`
`Case IPR 2016-00240
`Patent 7,772,209
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`NEPTUNE GENERICS, LLC,
`APOTEX INC., APOTEX CORP., TEVA PHARMACEUTICALS,
`FRESENIUS KABI USA, LLC, and WOCKHARDT BIO AG
`Petitioners,
`
`v.
`
`ELI LILLY & COMPANY,
`Patent Owner.
`__________________
`
`Case No: IPR2016-002401
`Patent No. 7,772,209
`__________________
`
`
`PATENT OWNER’S MOTION FOR OBSERVATIONS ON THE
`DEPOSITION OF PETITIONER NEPTUNE GENERIC’S EXPERT
`W. ARCHIE BLEYER, M.D.
`
`
`
`
`1 Cases IPR2016-01191, IPR2016-01337, and IPR2016-01343 have been joined
`
`with the instant proceeding.
`
`
`
`Case IPR 2016-00240
`Patent 7,772,209
`Pursuant to 77 Fed. Reg. 48756, Patent Owner Eli Lilly & Company
`
`(“Lilly”) submits this motion for observations regarding cross-examination of
`
`Petitioner Neptune Generic’s reply declarant W. Archie Bleyer, M.D.
`
`Observation 1. Dr. Bleyer testified that in the “homocysteine-to-
`
`methionine reaction,” “a methyl is removed from 5-methyltetrahydrofolate and
`
`place on to homocysteine to create methionine,” so “the product of the reaction is
`
`you get homocysteine converted to methionine, and you get methyltetrahydrofolate
`
`converted to tetrahydrofolate.” Ex. 2135 at 50:5-18. Dr. Bleyer further testified
`
`that “tetrahydrofolate can be used by the cell to make DNA precursors.” Id. at
`
`50:19-21. Dr. Bleyer then agreed that “[i]f the cell had methyltetrahydrofolate in it
`
`and sufficient B12 to allow the homocysteine-to-methionine reaction to occur, that
`
`reaction would go forward whether or not DHFR was blocked by an inhibitor.” Id.
`
`at 52:5-19. This testimony is relevant because it supports Patent Owner’s
`
`argument that the ability of vitamin B12 to release folate is not blocked when
`
`DHFR is inhibited. Paper 32 at 26-27. Thus, even if Neptune were correct that the
`
`POSA would not expect folic acid to reduce pemetrexed’s efficacy because of
`
`pemetrexed’s ability to block DHFR, the POSA would still expect vitamin B12 to
`
`reduce efficacy. Id.
`
`Observation 2. Dr. Bleyer agreed—in discussing an article by Dr. Sidney
`
`Farber (Ex. 2042)—that “Dr. Farber's conclusion that it was the folate that caused
`
`
`
`2
`
`
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`Case IPR 2016-00240
`Patent 7,772,209
`the acceleration phenomenon [i.e., tumor growth] is what gave him the idea for
`
`antifolates in the first place.” Ex. 2135 at 59:19-24; id. at 60:9-17. This testimony
`
`is relevant because it supports Patent Owner’s argument that the POSA would have
`
`been concerned that pretreating with folic acid would have enhanced the growth of
`
`the patient’s cancer. Paper 32 at 21-22.
`
`
`
`Observation 3. Dr. Bleyer agreed that when a vitamin B12 deficient patient
`
`is administered vitamin B12, “more tetrahydrofolate would be created through the
`
`homocysteine-to-methionine reaction.” Ex. 2135 at 68:13-17. Dr. Bleyer further
`
`agreed that he would “expect that to occur in a significant percentage of the cancer
`
`patients you saw because you thought a significant percentage had a vitamin B12
`
`deficiency.” Id. at 68:19-69:1. This testimony is relevant because it supports
`
`Patent Owner’s point that administering vitamin B12 can make more folate
`
`available by converting inactive folate to active folate, and thereby dramatically
`
`reduce pemetrexed’s efficacy. Paper 32 at 6-8, 22-23. The testimony is also
`
`relevant because it contradicts Neptune’s argument that the “methyl trap”—i.e.,
`
`what Neptune describes as a situation in which “administering vitamin B12 to a B12-
`
`deficient patient can potentially cause usable folate to be released”—is “very rare.”
`
`Paper 47 at 27.
`
`Observation 4. Dr. Bleyer testified:
`
`
`
`3
`
`
`
`Case IPR 2016-00240
`Patent 7,772,209
`
`Q. Okay. And second sentence says, "Folate
`therapy will reliably reduce plasma homocysteine levels;
`however, this would also rescue cells from the cytotoxic
`effects of methotrexate." Have I read that correctly?
