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 No. IPR2021-01507
`U.S. Patent No. 8,524,733
`__________________
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`
`
`
`
`

`

`
`
`Case No. IPR2021-01507
`U.S. Patent No. 8,524,733
`
`TABLE OF CONTENTS
`TABLE OF AUTHORITIES ................................................................................... iii
`PATENT OWNER’S EXHIBIT LIST ...................................................................... v
`INTRODUCTION ..................................................................................................... 1
`BACKGROUND ....................................................................................................... 3
`I.
`Tetrabenazine. .................................................................................................. 3
`II.
`Deuteration. ..................................................................................................... 7
`III. The ’733 Patent. ............................................................................................. 13
`A.
`The Challenged Claims. ...................................................................... 13
`B.
`Summary of Relevant Prosecution History. ........................................ 14
`ARGUMENT ........................................................................................................... 15
`IV. The Board Should Exercise its Discretion Under §§ 325(d) and 314(a)
`to Deny Institution. ........................................................................................ 15
`A.
`The Office Substantively Considered the Same Prior Art and
`Arguments Raised in the Petition. ....................................................... 16
`1.
`Petitioners’ Tetrabenazine References Were Before the
`Examiner. .................................................................................. 17
`Petitioners’ Deuteration References Are Cumulative. .............. 18
`Petitioners’ Arguments Overlap with the Arguments
`Made During Prosecution. ........................................................ 22
`The Petitioners Cannot Demonstrate that the Office Erred in a
`Manner Material to the Patentability of the Challenged Claims. ........ 24
`1.
`Petitioners’ Art and Arguments Were Closely Evaluated. ....... 25
`2.
`Petitioners Fail to Identify Any Material Error that
`Warrants Reconsideration. ........................................................ 25
`
`2.
`3.
`
`B.
`
`i
`
`

`

`
`
`C.
`
`B.
`
`C.
`
`V.
`
`The Board Should Exercise its Discretion to Deny Institution
`Due to Petitioners’ Attempted Extortion. ............................................ 33
`Petitioners Have Not Established a Reasonable Likelihood of
`Prevailing on Any Ground. ............................................................................ 34
`A.
`Petitioners’ Reference Provides a Blueprint for Solving
`Tetrabenazine’s Alleged Problems. .................................................... 35
`The POSA Would Not Have Been Motivated to Deuterate
`Tetrabenazine with a Reasonable Expectation of Success.................. 41
`1.
`Side Effects. .............................................................................. 41
`2.
`Duration of Action. ................................................................... 45
`3.
`Physicochemical Properties. ..................................................... 61
`Petitioners’ Arguments About the Sites of Deuteration Are
`Predicated on Hindsight. ..................................................................... 64
`D. Objective Indicia of Nonobviousness. ................................................ 72
`1.
`Unexpected Properties. ............................................................. 72
`2.
`Other Objective Indicia. ............................................................ 74
`CONCLUSION ........................................................................................................ 75
`
`
`
`Case No. IPR2021-01507
`U.S. Patent No. 8,524,733
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`
`
`ii
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`

