Trials@uspto.gov
`571-272-7822
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`Paper 9
`Date: March 9, 2022
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`APOTEX INC. AND APOTEX CORP.,
`Petitioner,
`v.
`
`AUSPEX PHARMACEUTICALS, INC.,
`Patent Owner.
`_____________
`
`IPR2021-01507
`Patent 8,524,733 B2
`____________
`
`
`Before GRACE KARAFFA OBERMANN, JOHN G. NEW,
`and CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.
`
`OBERMANN, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`35 U.S.C. § 325(d)
`
`
`571-272-7822
`
`
`
`
`Paper 9
`Date: March 9, 2022
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`APOTEX INC. AND APOTEX CORP.,
`Petitioner,
`v.
`
`AUSPEX PHARMACEUTICALS, INC.,
`Patent Owner.
`_____________
`
`IPR2021-01507
`Patent 8,524,733 B2
`____________
`
`
`Before GRACE KARAFFA OBERMANN, JOHN G. NEW,
`and CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.
`
`OBERMANN, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`35 U.S.C. § 325(d)
`
`
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`IPR2021-01507
`Patent 8,524,733 B2
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`I. INTRODUCTION
`Apotex Inc. and Apotex Corp. (collectively, “Petitioner”) filed a
`Petition (Paper 2, “Pet.”) for institution of an inter partes review of
`claims 1–3 of U.S. Patent No. 8,524,733 B2 (Ex. 1001, “the ’733 patent”).
`Auspex Pharmaceuticals, Inc. (“Patent Owner”) filed a Preliminary
`Response. Paper 6 (“Prelim. Resp.”). With Board authorization, Petitioner
`filed a Reply (Paper 7) and Patent Owner filed a Sur-reply (Paper 8) limited
`to addressing three issues, including whether we should exercise discretion
`and deny review under 35 U.S.C. § 325(d) (“Section 325(d)”). Ex. 3001.
`
`A. Real Parties-in-Interest
`The Petition indicates that Apotex Inc., Apotex Corp., Apotex
`
`Pharmaceutical Holdings Inc., and Aposherm Delaware Holdings Corp. are
`real parties-in-interest. Pet. 6. Patent Owner’s Mandatory Notice indicates
`that Auspex Pharmaceuticals “is the real party-in-interest,” however, “[o]ut
`of an abundance of caution,” Patent Owner identifies also “Teva Branded
`Pharmaceutical Productions R&D, Inc. as a real party-in-interest for the
`purposes of providing notice in this” proceeding. Paper 4, 1.
`
`B. Related Matters
`Petitioner states it is unaware of any related matters. Pet. 6. In a
`
`section of its Mandatory Notices titled “Related Matters,” Patent Owner
`identifies two U.S. patent applications, one expired and one abandoned, as
`well as “a patent infringement lawsuit filed in the District of New Jersey in
`Civil Action No. 3:21-cv-13240, Teva Branded Pharm. Products R&D, Inc.
`et al. v. Aurobindo Pharma Ltd. et al.” Patent Owner, however, “does not
`concede that any of” these matters “would affect, or be affected by, a
`decision in the present proceeding.” Paper 4, 1–2.
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`II. BACKGROUND
`A. The ’733 Patent (Ex. 1001)
`The ’733 patent is titled “Benzoquinoline Inhibitors of Vesicular
`
`Monoamine Transporter 2.” Ex. 1001, code (54). The ’733 patent claims
`priority to a provisional application filed on September 18, 2008. Id. at
`code (60), 1:4–7. The invention of the ’733 patent relates to “new
`benzoquinoline compounds” and “pharmaceutical compositions made
`thereof” that inhibit vesicular monoamine transporter 2 activity and,
`thereby, are useful “for the treatment of chronic hyperkinetic movement
`disorders.” Id. at 1:8–12; see id. at code (57) (Abstract).