`A. You did.
`Q. And would the person of ordinary skill have
`agreed with that?
`A. Because it is in this excellent journal, they
`would tend to agree with that. Let me read it again. Yes.
`Ex. 2135 at 121:22-122:8. This testimony is relevant because it supports Patent
`
`Owner’s point that administering folic acid to a patient receiving an antifolate
`
`would have reduced the antifolate’s efficacy. Paper 32 at 20-32. This testimony
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`also undermines Petitioner’s assertion that folic acid administration would not
`
`affect pemetrexed’s efficacy. Paper 47 at 12-14.
`
`Observation 5. Dr. Bleyer testified:
`
`Q. Okay. I want to make sure I understand,
`because there was a lot of parts of that. So which -- what
`are you relying on to say that you're starting to see -- I
`think you said, “kidney function is beginning to suffer,”
`then later you said, "beginning to go into renal failure."
`What are you talking about?
`A. The sentence that you brought to my attention
`that seven of 15 patients develop decreased creatinine
`clearance, which is the classic sign of renal dysfunction,
`more than half of the patients, seven of 15 patients
`4
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`
`
`
`
`Case IPR 2016-00240
`Patent 7,772,209
`develop renal function. That's a high rate, and those are
`the patients who had an elevation of all three vitamins,
`and I think a POSA would then worry -- suspect that the
`predictor is no longer as effective because now the drug
`is causing more problems, including the increased
`toxicity just from causing renal dysfunction.
`Ex. 2135 at 130:22-131:16. Dr. Bleyer further testified:
`
`Q. So this isn't talking about their baseline level
`of creatinine. It is referring to a drug-related toxicity as
`including a decrease in creatinine clearance, which is
`indicating that it's due to the drug; correct?
`A. Now that I'm reading it again with you, I
`think the first interpretation was more correct.
`Q. Right.
`A. Yes.
`Q. All right? And so the patients -- let me just --
`I want to make sure I have this correct. The decrease in
`creatinine clearance is an indication of a developing
`kidney problem, you said?
`A. Yes.
`Q. Okay. And the -- you are saying the
`developing kidney problem was due to the increased
`doses of the drug; is that what you said initially?
`A. I think I referred to the higher doses used in
`this report up to 925, which are known at the higher
`levels to cause kidney toxicity.
`
`
`
`5
`
`
`
`Case IPR 2016-00240
`Patent 7,772,209
`Q. Okay. And so just to orient to where we are
`right now, the person of skill would have thought that
`because of the higher doses used in this study, some
`patients were seeing a development of kidney toxicity.
`So far so good?
`A. Yes, so far so good.
`Id. at 133:10-134:16. Dr. Bleyer further testified:
`
`Q. Okay. Now, let's move to the next sentence. It
`says, “Based on information from these patients, addition
`of folic acid may reduce the usefulness of vitamin
`metabolites as predictors of toxicity.”
`And the question is, what is the relationship
`between that sentence and the point that we just were
`discussing?
`*
`*
`*
`A. Go back to my first answer, which I think is
`more correct than the alternate that I gave after the break.
`Once a drug cannot be cleared by the kidneys
`when that's its primary method of clearance, it in turn
`causes a toxicity beyond what it did to the kidney. It
`could cause the hematologic toxicities, and that's -- I
`think a POSA would obviously deduct from the use of
`pemetrexed.
`When that happens, when the pemetrexed causes
`kidney toxicity and, in turn, causes more other
`hematologic and nonhematologic toxicities, that
`
`
`
`6
`
`
`
`Case IPR 2016-00240
`Patent 7,772,209
`intervening step of causing its own additional toxicity
`may well make the prognostic factors less predictive. I
`think that's a POSA logical deduction.
`Once you complicate the matter and make the drug
`more toxic by that route, then you get into more trouble
`with the prognostic factor to begin with. If you will, it's a
`downstream toxicity that retrospectively makes those
`markers less predictive.
