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 SUR-REPLY TO PETITIONERS’ REPLY TO
`PATENT OWNER’S PRELIMINARY RESPONSE
`
`
`
`
`

`

`
`
`Case No. IPR2021-01507
`U.S. Patent No. 8,524,733
`
`TABLE OF AUTHORITIES
`
`Advanced Bionics, LLC v. Med-El Elektromedizinische Geräte GmbH,
`IPR2019-01469, Paper 6 (Feb. 13, 2020) ............................................................. 4
`Chemours Co. FC v. Daikin Indus., 4 F.4th 1370 (Fed. Cir. 2021) .......................... 5
`Molins PLC v. Textron, Inc., 48 F.3d 1172 (Fed. Cir. 1995) .................................... 1
`Sonos, Inc. v. Google, LLC, IPR2021-00963, Paper 9 (Nov. 9, 2021) ...................... 1
`
`
`
`i
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`

`

`
`
`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-
`
`ii
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`

`

`Case No. IPR2021-01507
`U.S. Patent No. 8,524,733
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`
`
`EX2011
`
`EX2014
`
`EX2015
`
`EX2016
`
`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”)
`
`EX2017
`
`EX2018
`
`EX2019
`
`EX2021
`
`EX2022
`
`iii
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`Case No. IPR2021-01507
`U.S. Patent No. 8,524,733
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`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”)
`File History Excerpts, Application No. 12/562,621: References
`Considered, April 10, 2012 and November 5, 2012 (highlighted)
`
`
`
`
`
`EX2023
`
`EX2024
`
`EX2025
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`
`
`iv
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`
`I.
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`Case No. IPR2021-01507
`U.S. Patent No. 8,524,733
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`Institution Should be Denied Under §§ 325(d) and 314(a)
`
`The PTO Considered Petitioners’ Art and Arguments. Petitioners originally
`
`argued that the Examiner “did not substantively consider any references disclosing
`
`the benefits of deuterating at methoxy groups.” Pet. 4. Petitioners now agree that
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`was wrong: several references before the Examiner—Foster 1984, Nelson 2003,
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`and Foster 1985—discussed methoxy/alkoxy deuteration. POPR 18-21; Reply 2.
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`Petitioners now contend the disclosures in Foster 1985 must have been overlooked,
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`or else the Examiner would have rejected the claims. Reply 2. That argument
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`(which ignores Foster 1984 and Nelson 2003 without basis) is meritless.
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`First, the Examiner indicated those references were considered, EX2025 at
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`5, 11, and Foster 1985 was discussed extensively in prosecution, POPR 20. That
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`establishes the Examiner considered the references. Molins PLC v. Textron, Inc.,
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`48 F.3d 1172, 1184 (Fed. Cir. 1995) (presumption Examiner considered initialed
`
`art); Sonos, Inc. v. Google, LLC, IPR2021-00963, Paper 9 at 9-10 (Nov. 9, 2021).
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`Second, the methoxy discussion in Foster 1985—which Petitioners do not
`
`address substantively—supports the patentability of the challenged claims. Foster
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`1985 makes clear that deuteration of methoxy groups is unpredictable and often
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`does not translate in vivo. See POPR 26-27. The premise of Petitioners’ § 325(d)
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`argument—that methoxy deuteration is uniquely beneficial—misrepresents Foster
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`1985 and the art as a whole, which Petitioners ignore in their Reply.
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`1
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`Petitioners argue that their deuteration references “provide unique teachings
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`Case No. IPR2021-01507
`U.S. Patent No. 8,524,733
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`
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`and/or experimental data,” Reply 2, but do not identify those “unique” teachings.
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`Petitioners concede that the Examiner was well aware of the potential effects of
`
`deuteration and had before her examples of methoxy deuteration. POPR 18-21.
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`Their further examples of non-tetrabenazine deuteration are thus cumulative.
`
`Petitioners Have Not Established that the Examiner Erred. Petitioners’ lead
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`argument—that Patent Owner’s (“PO”) data submitted in prosecution were
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`expected, Reply 2-5—falters at the outset because Petitioners fail to acknowledge,
