UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`_____________________________
`
`MYLAN PHARMACEUTICALS INC.,
`WOCKHARDT BIO AG, TEVA PHARMACEUTICALS USA, INC.,
`AUROBINDO PHARMA U.S.A. INC., and SUN PHARMACEUTICAL
`INDUSTRIES, LTD., SUN PHARMA GLOBAL FZE and
`AMNEAL PHARMACEUTICALS LLC,
`Petitioner,
`
`v.
`
`ASTRAZENECA AB,
`Patent Owner.
`
`_____________________________
`
`IPR2015-01340
`Patent RE44,1861
`_____________________________
`
`
`
`PETITIONERS’ RESPONSE TO MOTION FOR OBSERVATIONS
`REGARDING THE CROSS-EXAMINATION OF DAVID P. ROTELLA
`
`
`
`1 Petitioner Wockhardt from IPR2016-01209, Petitioner Teva from IPR2016-
`
`01122, Petitioner Aurobindo from IPR2016-01117, and Petitioner Sun/Amneal
`
`from IPR2016-01104 have each been joined as Petitioner to this proceeding.
`
`
`
`
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`_____________________________
`
`MYLAN PHARMACEUTICALS INC.,
`WOCKHARDT BIO AG, TEVA PHARMACEUTICALS USA, INC.,
`AUROBINDO PHARMA U.S.A. INC., and SUN PHARMACEUTICAL
`INDUSTRIES, LTD., SUN PHARMA GLOBAL FZE and
`AMNEAL PHARMACEUTICALS LLC,
`Petitioner,
`
`v.
`
`ASTRAZENECA AB,
`Patent Owner.
`
`_____________________________
`
`IPR2015-01340
`Patent RE44,1861
`_____________________________
`
`
`
`PETITIONERS’ RESPONSE TO MOTION FOR OBSERVATIONS
`REGARDING THE CROSS-EXAMINATION OF DAVID P. ROTELLA
`
`
`
`1 Petitioner Wockhardt from IPR2016-01209, Petitioner Teva from IPR2016-
`
`01122, Petitioner Aurobindo from IPR2016-01117, and Petitioner Sun/Amneal
`
`from IPR2016-01104 have each been joined as Petitioner to this proceeding.
`
`
`
`
`
`Petitioners submit this Response to Patent Owner AstraZeneca AB’s Motion
`
`for Observations Regarding the Cross-Examination of David P. Rotella
`
`(“Observations”) pursuant to the Scheduling Order (Paper 17) and the Joint Notice
`
`of Stipulation (Paper 57).
`
`Response to Observation #1 –Petitioners respond that Dr. Rotella only
`
`agreed that P32/98 “does not have a cyano group, that is correct.” EX2221 at 13:5-
`
`6.
`
`Response to Observation #2 –Petitioners respond that Dr. Rotella further
`
`testified that “The term bulky, is a term that a medicinal chemist in the year 2000,
`
`and the year 2016, that's a term that is commonly understood and it is sort of
`
`innately well understood. It's also a term that was used by others. For example,
`
`Mentlein in 1993 used the term bulky amino acid.” EX2221 at 14:4-22.
`
`Response to Observation #3 –Petitioners respond that the observation
`
`overlooks Dr. Rotella’s testimony “that a medicinal chemist in the year 2000, and
`
`in the year 2016, and in the year 1990, would understand that there is a significant
`
`and material difference in the bulkiness of those two groups based on their
`
`structures. And I would not equate the term large with bulky because they are --
`
`they describe two different features.” EX2221 at 16:13-20.
`
`Response to Observation #4 –Petitioners respond that Dr. Rotella further
`
`related a move from tert-butyl to adamantyl in terms of bulkiness: “And the
`
`
`
`-1-
`
`
`
`
`
`
`
`
`
`
`difference between this molecule and an adamantyl substitute, it's like saxagliptin
`
`derivative, is simply the addition of a cyclohexane ring to each of the atoms on that
`
`tertiary-butyl group. And so the prior art tells you that by increasing steric bulk at
`
`the P2 position, that increases stability. And since one would want to increase
`
`stability of a DPP-4 inhibitor by modifying the orientation of the cyano group, by
`
`fusion of a cyclopropane ring as illustrated by Hanessian, that's the result of an
`
`experiment that, for a small set of compounds, that one could identify a preferred
`
`compound. So that would -- sorry -- that would lead one to identify a preferred
`
`compound from a small set of experiments.” EX2221 at 75:15-76:20.
