`571-272-7822
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`Paper No. 45
`Entered: July 19, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MYLAN PHARMACEUTICALS INC.
`and MYLAN LABORATORIES LIMITED,
`Petitioner,
`
`
`
`v.
`
`
`
`UCB PHARMA GMBH,
`Patent Owner.
`____________
`
`Case IPR2016-005101
`Patent 6,858,650 B1
`____________
`
`
`Before KRISTINA M. KALAN, ROBERT A. POLLOCK, and
`MICHELLE N. ANKENBRAND, Administrative Patent Judges.
`
`ANKENBRAND, Administrative Patent Judge.
`
`FINAL WRITTEN DECISION
`Finding Claims 1–5 and 21–24 Not Unpatentable
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`Dismissing as Moot Patent Owner’s Motion to Exclude
`37 C.F.R. § 42.64(c)
`Granting Joint Motion to Seal and Entering Default Protective Order
`37 C.F.R. § 42.54
`
`
`
`1 Petitioners Alembic Pharmaceuticals Limited from IPR2016-01596,
`Torrent Pharmaceuticals Limited from IPR2016-01636, and Amerigen
`Pharmaceuticals Limited from IPR2016-01665 have been joined as
`Petitioners to this proceeding.
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`Patent 6,858,650 B1
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`I.
`INTRODUCTION
`This is a Final Written Decision in an inter partes review challenging
`the patentability of claims 1–5 and 21–24 (collectively, “the challenged
`claims”) of U.S. Patent No. 6,858,650 B1 (Ex. 1001, “the ’650 patent”). We
`have jurisdiction under 35 U.S.C. § 6. For the reasons that follow, we
`determine that Petitioner does not demonstrate, by a preponderance of the
`evidence, that claims 1–5 and 21–24 are unpatentable.
`A. Procedural History
`Mylan Pharmaceuticals Inc. and Mylan Laboratories Limited
`(“Mylan”) filed a Corrected Petition (Paper 5, “Pet.”) requesting an inter
`partes review pursuant to 35 U.S.C. § 311.2 On July 20, 2016, we instituted
`trial to determine (1) whether claims 1–5 and 21–24 are unpatentable under
`35 U.S.C. § 103(a) over the combination of Postlind,3 “Bundgaard
`
`
`2 In support of the Corrected Petition, Petitioner filed the declaration of its
`technical expert, Steven E. Patterson, Ph.D. (Ex. 1003), and the declaration
`of DeForest McDuff, Ph.D. (Ex. 1033) with respect to lack of commercial
`success.
`3 Postlind et al., Tolterodine, A New Muscarinic Receptor Antagonist, is
`Metabolized by Cytochromes P450 2D6 and 3A in Human Liver
`Microsomes, 26(4) DRUG METABOLISM & DISPOSITION 289–293 (1998)
`(Ex. 1010).
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`publications,”4,5,6 Detrol Label,7 and Berge;8 and (2) whether claims 1–5 and
`21–24 are unpatentable under 35 U.S.C. § 103(a) over the combination of
`Brynne,9 Bundgaard publications, and Johansson.10 Paper 12 (“Institution
`Decision” or “Inst. Dec.”).
`After the Institution Decision, Alembic Pharmaceuticals Limited
`(“Alembic”), Torrent Pharmaceuticals Limited (“Torrent”), and Amerigen
`Pharmaceuticals Limited (“Amerigen”) were each joined as petitioners to the
`proceeding. See Case IPR2016-01596, Paper 8; Case IPR2016-01636, Paper
`10; Case IPR2016-01665, Paper 8. Accordingly, we refer to Mylan,
`Alembic, Torrent, and Amerigen collectively as “Petitioner.”
`During trial, UCB Pharma GmbH (“Patent Owner”) filed a Response
`(Paper 20, “Resp.”),11 and Petitioner filed a Corrected Reply (Paper 28,
`“Reply”). Patent Owner filed a Motion to Exclude, which is fully briefed.
`
`
`4 In the Institution Decision, we interpreted Petitioner’s reference to
`“Bundgaard publications” as referring to Exhibits 1012 and 1020. Inst. Dec.