`

`
`
`Case No. IPR2021-01507
`U.S. Patent No. 8,524,733
`
`TABLE OF AUTHORITIES
`
`CASES
`Advanced Bionics, IPR2019-01469, Paper 6 (Feb. 13, 2020) ..................... 16, 24, 25
`Becton, Dickinson & Co. v. B. Braun Melsungen AG, IPR2017-01586,
`Paper 8 (Dec. 15, 2017) .......................................................................... 16, 20, 24
`Canon Inc. v. Papst Licensing GmbH & Co. KG, IPR2016-01202, Paper 15
`(Dec. 15, 2016) ................................................................................................... 19
`Cosmax Co. v. AmorePacific Corp., IPR2018-01516, Paper 8
`(Feb. 20, 2019) .................................................................................................... 20
`CSL Behring GmbH v. Shire Viropharma Inc. IPR2019-00459, Paper 8 (Jul.
`2, 2019) ............................................................................................................... 30
`Ex parte Allen, Appeal No. 2018-008208 (Application No. 14/712,101,
`July 1, 2020)........................................................................................................ 40
`In re Rouffet, 149 F.3d 1350 (Fed. Cir. 1998) ......................................................... 75
`Kinetic Concepts, Inc. v. Smith & Nephew, Inc., 688 F.3d 1342
`(Fed. Cir. 2012) ................................................................................................... 40
`Leo Pharm. Prods. v. Rea, 726 F.3d 1346 (Fed. Cir. 2013) ................................ 7, 74
`Microsoft Corp. v. Koninklijke Philips N.V., IPR2018-00277, Paper 11 (Jun.
`8, 2018) ............................................................................................................... 19
`Neptune Generic v. Auspex Pharmaceuticals, IPR2015-01313, Paper 25
`(Dec. 9, 2015) ..................................................................................................... 13
`Puma, Inc. v. Nike Inc., IPR2019-01042, Paper 10 (Oct. 31, 2019) ................. 18, 25
`Regeneron Pharms. v. Merus N.V., 864 F.3d 1343 (Fed. Cir. 2017) ...................... 22
`Roku Inc. v. Universal Electronics, Inc. IPR2019-01619, Paper 11 (Apr. 2,
`2020) ................................................................................................................... 21
`Unified Patents Inc. v. Berman, IPR2016-01571, Paper 10 (Dec. 14, 2016) .... 21, 24
`
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`Case No. IPR2021-01507
`U.S. Patent No. 8,524,733
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`
`Uniroyal, Inc. v. Rudkin-Wiley Corp., 837 F.2d 1044 (Fed. Cir. 1988) .................. 74
`Winner Int’l Royalty Corp. v. Wang, 202 F. 3d 1340 (Fed. Cir. 2000) ................... 40
`OTHER AUTHORITIES
`37 C.F.R. § 42.6(a)(3) .............................................................................................. 68
`35 U.S.C. § 103(c) ................................................................................................... 15
`35 U.S.C. § 314(a) ............................................................................................. 33, 34
`35 U.S.C. § 325(d) ................................................................ 2, 14, 15, 19, 20, 28, 34
`
`
`
`iv
`
`

`

`
`
`Exhibit
`EX2001
`
`EX2002
`
`EX2003
`
`EX2004
`
`EX2005
`
`EX2006
`
`EX2007
`EX2008
`
`EX2009
`
`EX2010
`
`Case No. IPR2021-01507
`U.S. Patent No. 8,524,733
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`PATENT OWNER’S EXHIBIT LIST
`
`Description
`Foster, A., Deuterium Isotope Effects in the Metabolism of Drug
`and Xenobiotics: Implication for Drug Design, Advances in
`Drug Research vol. 14 (1985) (“Foster 1985”)
`Sun, H. et al., Deuterium isotope effects in drug
`pharmacokinetics II: Substrate-dependence of the reaction
`mechanism influences outcome for cytochrome P450 cleared
`drugs, PLoS ONE 13:11 (2018) (“Sun 2018”)
`Schofield, J. et al., Effect of deuteration on metabolism and
`clearance of Nerispirdine (HP184) and AVE5638, Bioorganic &
`Medicinal Chem. 23:3831-3842 (2015) (“Schofield 2015”)
`Sharma, R. et al., Deuterium Isotope Effects on Drug
`Pharmacokinetics. I. System-Dependent Effects of Specific
`Deuteration with Aldehyde Oxidase Cleared Drugs, Drug
`Metabolism and Disposition 40:3 625-634 (2012) (“Sharma
`2012”)
`Vaz and Coon, On the Mechanism of Action of Cytochrome
`P450: Evaluation of Hydrogen Abstraction in Oxygen-
`Dependent Alcohol Oxidation, Biochemistry 6442-6449 (1994)
`(“Vaz”)
`Nelson and Trager, The Use of Deuterium Isotype Effects to
`Probe the Active Site Properties, Mechanism of Cytochrome
`P450-Catalyzed Reactions, and Mechanisms of Metabolically
`Dependent Toxicity, Drug Metabolism and Disposition 31:12
`1481-1498 (2003) (“Nelson 2003”)
`U. S. Patent No. 7,678,914 (Tung) (“’914 patent”)
`Smith and Sleath, Model Systems for Cytochrome P450
`Dependent Mono-oxygenases. Part 2. 1.2 Kinetic Isotope Effects
`for the Oxidative Demethylation of Anisole and [Me-2H3]Anisole
`by Cytochrome P450 Dependent Mono-oxygenases and Model
`Systems, J. Chem. Soc. 621-628 (1983) (“Smith”)
`Harada, N. et al., Kinetic Isotope Effects on Cytochrome P-450-
`catalyzed Oxidation Reactions, J. Bio. Chem. 259:5 3005-3010
`(1984) (“Harada”)
`Dowers and Jones, Kinetic Isotope Effects Implicate a Single
`Oxidant for Cytochrome P450-Mediated O-Dealkylation, N-
`Oxygenation, and Aromatic Hydroxylation of 6-
`
`v
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`