`
`Response to Observation #5 – Petitioners respond that that Dr. Rotella
`
`further testified that the term “bulky” was well understood to a medicinal chemist
`
`in 2000. EX2221 at 14:3-22.
`
`Response to Observation #6 – Petitioners respond that that Dr. Rotella
`
`explained that “even more preferred” in this context referred to Villhauer’s
`
`preference. EX2221 at 21:1-2. In his direct testimony, Dr. Rotella explained that
`
`bulkiness was the basis for focusing on Villhauer’s more preferred cyclohexyl and
`
`adamantyl embodiments. EX1074, ¶¶19-21.
`
`Response to Observation #7 –Petitioners respond that Dr. Rotella further
`
`testified that the images in EX2259 “represent static pictures, they do not represent
`
`the dynamics of a molecule in solution, and so I would hesitate to draw any firm
`
`
`
`-2-
`
`
`
`
`
`conclusions about what position in space the P2 groups would occupy.” EX2221 at
`
`
`
`
`
`24:1-6.
`
`Response to Observation #8 –Petitioners respond that the observation is ill-
`
`founded because Patent Owner does not point to any stability data in Villhauer for
`
`Dr. Rotella to have overlooked. Moreover, Dr. Rotella testified that “the prior art
`
`tells you that by increasing steric bulk at the P2 position, that increases stability.”
`
`EX2221 at 75:19-21.
`
`Response to Observation #9 –Petitioners respond that Dr. Rotella based his
`
`selection of a lead compound on the prior art. EX2221 at 13:7-19, 42:19-43:11.
`
`Response to Observation #10 –Petitioners respond that Dr. Rotella further
`
`testified that a medicinal chemist in 2000 was able to recognize that this structure
`
`includes a 5-membered ring and a 3-membered ring fused together, and that the
`
`IUPAC naming is “only nomenclature.” EX2221 at 31:10-24.
`
`Response to Observation #11 –Petitioners respond that Dr. Rotella testified
`
`that he agreed that compound 3 was identified by Ashworth as the optimal P1
`
`group “among the set of molecules that they’ve evaluated” (i.e. only within
`
`Ashworth II). EX2221 at 33:3-11. Dr. Rotella further testified that the stability of
`
`Ashworth compound 25 is superior to Ashworth compound 3. Id. at 34:6-8, 42:19-
`
`43:11.
`
`Response to Observation #12 –Petitioners respond that Dr. Rotella’s direct
`
`
`
`-3-
`
`
`
`testimony was that incorporation of sulfur into the P1 ring showed that changes in
`
`size could produce greater potency, not that all changes in ring size would do so.
`
`
`
`
`
`
`
`
`EX1074, ¶40.
`
`Response to Observation #13 –Petitioners respond that Patent Owner is
`
`pointing to an example of a Novartis combination (N-linked Villhauer P2 groups
`
`and 4-cyanothiazolidine P1 groups), which was not the subject of Dr. Rotella’s
`
`testimony.
`
`Response to Observation #14 –Petitioners respond that Dr. Rotella further
`
`testified that Augustyns was limited to what Augustyns studied and specifically
`
`noted that Augustyns had not looked at bicyclic compounds. EX2221 at 47:15-21
`
`& 49:12-20.
`
`Response to Observation #15 –Petitioners respond that Dr. Rotella further
`
`testified that a double bond would flatten and rigidify the ring differently compared
`
`to the fusing of a cyclopropane ring as in Hanessian. EX2221 at 59:1-11.
`
`Response to Observation #16 –Petitioners respond that Dr. Rotella testified
`
`that the failure in Hanessian was for a particular set of receptors. EX2221 at 63:1-
`
`3.