`5 n.3. We discuss those Exhibits individually in our analysis herein, and
`also reference the Bundgaard publications collectively.
`5 Bundgaard, Design of Prodrugs, Elsevier (1985) (Ex. 1012, “Bundgaard”).
`6 WO 92/08459, published May 29, 1992 (Ex. 1020, “Bundgaard PCT”).
`7 Detrol™ (tolterodine tartrate tablets) prescribing information (1998)
`(Ex. 1009).
`8 Berge et al., Pharmaceutical Salts, 66(1) J. PHARM. SCI. 1–19 (1977)
`(Ex. 1013).
`9 Brynne et al., Influence of CYP2D6 polymorphism on the pharmacokinetics
`and pharmacodynamics of tolterodine, 63(5) CLIN. PHARMACOL. &
`THERAPEUTICS 529–539 (1998) (Ex. 1011).
`10 WO 94/11337, published May 26, 1994 (Ex. 1005).
`11 With the Response, Patent Owner filed the declarations of Hans Maag,
`Sc.D. (Ex. 2021), William R. Roush, Ph.D. (Ex. 2022), Scott A.
`MacDiarmid, M.D., FRCPSC (Ex. 2023), Leonard J. Chyall, Ph.D.
`(Ex. 2024), and Claus O. Meese, Ph.D. (Ex. 2025).
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`Paper 37 (Motion); Paper 39 (Response); Paper 40 (Reply). The parties also
`filed a Joint Motion to Seal and for Entry of a Protective Order. Paper 34.
`The record further includes a transcript of the final oral hearing conducted
`on April 5, 2017. Paper 43 (“Tr.”).
`B. Related Proceedings
`Patent Owner asserts that
`[Patent Owner] and Pfizer Inc. (“Pfizer”), the exclusive
`licensee of the ‘650 patent, have sued Mylan Pharmaceuticals
`Inc. for infringement of the ‘650 patent in the following actions:
`Pfizer, Inc. and UCB Pharma GMBH v. Mylan Pharmaceuticals,
`Inc., No. 1:15-cv-00079-GMS (D. Del.) and Pfizer Inc. and UCB
`Pharma GMBH v. Mylan Pharmaceuticals Inc., Case No. 1:15-
`cv-00013-IMK (N.D.W.Va.).
`Paper 7, 2; see Pet. 1–2 (noting that Pfizer is the NDA filer).
`The ’650 patent also is asserted in Pfizer, Inc. v. Sandoz, Inc., No.
`1:13-cv-01110-GMS (D. Del.),12 and was asserted in the now-dismissed
`action, Pfizer, Inc. v. Dr. Reddy’s Laboratories, Ltd., No. 1:15-cv-01067-
`GMS (D. Del.). Paper 7, 2.
`In addition to the case before us, we instituted an inter partes review
`in the following matters involving patents generally directed to
`3,3-diphenylpropylamine compounds: Case IPR2016-00512 (U.S. Patent
`No. 7,384,980 B2) (“the ’980 patent”); Case IPR2016-00514 (U.S. Patent
`
`
`12 Patent Owner provides, as Exhibit 2001, the District Court’s
`Memorandum finding that the defendants in that proceeding “failed to
`present a prima facie case that the asserted claims of the patents-in-suit are
`invalid as obvious.” Ex. 2001, 19. The district court reached that
`determination on a different record and applied different standards, but the
`arguments and references applied overlap with those before us. See
`Ex. 2001. Accordingly, although we are not bound by those findings, we
`find the district court’s analysis informative.
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`No. 7,855,230 B2); Case IPR2016-00516 (U.S. Patent No. 8,338,478 B2),
`and Case IPR2016-00517 (U.S. Patent No. 7,985,772 B2).
`Patent Owner updated its mandatory notices on February 16, 2017, to
`reflect that Case No. 1:15-cv-00079-GMS concluded with a general verdict
`in favor of Plaintiffs, and that Patent Owner and Pfizer filed suit against
`Torrent and Torrent Pharma Incorporated for infringement of the ’650
`patent, as well as the patents challenged in Case IPR2016-00512, Case
`IPR2016-00514, Case IPR2016-00516, and Case IPR2016-00517. Paper 33,
`2. That action is captioned Pfizer, Inc. v. Torrent Pharm. Ltd., No. 1:17-cv-
`00112-GMS (D. Del.). Id.