`Case No. IPR2021-01507
`U.S. Patent No. 8,524,733
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`
`
`EX2011
`
`EX2014
`
`EX2015
`
`EX2016
`
`EX2017
`
`EX2018
`
`EX2019
`
`EX2012
`EX2013
`
`Methoxyquinoline, Drug Metabolism and Disposition 34:8 1288-
`1290 (2006) (“Dowers”)
`Shao, L et al., Derivatives of tramadol for increased duration of
`effect, Bioorganic & Medicinal Chem. Letters 16:691-694 (2006)
`(“Shao”)
`Ingrezza (valbenazine) Label (2017) (“Ingrezza Label”)
`Strategies to Protect the Health of Deployed U.S. Forces:
`Assessing Health Risks to Deployed U.S. Forces – Workshop
`Proceedings (2000) (“Rozman”)
`Berg, J. et al., Biochemistry, Ch. 8 Enzymes: Basic Concepts and
`Kinetics (2002) (“Berg”)
`Somers, G. et al., A Handbook of Bioanalysis and Drug
`Metabolism, Ch. 15 In vitro techniques for investigating drug
`metabolism (2019) (“Somers”)
`Pang, K. S. et al., Metabolite Kinetics: Formation of
`Acetaminophen from Deuterated and Nondeuterated Phenacetin
`and Acetanilide on Acetaminophen Sulfation Kinetics in the
`Perfused Rat Liver Preparation, J. Pharmacology and
`Experimental Therapeutics 14-19 (1982) (“Pang”)
`Helfenbein, J. et al., Isotopic Effect Study of Propofol
`Deuteration on the Metabolism, Activity, and Toxicity of the
`Anesthetic, J. Med. Chem. 5806-5808 (2002) (“Helfenbein
`2002”)
`Cherrah, Y. et al., Study of Deuterium Isotope Effects on Protein
`Binding by Gas Chromatography/Mass Spectrometry. Caffeine
`and Deuterated Isotopomers, Biomed. and Environmental Mass
`Spectrometry 653-657 (1987) (“Cherrah”)
`Borgstrom, L. et al., Comparative Pharmacokinetics of
`Unlabeled and Deuterium-Labeled Terbutaline: Demonstration
`of a Small Isotope Effect, J. Pharm. Sci. 952-954 (1988)
`(“Borgstrom”)
`EX2020 Misra, A. et al., Drug delivery to the central nervous system: a
`review, J. Pharm. Pharmaceut. Sci. 6(2):252-273 (2003)
`(“Misra”)
`Teva Reports Third Quarter 2021 Financial Results (“Teva SEC
`Filing”)
`Search Results for “tetrabenazine”, FDA.gov (“FDA listing of
`generic tetrabenazine products”)
`
`EX2021
`
`EX2022
`
`vi
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`Case No. IPR2021-01507
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`
`EX2023
`
`EX2024
`
`Joint Proposed Discovery Plan, Teva Branded Pharmaceutical
`Products R&D Inc. v. Lupin et al., D.N.J. 21-cv-13247; D.N.J.
`21-cv-13240 (October 12, 2021) (“Joint Proposed Discovery
`Plan”)
`Information Disclosure Statement, Application No. 12/562,621
`(March 27, 2012) (“03/27/2012 IDS”)
`
`
`
`
`
`vii
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`