`Tetrabenazine was a known and “commonly prescribed”
`benzoquinoline compound for treating Huntington’s disease, one of several
`“chronic hyperkinetic movement disorders.” Id. at 1:13–19, 6:56–67. The
`structure of tetrabenazine follows:
`
`
`Ex. 1001, 1:13–32. The above illustration shows the structure of
`“Tetrabenazine (Nitoman, Zenazine, Ro 1-9569), 1,3,4,6,7,1 1b-Hexahydro-
`9,10-dimethyoxy-3-(2-methylporpyl)-2H-benzo[a]quinoline,” which “is a
`vesicular monoamine transporter 2” inhibitor. Id. at 1:13–16.
`
`At the time of the invention, an ordinarily skilled artisan would have
`had a basic understanding of the in vivo metabolic pathways of
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`tetrabenazine and adverse side effects associated with its administration. Id.
`at 1:36–46. That artisan would have known that the body expresses enzymes
`to eliminate foreign substances, including therapeutic agents, in metabolic
`reactions that frequently involve the oxidation of a carbon-hydrogen bond.
`Id. at 1:48–56. “The resultant metabolites may be stable or unstable under
`physiological conditions, and can have substantially different
`pharmacokinetic, pharmacodynamic, and acute and long-term toxicity
`profiles relative to the parent compounds.” Id. at 1:56–60.
`The ordinarily skilled artisan further would have been aware that
`deuterium1 forms a stronger bond with carbon than hydrogen (id. at 2:14–
`16) and that, therefore, its substitution for hydrogen in the carbon-hydrogen
`bond of pharmaceutical compounds produces a kinetic isotope effect that
`“will cause a decrease in the reaction rate” (id. at 2: 19–20). At the time of
`the invention, “[d]euteration of pharmaceuticals” was known “to improve
`pharmacokinetics (PK), pharmacodynamics (PD), and toxicity profiles” and
`had “been demonstrated previously with some classes of drugs.” Id. at 2:53–
`55. For example, deuteration had been used successfully “to decrease the
`hepatotoxicity of halothane, presumably by limiting the production of
`reactive species such as trifluoroacetyl chloride.” Id. at 2:55–57.
`It was known also that, due to “the promiscuous nature of many
`metabolic reactions” and, in particular, the phenomenon of “metabolic
`switching,” deuteration “may not be applicable to all drug classes.” Id.
`at 2:57–65. “Metabolic switching occurs when xenogens, sequestered by
`Phase I enzymes, bind transiently and re-bind in a variety of conformations
`
`1 Deuterium (D) is a heavier isotope of hydrogen with one additional
`neutron. Ex. 1004, 2:28–30; Ex. 1027, 10.
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`prior to the chemical reaction (e.g., oxidation).” Id. at 2:60–63. The effects
`of deuteration may result in a “new metabolic profile” for any particular
`class of drugs that imparts “more or less toxicity.” Id. at 3:1. The ’733
`patent states, “Such pitfalls are non-obvious and are not predictable a priori
`for any drug class.” Id. at 3:2–3.
`The claims are directed to a specific deuteration pattern for
`tetrabenazine in which each hydrogen in adjacent methoxy groups, but no
`other hydrogen position, is deuterated. Id. at 50:40–64 (claims 1–3). “Based
`on discoveries made in our laboratory, as well as considering the literature,”
`the inventors of the ’733 patent assert they discovered that “tetrabenazine is
`metabolized in humans at the isobutyl and methoxy groups.” Id. at 3:16–18.
`Taking account of that discovery, the invention allegedly limits production
`of certain metabolites by employing “deuteration patterns” having “strong
`potential to slow the metabolism of tetrabenazine and attenuate interpatient
`variability.” Id. at 3:16–43.
`The ’733 patent discloses:
`In certain embodiments, the deuterated compounds disclosed
`herein maintain the beneficial aspects of the corresponding non-
`isotopically enriched molecules while substantially increasing
`the maximum tolerated dose, decreasing toxicity, increasing the
`half-life (T1/2), lowering the maximum plasma concentration
`(Cmax) of the minimum efficacious dose (MED), lowering the
`efficacious dose and thus decreasing the non-mechanism-
`related toxicity, and/or lowering the probability of drug-drug
`interactions.