`
`C. The ’650 Patent
`The ’650 patent, titled “Stable Salts of Novel Derivatives of
`3,3-diphenylpropylamines,” issued on February 22, 2005. Ex. 1001.
`The ’650 patent generally is directed to “highly pure, crystalline stable
`compounds of novel derivatives of 3,3-diphenylpropylamines in the form of
`their salts, a method for the[ir] manufacture[,] and highly pure, stable
`intermediate products.” Id. at Abstract, 1:10–14.
`The specification discloses that the compounds “are valuable
`prodrug[s] for the treatment of urinary incontinence and other spasmodic
`complaints” that “overcome the disadvantage[s] of the active substances
`available to date.” Id. at 1:17–20. Those disadvantages include “inadequate
`absorption of the active substance by biological membranes or the
`unfavoura[b]le metabolism of [the active substance].” Id. at 1:20–22.
`According to the specification, the compounds also “have improved
`pharmacokinetic characteristics compared with Oxybutynin and
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`Tolterodin[e],” two muscarinic receptor antagonists used to treat patients
`with overactive bladder. Id. at 1:23–25; Ex. 1009, 2; Ex. 1014, 528.
`D. Illustrative Claim
`Of the challenged claims, claim 1 is independent and recites:
`1. Compounds of general formula I
`
`
`in which R denotes C1–C6-alkyl, C3–C10-cycloalkyl,
`substituted or unsubstituted phenyl and X− is the acid
`residue of a physiologically compatible inorganic or
`organic acid.
`Id. at 23:15–32.
`
`Claims 2 and 3 narrow claim 1 by specifying that X− is an acid ester
`chosen from an enumerated list of acids, including hydrochloric acid and
`fumaric acid, and requiring that the compounds have specific chirality (i.e.,
`the (R) enantiomer), respectively. Id. at 23:33–65. Claims 4 and 5 depend
`from claim 3 and, therefore, inherit the chirality limitation of claim 3. Like
`claim 2, claim 4 specifies that X− is an acid ester chosen from an enumerated
`list of acids, including hydrochloric acid and fumaric acid. Id. at 23:66–
`24:13. Claim 5 further narrows the compounds to the fumarate or
`hydrochloride salts. Id. at 24:14–19. Claims 21–23 recite methods of
`treating urinary incontinence disorder using the compounds of claims 1, 3,
`and 5, respectively. Id. at 30:30–41. Claim 24 recites the method of any one
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`of claims 21–23 and limits the urinary incontinence disorder to urge
`incontinence. Id. at 30:42–43.
`The compositions of claims 1–5 encompass fesoterodine fumarate
`(R-(+)-2-(3-(diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-
`phenylisobutyrate ester hydrogen fumarate)) distributed by Pfizer Labs
`under the brand Toviaz. See Pet. 5; Ex. 1024, 8, 19.
`
`II. DISCUSSION
`Petitioner bears the burden of proving unpatentability of the
`challenged claims, and that burden never shifts to Patent Owner. Dynamic
`Drinkware, LLC v. Nat’l Graphics, Inc., 800 F.3d 1375, 1378 (Fed. Cir.
`2015). To prevail, Petitioner must establish the facts supporting its
`challenge by a preponderance of the evidence. 35 U.S.C. § 316(e);
`37 C.F.R. § 42.1(d). Below, we explain why Petitioner has not met its
`burden with respect to the challenged claims.
`A. Level of Ordinary Skill in the Art
`We begin our analysis by addressing the level of ordinary skill in the
`art. For the purpose of this decision, we accept Petitioner’s undisputed
`contention that:
` [a] person of ordinary skill in the art would have a Ph.D. in
`chemistry, medicinal chemistry, pharmacology, or a related
`field, and at least one year of industrial exposure to drug
`discovery, drug design, and synthesis. In lieu of an advanced
`degree, the individual may have additional years of industry
`experience, including, for example, in drug discovery, drug
`synthesis, and structure-activity work.