`
`
`INTRODUCTION
`
`Case No. IPR2021-01507
`U.S. Patent No. 8,524,733
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`Deutetrabenazine is the active ingredient in AUSTEDO, which is approved
`
`for the treatment of chorea associated with Huntington’s disease and tardive
`
`dyskinesia in adults. Deutetrabenazine is, to-date, the only drug approved by FDA
`
`containing deuterium, a heavy isotope of hydrogen. The challenged claims of U.S.
`
`Patent No. 8,524,733 (the “’733 patent”) cover deutetrabenazine.
`
`Petitioners’ obviousness case begins with tetrabenazine, which had been
`
`used for decades before the priority date to treat hyperkinetic movement disorders.
`
`During those decades, not a single piece of literature suggested that tetrabenazine’s
`
`properties could be improved with deuteration. Inventors at Auspex discovered
`
`that deuteration of tetrabenazine at particular atoms produced substantial and
`
`desirable changes. The resulting molecule, later called deutetrabenazine, was more
`
`metabolically stable in in vitro preparations, and that improved stability translated
`
`to a substantially enhanced duration of action when administered to humans,
`
`facilitating less frequent dosing than tetrabenazine. Deutetrabenazine also
`
`exhibited notable improvements to tetrabenazine’s side-effect profile. Following
`
`its 2017 approval, Patent Owner’s AUSTEDO deutetrabenazine product largely
`
`supplanted tetrabenazine in the marketplace, despite the latter being available as a
`
`low-cost generic.
`
`1
`
`

`

`Petitioners assert that the challenged claims covering deutetrabenazine were
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`Case No. IPR2021-01507
`U.S. Patent No. 8,524,733
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`
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`obvious in view of tetrabenazine publications in combination with non-
`
`tetrabenazine deuteration literature. As a threshold matter, the Board should
`
`exercise its discretion to deny institution pursuant to 35 U.S.C. § 325(d). Much of
`
`the art Petitioners cite (Zheng, Gano, and Schwartz) was before the Examiner, and
`
`the remaining references (Naicker ’921, Kohl, Foster AB, and Gant ’991) address
`
`deuteration of non-tetrabenazine molecules and are cumulative to the numerous
`
`deuteration-related references the Examiner considered closely. To obscure the
`
`plainly repetitive nature of their obviousness challenge, Petitioners assert that their
`
`references, unlike those before the Examiner, disclose “the benefits of deuteration
`
`at methoxy groups.” Pet. 40. This argument is meritless—many references before
`
`the Examiner discussed deuteration of methoxy groups and, in any event,
`
`Petitioners vastly overstate the uniqueness of methoxy deuteration. Petitioners also
`
`assert that the Examiner erred in crediting Patent Owner’s unexpected results. Pet.
`
`36. This argument likewise fails. In view of the unpredictability of deuteration,
`
`the POSA would not have expected the changes in pharmacokinetics or side-
`
`effects that Patent Owner observed, which are attributable to the claimed
`
`deutetrabenazine molecule.
`
`Petitioners’ arguments also fail on the merits. In each of Petitioners’ three
`
`(largely similar) Grounds, they argue that the POSA would have started with
`
`2
`
`

`

`
`tetrabenazine and deuterated its methoxy groups—and only its methoxy groups—
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`Case No. IPR2021-01507
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`to improve its side-effect profile and extend its duration of action. That argument
`
`is incorrect for at least three reasons. First, Petitioners’ lead reference, Gano,
`
`already disclosed a solution—replacing tetrabenazine’s ketone moiety with an
`
`ester—to the tetrabenazine drawbacks Petitioners identify, which is incompatible
`
`with the claimed invention. Second, the POSA had no motivation to pursue
`
`Petitioners’ purportedly obvious deuteration strategy with a reasonable expectation
`
`of success. The POSA would not have expected deuteration to alleviate
`
`tetrabenazine’s side effects or extend its duration of action in vivo, and the POSA
`
`would have been wary about the negative physicochemical changes that could
`
`accompany deuteration of tetrabenazine’s methoxy groups. Third, the POSA
`
`would not have selected the claimed deuteration pattern (both methoxy groups, but
`
`not isobutyl) because it is inconsistent with the prior art’s disclosure of
`
`tetrabenazine’s metabolic profile. Various objective indicia further support the
`
`non-obviousness of the claimed invention.
`
`BACKGROUND
`
`I.
`
`Tetrabenazine.
`
`Tetrabenazine is a very old drug. First synthesized by Hoffmann-La Roche
`
`in the 1950s, tetrabenazine proved to be a “potent, reversible inhibitor of
`
`catecholamine uptake by vesicular monoamine transporter-2 (VMAT2),” EX1007
`
`3
`
`