`Id. at 4:44–52. “The carbon-hydrogen bonds of tetrabenazine contain a
`naturally occurring distribution of hydrogen isotopes,” including deuterium
`in a range of “about 0.0156%.” Id. at 3:4–7. The claimed compound
`requires that six carbon-hydrogen bond positions in the tetrabenazine
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`molecule have “deuterium enrichment of no less than about 90%.” Id.
`at 50:57 (claim 1); see id. at 50:59–61 (claim 2, requiring “deuteration
`enrichment of no less than about 98%” at those same six positions).
`To be clear, the challenged claims are directed to a specific
`deuteration pattern in tetrabenazine that involves O-demethylation of both
`methoxy groups but does not involve deuteration of the carbon-hydrogen
`bonds of the carbonyl group, the isopropyl group, or any other carbon-
`hydrogen position in the molecule. Id. at 50:40–64 (claims 1–3). That
`becomes critically important to our analysis, because as explained in detail
`below, no reference presented to the Examiner, and no reference asserted in
`the Petition, discloses deuteration – in any pattern – for tetrabenazine or any
`other drug in its class of benzoquinoline inhibitors.
`
`B. Challenged Claims
`Petitioner challenges claims 1–3 of the ’733 patent. Pet. 7. Claim 1,
`
`which we reproduce below, is illustrative of the claimed subject matter.
`1. A compound having the structural formula:
`
`
`or a salt thereof, wherein each position represented as D
`has deuterium enrichment of no less than about 90%.
`Ex. 1001, 50:41–58. Claim 2 depends from claim 1 and requires that “each
`position represented as D has deuterium enrichment of no less than
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`about 98%.” Id. at 50:59–61. Claim 3 specifies “[a] pharmaceutical
`composition” that includes “a compound as recited in claim 1 together with
`a pharmaceutically acceptable carrier.” Id. at 50:62–64.
`
`C. Asserted Grounds of Unpatentability
`Petitioner asserts three grounds under 35 U.S.C. § 1032, as follows:
`
`
`
`Ground
`
`References
`Zheng3, Naicker4,
`Kohl5
`Zheng, Foster AB6, Kohl
`Gano7, Schwartz8, Gant9
`
`Claims
`Challenged
`1–3
`1
`1–3
`2
`1–3
`3
`
`2 The Leahy-Smith America Invents Act (“AIA”), Pub. L. No. 112-29, 125
`Stat. 284 (September 16, 2011), includes revisions to Section 103 that
`became effective on March 16, 2013. Petitioner argues, and Patent Owner
`does not contest, that the pre-AIA statutory provisions apply in this case.
`Pet. 1. Neither party indicates the result would change, however, based on
`which version of the statute the Board applies for purposes of deciding
`whether to institute review.
`3 Zheng, G. et al., Vesicular Monoamine Transporter 2: Role as a
`Novel Target for Drug Development, THE AAPS JOURNAL,
`8(4):E682-E692 (2006) (Ex. 1003).
`4 US Patent No. 6,503,921, issued Jan. 7, 2003 (Ex. 1004).
`5 WO 2007/012650, published Feb. 1, 2007 (Ex. 1005).
`6 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) (Ex. 1006).
`7 US Patent No. 8,039,627, issued Oct. 18, 2011 (Ex. 1007).
`8 Schwartz, D.E. et al., Metabolic studies of tetrabenazine, a
`psychotropic drug in animals and man, BIOCHEMICAL
`PHARMACOLOGY, 15:645-655 (1966) (Ex. 1008).
`9 U.S. Pat. Pub. 2008/0280991, published Nov. 13, 2008 (Ex. 1009). Patent
`Owner states that it “does not dispute that Gant is prior art” for purposes of
`trial institution, “but in the event of institution,” Patent Owner will show that
`Gant is not prior art “pursuant to 35 U.S.C. § 103(c).” Prelim. Resp. 15 n.4.
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`Pet. 21. The Petition is supported by the Declaration of Dr. Jeffrey P. Jones.
`Ex. 1002.
`
`III. DENIAL UNDER SECTION 325(d)
`We have authority to institute an inter partes review only where
`“there is a reasonable likelihood that the petitioner would prevail with
`respect to at least 1 of the claims challenged in the petition.” 35 U.S.C.