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`much less rebut, the POPR’s evidence regarding the unpredictability of
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`deuteration. That unpredictability was described by Dr. Bradbury in prosecution,
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`discussed in numerous articles, and has been recognized by this Board. POPR 8-
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`13. Even if the POSA expected, based on Petitioners’ in vitro references, some in
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`vitro effect from deuterating tetrabenazine—and the POSA would not have had
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`such an expectation, in view of the multiple unrebutted examples in the POPR
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`where deuteration of alkoxy groups failed to improve in vitro metabolic stability,
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`e.g., POPR 50 (Kohl), 53-54 (’914 patent), 54-57 (Smith, Harada)—the POSA
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`would not have expected such an effect to also occur in vivo. Despite decades of
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`deuteration research, Petitioners fail to cite even a single example of an in vitro
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`methoxy deuteration effect translating into a living system. On the other hand, PO
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`cited examples, POPR 26, 29 (Pang, Shao), where an in vitro effect did not so
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`2
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`translate. Petitioners note that PO submitted in vitro data in prosecution, Reply 4,
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`Case No. IPR2021-01507
`U.S. Patent No. 8,524,733
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`but ignore Dr. Bradbury’s accompanying testimony that such effects, while
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`surprising, rarely carry over in vivo, POPR 8-9. Petitioners argue that the POSA
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`“analyzes such in vitro data to know what to reasonably expect in vivo,” Reply 5,
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`but that assertion is unsupported by any citation. What the literature actually
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`taught was that in vitro deuteration effects typically do not translate in vivo and
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`that such effects are not predictable. POPR 9-10; EX1024 at 107 (“not expected to
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`be an effective strategy”); EX2003 at 3831 (“difficult to put into practice in vivo”).
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`Rather than addressing the unpredictability of deuteration, Petitioners rehash
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`their original references. Reply 3. They cite Naicker ’921’s general discussion of
`
`pharmacokinetics, but that reference provides no biological data and does not
`
`address the predictability of deuteration in vivo. POPR 49. Petitioners cite Kohl’s
`
`in vitro data, Reply 3, but Kohl does not indicate that its results would translate in
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`vivo, and Petitioners concede that several of Kohl’s methoxy deuterations did not
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`even produce an effect in vitro. POPR 50; Reply 4. Petitioners argue that Foster
`
`AB’s in vitro effect “was predictive of the doubled half-life obtained in PO’s in
`
`vivo study,” Reply 3, but this is plain hindsight—the POSA would not have known
`
`of PO’s data. Indeed, there is no indication that Foster AB’s deuterated molecules
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`would exhibit an improvement in vivo, and Petitioners ignore entirely the Km
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`decrease in Foster AB, which likely would have negated an in vivo effect. POPR
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`3
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`29, 53. Petitioners argue that Naicker ’921’s statement about “toxic side effects”
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`Case No. IPR2021-01507
`U.S. Patent No. 8,524,733
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`predicts PO’s side-effect data, Reply 4, but concede that the way deuteration may
`
`decrease toxicity is by slowing the production of toxic metabolites and that there
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`was no evidence demethylated tetrabenazine was toxic. POPR 30-31, 43.
`
`Petitioners fault the Examiner for crediting PO’s side-effect data, due to
`
`differences in dose and dosage form, Reply 5, but concede that these differences
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`were presented to the Examiner. POPR 31. They criticize the Examiner’s
`
`treatment of dose as “terse,” Reply 5, but do not dispute that it was proper to
`
`compare doses exhibiting similar AUCs. POPR 31-32. Petitioners argue that