`
`Response to Observation #17 –Petitioners respond that Dr. Rotella further
`
`testified that these compounds from Magnin represent a “routine investigation of a
`
`comparatively small set of compounds, which is what medicinal chemists do all the
`
`
`
`-4-
`
`
`
`
`
`
`
`
`
`
`time.” EX2221 at 67:3-6. Dr. Rotella further testified that medicinal chemists do
`
`not need to be able to predict beforehand the best outcome for routine investigation
`
`of a very small number of compounds. Id. at 67:7-19. He further testified that “the
`
`motivation to investigate the P1 position is a routine part of medicinal chemistry.
`
`And so faced with that art, and faced with this information, since others have
`
`shown, as we've outlined before, that you can -- that if you add single substituents,
`
`that leads to less effective inhibitors. If you change the ring size, that leads to less
`
`effective inhibitors. And medicinal chemists in 2000, in 1990, and in 2016 realized
`
`that the alternative approach is to fuse a ring to a system that contains a ring. And
`
`Hanessian provided the means to do that chemically. The motivation to do so is
`
`based on what was known in the art to attempt to improve both potency and
`
`stability, and it's reasonable to expect that that modification of fusing a ring might
`
`address those issues.” Id. at 68:1-17.
`
`Response to Observation #18 –Petitioners respond that Dr. Rotella testified
`
`that the art already knew that optimizing the P2 group mattered for potency.
`
`EX2221 at 73:8-10. As noted in response to Observation #17, Dr. Rotella
`
`explained that selecting the best alternative from a small number of compounds
`
`was routine in medicinal chemistry. EX2221 at 67:3-19.
`
`Response to Observation #19 –Petitioners respond again that Dr. Rotella
`
`testified that bulk rather than the tertiary/quaternary carbon distinction was
`
`
`
`-5-
`
`
`
`
`
`
`
`
`
`
`important: “And the difference between this molecule and an adamantyl substitute,
`
`it's like saxagliptin derivative, is simply the addition of a cyclohexane ring to each
`
`of the atoms on that tertiary-butyl group. And so the prior art tells you that by
`
`increasing steric bulk at the P2 position, that increases stability. And since one
`
`would want to increase stability of a DPP-4 inhibitor by modifying the orientation
`
`of the cyano group, by fusion of a cyclopropane ring as illustrated by Hanessian,
`
`that's the result of an experiment that, for a small set of compounds, that one could
`
`identify a preferred compound. So that would -- sorry -- that would lead one to
`
`identify a preferred compound from a small set of experiments.” EX2221 at 75:15-
`
`76:20.
`
`Response to Observation #20 –Petitioners respond again that Dr. Rotella
`
`testified that bulk rather than the tertiary/quaternary carbon distinction was
`
`important: “And the difference between this molecule and an adamantyl substitute,
`
`it's like saxagliptin derivative, is simply the addition of a cyclohexane ring to each
`
`of the atoms on that tertiary-butyl group. And so the prior art tells you that by
`
`increasing steric bulk at the P2 position, that increases stability. And since one
`
`would want to increase stability of a DPP-4 inhibitor by modifying the orientation
`
`of the cyano group, by fusion of a cyclopropane ring as illustrated by Hanessian,
`
`that's the result of an experiment that, for a small set of compounds, that one could
`
`identify a preferred compound. So that would -- sorry -- that would lead one to
`
`
`
`-6-
`
`
`
`identify a preferred compound from a small set of experiments.” EX2221 at 75:15-
`
`
`
`
`
`
`
`
`76:20.
`
`Response to Observation #21 –Petitioners respond that Dr. Rotella further
`
`testified that because the crystal structure for the receptor was not available at the
`
`time, “[o]ne simply reads out their potency as a measure of that interaction” with
`
`the enzyme. EX2221 at 83:23-84:5.
`
`Response to Observation #22 –Petitioners respond that Dr. Rotella agreed
`
`that a figure showed different binding. EX2221 at 85:19-25.
`
`Response to Observation #23 –Petitioners respond that Dr. Rotella noted that
`
`the He paper was not part of the prior art. EX2221 at 89:1-5.
`
`Response to Observation #24 –Petitioners respond again that Dr. Rotella
`
`noted the metabolism data was not part of the prior art. EX2221 at 90:7-11.
`
`Response to Observation #25 –Petitioners respond again that Dr. Rotella
`
`noted the exhibit was not part of the prior art. EX2221 at 93:20-23.
