UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________
`
`APOTEX INC. AND APOTEX CORP.,
`Petitioners
`
`v.
`
`AUSPEX PHARMACEUTICALS, INC.,
`Patent Owner
`_____________________
`
`Case IPR2021-01507
`U.S. Patent No. 8,524,733
`Issued: September 3, 2013
`
`Title:
`BENZOQUINOLINE INHIBITORS OF VESICULAR MONOAMINE TRANSPORTER 2
`
`PETITIONER’S REPLY TO PATENT OWNER’S
`PRELIMINARY RESPONSE
`
`
`
`
`
`
`
`
`
`
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________
`
`APOTEX INC. AND APOTEX CORP.,
`Petitioners
`
`v.
`
`AUSPEX PHARMACEUTICALS, INC.,
`Patent Owner
`_____________________
`
`Case IPR2021-01507
`U.S. Patent No. 8,524,733
`Issued: September 3, 2013
`
`Title:
`BENZOQUINOLINE INHIBITORS OF VESICULAR MONOAMINE TRANSPORTER 2
`
`PETITIONER’S REPLY TO PATENT OWNER’S
`PRELIMINARY RESPONSE
`
`
`
`
`
`
`
`
`
`
`LIST OF EXHIBITS
`
`
`Exhibit No. Description
`
`1004
`
`1005
`
`1006
`
`1009
`
`1027
`
`Naicker, S. et al., U.S. Patent No. 6,503,921, “Deuterated rapamycin
`compounds, methods and uses thereof” (“Naicker ’921”)
`
`Kohl, B. et al., Int’l. Pub. No. WO 2007/012650, “Isotopically
`Substituted Proton Pump Inhibitors” (“Kohl”)
`
`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”)
`
`Gant, T.G. et al., U.S. Pat. Pub. No. 2008/0280991, “Substituted
`Naphthalenes” (“Gant ’991”)
`
`Excerpts of the Application File History for the ’733 Patent, U.S.
`App. No. 12/562,621 (the “FH Excerpts”)
`
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`- ii -
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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
`
`to deuterated tetrabenazine are unpatentable. As to § 325(d), there is no evidence
`
`the Examiner specifically considered teachings or arguments relating to the many
`
`expected benefits of deuterating methoxy groups. So it is no surprise that she erred
`
`in accepting PO’s evidence of “unexpected” results arising from deuterating
`
`tetrabenazine’s methoxy groups. As to secondary considerations, they fail for lack
`
`of nexus or factual support. The Board should thus institute inter partes review.2
`
`INSTITUTION SHOULD NOT BE DENIED UNDER § 325(D)
`
`First, PO argues that the substance of Apotex’s references and arguments
`
`were before the Examiner. POPR 2, 16-24. But there is no evidence that she
`
`specifically considered teachings or arguments relating to expected benefits of
`
`deuterating methoxy groups. Apotex’s combination references teaching those
`
`benefits, Naicker ’921, Kohl, Foster AB, and Gant ’991, were not before the
`
`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.
`
`
`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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`- 1 -
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`
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`POPR 20 (citing EX1027 at 51-53). But there is no evidence that she analyzed that
`
`portion of the disclosure. Her discussion of Foster 1985 focused solely on how it
`
`would have motivated a POSA to deuterate tetrabenazine to improve metabolic
`
`stability; notably, the word “methoxy” never appears. The only reasonable
`
`conclusion is that she overlooked that disclosure. PO also discounts Naicker ’921,
`
`Kohl, Foster AB, and Gant ’991 as cumulative. POPR 21. But those disclosures
`
`provide unique teachings and/or experimental data about the numerous benefits of
`
`deuterating methoxy groups. If the Examiner had specifically considered those
`
`teachings, she would have rejected PO’s evidence of “unexpected” results.
`
`Second, relying largely on attorney argument unsupported by any expert, PO
`
`argues that the Examiner correctly allowed the claims based on PO’s evidence of
`
`unexpected results. POPR 25-33. But as explained in Apotex’s petition, the
`
`Examiner initially, and correctly, rejected PO’s results as “expected and not
`
`unexpected,” as they were fully disclosed in the prior art. Pet. 36-40, 47-49, 59-60.