`§ 314(a) (2018). The Board, however, is “never compelled” to institute a
`review. Harmonic Inc. v. Avid Tech., Inc., 815 F.3d 1356, 1367 (Fed. Cir.
`2016). The Board has discretion to “take into account whether, and reject the
`petition or request because, the same or substantially the same prior art or
`arguments previously were presented to the Office.” 35 U.S.C. § 325(d).
`Patent Owner requests that we exercise our discretion and enter a
`denial of review under Section 325(d). Prelim. Resp. 8–23. We assess that
`request based solely on the information presented in the Petition,
`Preliminary Response, Reply, and Sur-reply. The findings and conclusions
`set forth in this Decision are provided for the exclusive purpose of
`explaining our reasons for exercising our discretion under Section 325(d).
`
`A. Overview of the Prior Art
`As a preface to our overview of the prior art, we highlight that the
`
`Examiner was well aware of “[m]any references” that “teach deuteration of
`known pharmaceutical drugs.” Ex. 1027, 13 (prosecution history). 10 The
`challenges set forth in the Petition advance four allegedly new references
`that, according to Petitioner, teach deuteration of known pharmaceutical
`
`
`10 When citing the prosecution history, we refer to page numbers added by
`Petitioner (Ex. 1027) or Patent Owner (Ex. 2025).
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`compounds; but, as it was before the Examiner, we are directed to no
`reference that discusses any deuteration pattern specifically in tetrabenazine
`or any other compound in its class. Pet. 25–62.
`Petitioner advances three references—Zheng, Schwartz, and Gano
`(i.e., the “tetrabenazine references”)—that discuss the metabolic pathways of
`tetrabenazine, each of which admittedly “was cited during prosecution.” Id.
`at 26, 51. In fact, the ’733 patent contains a section that expressly cites
`Zheng and Schwartz and discusses the known metabolic pathways and side
`effects of tetrabenazine as disclosed in those references. Ex. 1001, 1:34–46.
`Petitioner also advances four allegedly new references—Naicker, Kohl,
`Foster AB, and Gant (i.e., the “deuteration references”)—that discuss a wide
`array of deuteration patterns in pharmaceutical compounds outside of
`tetrabenazine’s drug class, which are relied upon to show that “[t]he prior art
`provided a narrow, straight-line path for arriving at” the specific deuteration
`pattern in tetrabenazine that is required by the claims. Pet. 1; see id. at 30,
`32, 44, 55 (Petitioner’s illustrations, purporting to show the structures of the
`deuterated compounds disclosed in Naicker, Kohl, Foster AB, and Gant).
`In the following subparts, we discuss in greater detail each reference
`asserted in the patentability challenges, addressing first the tetrabenazine
`references that were before the Examiner then turning to the deuteration
`references.
`
`(1) Zheng (Ex. 1003)
`Zheng was before the Examiner and a focus of examination. Ex. 1027,
`
`11–13, 51. Zheng relates to tetrabenazine but does not discuss deuteration of
`any compound. See generally Ex. 1003.
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`Zheng teaches that tetrabenazine was known “to treat hyperkinetic
`movement disorders, such as chorea associated with Huntington’s disease.”
`Ex. 1003, E683. In particular, according to Zheng, tetrabenazine depletes
`“cerebral monoamines . . . by reversibly inhibiting” vesicular monoamine
`transporter 2. Id. Zheng describes known side effects associated with such
`treatment, including “sedation, depression, akathisia, and parkinsonism.” Id.
`We reproduce below Zheng’s Figure 1.
`
`
`Ex. 1003, Fig. 1. Figure 1 illustrates the structure of tetrabenazine with
`relevant carbon atoms numbered. The three carbon rings of tetrabenazine are
`labeled A, B, and C in Figure 1. Throughout this Decision, we refer to the
`carbon atoms in tetrabenazine by reference to the numbers assigned in
`Zheng’s Figure 1.
`
`Zheng indicates that the carbonyl group at position 2 in Figure 1 “is
`rapidly and extensively metabolized to its reduced form,” which
`“theoretically” may “exist as 4 possible stereoisomers.” Id. at E684. Zheng
`further indicates that the “methoxy groups at positions 9 and 10 appear to be
`essential” for dopamine-depleting activity. Id. at E685.
