Trials@uspto.gov
`571-272-7822
`
`
`
`
`Paper 37
`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 IPR2016-00517
`Patent 7,985,772 B2
`____________
`
`
`Before KRISTINA M. KALAN, ROBERT A. POLLOCK, and
`MICHELLE N. ANKENBRAND, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`FINAL WRITTEN DECISION
`Finding Claims 1, 3, 4, and 6–8 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
`
`
`571-272-7822
`
`
`
`
`Paper 37
`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 IPR2016-00517
`Patent 7,985,772 B2
`____________
`
`
`Before KRISTINA M. KALAN, ROBERT A. POLLOCK, and
`MICHELLE N. ANKENBRAND, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`FINAL WRITTEN DECISION
`Finding Claims 1, 3, 4, and 6–8 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
`
`
`
`IPR2016-00517
`Patent 7,985,772 B2
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`I. INTRODUCTION
`Mylan Pharmaceuticals Inc. and Mylan Laboratories Limited
`(“Mylan” or “Petitioner”) filed a Corrected Petition requesting an inter
`partes review of claims 1, 3, 4, and 6–8 of U.S. Patent No. 7,985,772 B2
`(Ex. 1001, “the ’772 patent”). Paper 5 (“Pet.”). UCB Pharma GmbH,
`(“UCB” or “Patent Owner”) filed a Preliminary Response to the Petition.
`Paper 9 (“Prelim. Resp.”). We instituted an inter partes review of claims 1,
`3, 4, and 6–8 on the grounds of unpatentability alleged in the Petition. Paper
`12 (“Inst. Dec.”). After institution of trial, Patent Owner filed a Patent
`Owner Response (Paper 17, “PO Resp.”) and Petitioner filed a Reply (Paper
`21, “Reply”). An oral hearing was held on April 5, 2017. A transcript of the
`hearing has been entered into the record. Paper 36 (“Tr.”).
`The Board has jurisdiction under 35 U.S.C. § 6. In this Final Written
`Decision, issued pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73, we
`determine that Petitioner has not shown by a preponderance of the evidence
`that claims 1, 3, 4, and 6–8 of the ’772 patent are unpatentable under
`35 U.S.C. § 103.
`
`II. BACKGROUND
`
`A. Related Matters
`Patent Owner asserts that
`UCB and Pfizer Inc. (“Pfizer”), the exclusive licensees of the ‘772
`patent, have sued Mylan Pharmaceuticals Inc. for infringement of
`the ‘772 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 8, 2; see Pet. 1–2 (noting that Pfizer is the NDA holder).
`
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`The ’772 patent is also at issue in Pfizer, Inc. v. Sandoz, Inc., No. 1:13-
`cv-01110-GMS (D. Del.),1 and in the now-dismissed action, Pfizer, Inc. v.
`Dr. Reddy’s Laboratories, Ltd., No. 1:15-cv-01067 (GMS) (D. Del.). Paper
`8, 2.
`
`In addition to the case before us, we instituted inter partes review in
`the following matters involving patents with substantially the same
`specification as the ’772 patent at issue here:
`Case No. IPR2016-00512 (U.S. Patent No. 7,384,980 B2);
`Case No. IPR2016-00514 (U.S. Patent No. 7,855,230 B2); and
`Case No. IPR2016-00516 (U.S. Patent No. 8,338,478 B2).
`We also instituted inter partes review in IPR2016-00510 (U.S. Patent
`No. 6,858,650 B1), a matter involving another UCB patent generally
`directed, as are the above patents, to 3,3-diphenylpropylamine compounds.2
`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 UCB Pharma GmbH and Pfizer Inc., the
`exclusive licensee of the asserted patents, filed suit against Torrent
`Pharmaceuticals Limited and Torrent Pharma Incorporated for infringement
`
`
`1 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. Although the district court reached this determination on a
`different record and applied different standards, the arguments and references
`applied overlap with those before us. See Ex. 2001. Accordingly, while we
`are not bound to these findings, we find the court’s analysis informative.
`2 Petitioners Alembic Pharmaceuticals Limited from IPR2016-01596, Torrent
`Pharmaceuticals Limited from IPR2016-01636, and Amerigen
`Pharmaceuticals Limited from IPR2016-01665 were joined as Petitioners to
`IPR2016-00510. IPR 2016-00510, Papers 24–26.
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`of the asserted patents in Pfizer, Inc. and UCB Pharma GmbH v. Torrent
`Pharm. Ltd., No. 1:17-cv-00112-GMS (D. Del.). Paper 26, 2.
