`
`Case IPR 2016-00240
`Patent 7,772,209
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`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
`JOEL B. MASON, M.D.
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`
`
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`1 Cases IPR2016-01191, IPR2016-01337, and IPR2016-01343 have been joined
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`with the instant proceeding.
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`
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`Case IPR 2016-00240
`Patent 7,772,209
`Pursuant to 77 Fed. Reg. 48756, Patent Owner Eli Lilly & Company
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`(“Lilly”) submits this motion for observations regarding cross-examination of
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`Petitioner Neptune Generic’s reply declarant Joel B. Mason, M.D.
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`Observation 1. Dr. Mason testified:
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`Q. Let me ask a different question. In a patient
`who is vitamin B12 replete, adding more vitamin B12
`isn’t going to affect homocysteine levels.
`*
`*
`*
`A. Again, let me just make sure I understood the
`question. So in a B12 replete patient, adding additional
`B12 is not going to further lower homocysteine levels; is
`that what you're saying?
`Q. Well, is it going to have any effect on
`homocysteine levels?
`A. In general, as far as I can recollect, it will not.
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`Ex. 2134 at 26:24-27:13 (objection omitted). This testimony is relevant to Lilly’s
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`argument that, in order for vitamin B12 to have a beneficial effect on toxicity, it
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`would have to concomitantly release reduced folates that would counteract
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`pemetrexed’s efficacy, and thus would not have been obvious to administer. Paper
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`32 at 2, 6-8, 20-28. This testimony also is relevant because it demonstrates that Dr.
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`Mason’s opinions are premised upon an understanding that the vitamin B12 would
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`not be expected to have any effect in patients who are not vitamin B12 deficient, a
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`position that contradicts the statement in Neptune’s Reply that the POSA would be
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`Case IPR 2016-00240
`Patent 7,772,209
`motivated to administer vitamin B12 only to patients who are not vitamin B12
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`deficient. Paper 47 at 27.
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`Observation 2. Dr. Mason testified:
`
`Q. A patient walks into a doctor’s office as of 1999
`and is given vitamin B12.
`A. Yeah.
`Q. Whether or not that patient shows signs of
`vitamin B12 deficiency in an MMA study, for example,
`or some other biochemical assay, the person of ordinary
`skill doesn’t know for sure whether that administration of
`vitamin B12 is going to make more tetrahydrofolate
`available.
`*
`*
`*
`A. I think that there are insufficient studies for
`either myself or the POSA to know whether the actual
`availability of THF to the cell, okay, to that hypothetical
`patient’s cells, would be increased by the administration
`of vitamin B12.
`
`Ex. 2134 at 33:5-33:21 (objection omitted). Dr. Mason further
`testified:
`
`Q. If vitamin B12 were administered to a patient
`and that has the effect of releasing some tetrahydrofolate,
`the person of ordinary skill in the art would not have a
`way to quantify how much would be released.
`*
`*
`*
`
`
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`3
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`Case IPR 2016-00240
`Patent 7,772,209
`A. The POSA would in all likelihood not have the
`appropriate tests available to make that determination.
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`Id. at 36:10-18 (objection omitted). This testimony is relevant to Lilly’s argument
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`that the administration of vitamin B12 to a patient may release an unpredictable
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`amount of reduced folate, which would then be available to cancer cells to reverse
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`the efficacy of pemetrexed and/or accelerate cancer growth; the POSA therefore
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`would have seen vitamin B12 pretreatment as “worrisome,” not obvious. Paper 32
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`at 22-24.
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`Observation 3. Dr. Mason testified that “if you were to give a patient
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`taking pemetrexed a reduced folate such as leucovorin or tetrahydrofolate, that
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`could have the effect of negating its effect” and that “administration of a reduced
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`form of folate such as leucovorin, which is 5-formyltetrahydrofolate, would bypass
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`the block that otherwise is seen by folic acid because folic acid needs that DHFR
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`activity to be converted into a form that can be utilized by the cell.” Ex. 2134 at
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`49:12-25. This testimony is relevant to Lilly’s argument that the administration of
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`folic acid pretreatment (which has the effect of increasing the supply of reduced
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`folates, even if Neptune is correct that DHFR blocks the reduction of folic acid
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`once pemetrexed is administered), and the administration of vitamin B12 (which
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`releases tetrahydrofolate, a reduced folate), would have been understood to
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`undermine the effect of pemetrexed on cancer cells and thus reduce pemetrexed’s
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`Case IPR 2016-00240
`Patent 7,772,209
`efficacy, thus rendering folic acid and vitamin B12 pretreatment non-obvious.
