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`_____________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`_____________________
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`APOTEX INC. AND APOTEX CORP.,
`Petitioners
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`v.
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`AUSPEX PHARMACEUTICALS, INC.,
`Patent Owner
`_____________________
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`Case IPR2021-01507
`U.S. Patent No. 8,524,733
`Issued: September 3, 2013
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`Title:
`BENZOQUINOLINE INHIBITORS OF VESICULAR MONOAMINE TRANSPORTER 2
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`PETITIONER’S REPLY TO PATENT OWNER’S
`PRELIMINARY RESPONSE
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`LIST OF EXHIBITS
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`Exhibit No. Description
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`1004
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`1005
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`1006
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`1009
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`1027
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`Naicker, S. et al., U.S. Patent No. 6,503,921, “Deuterated rapamycin
`compounds, methods and uses thereof” (“Naicker ’921”)
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`Kohl, B. et al., Int’l. Pub. No. WO 2007/012650, “Isotopically
`Substituted Proton Pump Inhibitors” (“Kohl”)
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`Foster A.B. et al., Isotope effects in O- and N-demethylations
`mediated by rat liver microsomes: An application of direct insertion
`electron impact mass spectrometry, CHEM.-BIOL. INTERACTIONS,
`9:327-340 (1974) (“Foster AB”)
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`Gant, T.G. et al., U.S. Pat. Pub. No. 2008/0280991, “Substituted
`Naphthalenes” (“Gant ’991”)
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`Excerpts of the Application File History for the ’733 Patent, U.S.
`App. No. 12/562,621 (the “FH Excerpts”)
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`Apotex replies to two arguments1 in Patent Owner’s (“PO’s) preliminary
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`response, which seeks denial of Apotex’s petition asserting that PO’s patent claims
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`to deuterated tetrabenazine are unpatentable. As to § 325(d), there is no evidence
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`the Examiner specifically considered teachings or arguments relating to the many
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`expected benefits of deuterating methoxy groups. So it is no surprise that she erred
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`in accepting PO’s evidence of “unexpected” results arising from deuterating
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`tetrabenazine’s methoxy groups. As to secondary considerations, they fail for lack
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`of nexus or factual support. The Board should thus institute inter partes review.2
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`INSTITUTION SHOULD NOT BE DENIED UNDER § 325(D)
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`First, PO argues that the substance of Apotex’s references and arguments
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`were before the Examiner. POPR 2, 16-24. But there is no evidence that she
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`specifically considered teachings or arguments relating to expected benefits of
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`deuterating methoxy groups. Apotex’s combination references teaching those
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`benefits, Naicker ’921, Kohl, Foster AB, and Gant ’991, were not before the
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`Examiner, and no arguments were made regarding those teachings. PO asserts that
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`Foster AB is discussed in Foster 1985, a reference she considered in a rejection.
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`1 Apotex disagrees with PO’s other arguments, resting on its Petition for them.
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`2 Out of desperation, PO makes an outlandish allegation of extortion. POPR 33.
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`But Apotex did not seek money; it sought a license to market a generic product.
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`POPR 20 (citing EX1027 at 51-53). But there is no evidence that she analyzed that
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`portion of the disclosure. Her discussion of Foster 1985 focused solely on how it
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`would have motivated a POSA to deuterate tetrabenazine to improve metabolic
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`stability; notably, the word “methoxy” never appears. The only reasonable
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`conclusion is that she overlooked that disclosure. PO also discounts Naicker ’921,
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`Kohl, Foster AB, and Gant ’991 as cumulative. POPR 21. But those disclosures
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`provide unique teachings and/or experimental data about the numerous benefits of
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`deuterating methoxy groups. If the Examiner had specifically considered those
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`teachings, she would have rejected PO’s evidence of “unexpected” results.
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`Second, relying largely on attorney argument unsupported by any expert, PO
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`argues that the Examiner correctly allowed the claims based on PO’s evidence of
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`unexpected results. POPR 25-33. But as explained in Apotex’s petition, the
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`Examiner initially, and correctly, rejected PO’s results as “expected and not
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`unexpected,” as they were fully disclosed in the prior art. Pet. 36-40, 47-49, 59-60.
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`The Examiner inexplicably erred in not maintaining her position.3 Attempting to
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`3 In short, the Examiner rejected PO’s in vitro and in vivo data submitted in a first
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`declaration as “quite expected.” EX1027 at 26-32, 53-54. PO submitted side
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`effect data in a second declaration, and she allowed the claims. Id. at 63-71, 126.
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`This was inexplicable, as those data were expected and had no nexus. See infra.
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`justify this error, PO makes two basic assertions: (1) that Apotex improperly relies
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`upon the teachings of references such as Naicker ’921, Kohl, and Foster AB and
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`(2) that Apotex’s arguments should be rejected because they rely upon in vitro data
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`instead of in vivo data. POPR 27-31. Both assertions are without merit.