`Pet. 6 (citing Ex. 1003 ¶ 23); see Resp. 6.
`Based on our review of the ’650 patent, the types of problems and
`solutions described in the ’650 patent and cited prior art, we adopt
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`Petitioner’s definition of a person of ordinary skill in the art at the time of
`the claimed invention. We note that the applied prior art also reflects the
`appropriate level of skill at the time of the claimed invention. See Okajima
`v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001).
`B. Claim Construction
`The Board interprets claim terms in an unexpired patent according to
`the broadest reasonable construction in light of the specification of the patent
`in which they appear. See Cuozzo Speed Techs., LLC v. Lee, 136 S.Ct. 2131,
`2144–46 (2016) (upholding the use of the broadest reasonable interpretation
`standard); 37 C.F.R. § 42.100(b). Under that standard, and absent any
`special definitions, we give claim terms their ordinary and customary
`meaning, as would be understood by one of ordinary skill in the art at the
`time of the invention. See In re Translogic Tech., Inc., 504 F.3d 1249, 1257
`(Fed. Cir. 2007). Only those terms which are in controversy need to be
`construed, and only to the extent necessary to resolve the controversy. See
`Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir.
`1999).
`Petitioner submits that the “claims in the ʼ650 patent are presumed to
`take on their ordinary and customary meaning based on the broadest
`reasonable interpretation of the claim language.” Pet. 6. Patent Owner
`“does not dispute Petitioner’s position that no claim terms require
`construction, which the Board also accepted for purposes of institution.”
`Resp. 7 (citing Pet. 6; Inst. Dec. 7). In our Institution Decision, we
`determined that “no claim term requires express construction.” Inst. Dec. 7.
`After reviewing the entire record developed during trial, we affirm our
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`determination from the Institution Decision that no claim term requires
`express construction to resolve the parties’ dispute.
`C. Legal Standards
`A patent claim is unpatentable under 35 U.S.C. § 103(a) if the
`differences between the subject matter sought to be patented and the prior art
`are such that the subject matter as a whole would have been obvious to a
`person of ordinary skill in the art at the time the invention was made. KSR
`Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007). Obviousness is resolved
`based on underlying factual determinations, including: (1) the scope and
`content of the prior art; (2) any differences between the claimed subject
`matter and the prior art; (3) the level of ordinary skill in the art; and
`(4) objective evidence of nonobviousness, i.e., secondary considerations.
`See Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966). A decision on
`the ground of obviousness must include “articulated reasoning with some
`rational underpinning to support the legal conclusion of obviousness.” In re
`Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006). The obviousness analysis
`“should be made explicit” and it “can be important to identify a reason that
`would have prompted a person of ordinary skill in the relevant field to
`combine the elements in the way the claimed new invention does.” KSR,
`550 U.S. at 418. We analyze the asserted grounds of unpatentability in
`accordance with the above-stated principles.
`D. Overview of Asserted References
`We begin our discussion with a brief summary of the asserted
`references.13
`
`
`13 Unless otherwise noted, we refer to the original page numbers in each
`reference, and not the page numbers Petitioner has added to the document.
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`Postlind (Ex. 1010)
`1.
`Postlind investigates the metabolism of tolterodine in human liver
`microsomes having varying P450 cytochrome activities. Ex. 1010, Abstract.
`Postlind illustrates the results of these studies in Figure 1, reproduced below.
`
`
`Figure 1 illustrates that “[m]etabolites are formed via two pathways:
`oxidation of the 5-methyl group to a 5-hydroxymethyl derivative (5-HM)
`[i.e., 5-HMT]” by cytochrome P450 2D6 (“CYP2D6” or “2D6”) “and
`dealkylation of the nitrogen” by cytochrome P450 CYP3A4 (“CYP3A4”).