`Id. at 134:17-135:24 (objection omitted). This testimony is relevant to Lilly’s
`
`argument, and supports the testimony of Dr. Chabner, that the POSA would not
`
`expect folic acid supplementation to permit a useful escalation of pemetrexed’s
`
`dose, because (1) dose escalation is not useful without an increase in efficacy; (2)
`
`the POSA would expect folic acid to reduce efficacy, thus counteracting any
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`efficacy benefit that might arise from a higher dose; and (3) worse, the Hammond
`
`study revealed signs of kidney toxicities at higher doses that would not have been
`
`ameliorated by folic acid (or vitamin B12) pretreatment. Ex. 2120 ¶¶ 49, 73-74, 76-
`
`82. The testimony also therefore undermines Neptune’s argument that “folic acid
`
`supplementation permits pemetrexed dose escalation and ameliorates toxicity,” and
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`that this is “consistent with an improvement in the therapeutic index.” Paper 47 at
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`9, 14-15, 17.
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`
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`Observation 6. Dr. Bleyer agreed that “the person of ordinary skill would
`
`have not been able to conclude from the data in Hammond that the addition of folic
`
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`7
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`
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`Case IPR 2016-00240
`Patent 7,772,209
`acid increased the therapeutic index of pemetrexed relative to that in Rinaldi.” Ex.
`
`2135 at 152:23-153:6. This testimony is relevant because it undermines
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`Petitioner’s assertion that folic acid pretreatment improved pemetrexed’s
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`therapeutic index. Paper 47 at 14-16.
`
`Observation 7. Dr. Bleyer testified:
`
`Q. Well, but Dr. Hammond -- maybe you disagree
`with this. If you do, tell me, but isn't it correct that
`Hammond does not show that you get greater efficacy
`with higher doses of pemetrexed plus folic acid than you
`get with pemetrexed alone?
`A. I agree with that. There –
`*
`*
`*
`A. There is nothing in the Hammond report that
`demonstrates better efficacy in terms of response
`evaluation in the patients studied. That was not the goal
`of either of the two Hammond reports.
`
`Ex. 2135 at 156:3-16 (objection omitted). This testimony is relevant because it
`
`supports Patent Owner’s argument that folic acid pretreatment reduces
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`pemetrexed’s efficacy and because it undermines Petitioner’s assertion that folic
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`acid pretreatment improved pemetrexed’s therapeutic index. Paper 32 at 20-32;
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`Paper 47 at 14-16.
`
`Observation 8. Dr. Bleyer testified concerning Laohavinij (Ex. 2031):
`
`
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`8
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`
`
`Case IPR 2016-00240
`Patent 7,772,209
`Q. In fact, they're reporting some disappointment
`with the level of efficacy; correct?
`A. They're expressing a concern that maybe the
`efficacy wasn't as good as they had hoped it to be, yes,
`that's right.
`Ex. 2135 at 164:17-22. This testimony is relevant because it supports Patent
`
`Owner’s point that folic acid pretreatment reduces antifolates’ efficacy, as
`
`corroborated by the results in Laohavinij. Paper 32 at 9-10.
`
`Observation 9. Dr. Bleyer testified:
`
`Q. So would the person of ordinary skill have
`thought, based on all of this, that there was a strong
`rationale for pretreating methotrexate patients with folic
`acid in 1999?
`*
`*
`*
`A. There is a rationale to make sure the patient has
`good folate stores to begin with.
`Q. Okay. And would the person of ordinary skill
`have thought there was a good rationale to do that by
`pretreating them with folic acid?
`*
`*
`*
`A. I think there was a rationale to do that, yes.
`
`Ex. 2135 at 227:3-19 (objections omitted). This testimony is relevant because it
`
`supports Patent Owner’s argument that folic acid pretreatment would not have
`
`been obvious with pemetrexed because prior antifolates had not been studied or
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`
`
`9
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`
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`Case IPR 2016-00240
`Patent 7,772,209
`used with folic acid. In particular, the same reasoning that Dr. Bleyer seeks to
`
`apply to pemetrexed to justify folic acid pretreatment equally applied to the prior
`
`art drug methotrexate and yet artisans did not use folic acid pretreatment with
`
`methotrexate.
`
`Observation 10. Dr. Bleyer testified:
`
`Q. Well, let me -- let me ask you this, doctor: Do
`you think that the Laohavinij study of 5 milligrams a day
`for 14 days is relevant to how much folic acid one should
`give with pemetrexed?
`*
`*
`*
`A. I, I would agree it is relevant because if you had
`nothing else to base the next study with the successor
`antifolate, you would start with where you left off.
`Q. And, in fact, in Hammond, they started with 5
`milligrams per day.
`A. Yeah. They -- it's -- they probably based it on
`some of this reasoning.
