reaction order."
`
`Q.
`
`So how does that apply to the opinions that you provided
`
`in this case?
`
`A.
`
`Well, what I said in this article is that you have to
`
`carry the reaction through several half-lives just to see any
`
`differences between reaction models -- or order models.
`
`Certainly, if you are not seeing any change at all,
`
`you can't assign any sort of order. It's just, you know,
`
`zero is zero is zero.
`
`Q.
`
`Is the same thing you are saying in the article the same
`
`thing you are saying about dexmed?
`
`A.
`
`Q.
`
`That's correct.
`
`Now, some clarifications to wrap up.
`
`There were questions yesterday about the IND. And
`
`the IND disclosed an ampoule.
`
`You have testified about that?
`
`A.
`
`Q.
`
`Yes.
`
`Was the ampoule already used to administer the drug to
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`Kipp - redirect by Aly
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`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 20 of 36 PageID #:5492
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`animals, according to the IND?
`
`A.
`
`Q.
`
`Yes.
`
`Were the ampoules in the IND used to administer to
`
`people?
`
`A.
`
`Q.
`
`Yes, it was.
`
`Now, you did -- counsel asked about clinical trials.
`
`To your knowledge, was the ampoule itself being
`
`tested in clinical trials, or was it about other tests in use
`
`in humans?
`
`A.
`
`Well, they wanted to find out if there was -- it was
`
`basically safety testing. And they also were running
`
`stability -- clinical stability studies on the samples that
`
`were being used in the study.
`
`Q.
`
`A.
`
`Q.
`
`And those were already reported in the IND?
`
`Yes.
`
`Now, as far as the further ongoing work and the clinical
`
`trials that were ongoing clinical trials, I think counsel
`
`asked you about the dosing that was yet to be determined or
`
`that was being investigated?
`
`A.
`
`Q.
`
`Yes.
`
`Is there any dosing in the claim that's being asserted
`
`from the '106 patent?
`
`A.
`
`Dosing -- the concentration is asserted but not the
`
`dosing.
`
`Q.
`
`Is there any dosing that's in the claim from the
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`Kipp - redirect by Aly
`457
`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 21 of 36 PageID #:5493
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`'049 patent?
`
`A.
`
`No. The dosing is not asserted in the claims. There is
`
`a formulation concentration.
`
`Q.
`
`Are the types of claims that are left, the two claims
`
`that are left, are they method claims or composition claims?
`
`A.
`
`Q.
`
`The two claims that are left in --
`
`That are left in the case, Claim 6 of the '106 and
`
`Claim 8 of the '049.
`
`A.
`
`Claim 6, refresh my memory, because I can't remember
`
`exactly what the claim states.
`
`MR. ALY: Let's look at DDX209.
`
`BY MR. ALY:
`
`Q.
`
`Claim 8 of the '049 patent, Dr. Kipp, is that a method
`
`or a composition?
`
`A.
`
`Well, obviously it asserts a composition, ready-to-use
`
`liquid pharmaceutical composition --
`
`Q.
`
`A.
`
`Q.
`
`And --
`
`-- from Claim 1.
`
`I am sorry to interrupt.
`
`MR. ALY: And then let's look at DDX217 for the
`
`'106 patent.
`
`BY MR. ALY:
`
`Q.
`
`A.
`
`Is that a method claim or a composition claim?
`
`It's a composition claim, referring to a liquid
`
`pharmaceutical composition that's ready-to-use.
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`Kipp - redirect by Aly
`458
`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 22 of 36 PageID #:5494
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`Q.
`
`How far along -- and just to be clear on ready-to-use,
`
`does ready-to-use --
`
`MR. ALY: Let's look at the Court's claim
`
`construction on DDX211.
`
`BY MR. ALY:
`
`Q.
`
`What does the term "ready-to-use" mean in the analysis
`
`that you did?
`
`A.
`
`It says, "Formulated to be suitable for administration
`
`to a patient without dilution or reconstitution."
`
`Q.
`
`Now, in terms of an IND, how far along does a product --
`
`this is the dexmed and the container -- how far along does
`
`that have to be to use it in an IND study?
`
`A.
`
`Well, I mean, they have to already have developed a
`
`formulation for use in an IND, and they put up stability
`
`samples to show stability during the study to catch any -- to
`
`look for out-of-limits changes. So they studied the
`
`stability of what they are testing with humans.
`
`Q.
`
`The results of the product composition, manufacturer,
`
`and stability, those were in the IND, and you opined about
`
`that yesterday?
`
`A.
`
`Q.
`
`Yes.
`
`Finally, Dr. Kipp, there was discussion about different
`
`types of glass and treatments. I wanted to just clarify.
`
`What is your understanding about whether glass
`
`Type 1 would work for the 2 percent limitation, whether it's
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`Kipp - redirect by Aly
`459
`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 23 of 36 PageID #:5495
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`treated or not treated?
`
`A.
`
`Well, in my opinion, Type 1 glass has to follow rigorous
`
`USP guidelines to be classified as such and have low levels
`
`of alkali in the glass.
`
`I would fully expect it to be inert when it comes
`
`to dexmedetomidine. In fact, we didn't use treated Type 1
`
`glass in nitroglycerin -- in our nitroglycerin studies or in
`
`our controls, because we didn't need to. It was just -- it
`
`was inert to begin with.