`Id. at 289; see also id. at 292 (concluding that the dealkylation reaction “is
`predominantly catalyzed by CYP3A4 in human liver microsomes.”)14
`
`
`14 Petitioner’s technical expert, Dr. Patterson, emphasizes that 5-HMT is also
`N-dealkylated by CYP3A4. Ex. 1003 ¶ 111; see id. ¶¶ 45–47 (citing Brynne
`et al., Pharmacokinetics and pharmacodynamics of tolterodine in man: a
`new drug for the treatment of urinary bladder overactivity, 35(7) INT’L J.
`CLIN. PHARMACOL. THERAP. 287–295 (1997) (Ex. 1007, “Brynne 1997”));
`Ex. 1007, 291 Fig. 2.
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`Postlind notes that “[c]linical studies have demonstrated that
`individuals with reduced CYP2D6-mediated metabolism represent a high-
`risk group in the population with a propensity to develop adverse drug
`effects” and a “number of drugs [have been] identified as being affected by
`CYP2D6 polymorphism. . . .” Id. at 292. Accordingly, “[t]he possibility of
`clinical drug interaction at the enzyme level [] exists, especially if
`tolterodine is administered at the same time as a compound that is
`preferentially metabolized by CYP2D6 or to individuals associated with the
`CYP2D6 poor metabolizer phenotype.” Id.
`Postlind further notes that CYP3A enzymes (e.g., CYP3A4) also have
`been associated with adverse drug interactions; “[h]owever, the large
`amount of CYP3A in the liver and the fact that tolterodine is predominantly
`eliminated via oxidation by CYP2D6 makes it less likely that clinically
`significant drug-drug interactions would occur with CYP3A substrates in
`individuals with the CYP2D6 extensive metabolizer phenotype.” Id.
`2.
`Brynne (Ex. 1011)
`Brynne investigates the effect of CYP2D6 heterogeneity on the
`pharmacokinetics of tolterodine, as well as potential differences in selected
`pharmacodynamic properties (heart rate, visual accommodation, and
`salivation) of tolterodine as compared to 5-HMT. See Ex. 1011, Abstract.
`Brynne’s study involved “[s]ixteen male subjects (eight extensive
`metabolizers and eight poor metabolizers) [who] received 4 mg tolterodine
`by mouth twice a day for 8 days followed by a single intravenous infusion of
`1.8 mg tolterodine for 30 minutes after a washout period.” Id.
`With respect to the muscarinic side effect dry mouth, Brynne reports
`that “[a] distinct drug effect was [] obtained for four of eight extensive
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`metabolizers and most of the poor metabolizers after oral administration.
`For extensive metabolizers, the effect was equally pronounced after
`intravenous compared with oral administration, whereas salivation was less
`affected among poor metabolizers after the infusion.” Id. at 535. In
`considering the relation between the severity of dry mouth and unbound
`serum levels of the two compounds, Brynne reports that “[t]here was a weak
`correlation between tolterodine concentration and effect on salivation.
`A stronger correlation was seen with [5-HMT] and effect.” Id. at 536.
`Nevertheless, “[o]nly minor differences in pharmacodynamic effects after
`tolterodine dosage were observed between the groups. Tolterodine caused a
`similar decrease in salivation in both panels. The decrease occurred when
`the concentration of unbound tolterodine and 5-hydroxymethyl metabolite
`among extensive metabolizers was comparable with that of tolterodine
`among poor metabolizers.” Id., Abstract. Brynne suggests that “the
`similarity in salivary effects between the two phenotypic groups” may be
`explained by the 10-fold greater serum protein binding of tolterodine as
`compared to 5-HMT. Id. at 535–536.
`Brynne also notes a shift in the effect curve with respect to visual
`accommodation with five of the poor metabolizers reporting abnormal visual
`accommodation. Id. at 536, 538. The authors posit that “the most likely
`explanation is the physicochemical differences between tolterodine and
`[5-HMT]. Tolterodine is tenfold more lipophilic than [5-HMT], and
`consequently tolterodine penetrates membranes more rapidly.” Id. at 538.
`Brynne concludes that:
`Despite the influence of CYP2D6 polymorphism on the
`pharmacokinetics of tolterodine, this does not appear to be of
`great pharmacodynamic importance. This is because either high
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`concentrations of the parent compound are mainly responsible
`for
`the effect among poor metabolizers or substantial
`concentrations of the active metabolite [5-HMT] are responsible
`for the effect among extensive metabolizers.