`
`The Examiner inexplicably erred in not maintaining her position.3 Attempting to
`
`
`3 In short, the Examiner rejected PO’s in vitro and in vivo data submitted in a first
`
`declaration as “quite expected.” EX1027 at 26-32, 53-54. PO submitted side
`
`effect data in a second declaration, and she allowed the claims. Id. at 63-71, 126.
`
`This was inexplicable, as those data were expected and had no nexus. See infra.
`
`- 2 -
`
`
`
`justify this error, PO makes two basic assertions: (1) that Apotex improperly relies
`
`upon the teachings of references such as Naicker ’921, Kohl, and Foster AB and
`
`(2) that Apotex’s arguments should be rejected because they rely upon in vitro data
`
`instead of in vivo data. POPR 27-31. Both assertions are without merit.
`
`As an initial matter, Apotex properly relied upon those references, as each
`
`teaches what in vivo and in vitro results a POSA would expect upon deuterating
`
`methoxy groups, including the results PO submitted to the Examiner. As for
`
`Naicker ’921, it teaches that deuterating such groups “alters the pharmacokinetic
`
`parameters of the drug,” as well as increases potency and stability while reducing
`
`toxicity and clearance. EX1004 at 4:28-30, 32-36; id. at 4:30-32 (“Lower rates of
`
`oxidation, metabolism and clearance result in greater and more sustained biological
`
`activity.”). Consistent with Naicker ’921, Kohl used a predictive human liver
`
`microsome model, reporting that methoxy group deuteration reduced metabolism
`
`by 50%. EX1005 at Exs. 1 & 2 (synthesis), Table 1 (microsome data). This is the
`
`same result PO obtained in microsomes and submitted to the Examiner. EX1027
`
`at 17, 31-32 (at least 50% metabolite reduction). Foster AB used a rat liver
`
`microsome model, reporting that methoxy group deuteration resulted in “[i]sotope
`
`effects of ~2.” EX1006 at 327. This was predictive of the doubled half-life
`
`obtained in PO’s in vivo study and submitted to the Examiner. EX1027 at 18, 32.
`
`- 3 -
`
`
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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
`
`reduced. POPR 27, 29-31. But PO cites to no precedent holding that such clear
`
`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
`
`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
`
`Foster AB’s in vitro data. PO criticizes Kohl because it reports mixed results. Id.
`
`at 27. But whether a result is expected is based upon a reasonable, not impossible,
`
`standard. Viewed with Naicker ’921, Foster AB, and the many references teaching
`
`deuteration benefits, and Kohl’s report of the same reduction in in vitro
`
`metabolism PO found, the fact that its results were not uniformly positive does not
`
`alter the obvious conclusion that PO’s in vivo and in vitro results were expected.
`
`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.
`
`PO’s argument is a curious one, as PO relied on in vitro data in an attempt to
`
`- 4 -
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`
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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
`
`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
`
`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.
`
`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
`
`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
`
`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.
`
`- 5 -
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`
`
`
`
`Dated: January 7, 2022
`STEPTOE & JOHNSON LLP
`1114 Avenue of the Americas
`
`New York, NY 10036
`
`
`Telephone: 212-506-3900
`
`Fax: 212-506-3950
`Email: SJDeutetrabenazineIPR@Steptoe.com
`
`
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`Respectfully submitted,
`
`
`
`
`/Vishal Gupta/
`Vishal Gupta (Reg. No. 67,284)
`Lead Counsel for Petitioners
`
`- 6 -
`
`
`
`CERTIFICATE OF SERVICE
`
`I certify that, on January 7, 2022, a true and correct copy of the foregoing
`
`was served by delivering a copy via electronic mail on the following attorneys of
`
`record:
`
`
`David I. Berl (dberl@wc.com)
`Thomas S. Fletcher (tfletcher@wc.com)
`Shaun P. Mahaffy (smahaffy@wc.com)
`TevaAustedo@wc.com
`
`
`Respectfully submitted,
`
`
`
`
`/Vishal Gupta/
`Vishal Gupta (Reg. No. 67,284)
`Lead Counsel for Petitioners
`
`
`
`
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