`
`B. The ’772 Patent
`The ’772 patent, entitled “Derivatives of 3,3-Diphenylpropylamines,”
`issued on July 26, 2011, with Claus Meese and Bengt Sparf as the listed co-
`inventors. Ex. 1001. The ’772 patent is generally directed to “derivatives of
`3,3-diphenylpropylamines, methods for their preparation, pharmaceutical
`compositions containing the novel compounds, and the use of the compounds
`for preparing drugs.” Id. at Abstract.
`The Specification discloses that “normal urinary bladder contractions
`are mediated mainly through cholinergic muscarinic receptor stimulation.”
`Id. at 1:23–24. Because the same muscarinic receptors appear to also
`mediate contractions of the overactive bladder and associated symptoms of
`urinary frequency, frequency urge, and urge incontinence, antimuscarinic
`drugs have been proposed for the treatment of bladder overactivity. Id. at
`1:25–30. “Among the antimuscarinic drugs available on the market,
`oxybutynin is currently regarded as the gold standard for pharmacological
`treatment of urge incontinence and other symptoms related to bladder
`overactivity” but its usefulness is limited by antimuscarinic side effects, most
`particularly, dry mouth. Id. at 1:31–34.
`“Tolterodine is a new, potent and competitive, muscarinic receptor
`antagonist intended for the treatment of urinary urge incontinence and
`[bladder wall muscle] hyperactivity. Preclinical pharmacological data show
`that tolterodine exhibits a favourable tissue selectivity in vivo for the urinary
`bladder over the effect on the salivation” as compared to oxybutynin. Id. at
`1:42–48.
`
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`A major metabolite of tolterodine, the 5-hydroxymethyl derivative
`5-HMT (“5-HMT”), shows in vitro and in vivo pharmacological profiles
`almost identical to those of tolterodine. Id. at 1:55–59 (citing Nilvebrant et
`al., 1997, Eur. J. Pharmacol. 327 (1997), 195–207). “WO 94/11337 proposes
`[5-HMT] as a new drug for urge incontinence.” Id. at 1:63–64.
`The chemical structures of tolterodine and its active metabolite,
`5-HMT (indicated below by “5-HM”), are shown below:
`
`
`
`See, e.g., Pet. 19; Ex. 1010, 289; Ex. 1011, 530. As illustrated above,
`tolterodine has a single hydroxyl group at the 2-position carbon of the
`methylated phenolic ring, whereas 5-HMT bears a second hydroxyl moiety
`on the 5-position methyl group of that ring.
`
`C. Illustrative Claim
`Claim 1 recites:
`1. 3,3-Diphenylpropylamines of the general formula
`
`
`
`wherein:
`R1 is a hydrogen and R2 is C1-C6 alkylcarbonyl; or
`R1 is C1-C6 alkylcarbonyl and R2 is hydrogen;
`
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`their salts with physiologically acceptable acids, their free
`bases and, when the 3,3-Diphenylpropylamines are in
`the form of optical isomers, the racemic mixture and the
`individual enantiomers.
`
`Claim 2 specifies that R1 is a hydrogen and R2 is C1-C6 alkylcarbonyl;
`claims 4, 6, and 7 recite methods of treating urinary incontinence using the
`compounds of claims 1 and 2; and claim 8 recites a pharmaceutical
`composition comprising those compounds and a pharmaceutically acceptable
`carrier.
`The compositions of claims 1 and 2 encompass fesoterodine fumarate
`(R-(+)-2-(3-(diisopropylamino-1-phenylpropyl)-4-hydroxymethl-
`phenylisobutyrate ester hydrogen fumarate) distributed by Pfizer Labs under
`the tradename Toviaz. See Pet. 6; PO Resp. 62; Ex. 1024, 8, 19.
`
`D. Instituted Grounds of Unpatentability
`We instituted inter partes review of claims 1, 3, 4, and 6–8 of the ’772
`patent on the following grounds:
`
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`Basis
`§ 103
`
`§ 103
`
`Claims Challenged
`1, 3, 4, and 6–8
`
`1, 3, 4, and 6–8
`
`References
`Postlind,3 “Bundgaard
`publications,”4,5,6 Detrol
`Label,7 and Berge8
`Brynne,9 Bundgaard, and
`Johansson10
`In support of its challenges, Petitioner relies also on 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. Patent Owner relies on the Declaration of Dr. Hans Maag
`(Ex. 2021), the Declaration of William R. Roush, Ph.D. (Ex. 2022), the
`Declaration of Dr. Scott A. MacDiarmid (Ex. 2023), the Declaration of
`Leonard J. Chyall, Ph.D. (Ex. 2024), and the Declaration of Claus O. Meese,
`Ph.D. (Ex. 2025).
