`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`COALITION FOR AFFORDABLE DRUGS VIII LLC, Petitioner
`
`v.
`
`TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA,
`Patent Owner, based on Electronic Records of PTO
`U.S. Patent 7,932,268 to Rader
`Filing Date: June 21, 2007
`Issue Date: April 26, 2011
`TITLE: METHODS FOR TREATING DISORDERS OR DISEASES ASSOCIATED
`WITH HYPERLIPIDEMIA AND HYPERCHOLESTEROLEMIA WHILE MINIMIZING
`SIDE EFFECTS
`_____________________
`
`Inter Partes Review No.: IPR2015-01836
`
`
`
`
`
`PETITIONER’S OBSERVATIONS ON
`
`CROSS-EXAMINATION OF DR. THOMAS A. BAILLIE
`
`
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`
`
`Petitioner, COALITION FOR AFFORDABLE DRUGS VIII LLC hereby
`
`files observations on the testimony given by Patent Owner’s Declarant Dr. Thomas
`
`A. Baillie (Exhibit 1057) at a deposition held on October 25, 2016.
`
`
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`(1) Testimony from Dr. Baillie Indicating That He Could Not Identify
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`The Critical Features of the Claims Relating That Allegedly Resulted In
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`Unexpected Results. At the following transcript locations, when asked about the
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`importance of certain features of the claimed dosing protocal, Dr. Baillie could not
`
`provide a definitive answer:
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`Q. Is this third dosing level in the claimed regimen critical to promoting
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`biological adaptation for lomitapide?
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`MR. MITROKOSTAS: Objection to the form.
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` A. I don't know if it's critical or not critical. I assumed it was derived
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`from clinical experimentation, but that's my assumption. (Exh. 1057, p.
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`22:5-11(emphasis added))
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`*
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`*
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`*
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`Q. Yes.
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`Is the two-fold sequential dose increase that is required by the substitute
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`claims important to the underlying concept of using a step-wise forced
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`titration dosing regimen to promote biological adaptation?
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`1
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`
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`A. So the -- the question here relates to “two-fold.” I think that's what is
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`implied in your question. And that factor of two-fold is not necessarily
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`applicable to all types of forced-dose titrations. The fact it could be less,
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`conceivably, it could be somewhat more. In the case of lomitapide, it was
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`found by Dr. Rader's clinical studies that that was an appropriate dose
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`escalation factor. (Exh. 1057, p. 13:15-14:5 (emphasis added))
`
`*
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`*
`
`*
`
`Q. So does this change your opinion as to whether the two-fold sequential
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`dose increase is important to the underlying concept of using a step-wise
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`forced titration dosing regimen to promote biological adaptation in
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`lomitapide?
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`A. It suggests to me that the two-fold number is not absolute, that the two-
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`fold number is one that clearly was effective in accomplishing the goals of
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`the study, but the number of two is not an absolute number. It could have
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`been two and a half or perhaps three or perhaps one and a half, but two-
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`fold worked as demonstrated by Dr. Rader's clinical studies. So I don't
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`think it's absolute. (Exh. 1057, p. 27:4-16 (emphasis added))
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`
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`The testimony is relevant as to whether the recited dosing regimen is
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`anything more than routine.
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`2
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`
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`(2) Testimony from Dr. Baillie Indicating That He Could Not Exclude
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`An Extremely Low Fat Diet As The Cause Of The Alleged Amelioration Of
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`Side Effects. At the following transcript locations, when asked about the
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`differences between the diet of the subjects in the earlier BMS trials as compared
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`to the later U. Penn trials, Dr. Baillie could not provide a definitive answer:
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`Q. So my question was, do you know if the BMS clinical trials with
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`lomitapide required the same low-fat diet as that of Dr. Rader's clinical
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`trials for lomitapide?
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`A. I don't know if they required the same low-fat diet. (Exhibit 1057, p.
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`30:2-7 (emphasis added))
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`*
`
`*
`
`*
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`Q. It says, "All subjects entered for a seven-day dietary lead-in with an AHA
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`Step I diet which was maintained throughout the study.”
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`Is this the low-fat diet that you're referring to in your declaration with
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`regard to BMS's clinical trials?
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` A. Yes. This AHA Step I diet would be a low-fat diet.
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`Q. Do you know how much fat is permitted in an AHA Step I diet in
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`terms of total calories?
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`3
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`
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`A. No, I don't actually know that number. But I believe it's very low. I
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`think it's something in the order of 5 to 10 percent of daily caloric intake.
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`That number may not be correct but it's certainly very low.
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`Q. And why do you believe that it's 5 to 10 percent?
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`A. Simply because I recall reading that in one of these documents and I can't
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`really cite which specific one at this point.
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`Q. One of the documents that's --
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`A. That was in the list of documents that I considered in writing the
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`declaration. Perhaps it was in one of the publications that came from Dr.
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`Rader's clinical trials, but I'm not sure that's the source.
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`Q. But the trial here that's identified in Penn Exhibit 2078 is not one of
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`Dr. Rader's trials, correct?