`

`
`(Gano), 1:26-29. Clinical trials subsequently “demonstrated the beneficial effects
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`of [tetrabenazine] for patients with chorea,” and tetrabenazine gained approval for
`
`treating chorea in 1971. EX1017 (Paleacu) at 548. Tetrabenazine had several
`
`known side effects, including “drowsiness/sedation, weakness, parkinsonism,
`
`depression, and acute akathisia.” Id. at 549. Due to its relatively short half-life,
`
`tetrabenazine “ha[d] to be administered two to three times a day.” Id. at 546.
`
`The structure of tetrabenazine appears below:
`
`When administered to patients, the ketone moiety (in red) is rapidly metabolized,
`
`creating four stereoisomers1 of a molecule known as dihydrotetrabenazine
`
`
`
`(HTBZ):
`
`
`1 This reaction yields four stereoisomers, not two, because tetrabenazine is
`
`typically a racemic mixture. EX1003 (Zheng) at E684.
`
`4
`
`

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`
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`Those stereoisomers have different pharmacological profiles. For example, the
`
`(2R,3R,11bR)-HTBZ was known to exhibit the highest VMAT2 receptor affinity,
`
`whereas other stereoisomers exhibited lower VMAT2 affinity, as well as off-target
`
`binding to dopamine receptors recognized as a potential cause of tetrabenazine’s
`
`side-effects. See EX1007, 1:39-41, 17:30-18:31.
`
`
`
`In addition to metabolism at the ketone, Schwartz also disclosed that
`
`tetrabenazine was metabolized at one (C-9) methoxy group (via demethylation)
`
`and the isobutyl group (via hydroxylation). EX1008 (Schwartz) at 650. Those
`
`locations are indicated below (C-9 methoxy group (blue) & isobutyl group
`
`(green)):
`
`5
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`
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`Neither Schwartz nor any other reference cited by Petitioners quantified the
`
`metabolites of tetrabenazine. Id. at 653. Petitioners likewise fail to cite any
`
`reference discussing which enzyme(s) are responsible for metabolizing
`
`tetrabenazine.
`
`
`
`The prior art suggested various options for improving tetrabenazine. For
`
`example, Petitioners’ Zheng reference described various tetrabenazine analogs—
`
`principally with modifications to or near the ketone moiety—exhibiting high
`
`potency. EX1003 at E684-85. Petitioners’ Gano reference likewise disclosed
`
`several tetrabenazine derivatives, which replaced the ketone moiety with an ester
`
`functional group. EX1007, 2:1-50. Gano reported that one compound in
`
`particular—a prodrug valine ester of the (+) alpha-HTBZ stereoisomer—provided
`
`improved VMAT2 selectivity and a longer half-life than tetrabenazine. Id., 7:58-
`
`8:5. Gano explained that this modification could improve upon tetrabenazine’s
`
`side-effect profile and permit once-daily dosing. Id.
`
`6
`
`