`
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`(2) Schwartz (Ex. 1008)
`Schwartz, like Zheng, was before the Examiner and a focus of
`
`examination. Ex. 1027, 11–13, 51. Schwartz relates to tetrabenazine but does
`not discuss deuteration of any compound. See generally Ex. 1008.
`Schwartz illustrates the scheme of tetrabenazine metabolism, which
`we reproduce below.
`
`Ex. 1008, 650 (Figure). The above Figure illustrates the scheme of
`tetrabenazine metabolism as disclosed in Schwartz. The scheme illustrates
`the structure of nine metabolites of tetrabenazine labeled I through IX.
`Metabolites III, IV, V, and IX show aliphatic hydroxylation of the isobutyl
`group at position 3. Metabolites I, II, IV, V, VII, and VIII show reduction of
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`the carbonyl group at position 2. Metabolites VI, VII, VIII, and IX show
`demethylation of the methoxy group at position 9. The scheme indicates that
`demethylation of the methoxy group does not occur at position 10.
`Significantly, for purposes of this Decision, we find, on this record,
`that tetrabenazine metabolism occurs by aliphatic hydroxylation of the
`isobutyl group at position 3, reduction of the carbonyl group at position 2,
`and demethylation at the methoxy group at position 9. Ex. 1008, 650
`(Figure). This finding is consistent with disclosures in the written description
`of the ’733 patent. Ex. 1001, 1:20–40 (citing Schwartz), 3:16–18 (referring
`to “discoveries made in our laboratory, as well as . . . the literature”).
`(3) Gano (Ex. 1007)
`For purposes of this Decision, we accept Petitioner’s assertion that
`
`Gano was before the Examiner during patent prosecution but never
`substantively discussed in any Office action. Pet. 51. Gano addresses
`tetrabenazine but does not discuss deuteration of any compound. See
`generally Ex. 1007.
`Gano describes tetrabenazine as a drug “used for decades” as “a
`potent, reversible inhibitor of catecholamine uptake by vesicular monoamine
`transporter-2.” Ex. 1007, 1:24–28. Similar to Zheng, Gano reports that
`“[s]ide effects associated with” tetrabenazine “include sedation, depression,
`akathisia, and parkinsonism.” Id. at 1:32–33; see Ex. 1003, E683 (Zheng’s
`similar disclosure). Gano identifies “a need for analogs of tetrabenazine that
`exhibit a longer half-life than tetrabenazine.” Id. at 1:58–59.
`Gano further states, “The compounds of this invention have the
`following structure (I):”
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`Ex. 1007, 3:2–15. Structure (I) illustrates an analog of tetrabenazine in
`which the carbonyl group at position 2 is replaced with an ester functional
`group. None of the structures illustrated in Gano indicates demethylation of
`either the position 9 or 10 methoxy group. See generally id. (all figures)
`(positions 2, 9, and 10 are relative to Zheng’s Figure 1, supra 10).
`
`Gano indicates that its solution for extending the half-life of
`tetrabenazine involves replacing the carbonyl group at position 2 with an
`ester functional group, which according to Gano, “may be particularly
`beneficial because it may allow an administration regimen that requires
`fewer doses per day than tetrabenazine.” Id. at 7:64–66. In particular,
`“because of the unexpectedly longer duration of action afforded by these
`compounds, once daily dosing may be attainable.” Id. at 8:3–5.
`(4) Naicker (Ex. 1004)
`Naicker was not before the Examiner during patent prosecution.
`
`Naicker relates to the deuteration of rapamycin, a pharmaceutical compound
`useful, for example, in “inducing immunosuppression” and treating
`“transplantation rejection.” Ex. 1004, code (57) (Abstract). Naicker does not
`discuss tetrabenazine or any other benzoquinoline compound. See generally
`Ex. 1004. Petitioner advances Naicker’s Figure 1 (annotated) as follows.
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`Pet. 30 (reproducing Ex. 1004, Fig. 1). Figure 1 of Naicker illustrates the
`chemical structure of 7-deuteromethyl rapamycin. Id. at 4:39–40. Petitioner
`annotates Figure 1 to highlight the cite of deuteration taught by Naicker,
`which involves O-demethylation of one methoxy group.