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`A. That is correct, yes, so it may not have been from one of his trials. I'm
`
`sorry, I can't recall exactly where I read that.
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`Q. Okay. But you didn't look up on your own how much fat is permitted
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`in an AHA Step I diet, did you?
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`A. I did not, no.
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`Q. If I told you a Step I diet permits 30 percent of total calories from fats,
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`would that surprise you?
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`4
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`
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`A. Not particularly. I thought it was somewhat less than that, but I'll take
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`your word for it. (Exh. 1057, p. 30:24-32:17(emphasis added))
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`
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`The testimony is relevant because it indicates that Patent Owner’s expert,
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`Dr. Baillie does not know the amount of fat allowed in the diet of BMS trials of
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`lomitapide despite its importance to the presence of side effects.
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`
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`(3) Testimony From Dr. Baillie Indicating That He Discounted Dr.
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`Rader’s Own Explanation That The GI Side Effects In The BMS Trials Were
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`Caused By Fat In The Diet. At the following transcript locations, Dr. Baillie
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`ignores evidence that amelioration of side effects was due to an aggressive
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`restriction of fat in the diet of subjects taking lomitapide:
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`Q. Can you describe what it is.
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`A. This is a patient consent form for a study to be conducted under Dr.
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`Rader's guidance, determining the safety and tolerability and efficacy of
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`lomitapide in patients with homozygous FH defect.
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`Q. Okay. If you would turn to page 4 of 6 or 3 of 5.
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`A. Yes, I have that.
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`Q. Okay. And there's a section that says "Risks." Do you see that?
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`A. Yes.
`
`5
`
`
`
`
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`Q. And then in the middle there's a section or a sentence that begins "both
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`liver function tests." Do you see that?
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`A. I do.
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`Q. "Both liver function tests and levels of fat in the liver found in the study
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`using the medication BMS-201038" --
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`That's lomitapide, correct?
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`A. It is.
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`Q. --"were not at a dangerous level. There were no deaths or serious side
`
`effects that occurred in the study. Some subjects taking the medication
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`also reported stomach pain, diarrhea, nausea and fatigue, being tired. It
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`is believed these results occurred because the amount of fat in the diet
`
`was not restricted. We believe that by following the low-fat diet
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`described in this consent form there should not be significant symptoms
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`of those described above."
`
`Do you see that?
`
`A. I do
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`Q. Did you consider this section in in developing your opinion as
`
`expressed in paragraph 73 and 74 of your declaration?
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`A. Yes. I was aware of this before I wrote the declaration. (Exh. 1057, p.
`
`36:23-38:15 (emphasis added))
`
`6
`
`
`
`
`
`*
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`*
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`*
`
`Q. So if I'm understanding your previous answer, you believe that the
`
`patients in the BMS trial were also following this particular diet where they
`
`removed most of the fat from their diet.
`
`A. That would be my belief.
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`Q. Can you tell me what the basis for that belief is?
`
`A. Well, as I just said, I think that if the company were developing a drug
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`that is known to have this particular GI related side effect, that is
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`manifest by an accumulation of fat that it would have been poor clinical
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`practice, if nothing else, not to restrict the diet in terms of fat intake,
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`because otherwise, if the individuals were consuming any diet of their
`
`choice it would be very hard to interpret the safety aspects of the trial. So
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`good clinical practice in my opinion would have required a standardized
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`diet which in this case would be low-fat. (Exh. 1057, p. 40:20-41:14
`
`(emphasis added))
`
`
`
`This
`
`testimony
`
`is relevant because
`
`it
`
`indicates Dr. Baillie makes
`
`unsubstantiated assumptions to arrive at his conclusion that the forced-dose
`
`titration ameliorates side effects.
`
`7
`
`
`
`
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`(4) Testimony Indicating That The Claimed Dosing Is Not Different
`
`From Prior Art Forced Dose Titration. At the following transcript locations, Dr.
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`Baillie indicates that he believes the claims allow for a reduction in dose due to
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`side effects from taking lomitapide:
`
`Q. "If patients had confirmed alanine transaminase (ALT) or aspartate
`
`transaminase (AST) 5 elevation between 5.0 and 9.9 times the ULN, or
`
`greater than 100 U per L, but less than 200 U per L above the baseline value,
`
`the dose of lomitapide was reduced to the previously tolerate dose level with
`
`the possibility to re-escalate once transaminase elevations were resolved."
`
`Do you see that?
`
`A. Yes.
`
`Q. Is it still a forced does titration if it permits a reduction in dose to a
`
`previously tolerated dose level?
`
`A. The dose titration regimen as outlined in the claims does not prevent
`
`the dose being temporarily reduced if side effects become evident that
`
`are of concern. In order to actually complete the forced dose titration
`
`protocol the patient then would have to subsequently be titrated back up
`
`again, which I believe was what happened in this particular trial. (Exh.
`
`1057, p. 43:18-44:14(emphasis added))
`
`
`
`8
`
`
`
`
`
`This testimony is relevant because to the alleged unexpected results of the
`
`claimed invention as compared to prior art forced-dose titration protocols and
`
`amelioration of side effects.