`

`By contrast, no prior art had ever suggested Petitioners’ purportedly
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`
`
`obvious solution of deuterating tetrabenazine. The absence of any such teaching is
`
`particularly notable given the length of time that had elapsed since the discovery of
`
`tetrabenazine and its shortcomings. See Leo Pharm. Prods. v. Rea, 726 F.3d 1346,
`
`1356 (Fed. Cir. 2013). This absence of any teaching is unsurprising because
`
`deuteration was considered to be a highly unpredictable and unreliable approach
`
`for modifying the properties of drugs, which had never resulted in a marketed
`
`product before AUSTEDO.
`
`II. Deuteration.
`
`To improve the side-effect and pharmacokinetic profile of tetrabenazine,
`
`Petitioners assert that the POSA would have ignored the molecular modifications
`
`suggested by their own references and instead altered tetrabenazine by substituting
`
`certain hydrogens with deuterium. Pet. 8. The rationale behind this approach is
`
`that deuterium forms stronger bonds with carbon than hydrogen and thus—under
`
`certain conditions—may slow enzymatic reactions that involve breaking that
`
`carbon-hydrogen bond. EX1001 (’733 patent), 2:11-28. That change in reaction
`
`rate is known as a deuterium kinetic isotope effect (often, “isotope effect”). Id.
`
`Petitioners claim that, by the priority date, “many therapeutics had been
`
`modified by deuteration to improve activity and reduce side effects.” Pet. 1. That
`
`assertion is made without any literature citation. And for good reason—as of the
`
`7
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`