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`Paper 32 at 20-32.
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`Observation 4. Dr. Mason testified that, if a patient were pretreated with
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`folic acid, “[a] large part” of that folic acid “would be converted to a reduced
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`form.” Ex. 2134 at 95:4-8, 100:14-18. Dr. Mason further testified that the enzyme
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`DHFR “can act in a matter of seconds on folic acid” and is “a reaction that
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`potentially can move along very quickly.” Id. at 95:21-96:23. Thus, if folic acid
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`pretreatment were administered to a patient beginning two days before pemetrexed,
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`“[t]here certainly would be a dramatic drop in homocysteine over the course of
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`those two days.” Id. at 97:18-99:11. This testimony is relevant because it
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`undermines Dr. Mason’s assertion that “blockage of DHFR by pemetrexed impairs
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`the ability of folic acid to be effectively utilized within the folate metabolic
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`network by preventing folic acid (unusable by the body in DNA synthesis) from
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`being reduced to its useable form, tetrahydrofolate,” which is a reason Dr. Mason
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`asserts folic acid pretreatment would not impair pemetrexed’s efficacy. See Ex.
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`1078 ¶ 46. In the case of folic acid pretreatment, to which the challenged claims
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`are directed, Dr. Mason’s testimony indicates that folic acid already would have
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`been converted to a reduced form by the time pemetrexed is administered, and thus
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`would be available to serve as an antidote to pemetrexed even if Neptune’s
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`assertions regarding blockage of DHFR were accurate. Paper 32 at 1-2, 25-26.
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`Case IPR 2016-00240
`Patent 7,772,209
`Observation 5. Dr. Mason testified that he believed “the POSA would have
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`been treating a lot, many, most of his patients about to embark on pemetrexed with
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`vitamin B12.” Ex. 2134 at 182:11-14. Dr. Mason further testified:
`
`Q. What was the common practice in terms of
`whether vitamin B12 pretreatment was used with
`methotrexate as of 1999?
`A. I believe the common practice was pretreatment
`with folic acid and B12.
`
`Id. at 186:17-21. This testimony is relevant to Dr. Mason’s expertise and
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`credibility. As Dr. Chabner testified, “the use of vitamin B12 pretreatment with
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`pemetrexed or any other antifolate for the treatment of cancer [was] unknown in
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`the prior art.” Ex. 2120 ¶ 83. Moreover, it is undisputed that the common practice
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`with methotrexate was to use leucovorin rescue, not folic acid or vitamin B12
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`pretreatment. Id. ¶¶ 57, 61, 83; Ex. 1077 ¶ 61. Dr. Mason’s mistaken belief on
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`this critical fact substantially undermines his credibility in speaking about issues on
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`this topic.
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`Observation 6. Dr. Mason testified that in a paper published in 2007, he
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`reported on an association between “folic acid fortification in North America and
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`an unexpected rise in the incidence of colorectal cancer.” Ex. 2134 at 163:5-11;
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`see generally id. at 162:4-180:6. Dr. Mason further testified that “[i]t is clear that
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`folate can help promote the proliferation of rapidly dividing cells.” Id. at 165:25-
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`
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`6
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`Case IPR 2016-00240
`Patent 7,772,209
`166:2. Dr. Mason further testified that “information from various sources over the
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`years . . . alluded to this possibility,” including “sources going back before 1999.”
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`Id. at 167:24-168:14. This testimony is relevant to Lilly’s argument that one
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`reason why folic acid pretreatment would not have been obvious as an aspect of
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`pemetrexed cancer chemotherapy is that the POSA would have believed that it
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`would risk accelerating the growth of the tumor. Paper 32 at 21-22.