`
`Figure 1 shows that Naicker selects one of three methoxy groups of
`rapamycin for deuteration. Id. at Fig. 1. Naicker states, “Deuteration of the
`rapamycin molecule results in altered physicochemical and pharmacokinetic
`properties which enhance its usefulness in the treatment of transplantation
`rejection, host vs. graft disease, graft vs. host disease, leukemia/lymphoma,
`hyperproliferative vascular disorders, autoimmune diseases, diseases of
`inflammation, solid tumors, and fungal infections.” Id. at 4:11–17.
`Rapamycin is metabolized “to at least six metabolites.” Id. at 2:14–15.
`“In rapamycin, demethylation of methoxy group at C-7 Carbon will lead to
`the change in the conformation of the” molecule “due to the interaction of
`the released C-7 hydroxyl group with the neighbouring pyran ring system
`which is in equilibrium with the open form of the ring system.” Id. at 2:19–
`24. “The C-7 hydroxyl group will also interact with the triene system and
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`possibly alter the immunosuppressive activity of rapamycin.” Id. at 2:24–26.
`According to Naicker, “This accounts for the degradation of rapamycin
`molecule and its altered activity.” Id. at 2:26–27. “Deuteration is targeted at
`various sites of the rapamycin molecule to increase the potency of [the]
`drug,” among other benefits. Id. at 4:32–36.
`(5) Kohl (Ex. 1005)
`Kohl was not before the Examiner during patent prosecution. Kohl
`
`“relates to isotopically substituted proton pump inhibitors,” such as
`pantoprazole, which “are of considerable importance in the therapy of
`disorders associated with an increased secretion of gastric acid.” Ex. 1005,
`1; see Pet. 55 (identifying pantoprazole as a compound of interest). We are
`directed to no information that Kohl mentions tetrabenazine or any other
`benzoquinoline compound. See generally Ex. 1005.
`Petitioner advances Kohl for the proposition that the reference
`“provides additional motivation with its biological data demonstrating the
`benefits of deuterating at a methoxy group.” Pet. 32. Specifically, Petitioner
`alleges that Kohl discloses the following examples of deuteration in
`pantoprazole:
`
`Pet. 32 (citing Ex. 1005, 13–14, 40). Petitioner’s figure compares the
`structure of pantoprazole (on the left) to the structure of two examples of
`deuterated analogs of pantoprazole (on the right) where the examples “are
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`identical except for the stereochemistry (not shown).” Id. (citing Ex. 1002
`¶ 81). Petitioner annotates the examples to highlight (in red) that one of two
`adjacent methoxy groups is deuterated. Id.
`(6) Foster AB (Ex. 1006)
`Foster AB was not before the Examiner during patent prosecution.
`
`Foster AB is an article that relates to methoxy-deuteration of p-nitroanisole,
`p-methoxyacetanilide, and p-dimethoxybenzene, and respective trideutero-
`methyl derivatives. Ex. 1006, 327. Petitioner generates a comparison
`illustration pertaining to Foster AB, which we reproduce below.
`
`
`Pet. 44 (citing Ex. 1002 ¶ 99). The above illustration shows the structure of
`the deutetrabenazine compound specified in the challenged claims (on the
`left) and Petitioner’s renditions of structures of deuterated compounds
`allegedly disclosed in Foster AB (on the right). Petitioner highlights (in red)
`that every methoxy group of each compound is fully deuterated.
`Foster AB does not discuss tetrabenazine or any other benzoquinoline
`compound. See generally Ex. 1006.
`
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`(7) Gant (Ex. 1009)
`Gant was not before the Examiner during patent prosecution. Gant
`
`discloses deuteration patterns for agomelatine and discloses a broad range of
`deuteration patterns at every position of the molecule, reproduced below.