`
`priority date, not a single deuterated drug ever had been approved by FDA. To this
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`U.S. Patent No. 8,524,733
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`day, AUSTEDO remains the only such approved drug. The absence of any other
`
`such approval is particularly notable given that—according to Petitioners—
`
`deuteration was “popularized in the 1960s.” Pet. 1. Even beyond FDA-approved
`
`drugs, conspicuously absent from the Petition are any examples of deuterated
`
`drugs that actually exhibited improved properties in living systems.
`
`Why had no deuterated drugs reached the market by the priority date? The
`
`Petition is silent. The reality is that, far from a simple “paint by numbers”
`
`exercise, Pet. 2, deuteration was (and remains) a highly unpredictable endeavor
`
`that can (and typically does) fail to produce an enhanced therapeutic profile in
`
`vivo. This unpredictability was explained in a declaration submitted during
`
`prosecution by Dr. Margaret Bradbury:
`
`[T]he effect of deuterium substitution on the in vitro or the
`in vivo stability of compounds cannot be reasonably
`predicted based on the structure of the compound, the site
`at which deuterium is installed, or prior knowledge of the
`metabolic pathways of the compound. I am not aware that
`any person working in the field of deuterated compounds,
`whether at Auspex Pharmaceuticals or elsewhere, could
`reasonably predict whether metabolic stability could be
`increased by deuteration without conducting the necessary
`experiments. . . . A large proportion of the over 300
`compounds that Auspex has tested in the human liver
`microsome assay do not demonstrate any significant
`differences in stability from their non-deuterated pairs. Of
`those compounds chosen for pharmacokinetic study in
`rodents based on in vitro stability results, only a small
`
`8
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`
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`vivo pharmacokinetic
`percentage demonstrate
`in
`differences as compared to their non-deuterated forms.
`EX1027 (FH Excerpts) at 30-31. Substantial literature confirms Dr. Bradbury’s
`
`analysis. For example, a 1985 review paper provided the following assessment: “It
`
`is now becoming clear that the scope for using [deuterium isotope effects]
`
`effectively in drug design to block adverse metabolism or to deflect metabolism
`
`away from toxic products (metabolic switching) is very limited,” EX2001 (Foster
`
`1985) at 35. More than twenty years later, in 2006, Michael Fisher and co-
`
`authors—all of whom worked at pharmaceutical companies—echoed Foster’s
`
`pessimistic assessment, stating that “deuterium isotope effect theory and the
`
`mechanism of CYP enzymes taken together suggest that this strategy [of
`
`deuteration] will usually not result in significant alterations in overall metabolic
`
`clearance of the substrate.” EX1024 (Fisher) at 101-02, 107. Literature after the
`
`priority date is in accord.2 E.g., EX2002 (Sun 2018) at 1 (“[T]he potential for an
`
`isotope effect on the intrinsic clearance cannot be predicted[.]”); EX2003
`
`(Schofield 2015) at 3831 (“[The] simple rationale [for using deuteration] is
`
`
`2 The discussions of unpredictability in post-priority references apply before the
`
`priority date as well, as the field did not somehow become less predictable after
`
`2008.
`
`9
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`difficult to put into practice in vivo: the vast majority of metabolic reactions
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`Case No. IPR2021-01507
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`responsible for clearance are mediated by one or several enzymes of the
`
`cytochrome P450 family which present such a wide range of reactivities, that
`
`simply slowing one pathway may not result in appreciable alteration of the ADME
`
`property being targeted.”).
`
`Deuteration was (and is) considered such an unpredictable and unproductive
`
`strategy for modifying drug metabolism due to the many obstacles that can cause
`
`deuteration to fail to yield an effect in vivo. See generally EX2004 (Sharma 2012)
`
`at 625 (discussing the “[m]ultiple factors” that “mute the magnitude of this isotope
`
`effect”). Most deuterated molecules cannot overcome each and every obstacle, and
`
`it was difficult—if not impossible—to predict whether a molecule would overcome
`
`any of those obstacles, much less all of them. Among other reasons, deuteration
`
`may fail to improve a molecule’s pharmacokinetic profile in vivo because:
`
`- Rate-Limiting Step. Deuteration only yields an isotope effect if
`
`“breaking of the C-D bond is the rate limiting step.” EX1014 (Chou) ¶
`
`10. Even if breakage of the C-D bond is rate-limiting, the presence of
`
`other rate-limiting steps in the enzymatic process can result in the isotope
`
`effect “being suppressed, or masked.” EX1024 at 102. This issue
`
`generally prevents successful deuteration: “The maximal velocity of
`
`most enzyme reactions is dependent on several rate-contributing or
`
`10
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`Case No. IPR2021-01507
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`partially rate-limiting steps,” which typically leads to reductions in
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`observed isotope effects that are “not predictable.” EX2001 at 34.
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`Whether C-D bond cleavage is rate-limiting depends on the particular
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`substrate and enzyme involved in the reaction. EX2005 (Vaz) at 6442.
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`- Metabolic Switching. Even if deuteration otherwise would yield an
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`isotope effect by slowing metabolism at the targeted site, it also “will
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`often result in metabolic switching to an alternate metabolite, with no net
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`change in substrate consumption.” EX1024 at 104; EX2001 at 6 (“When
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`a drug is metabolized by two or more alternative pathways a possible
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`consequence of deuteration is ‘metabolic switching.’”); EX1014 ¶ 5;
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`EX2003 at 3838 (“‘metabolic switching’ is well documented and . . . can
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`thwart attempts to increase drug half-life by deuteration”). In addition to
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`undermining any effect on total clearance of substrate, metabolic
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`switching can lead to different proportions of known metabolites or new
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`metabolites that “may impart more or less toxicity.” EX1009 (Gant ’991)
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`¶ 90.
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`- Enzyme kinetics. It was also known that deuteration could lower the
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`Km
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`3 value of enzymatic reactions, which can indicate stronger binding of
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`the substrate to the enzyme. See EX2001 at 6, 19. Reducing Km can
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`result in the “masking of the intrinsic deuterium isotope effect . . . on the
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`intrinsic clearance[.].” EX2002 at 2.
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`- Competing metabolic pathways. Some molecules are metabolized by
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`multiple metabolic enzymes. To the extent other pathways or
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`mechanisms participate in the clearance of a compound, those other
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`pathways may compensate for any reduced metabolism caused by
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`deuteration and negate the overall effect on clearance, or even increase