`Id.; see id. at Abstract.
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`Detrol Label (Ex. 1009)
`3.
`Detrol Label discusses the structural formula, pharmacokinetics, and
`pharmacology of tolterodine, provided as tolterodine tartrate “for the
`treatment of patients with an overactive bladder with symptoms of urinary
`frequency, urgency, or urge incontinence.” Ex. 1009, 5.15 The reference
`states that:
`Tolterodine is extensively metabolized by the liver following
`oral dosing. The primary metabolic route involves the oxidation
`of the 5-methyl group and is mediated by the cytochrome P450
`2D6 and leads to the formation of a pharmacologically active
`5-hydroxymethyl metabolite [i.e., 5-HMT]. Further metabolism
`leads to formation of the 5-carboxylic acid and N-dealkylated
`5-carboxylic acid metabolites, which account for 51% ± 14% and
`29% ± 6.3% of the metabolites recovered in the urine,
`respectively.
`Id. at 2. Detrol Label notes that about 7% of the population lack cytochrome
`P450 2D6 activity and are designated “poor metabolizers” as compared to
`the general population (“extensive metabolizers”). Id. Pharmacologic
`studies reveal that tolterodine is metabolized at a slower rate in poor
`metabolizers resulting in “significantly higher serum concentrations of
`tolterodine and negligible concentrations of [5-HMT].” Id. But “[b]ecause
`of differences in the protein-binding characteristics of tolterodine and
`[5-HMT], the sum of unbound serum concentrations of tolterodine and
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`15 Because the Detrol Label does not include any page numbers, we refer to
`the page numbers Petitioner added to the document.
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`[5-HMT] is similar in [both populations].” Id. Moreover, “[s]ince
`tolterodine and [5-HMT] have similar antimuscarinic effects, the net activity
`of DETROL Tablets is expected to be similar in extensive and poor
`metabolizers.” Id.
`In addressing potential drug-drug interactions related to 2D6
`heterogeneity, Detrol Label states that “[t]olterodine is not expected to
`influence the pharmacokinetics of drugs that are metabolized by cytochrome
`P450 2D6.” Id. at 3. The reference further discloses that fluoxetine is a
`potent inhibitor of cytochrome P450 2D6 activity and has been shown to
`significantly inhibit the metabolism of tolterodine to 5-HMT such that the
`pharmacokinetics of the drug in extensive metabolizers resembles that of
`poor metabolizers. Id. The reference, nevertheless, states that “[n]o dose
`adjustment is required when DETROL and fluoxetine are coadministered.”
`Id. Although Detrol Label does not suggest altering tolterodine dosages for
`2D6 poor metabolizers, because a substantial portion of the drug is
`N-dealkylated by cytochrome P450 3A4, it recommends dose reduction for
`patients taking drugs that inhibit 3A4. Id. at 2, 5, 7.
`4.
`Bundgaard (Ex. 1012)
`Bundgaard describes prodrug design for drug delivery. Ex. 1012, v.
`According to Bundgaard, “[a] prodrug is a pharmacologically inactive
`derivative of a parent drug molecule that requires spontaneous or enzymatic
`transformation within the body in order to release the active drug, and that
`has improved delivery properties over the parent drug molecule.” Id.
`Bundgaard explains that prodrugs bridge the gap between drug action and
`efficient delivery to a desired target site:
`A molecule with optimal structural configuration and
`physicochemical properties for eliciting the desired therapeutic
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`response at its target site does not necessarily possess the best
`molecular form and properties for its delivery to its point of
`ultimate action. Usually, only a minor fraction of doses
`administered reaches the target area and, since most agents
`interact with non-target sites as well, an inefficient delivery may
`result in undesirable side effects. This fact of differences in
`transport and in situ effect characteristics for many drug
`molecules is the basic reason why bioreversible chemical
`derivatization of drugs, i.e., prodrug formation, is a means by
`which a substantial improvement in the overall efficacy of drugs
`can often be achieved.
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`Id.