`
`
`Ex. 1009, code (57), ¶¶ 3–5. The above illustration shows the structure of
`Gant’s Formula I, which includes fifteen hydrogen atoms at positions R1
`through R15. Gant discloses deuteration of one, all, or any combination of
`hydrogen positions R1 through R15. See id. ¶¶ 6–7, 93–95, 97, 100, 246,
`289, 292, 315, 318, 325, 328, 335; see especially id. ¶¶ 338, 346 (illustrating
`and claiming a broad spectrum of deuteration patterns). Only some include
`deuteration of the positions R1–R3 of the methoxy group. Id. ¶¶ 338, 346.
`
`From the broad spectrum of deuteration patterns disclosed in Gant
`(see id.), Petitioner selects two as illustrating that Gant “discloses
`deuteration of a methoxy group.” Pet. 55. Petitioner acknowledges, however,
`that Gant subjects “other positions” to deuteration. Id. Petitioner generates a
`comparison illustration pertaining to Gant, which we reproduce below.
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`Pet. 55 (citing Ex. 1002 ¶ 118). The above illustration shows the structure of
`agomelatine (on the left), the structure of Gant’s Example 4 compound (in
`center), and the structure of Gant’s Example 9 compound (on the right).
`Petitioner labels Example 4 as “deuterated methoxy group” and Example 9
`as “deuterated methoxy and other aliphatic positions.” Petitioner highlights
`(in red) the sole methoxy group, which is deuterated, in Gant’s Example 4
`compound (that is, deuteration occurs at positions R1–R3 in Formula I) and
`further highlights (in red) seven additional positions that are deuterated in
`Gant’s Example 9 (that is, positions R1–R3 of the methoxy group as well as
`positions R10–13 and R15–R17 in Formula 1).
`Gant discloses, illustrates, and claims a broad spectrum of deuteration
`patterns for agomelatine in which the sole methoxy group sometimes, but
`not always, is deuterated. Id. ¶¶ 4–7, 338, 346. Gant also sometimes, but not
`always, deuterates every other hydrogen position in the molecule. Id.
`Gant does not discuss tetrabenazine or any other benzoquinoline
`compound. See generally Ex. 1009.
`
`B. Overview of the Prosecution History
`Zheng and Schwartz were a focus of examination and are central to
`
`Petitioner’s challenges. Pet. 26, 51; Ex. 1027, 9, 11–14, 51. Gano was cited
`
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`to the Examiner but not discussed substantively in any Office action. Pet. 51.
`The examination, however, focused on a textbook identified by both parties
`in this proceeding as “Foster 1985.” Prelim. Resp. 20 (citing Ex. 200111);
`Reply 2; see Ex. 1027, 8, 19, 21, 51–53 (applying Foster 1985).
`Foster 1985 contains a section devoted to known benefits and
`disadvantages of deuteration of methoxy groups in drugs. Ex. 2001, 1, 19–
`21. That section of Foster 1985, which undeniably was presented to the
`Examiner, cites both Foster AB and Mitoma12, which Petitioner advances in
`this proceeding as allegedly new references that would have provided
`information about the deuteration of methoxy groups in unrelated drug
`classes sufficient to change the trajectory of the examination. Ex. 2001, 19;
`see, e.g., Pet. 4 (reproducing figures from both references).
`The prosecution history demonstrates that the Examiner possessed a
`firm understanding of the known technical principles bearing on the
`deuteration of methoxy groups in unrelated classes of drugs. The Examiner
`twice rejected the challenged claims as obvious, citing, for example, Zheng,
`Schwartz, and Foster 1985, based on the argument that deuteration of the
`methoxy groups of tetrabenazine would have been known to slow down
`metabolism of the molecule, reduce its side effects, and improve its activity.
`Ex. 1027, 9–14, 51–54.
`
`
`11 Foster, A., Deuterium Isotope Effects in the Metabolism of Drug and
`Xenobiotics: Implication for Drug Design, ADVANCES IN DRUG RESEARCH
`vol. 14 (1985).
`12 Mitoma, C. et al., Effect of deuteration of the O-CH3 group on the
`enzymic demethylation of o-nitroanisole, BIOCHEM. BIOPHYS. ACTA,
`136:556–567 (1967) (Ex. 1012).