`
`And you would only do a sulfur -- a treatment with
`
`sulfur trioxide or ammonium sulfate. You would only treat it
`
`if you wanted an extra measure of assurance that you see less
`
`alkali metals coming out of the glass.
`
`But that was rarely necessary in the cases that I
`
`looked at.
`
`Q.
`
`And for the alkali metals coming out of the glass, would
`
`that affect pH or stability?
`
`A.
`
`It would affect pH. I talked about that earlier. With
`
`the ion exchange between protons in solution and sodium ions
`
`in the glass, it's going to ship the pH up.
`
`But that's only important where you have an
`
`unbuffered solution. Nearly all the solutions that I have
`
`dealt with are buffered.
`
`So if you have -- with dexmedetomidine, the pH
`
`range is also very wide. It's 2 to 10. So certainly it's
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`Kipp - redirect by Aly
`460
`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 24 of 36 PageID #:5496
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`going to stay well within that range.
`
`Q.
`
`Now, Hospira has the unbuffered solution.
`
`What is the percent loss at five months that they
`
`see, based on the data that you reviewed?
`
`A.
`
`Well, based on the data, I am not seeing any loss -- any
`
`noticeable loss.
`
`Q.
`
`So as far as the use of a sulfur-treated Type 1 glass,
`
`does that at all affect the stability opinions that you
`
`provided?
`
`A.
`
`Q.
`
`No. No, it does not.
`
`Now, if somebody wanted to take the extra precaution, as
`
`you described it, would they know to use sulfur-treated
`
`glass, or is that something new?
`
`A.
`
`No, that's nothing arcane at all. I mean, it's known
`
`that you can use sulfur-treated glass to leach out, preleach
`
`before use, the sodium ions in the glass.
`
`MR. ALY: Let's look at JTX24.13.
`
`BY MR. ALY:
`
`Q.
`
`This was the Sacha article that came up on cross.
`
`On the top left, there is the Type 1 glass
`
`paragraph.
`
`A.
`
`Q.
`
`Okay.
`
`And in terms of the first sentence, what is that
`
`reporting, Dr. Kipp?
`
`A.
`
`It says, "Type 1 glass will be suitable for all
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`Kipp - recross by Horton
`461
`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 25 of 36 PageID #:5497
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`products, although sulfur dioxide treatment sometimes is used
`
`for even greater resistance to glass leachables."
`
`Q.
`
`How does that compare to the testimony you just
`
`provided?
`
`A.
`
`Q.
`
`It confirms totally what I have said.
`
`Let's look at the last two sentences that are provided
`
`here as well. That's referring to manufacturer-
`
`to-manufacturer variation. Counsel asked about this as well.
`
`When you explained the USP, what does Sacha teach
`
`in the last sentence about the USP protocol?
`
`A.
`
`Well, it says that, "Therefore, it may be necessary to
`
`specify both USP type and a specific manufacturer of glass
`
`for highly chemically sensitive parenteral formulations."
`
`Q.
`
`In your experience and based on all of the analysis you
`
`have done in this case, is dexmed a highly chemically
`
`sensitive molecule?
`
`A.
`
`No. It's just the opposite. It's rock stable, as I
`
`said before.
`
`MR. ALY: I have nothing further.
`
`Thank you, Dr. Kipp.
`
`THE COURT: Recross-examination?
`
`MS. HORTON: Just briefly, your Honor.
`
`RECROSS-EXAMINATION
`
`BY MS. HORTON:
`
`Q.
`
`Dr. Kipp, you mentioned the stress tests again in your
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`Kipp - recross by Horton
`462
`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 26 of 36 PageID #:5498
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`redirect testimony, right?
`
`A.
`
`Q.
`
`Yes.
`
`Those were at 60 degrees and had peroxide in them,
`
`right?
`
`A.
`
`Q.
`
`Yes.
`
`And the peroxide that was used there was a very low
`
`concentration. In fact, less than the concentration you buy
`
`in the drugstore, right?
`
`A.
`
`It was half the concentration of the drug. So it was a
`
`substantial concentration relative to the drug in solution.
`
`That's what the important aspect of this is.
`
`Q.
`
`Okay. But less than the concentration you can buy off
`
`the shelf in Walgreens?
`
`A.
`
`Q.
`
`Yes, but you have to think in relative terms.
`
`And the 4.5 percent loss we saw in the development
`
`report right before I sat down, that was at 40 degrees,
`
`right? The accelerated study?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`Is that the table you showed me?
`
`Yes.
`
`Yes.
`
`And that didn't have peroxide, right?
`
`That didn't have peroxide. That was for inverted
`
`samples.
`
`And again, that could entail normal data
`
`variability. You have to look at all the data collectively,
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`Kipp - recross by Horton
`463
`Case: 1:16-cv-00651 Document #: 139 Filed: 08/07/18 Page 27 of 36 PageID #:5499
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`do a regression, and see whether that deviation is
`
`significant or not.
`
`Q.
`
`And the error there might show that it was even more
`
`loss, right?
`
`A.
`
`It may also go the other way as well. We are talking
`
`about a 3 percent variability from point to point.
`
`Q.
`
`And you talked a little bit about inverted and upright.
`
`And I just want to make sure. You are not saying
`
`the drug is never going to touch the stopper, right?
`
`A.
`
`Well, if you spla
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