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`Bundgaard teaches that esters are popularly used in the design of
`prodrugs because the body contains numerous, widely distributed esterases
`that can cleave such prodrugs to their active forms. Id. at 3–4. With respect
`to parent drugs containing a hydroxyl moiety, exemplary prodrugs have
`employed, for example, carboxylate, carbonate, phosphate, diacetyl, amino
`acid, ditoluyl, dipivaloyl, aromatic, and hemisuccinate esters. See id. at 3,
`Table 2.
`Bundgaard further teaches that “[e]ster formation has long been
`recognized as an effective means of increasing the aqueous solubility of
`drugs containing a hydroxyl group, with the aim of developing prodrug
`preparations suitable for parenteral administration.” Id. at 7. This approach
`makes it “feasible to obtain derivatives with almost any desirable
`hydrophilicity or lipophilicity as well as in vivo lability.” Id. at 4. “The
`most commonly used esters for increasing aqueous solubility of alcoholic
`drugs are hemisuccinates, phosphates, dialkylaminoacetates and amino acid
`esters.” Id. at 8.
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`Bundgaard PCT (Ex. 1020)
`5.
`Bundgaard PCT describes ester and diester prodrug derivatives of
`morphine for transdermal delivery. Ex. 1020, 1–5, 7–8, 10, 15. In contrast
`to morphine, “the morphine esters [were] more lipophilic than the parent
`drug in terms of octanol-aqueous buffer partition coefficients” and “the 3-
`hexanoyl, 3,6-dihexanoyl and other 3,6-dipropionyl morphine esters readily
`penetrated human skin.” Id. at 9–10.
`6.
`Berge (Ex. 1013)
`In a review of pharmaceutical formulation salts, Berge states that:
`The chemical, biological, physical, and economic characteristics
`of medicinal agents can be manipulated and, hence, often
`optimized by conversion to a salt form. Choosing the appropriate
`salt, however, can be a very difficult task, since each salt imparts
`unique properties to the parent compound.
`Salt-forming agents are often chosen empirically. Of the many
`salts
`synthesized,
`the preferred
`form
`is
`selected by
`pharmaceutical chemists primarily on a practical basis: cost of
`raw materials, ease of crystallization, and percent yield. Other
`basic considerations include stability, hygroscopicity, and
`flowability of the resulting bulk drug. Unfortunately, there is no
`reliable way of predicting the influence of a particular salt
`species on the behavior of the parent compound. Furthermore,
`even after many salts of the same basic agent have been prepared,
`no efficient screening techniques exist to facilitate selection of
`the salt most likely to exhibit the desired pharmacokinetic,
`solubility and formulation profiles.
`Ex. 1013, 1. Berge Table I is a list of FDA-approved, commercially
`marketed salts, along with an indication of how frequently those salts were
`used in the pharmaceutics industry as of 1974. Id. at 2. Table I indicates
`that fumarate salts were used 0.25% of the time. Id.
`
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`Johansson (Ex. 1005)
`7.
`Johansson discloses compounds of the general formula I reproduced
`below:
`
`
`
`Ex. 1005, 1:18–2:4. General formula I represents a class of
`3,3-diphenylpropylamines. Id. at Abstract. In formula I, “R1 signifies
`hydrogen or methyl, R2 and R3 independently signify hydrogen, methyl,
`methoxy, hydroxy, carbamoyl, sulphamoyl or halogen, and X represents a
`tertiary amino group.” Id. at 1:27–30. Johansson further discloses that
`preferred tertiary amino groups of formula I include the group reproduced
`below:
`
`
`Id. at 2:26–3:5. Johansson teaches that such compounds “can form salts
`with physiologically acceptable acids . . . . Examples of such acid addition
`salts include the hydrochloride, hydrobromide, hydrogen fumarate, and the
`like.” Id. at 2:5–10. According to Dr. Patterson, Johansson’s general
`formula encompasses 5-HMT (Ex. 1003 ¶¶ 133–136), which Patent Owner
`does not contest (see Resp. 60 (referencing “Johansson’s disclosure of
`potential salts of 5-HMT”)).