`
`
`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
`(“Postlind”).
`4 In the Institution Decision, we interpreted Petitioner’s reference to
`“Bundgaard publications” as referring to Exhibits 1012 and 1020. Inst. Dec.
`6 n.3. We discuss those Exhibits individually in our analysis herein.
`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 (“Detrol Label”).
`8 Berge et al., Pharmaceutical Salts, 66(1) J. PHARM. SCI. 1–19 (1977).
`Ex. 1013 (“Berge”).
`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 (“Brynne”).
`10 Johansson et al., WO 94/11337, published May 26, 1994. Ex. 1005
`(“Johansson”).
`
`
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`E. 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 ¶ 20); see Prelim. Resp. 9; PO Resp. 6.
`Based on our review of the ’772 patent, the types of problems and
`solutions described in the ’772 patent and cited prior art, we adopt
`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).
`
`III. ANALYSIS
`
`A. Claim Interpretation
`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
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`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 ʼ772 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.” PO Resp. 7
`(citing Pet. 6; Inst. Dec. 7). In our Decision on Institution, we determined
`that “for purposes of this Decision, none of the terms in the challenged claims
`require express construction at this time.” Inst. Dec. 7. As in the Decision
`on Institution, we apply the broadest reasonable interpretation standard here,
`and see no reason to construe explicitly any claim term.
`
`B. Principles of Law
`A 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 at the time the
`invention was made to a person having ordinary skill in the art to which said
`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`(2007). The question of obviousness is resolved on the basis of 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. 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
`
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`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.
`
`C. Overview of the Asserted References
`We begin our discussion with a brief summary of the references
`asserted.11
`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)
`
`
`11 Unless otherwise noted, we refer to the original page numbers in each
`reference, and not the page numbers Petitioner has added to the document.
`
`
`
`10
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`[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.”)12
`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.
`
`
`12 Petitioner’s technical expert, Dr. Patterson, emphasizes that 5-HMT is also
`N-dealkylated by CYP3A4. Ex. 1003 ¶ 111; see id. at ¶¶ 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. 287–95 (1997) (Ex. 1007, “Brynne
`1997”); Ex. 1007, 291 Fig. 2.
`
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`11
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`Brynne (Ex. 1011)
`2.
`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
`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
`
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`12
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`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
`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.
`3.
`Detrol Label (Ex. 1009)
`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, 5.13 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
`
`13 Because the Detrol Label does not include any page numbers, we refer to
`the page numbers Petitioner added to the document.
`
`
`
`13
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`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 [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
`
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`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
`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.
`
`Id.
`
`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
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`acid, ditolulyl, 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.
`5.
`Bundgaard PCT (Ex. 1020)
`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
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`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.
`7.
`Johansson (Ex. 1005)
`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
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`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 PO Resp. 58 (referencing “Johansson’s disclosure of potential
`salts of 5-HMT”)).
`
`D. Analysis of Alleged Obviousness over Postlind, Bundgaard Publications,
`Detrol Label, and Berge (Ground 1)
`Petitioner asserts that claims 1, 3, 4, and 6–8 would have been obvious
`over the combination of Postlind, Bundgaard, Bundgaard PCT, Detrol Label,
`and Berge. See Pet. 3, 22–38. 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 22–38. Petitioner also argues that it would
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`have been obvious for one of ordinary skill in the art to treat a patient
`suffering from urinary incontinence with fesoterodine fumarate as
`encompassed by in claims 4, 6, and 7. Id. at 38–40.
`A determination of whether a new chemical compound would have
`been obvious over the prior art typically follows a two prong inquiry
`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).
`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 with the 5-HMT metabolite in order to avoid the potential for 2D6
`drug-drug interactions or the propensity of 2D6 poor metabolizers to develop
`adverse side effects when using drugs subject to this pathway. Pet. 23–25.
`In particular, Petitioner relies on Postlind, which provides the general caution
`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 states that a “number
`of drugs” have been identified as “being affected by CYP2D6
`polymorphism.” Ex. 1010, 292. In light of that experience with other drugs
`metabolized via the 2D6 pathway, Postlind suggests that for tolterodine,
`“[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 poor CYP2D6 poor metaboli
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