`
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`In an initial Office action, the Examiner observed, “[D]euteration of
`drugs is a well known technique to obtain enhanced pharmaceutical
`properties.” Id. at 10. The Examiner also observed that the known metabolic
`pathways of tetrabenazine involve rapid and extensive reduction of the
`carbonyl group (citing Zheng) and “O-demethylation of the methoxy groups,
`as well as hydroxylation of the isobutyl group” (citing Schwartz). Id. at 11.
`Given that Zheng and Schwartz “teach that the methoxy group is in the
`metabolite,” the Examiner reasoned, an ordinarily skilled artisan would have
`been prompted “to replace specific H’s with deuterium to see if it had any
`effect on toxicity, lipophilic effect or in general” would “improve or change
`the activity of the compound.” Id. at 12–13. The Examiner further
`emphasized, “Many references teach deuteration of known pharmaceutical
`drugs.” Id. at 13. “In the absence of a showing of unexpected results,” the
`Examiner reasoned, “it cannot be seen how the claims can be patentable.” Id.
`Patent Owner responded to this Office action by participating in a first
`interview with the Examiner and submitting a First Declaration of
`Dr. Margaret Bradbury, indicating that “one of skill in the art would not be
`able to predict whether deuteration at any particular site in a molecule would
`cause a net increase in metabolic stability of that molecule.” Id. at 20.
`Dr. Bradbury explained why “the 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.”
`Id. at 21 (quoting id. at 30–31 (First Bradbury Declaration ¶ 6)).
`Dr. Bradbury supported her opinions with experimental results that
`included data from a randomized, double blind Phase I clinical study in
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`human subjects, which compared the effects of the claimed d6-
`deutetrabenazine compound to a non-deuterated dosage form of
`tetrabenazine. Ex. 1027, 33–48. Patent Owner argued to the Examiner that
`the teachings “of Zheng and Schwartz that tetrabenazine is metabolized at
`the O-methyl groups does not support a conclusion that deuteration of those
`specific positions would be expected by [a] skilled artisan to result in a
`compound with increased overall metabolic stability.” Id. at 22. Patent
`Owner also pointed out that Foster 1985 “describes the phenomenon of
`metabolic switching, which compensates for a reduced rate of metabolism at
`one site in a molecule by increasing the rate of metabolism at a different
`site,” which “typically results in no significant net effect on the overall
`metabolism of a compound.” Id. (citing Ex. 2001, 6–8). Patent Owner
`argued, “[T]he prior art examples relating to the deuterium isotope effect on
`metabolic stability show mixed and unpredictable results.” Id. at 24.
`By way of support, Patent Owner quoted Foster 1985, which states,
`“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.” Ex. 2001, 35; Ex. 1027, 19, 21 (Patent Owner, twice quoting this
`portion of Foster 1985). In some studies, “a deuterium isotope effect (DIE)
`was observed at the site of metabolism near the deuterium substitution,”
`Patent Owner argued, but “[t]he fact that a DIE is observed in a compound
`cannot be extrapolated to a conclusion that the deuterated version of the
`compound will demonstrate increased net stability.” Id. at 19. “This is due in
`large part to the phenomenon of metabolic switching.” Id. (citing
`Foster 1985 (Ex. 2001, 6–8)).
`
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`The Examiner acknowledged that Foster 1985 teaches “several
`different pathways and switching of the pathway[s],” but nonetheless
`determined that “this does not take away from the teaching that deuterated
`drugs would have a retarded metabolic reaction” as compared to the non-
`deuterated drug. Ex. 1027, 53. Thus, the Examiner reasoned, “The
`motivation to try is clearly presented in” Foster 1985. Id. On that basis, the
`Examiner finally rejected the claims. Id. at 54.
`Patent Owner thereafter participated in a second interview with the
`Examiner (id. at 67) and submitted a Second Declaration of Dr. Bradbury
`(id. at 63–71) directed to “(1) increases in half-life and AUC [area under
`curve] for the claimed compound as compared to tetrabenazine, with small
`changes in Cmzx and Tmax; and (2) additional clinical data showing reduced
`adverse effects” (id. at 60). Significantly, Patent Owner highlighted for the
`Examiner that the clinical trial data advanced in the First Bradbury
`Declaration compared a 15mg extended release dosage form of the claimed
`compoun
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