`Q. Okay. And so I guess my question to you,
`doctor, is: Would the experience with folic acid
`pretreatment with lometrexol have given guidance to the
`person of ordinary skill about what dose and schedule
`folic acid pretreatment would be required in order to
`reduce the toxicity of pemetrexed?
`*
`*
`*
`A. Yes.
`
`
`
`10
`
`
`
`Case IPR 2016-00240
`Patent 7,772,209
`
`Q. And how would it have done that?
`A. If the same group of investigators had just
`concluded what they claim here, that 5 is better than 2,
`the next time they use another antifolate, whether it is
`another GARFT inhibitor, LY309887, or a multi-targeted
`antifolate such as pemetrexed, that is logical to start with
`5 milligrams as they ended with the previous study.
`
`Ex. 2135 at 241:21-243:4 (objections omitted). This testimony is relevant because
`
`it supports Patent Owner’s argument that the POSA would start with the 5
`
`milligram dosage identified in Laohavinij and Hammond, instead of choosing the
`
`claimed dosages. Paper 32 at 47-48.
`
`Observation 11. Dr. Bleyer testified:
`
`Q. Is -- I just want to make sure I have this straight
`now. Your present view is that the skilled person would
`agree with page 61, paragraph "d," but would not agree
`with page 12, paragraph "c" as phrased? Is that where
`you currently are?
`A. I think I'm currently more towards the 61 as
`phrased likelihood that a POSA would agree more with
`that than the absolute statement that no matter how much
`folic acid is given, it can't overcome the competition. I
`think there's a balance. I, I don't –
`Q. Do you recall your thought process when you
`put together that "no matter how much" language?
`
`
`
`11
`
`
`
`Case IPR 2016-00240
`Patent 7,772,209
`A. Yes. Looking at the diagram which this serves
`as a legend, and knowing the constants for DHFR and for
`the other two enzymes that pemetrexed inhibits, point –
`first, first deduction is that it would take a massive
`amount, and in Dr. Chabner's terms, impossible to deliver
`it to a person to overcome the inhibition.
`Q. Is that still your position?
`A. No. I, I prefer 61 because it is inconsistent, and
`the POSA can't do both.
`Q. Right.
`A. Yes.
`Q. All right. So you prefer 61 over 12?
`A. Yes.
`Ex. 2135 at 257:7-258:13. This testimony is relevant because it contradicts Dr.
`
`Bleyer’s original statement that folic acid could not be reduced to a usable form
`
`while pemetrexed is being administered “no matter how much folic acid is given.”
`
`Ex. 1077 ¶ 19(c). This testimony is further relevant because it contradicts
`
`Petitioner’s assertion that “in the presence of pemetrexed, FA cannot reduce to
`
`FH4” and thus folic acid pretreatment could not harm pemetrexed’s efficacy. Paper
`
`47 at 13.
`
`Observation 12. Dr. Bleyer testified:
`
`Q. And so that would create -- if the goal was to
`provide as low a folic acid dose as possible, and then you
`
`
`
`12
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`
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`Case IPR 2016-00240
`Patent 7,772,209
`
`*
`
`gave B12 in addition, you would be adding in more
`folate; right?
`A. Yes.
`*
`*
`Q. Okay.
`A. Although -- you know, we talked about this
`before. That mechanism does depend on the B12 status
`of the patient.
`Q. Uh-huh. If the --
`A. And if the patient is deficient in B12, it is
`obvious that that would generate more tetrahydrofolate.
`Q. And if they were not, the B12 would just do
`nothing at all relative to homocysteine?
`*
`*
`*
`A. Yeah. You have to be very careful with
`"nothing at all."
`Q. Very, very little?
`A. Let's say little.
`
`Ex. 2135 at 258:24-259:23 (objections omitted). This testimony is relevant
`
`because it supports Patent Owner’s argument that the POSA would not have
`
`arrived at the claimed combination of doses in claims 9, 10, 12-15, and 17-22,
`
`which require a smaller amount of folic acid than was used in the Hammond
`
`reference but also require the use of vitamin B12, because it makes no sense to take
`
`steps to lower the dose of folic acid while simultaneously adding vitamin B12 to a
`
`
`
`13
`
`
`
`Case IPR 2016-00240
`Patent 7,772,209
`pretreatment regimen; adding vitamin B12 is tantamount to adding more folate.
`
`Paper 32 at 47-49.