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`differences in dosage form could lead to “different release profiles,” Reply 5, but
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`fail to explain—in either their Petition or Reply—how that could account for the
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`observed side-effect differences. The only such explanation—relegated to
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`Petitioners’ expert’s declaration—speculated that dosage form could affect Cmax.
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`POPR 32. As explained during prosecution, though, deutetrabenazine exhibited a
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`QTcF improvement compared to tetrabenazine notwithstanding its higher Cmax
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`(contra Petitioners’ expert’s explanation). Id. Petitioners ignore this issue entirely
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`and have not come close to meeting the high standard for demonstrating the
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`Examiner materially erred in crediting PO’s unexpected results. Advanced
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`Bionics, LLC v. Med-El Elektromedizinische Geräte GmbH, IPR2019-01469,
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`Paper 6 at 9 (Feb. 13, 2020) (no error if “reasonable minds can disagree”).
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`4
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`Extortion. Petitioners somehow disclaim having demanded money, Reply 1
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`Case No. IPR2021-01507
`U.S. Patent No. 8,524,733
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`
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`n.2, alleging instead that they wanted a “license to market a generic product.” Not
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`a license to this patent, nor to market deutetrabenazine, consistent with Petitioners’
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`failure to file an ANDA on deutetrabenazine and their absence from the ongoing
`
`litigation. Even crediting Petitioners’ characterization of their demand evinces the
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`bad-faith nature of this IPR and justifies discretionary denial.
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`II. Objective Indicia of Non-Obviousness
`
`Commercial Success. No one disputes that AUSTEDO is a commercially
`
`successful embodiment of the challenged patent. POPR 74. Petitioners fail to
`
`identify any other factors driving that success, Reply 5, much less advance
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`sufficient evidence to rebut the presumption of nexus. Chemours Co. FC v. Daikin
`
`Indus., 4 F.4th 1370, 1378 (Fed. Cir. 2021). If deutetrabenazine were obvious,
`
`others would have pursued it to achieve the success AUSTEDO is experiencing.
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`Failure of Others. Tetrabenazine’s drawbacks and deuteration technology
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`were long known by the priority date. POPR 74. The failure of others to deuterate
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`tetrabenazine in the intervening decades confirms the invention’s non-obviousness.
`
`Respect for Invention. ANDA filers have every incentive to challenge the
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`validity of patents to try to come to market sooner. Lupin’s failure to challenge the
`
`’733 patent thus evinces its non-obviousness. POPR 75. Petitioners offer no
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`coherent alternative explanation for Lupin’s acquiescence. Reply 5.
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`5
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` Date: January 18, 2022
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`Case No. IPR2021-01507
`U.S. Patent No. 8,524,733
`
`
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`Respectfully submitted,
`
`/David I. Berl/
`David I. Berl (Reg. No. 72,525)
`Thomas S. Fletcher (Reg. No. 72,383)
`Shaun P. Mahaffy (Reg. No. 75,534)
`WILLIAMS & CONNOLLY LLP
`725 Twelfth Street, N.W.
`Washington, DC 20005
`T: (202) 434-5000
`F: (202) 434-5029
`
`Counsel for Patent Owner
`Auspex Pharmaceuticals, Inc.
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`Case No. IPR2021-01507
`U.S. Patent No. 8,524,733
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`CERTIFICATION UNDER 37 C.F.R. § 42.24(d)
`
`Pursuant to 37 C.F.R. 42.6(e), the undersigned hereby certifies that a true
`
`and correct copy of the foregoing was served on January 18, 2022, by delivering a
`
`copy via electronic mail on the following attorney of record:
`
`Vishal Gupta
`STEPTOE & JOHNSON LLP
`1114 Avenue of the Americas
`New York, NY 10036
`212-506-3900 (Telephone)
`212-506-3950 (Facsimile)
`SJDeutetrabenazineIPR@steptoe.com
`
`/David I. Berl/
`David I. Berl
`Reg. No. 72,525
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`7
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