`
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`E. Analysis of Alleged Obviousness over Postlind, Bundgaard
`Publications, Detrol Label, and Berge (Ground I)
`Petitioner asserts that the combination of Postlind, Bundgaard,
`Bundgaard PCT, Detrol Label, and Berge would have rendered the subject
`matter of claims 1–5 and 21–24 obvious to a person of ordinary skill in the
`art. See Pet. 3, 21–43. In particular, Petitioner argues that it would have
`been obvious for one of ordinary skill in the art to (1) identify 5-HMT as a
`lead compound for drug development; (2) recognize that 5-HMT could have
`adverse effects due to its metabolism and poor oral bioavailability due to its
`lipophilicity profile; (3) address such concerns regarding adverse effects and
`poor oral bioavailability by esterifying 5-HMT to create a prodrug having
`increased lipophilicity and, subsequently, optimizing the ester moiety to
`arrive at a compound having a short-chain mono-ester derivative at only the
`5-hydroxyl position; and (4) select an acid-addition salt that provides the
`desired product stability. Id. at 21–38. Further, with regard to claims 3–5,
`22, and 23,16 which require compounds having a specific chirality, Petitioner
`argues that the ordinarily skilled artisan would have been led to the (R)
`enantiomer of fesoterodine. Id. at 37, 38, 41, 42. Petitioner also argues that
`it would have been obvious for one of ordinary skill in the art to treat a
`patient suffering from urinary incontinence generally (claims 21–23), and
`urge incontinence specifically (claim 24), with the compounds of claims 1,
`3, and/or 5, as recited in claims 21–24. Id. at 38–43.
`A determination of whether a new chemical compound would have
`been obvious over the prior art typically follows a two prong inquiry
`
`
`16 Claim 24 alternatively depends from any one of claims 21–23 and,
`therefore, does not require a specific chirality.
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`considering first, whether one of ordinary skill would have selected one or
`more lead compounds for further development and, second, whether the
`prior art would have supplied sufficient motivation to modify a lead
`compound to arrive at the compound claimed with a reasonable expectation
`of success. See Otsuka Pharm. Co., Ltd., v. Sandoz, Inc., 678 F.3d 1280,
`1291–92 (Fed. Cir. 2012).
`Based on our review of the arguments and evidence of record, we
`determine that Petitioner does not demonstrate, by a preponderance of the
`evidence, that the combination of Postlind, Bundgaard, Bundgaard PCT,
`Detrol Label, and Berge would have rendered obvious the subject matter of
`claims 1–5 and 21–24.
`1.
`Identification of 5-HMT as a Lead Compound
`In the first step of our analysis, we determine “whether a chemist of
`ordinary skill would have selected the asserted prior art compounds as lead
`compounds, or starting points, for further development efforts.” Id. at 1291.
`A lead compound comprises “a natural choice for further development
`efforts,” Altana Pharma AG v. Teva Pharm. USA, Inc., 566 F.3d 999, 1008
`(Fed. Cir. 2009), i.e., a prior art compound “that would be most promising to
`modify in order to improve upon its . . . activity and obtain a compound with
`better activity,” Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492
`F.3d 1350, 1357 (Fed. Cir. 2007). “In determining whether a chemist would
`have selected a prior art compound as a lead, the analysis is guided by
`evidence of the compound’s pertinent properties.” Otsuka Pharm., 678 F.3d
`at 1292; see also Eisai Co. v. Dr. Reddy’s Labs., Ltd., 533 F.3d 1353, 1359
`(Fed. Cir. 2008) (stating that even “post-KSR, a prima facie case of
`
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`obviousness for a chemical compound still, in general, begins with the
`reasoned identification of a lead compound”).
`Petitioner begins with the proposition that, in light of Postlind and the
`pharmacodynamic information in the Detrol Label, one of ordinary skill in
`the art would recognize that tolterodine was metabolized to an active
`metabolite, 5-HMT, having beneficial properties as compared to the parent
`compound. Pet. 22–24; see Ex. 1003 ¶¶ 40–43, 95–102. Petitioner argues
`that because the references disclose that tolterodine is metabolized to
`5-HMT by cytochrome CYP2D6, one of ordinary skill in the art would have
`elected to begin w