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`the production of toxic metabolites. See EX2004 at 625; EX2006
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`(Nelson 2003) at 1493 (deuterated compound “was shown to be more
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`genotoxic” due to an increase in glutathione conjugation).
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`- Blood flow. Even if deuteration slows overall intrinsic clearance in vitro,
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`no benefit follows where “clearance is limited by blood flow” through a
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`major organ, such as the liver. EX2004 at 632.
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`3 As explained below, Km is the concentration of substrate needed for an enzyme to
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`achieve half the maximal rate of reaction, and lower Km values correspond to
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`higher intrinsic clearance rates for an enzymatic reaction. Infra IV.B.2.
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`For the reasons above, before the filing date of the ’733 patent, it was not
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`Case No. IPR2021-01507
`U.S. Patent No. 8,524,733
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`possible to predict accurately an in vitro kinetic deuterium isotope effect, let alone
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`whether such an isotope effect would translate in vivo, as this Board similarly
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`concluded in the context of another deuteration patent. Neptune Generic v. Auspex
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`Pharmaceuticals, IPR2015-01313, Paper 25 at 18 (Dec. 9, 2015) (declining
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`institution because “the effect of the deuteration on the metabolic and
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`pharmacologic properties of a drug are unpredictable”).
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`III. The ’733 Patent.
`A. The Challenged Claims.
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`Claim 1 covers a specific deuterated analog of tetrabenazine depicted by the
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`structural formula below, wherein D is deuterium and each position represented as
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`D has deuterium enrichment of no less than about 90%:
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`Dependent claim 2 narrows the deuterium enrichment to no less than about
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`Case No. IPR2021-01507
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`98%. Claim 3 depends from claim 1 and recites a pharmaceutical composition
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`comprising the molecule above with a pharmaceutically acceptable carrier.
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`B.
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`Summary of Relevant Prosecution History.
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`As discussed further in Section I below, the Petition’s obviousness
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`arguments are substantively the same as those considered and rejected during
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`prosecution. Thus, the Petition should be denied under 35 U.S.C. § 325(d).
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`Following a restriction requirement, the Examiner twice rejected the claims
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`as obvious over Zheng and other secondary references that purportedly showed
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`that the POSA would have been motivated to try deuterating tetrabenazine
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`“because the compounds would be expected to have similar properties [to
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`tetrabenazine]” and would “have some expectation of improving the [m]etabolic
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`stability” of tetrabenazine. EX1027 at 13, 53. The Examiner stated that “[i]n the
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`absence of a showing of unexpected results it cannot be seen how the claims can be
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`patentable” as the submitted data was “expected and not unexpected.” Id. at 13,
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`54.
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`Auspex subsequently submitted clinical data showing that deutetrabenazine
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`(1) demonstrated an unexpectedly greater stability to metabolism as compared to
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`tetrabenazine by increasing the half-life and plasma AUC (area under the time-
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`concentration curve) with small changes in Cmax and Tmax and (2) reducing adverse
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`effects. Id. at 60-62. Both points were supported by a declaration from Dr.
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`Bradbury presenting in vivo test results and establishing that the claimed
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`compound possessed “unexpectedly superior properties to tetrabenazine which
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`could not have been predicted based on the cited prior art.” Id. at 63-71.
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`The Examiner withdrew the obviousness rejection and ultimately allowed
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`the claims. Id. at 125-26, 130.
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`ARGUMENT
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`IV. The Board Should Exercise its Discretion Under §§ 325(d) and 314(a) to
`Deny Institution.
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`The Board should deny institution under § 325(d) because Petitioners’
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`references and arguments are the same as, or cumulative to, what the Examiner
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`considered, and Petitioners have failed to demonstrate that the Examiner erred in
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`any material way.
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`Petitioners advance the following grounds:
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`Ground
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`References
`1
`Zheng in view of Naicker ’921 and Kohl
`2
`Zheng in view of Foster AB and Kohl
`3
`Gano in view of Schwartz and Gant ’9914
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`4 Petitioners contend Gant ’991 is § 102(e) prior art. Pet. 51. Patent Owner does
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`not dispute that Gant is prior art for this POPR, but in the event of institution, will
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`show that it is not pursuant to 35 U.S.C. § 103(c).
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`A. The Office Substantively Considered the Same Prior Art and
`Arguments Raised in the Petition.
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`The first part of the Advanced Bionics framework addresses whether the
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`same prior art or arguments were previously presented to the Office. As relevant
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`here, the Board considers “(a) the similarities and material differences between the
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`asserted art and the prior art involved during examination; (b) the cumulative
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`nature of the asserted art and the prior art evaluated during examination;” and “(d)
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`the extent of the overlap between the arguments made during examination and the
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`manner in which petitioner relies on the prio