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`As an initial matter, Apotex properly relied upon those references, as each
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`teaches what in vivo and in vitro results a POSA would expect upon deuterating
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`methoxy groups, including the results PO submitted to the Examiner. As for
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`Naicker ’921, it teaches that deuterating such groups “alters the pharmacokinetic
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`parameters of the drug,” as well as increases potency and stability while reducing
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`toxicity and clearance. EX1004 at 4:28-30, 32-36; id. at 4:30-32 (“Lower rates of
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`oxidation, metabolism and clearance result in greater and more sustained biological
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`activity.”). Consistent with Naicker ’921, Kohl used a predictive human liver
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`microsome model, reporting that methoxy group deuteration reduced metabolism
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`by 50%. EX1005 at Exs. 1 & 2 (synthesis), Table 1 (microsome data). This is the
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`same result PO obtained in microsomes and submitted to the Examiner. EX1027
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`at 17, 31-32 (at least 50% metabolite reduction). Foster AB used a rat liver
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`microsome model, reporting that methoxy group deuteration resulted in “[i]sotope
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`effects of ~2.” EX1006 at 327. This was predictive of the doubled half-life
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`obtained in PO’s in vivo study and submitted to the Examiner. EX1027 at 18, 32.
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`Rather than view these references as a whole as the law requires, PO
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`deconstructs their teachings individually. PO criticizes Naicker ’921 because it
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`does not report biological data or the specific side effects that PO found were
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`reduced. POPR 27, 29-31. But PO cites to no precedent holding that such clear
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`teachings of expectation must be accompanied by biological data. And Naicker
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`’921 teaches that reducing “toxic side effects” could be expected by deuterating
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`methoxy groups. A fair reading of that language would include somnolence and
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`dizziness, which could lead to injury and/or death. PO also asserts that Apotex has
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`not shown that Foster AB’s in vitro data translated in vivo, id. at 29, a puzzling
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`assertion since, as noted above, PO’s in vivo data show the predictive power of
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`Foster AB’s in vitro data. PO criticizes Kohl because it reports mixed results. Id.
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`at 27. But whether a result is expected is based upon a reasonable, not impossible,
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`standard. Viewed with Naicker ’921, Foster AB, and the many references teaching
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`deuteration benefits, and Kohl’s report of the same reduction in in vitro
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`metabolism PO found, the fact that its results were not uniformly positive does not
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`alter the obvious conclusion that PO’s in vivo and in vitro results were expected.
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`PO also argues that in vitro data fails to predict what can be expected in vivo
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`and criticizes Apotex for relying on references disclosing such data. POPR 28-29.
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`PO’s argument is a curious one, as PO relied on in vitro data in an attempt to
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`secure allowance of its claims. EX1027 at 17, 31-32. That is no surprise, as a
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`POSA analyzes such in vitro data to know what to reasonably expect in vivo.
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`Lastly, PO asserts that the Examiner did not err in crediting PO’s data,
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`which compared 15 mg of extended release deutetrabenazine with 25 mg of
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`immediate release tetrabenazine, as she purportedly accounted for those key
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`differences. POPR 31-32. But while she mentions dosing strength differences in
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`her vague, terse analysis, whether she accounted for their impact on PO’s results is
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`unclear. EX1027 at 124, 126. What is clear is that she does not mention or
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`account for dosage form differences, id., which result in very different release
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`profiles, Pet. 39-40 & n.13, 49, 60. Since she (and PO) failed to establish that the
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`“unexpected” results were due only to the claimed invention, as opposed to
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`dosage-related differences, she erred in relying on those results.
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`THROWAWAY SECONDARY CONSIDERATIONS
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`PO’s new secondary considerations, POPR 74-75, are without merit. As for
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`commercial success, PO showed no nexus, i.e., that sales were due to the claimed
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`invention, not other economic factors/unclaimed features. As for failure of others,
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`PO provided no evidence that others failed. As for “respect for the invention,” that
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`one ANDA filer declined to challenge the ’733 patent says nothing, as that may
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`relate to litigation strategy, not respect for the strength of the patented invention.
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`In view of the foregoing, the Board should institute inter partes review.
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`Dated: January 7, 2022
`STEPTOE & JOHNSON LLP
`1114 Avenue of the Americas
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`New York, NY 10036
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`Telephone: 212-506-3900
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`Fax: 212-506-3950
`Email: SJDeutetrabenazineIPR@Steptoe.com
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`Respectfully submitted,
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`/Vishal Gupta/
`Vishal Gupta (Reg. No. 67,284)
`Lead Counsel for Petitioners
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`CERTIFICATE OF SERVICE
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`I certify that, on January 7, 2022, a true and correct copy of the foregoing
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`was served by delivering a copy via electronic mail on the following attorneys of
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`record:
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`David I. Berl (dberl@wc.com)
`Thomas S. Fletcher (tfletcher@wc.com)
`Shaun P. Mahaffy (smahaffy@wc.com)
`TevaAustedo@wc.com
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`Respectfully submitted,
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`/Vishal Gupta/
`Vishal Gupta (Reg. No. 67,284)
`Lead Counsel for Petitioners
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