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`Observation 7. Dr. Mason testified that in the paper discussed above in
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`Observation 6, he cited the work of Dr. Sidney Farber in the 1940s as “the earliest
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`observation that you’re aware of, of the link between folic acid and accelerated
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`cancer growth.” Ex. 2134 at 179:8-17. Dr. Mason further testified that Dr.
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`Farber’s observation might explain a link between folate supplementation and
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`colorectal cancer that Dr. Mason had observed. Id. at 179:23-180:6. Dr. Mason
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`further testified that “colorectal cancer is a solid tumor.” Id. at 170:8-15. This
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`testimony is relevant because it contradicts the testimony of Dr. Bleyer that Dr.
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`Farber’s observation of acceleration is relevant only to leukemia, not to other
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`cancers such as the solid tumors for which pemetrexed is indicated. Ex. 1024 ¶ 89.
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`Date: February 14, 2017
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`Respectfully submitted,
`
`/David M. Krinsky/
`David M. Krinsky
`Reg. No. 72,339
`Back-up Counsel for
`Patent Owner
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`Case IPR 2016-00240
`Patent 7,772,209
`
`
`Williams & Connolly LLP
`725 Twelfth Street, N.W.
`Washington, D.C. 20005
`202-434-5338 (Telephone)
`202-434-5029 (Facsimile)
`dkrinsky@wc.com
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`Case IPR 2016-00240
`Patent 7,772,209
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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
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`
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`February 14, 2017 by delivering a copy via electronic mail on the following
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`attorneys of record for the Petitioners:
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`Sarah E. Spires
`Reg. No. 61,501
`240Neptune@skiermontderby.com
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`Skiermont Derby LLP
`2200 Ross Ave., Ste. 4800W
`Dallas, Texas 75201
`P: 214-978-6600/F: 214-978-6601
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`Attorneys for Neptune Generics, LLC
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`John D. Polivick
`Reg. No. 57,926
`jpolivick@rmmslegal.com
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`William A. Rakoczy
`Pro hac vice to be filed
`wrakoczy@rmmslegal.com
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`Rakoczy Molino Mazzochi Siwik LLP
`6 West Hubbard Street, Suite 500
`Chicago, IL
`P: 312-527-2157/F: 312-527-4205
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`Attorneys for Apotex Inc. and Apotex
`Corp.
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`Gary J. Speier
`Reg. No. 45,458
`gspeier@carlsoncaspers.com
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`Dr. Parvathi Kota
`Reg. No. 65,122
`240Neptune@skiermontderby.com
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`Deanne M. Mazzochi
`Reg. No. 50,158
`dmazzochi@rmmslegal.com
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`Patrick C. Kilgore
`Reg. No. 69,131
`pkilgore@rmmslegal.com
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`Mark D. Schuman
`Reg. No. 31,197
`mschuman@carlsoncaspers.com
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`Carlson, Caspers, Vandenburgh,
`Lindquist & Schuman
`225 South Sixth Street, Suite 4200
`Minneapolis, MN 55402
`P: 612-436-9600
`F: 612-436-9605
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`Cynthia Lambert Hardman
`Reg. No. 53,179
`chardman@goodwinprocter.com
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`Goodwin Procter LLP
`The New York Times Building
`620 Eighth Avenue
`New York, NY 10018-1405
`P: 212-813-8800
`F: 212-355-3333
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`Attorneys for Teva Pharmaceuticals
`USA, Inc. and Kabi Fresenius USA,
`LLC
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`Patrick A. Doody
`Reg. No. 35,022
`patrick.doody@pillsburylaw.com
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`Pillsbury Winthrop Shaw Pittman LLP
`1650 Tysons Boulevard
`McLean, VA 22102
`P: 703-770-7755/F: 703-770-7901
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`Counsel for Wockhardt Bio AG
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`Case IPR 2016-00240
`Patent 7,772,209
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`Bryan P. Collins
`Reg. No. 43,560
`bryan.collins@pillsburylaw.com
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`/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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