`
`Observation 13. Dr. Bleyer testified that he “w[as] not suggesting in
`
`paragraph 15.a [of his supplemental declaration] that the deaths that Dr. Chabner
`
`was referring to in the Phase III mesothelioma trial would have been known to the
`
`person of ordinary skill,” and that he “did not know that the n.8 on Exhibit 2020 is
`
`the mesothelioma trial.” Ex. 2135 at 273:9-19. This testimony is relevant because
`
`it undermines Dr. Bleyer’s purported disagreement with Dr. Chabner that the series
`
`of deaths that ultimately led Lilly to implement folic acid and vitamin B12
`
`pretreatment “was not available to the POSA as of June 1999.” See Ex. 1077 ¶ 15;
`
`Ex. 2120 n.8. The testimony is thus relevant to Lilly’s argument that as of the
`
`priority date, the POSA would have understood pemetrexed’s toxicities to be
`
`“manageable and tolerable.” Paper 32 at 10, 29-32.
`
`
`
`
`
`Date: February 14, 2017
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`14
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`Respectfully submitted,
`
`/David M. Krinsky/
`David M. Krinsky
`Reg. No. 72,339
`Back-up Counsel for
`Patent Owner
`
`Williams & Connolly LLP
`725 Twelfth Street, N.W.
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`Case IPR 2016-00240
`Patent 7,772,209
`Washington, D.C. 20005
`202-434-5338 (Telephone)
`202-434-5029 (Facsimile)
`dkrinsky@wc.com
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`Case IPR 2016-00240
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`CERTIFICATE OF SERVICE
`(37 C.F.R. § 42.6(e))
`
`The undersigned hereby certifies that the foregoing document was served on
`
`
`
`February 14, 2017 by delivering a copy via electronic mail on the following
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`attorneys of record for the Petitioners:
`
`Sarah E. Spires
`Reg. No. 61,501
`240Neptune@skiermontderby.com
`
`Skiermont Derby LLP
`2200 Ross Ave., Ste. 4800W
`Dallas, Texas 75201
`P: 214-978-6600/F: 214-978-6601
`
`Attorneys for Neptune Generics, LLC
`
`John D. Polivick
`Reg. No. 57,926
`jpolivick@rmmslegal.com
`
`William A. Rakoczy
`Pro hac vice to be filed
`wrakoczy@rmmslegal.com
`
`Rakoczy Molino Mazzochi Siwik LLP
`6 West Hubbard Street, Suite 500
`Chicago, IL
`P: 312-527-2157/F: 312-527-4205
`
`Attorneys for Apotex Inc. and Apotex
`Corp.
`
`Gary J. Speier
`Reg. No. 45,458
`gspeier@carlsoncaspers.com
`
`
`
`
`Dr. Parvathi Kota
`Reg. No. 65,122
`240Neptune@skiermontderby.com
`
`
`
`
`Deanne M. Mazzochi
`Reg. No. 50,158
`dmazzochi@rmmslegal.com
`
`Patrick C. Kilgore
`Reg. No. 69,131
`pkilgore@rmmslegal.com
`
`
`
`Mark D. Schuman
`Reg. No. 31,197
`mschuman@carlsoncaspers.com
`
`
`
`
`
`
`Carlson, Caspers, Vandenburgh,
`Lindquist & Schuman
`225 South Sixth Street, Suite 4200
`Minneapolis, MN 55402
`P: 612-436-9600
`F: 612-436-9605
`
`Cynthia Lambert Hardman
`Reg. No. 53,179
`chardman@goodwinprocter.com
`
`Goodwin Procter LLP
`The New York Times Building
`620 Eighth Avenue
`New York, NY 10018-1405
`P: 212-813-8800
`F: 212-355-3333
`
`Attorneys for Teva Pharmaceuticals
`USA, Inc. and Kabi Fresenius USA,
`LLC
`
`Patrick A. Doody
`Reg. No. 35,022
`patrick.doody@pillsburylaw.com
`
`Pillsbury Winthrop Shaw Pittman LLP
`1650 Tysons Boulevard
`McLean, VA 22102
`P: 703-770-7755/F: 703-770-7901
`
`Counsel for Wockhardt Bio AG
`
`
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`Case IPR 2016-00240
`Patent 7,772,209
`
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`
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`
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`Bryan P. Collins
`Reg. No. 43,560
`bryan.collins@pillsburylaw.com
`
`
`/David M. Krinsky/
`David M. Krinsky
`Reg. No. 72,339
`Back-up Counsel for Patent
`Owner
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`Date: February 14, 2017
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