`
`Response to Observation #26 –Petitioners respond again that Dr. Rotella
`
`noted the exhibit was not part of the prior art. EX2221 at 95:23-96:1.
`
`Response to Observation #27 –Petitioners respond that Dr. Rotella testified
`
`as a medicinal chemist, not as a clinician, and he correctly noted that evaluating
`
`drug labels was outside the scope of his declaration. EX2221 at 99:3-6.
`
`Response to Observation #28 –Petitioners respond that Dr. Rotella explained
`
`
`
`-7-
`
`
`
`
`
`
`
`
`
`
`that “the question I was asked to answer was not whether we had an FDA-
`
`approved drug, the question that I was asked to answer was, is the discovery of
`
`saxagliptin obvious.” EX2221 at 99:3-6.
`
`Response to Observation #29 –Petitioners respond that Dr. Rotella
`
`immediately clarified that “There are parts of the structures that are unrelated.
`
`There are parts that are similar.” EX2221 at 104:22-23.
`
`Response to Observation #30 –Petitioners respond that Dr. Rotella
`
`repeatedly made clear that he was relying on counsel’s representations to answer
`
`questions that were outside the scope of his declaration, but that drug candidates
`
`may be withdrawn from trials for commercial and strategic reasons. EX2221 at
`
`105:3-108:2.
`
`Response to Observation #31 –Petitioners respond that Dr. Rotella based his
`
`testimony on published prior art. EX2221 at 13:7-19, 42:19-43:11.
`
`Response to Observation #32 –Petitioners respond that Dr. Rotella worked
`
`for Bristol-Myers Squibb, not AstraZeneca.
`
`Respectfully submitted,
`
`
`
`Dated: 19 December 2016
`
`
`
`/ Richard Torczon /
`Richard Torczon, Reg. No. 34,448
`Counsel for Mylan
`
`
`
`
`
`
`
`
`
`-8-
`
`
`
`CERTIFICATE OF SERVICE
`37 CFR §42.6(e)(i)
`
`
`
`
`
`
`
`
`
`I certify that, on 19 December 2016, this PETITIONERS’ RESPONSE TO
`
`MOTION FOR OBSERVATIONS REGARDING THE CROSS-EXAMINATION
`
`OF DAVID P. ROTELLA was served on AstraZeneca at the following electronic
`
`service addresses:
`
`Charles E. Lipsey
`
`charles.lipsey@finnegan.com
`
`Eric E. Grondahl
`
`egrondahl@mccarter.com
`
`John D. Livingstone
`
`john.livingstone@finnegan.com
`
`Anthony A. Hartmann
`
`anthony.hartmann@finnegan.com
`
`M. David Weingarten
`
`david.weingarten@finnegan.com
`
`Nicole A. Conlon
`
`nicole.conlon@finnegan.com
`
`Daniel M. Silver
`
`dsilver@mccarter.com
`
`Kassandra M. Officer
`
`kassandra.officer@finnegan.com
`
`on Wockhardt at the following service electronic addresses:
`
`Frederick R. Ball
`
`FRBall@duanemorris.com
`
`Patrick C. Gallagher
`
`PCGallagher@duanemorris.com
`
`on Teva at the following service electronic addresses:
`
`Iain A. McIntyre
`
`IMcIntyre@carlsoncaspers.com
`
`Gary J. Speier
`
`GSpeier@carlsoncaspers.com
`
`
`
`-9-
`
`
`
`
`
`
`
`
`
`
`on Aurobindo at the following service electronic addresses:
`
`Sailesh K. Patel
`
`SPatel@schiffhardin.com
`
`Joel Wallace
`
`JWallace@schiffhardin.com
`
`George Yu
`
`GYu@schiffhardin.com
`
`
`and on Sun/Amneal at the following service electronic addresses:
`
`Samuel S. Park
`
`spark@winston.com
`
`Andrew R. Sommer
`
`asommer@winston.com
`
`Dated: 19 December 2016
`
`
`
`
`
`
`
`/ Richard Torczon /
`Richard Torczon, Reg. No. 34,448
`
`
`
`
`
`
`
`-10-
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