`
`
`
`(5) Testimony Indicating That Dr. Rader Used Animal Data To Develop
`
`A Dosing Amount Of Lomitapide In Humans. At the following transcript
`
`locations, Dr. Baillie indicates that he did not know that Dr. Rader relied on
`
`Wetterau animal studies in arriving at the target dose of his lomitapide dosing
`
`protocol.
`
`Q. This protocol was not performed by Bristol-Myers Squibb, correct?
`
`A. That's correct, yes. This was dated December 2nd, 2002, which was two
`
`years after BMS discontinued the development of lomitapide.
`
`Q. Can you turn to page 17 of 72. There's two page numbers, so I'm going to
`
`refer to 17 of 72 which is also page 14 of 57.
`
`Are you there?
`
`A. Yes, I'm there.
`
`Q. At the very top towards the end of the first paragraph it indicates, “We
`
`picked an upper dose of 1 milligram per kilogram based on data from
`
`the animal study by Wetterau revealing greater than 80 percent LDL
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`9
`
`
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`
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`cholesterol reduction using ten milligrams per kilogram with an ED50
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`of 1.9 milligram per kilogram.
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`Do you see that?
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`A. Yes.
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`Q. Did you consider this statement when you concluded that a person of
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`ordinary skill in the art would have no reasonable expectation that any
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`quantitative analysis based on Wetterau's rabbit data could result in a safe
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`and effective human dosing regimen?
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`A. I did not read that particular statement when I arrived at my
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`conclusions. Although, seeing this here, I think it's important to distinguish
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`between safety and efficacy because my comments with regard to the
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`translation of the animal data in Wetterau to what would be a safe human
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`dose was really based on the concern about how applicable the rabbit model
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`is to human with regard to safety.
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`This rabbit model that is described by Wetterau is used as a
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`pharmacodynamic model for human HoFH, and so it is being cited here in
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`this clinical protocol as the basis for the target LDL cholesterol reduction, if
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`I'm reading this correctly.
`
`Q. Is it fair to say that they used the study by Wetterau to pick a dose that
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`they thought would produce effective human dosing regimen?
`
`10
`
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`
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`MR. MITROKOSTAS: Objection to the form.
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`Q. For lomitapide.
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`A. I think that what Rader is doing in this document is using the
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`published data from Wetterau that was based on this genetic rabbit
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`model to project what kind of a human dose might give rise to an 80
`
`percent LDL cholesterol reduction.
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`Q. But you will agree that Dr. Rader used data from Wetterau to pick his
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`dose for the study, correct?
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`MR. MITROKOSTAS: Objection to the form.
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`A. It seems that he used data from Wetterau to project a ballpark dose
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`that would give rise to an 80 percent LDL cholesterol reduction. He says
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`in this sentence, “an upper dose of one mg per kg,” so presumably that was
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`derived from these animal studies at a higher dose of ten milligrams per
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`kilogram per day, I think it was. So he's looking for an upper bound. (Exh.
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`1057, p. 23:17- 26:5 (emphasis added))
`
`11
`
`
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`
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`This testimony is relevant because it contradicts Dr. Baillie’s opinion that a
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`person of ordinary skill in the art would have no reasonable expectation of success
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`in developing a dose based on Wetterau's rabbit data.
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`
`
`Date: October 28, 2016
`
`Respectfully Submitted,
`
`
`
`
`
`
`
`
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`
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`
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`
`
`
`
`
`
`Christopher Casieri
`
`
`12
`
`
`
`
`
`CERTIFICATE OF SERVICE
`
` The undersigned hereby certifies that the foregoing Observations on Cross
`
`Examination and the Deposition Transcript of Dr. Baillie (Exhibit 1057) was
`
`served on October 28, 2016 by delivering copies via electronic mail on the
`
`following attorneys of record for the Patent Owner.
`
`Lead Counsel
`William G. James
`(Reg. No. 55,931)
`GOODWIN PROCTER LLP
`901 New York Avenue NW
`Washington, DC 20001
`Tel: 202-346-4046
`Fax:202-346-4444
`wjames@goodwinprocter.com
`
`Backup Counsel
`Nicholas K. Mitrokostas
`(to seek pro hac vice admission)
`GOODWIN
`PROCTER
`LLP
`Exchange Place
`53 State Street
`Boston, MA 02109-2881
`Tel: 617-570-1913
`Fax:617-523-1231
`nmitrokostas@goodwinprocter.com
`
`Cynthia Lambert Hardman
`(Reg. No. 53,179)
`GOODWIN PROCTER LLP
`The New York Times Building
`620 Eighth Avenue
`New York, NY 10018-1405
`Tel: 212-459-7295
`Fax:212-355-3333
`chardman@goodwinprocter.com
`
`
`
`Date: October 28, 2016
`
`Respectfully Submitted,
`
`/Gregory J. Gonsalves/
`Dr. Gregory J. Gonsalves (Reg. No. 43,639)
`2216 Beacon Lane
`Falls Church, Virginia 22043
`(571) 419-7252
`gonsalves@gonsalveslawfirm.com
`
`
`13
`
`
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