Trials@uspto.gov
`571.272.7822
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`
`
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` Paper No. 12
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` Entered: July 20, 2016
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`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 RAMA G. ELLURU, KRISTINA M. KALAN, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`
`571.272.7822
`
`
`
`
`
` Paper No. 12
`
` Entered: July 20, 2016
`
`
`
`
`
`
`
`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 RAMA G. ELLURU, KRISTINA M. KALAN, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`
`
`Case IPR2016-00517
`Patent 7,985,772 B2
`
`
`
`
`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 have jurisdiction under 35 U.S.C. § 314, which provides that an
`
`inter partes review may not be instituted “unless . . . there is a reasonable
`
`likelihood that the petitioner would prevail with respect to at least 1 of the
`
`claims challenged in the petition.” Upon considering the Petition and the
`
`Preliminary Response, we determine that Petitioner has shown a reasonable
`
`likelihood that it would prevail in showing the unpatentability of claims 1, 3,
`
`4, and 6–8. Accordingly, we institute an inter partes review of those claims.
`
`A.
`
`Related Proceedings
`
`Patent Owner asserts that
`
`UCB and Pfizer Inc. (“Pfizer”), the exclusive licensee 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 filer).
`
`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.
`
`
`
`1 Patent Owner provides, as Exhibit 2001, the District Court’s
`Memorandum finding that the defendants in that proceeding “failed to
`
`2
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`Case IPR2016-00517
`Patent 7,985,772 B2
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`v. Dr. Reddy’s Laboratories, Ltd., No. 1:15-cv-01067 (GMS) (D. Del.).
`
`Paper 8, 2; Prelim. Resp. 7–8.
`
`In addition to the case before us, Petitioner requested institution of
`
`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).
`
`Petitioner also requested institution of inter partes review in IPR2016-
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`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.
`
`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
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`3,3-diphenylpropylamines, methods for their preparation, pharmaceutical
`
`compositions containing the novel compounds, and the use of the
`
`compounds for preparing drugs.” Ex. 1001, Abstract.
`
`
`
`The Specification discloses that “normal urinary bladder contractions
`
`are mediated mainly through cholinergic muscarinic receptor stimulation.”
`
`
`
`present a prima facie case that the asserted claims of the patents-in-suit are
`invalid as obvious.” Ex. 2001, 19; see Prelim. Resp. 7–8. Although the
`district court reached this determination on a different record and applying
`different standards, the arguments and references applied overlap with those
`before us. See Ex. 2001, Prelim. Resp. 1–2, 15–17, 21, 25, 33. Accordingly,
`while we are not bound to these findings, we find the court’s analysis
`informative.
`
`3
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`Id. at 1:23–24. Because the same muscarinic receptors appear to also
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`mediate contractions of the overactive bladder and associated symptoms of
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`urinary frequency, frequency urge, and urge incontinence, antimuscarinic
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`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
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`[bladder wall muscle] hyperactivity. Preclinical pharmacological data show
`
`that tolterodine exhibits a favourable tissue selectivity in vivo for the urinary
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`bladder over the effect on the salivation” as compared to oxybutynin. Id. at
`
`1:42–48.
`
`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 55–59 (citing Nilvebrant et al.,
`
`1997, Eur. J. Pharmacol. 327 (1997), 195–207). “WO 94/1 1337 proposes
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`[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:
`
`
`
`
`
`4
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`Case IPR2016-00517
`Patent 7,985,772 B2
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`See, e.g., Pet. 19; Ex. 1010, 289; Ex. 1011, 530. As illustrated above,
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`tolterodine has a single hydroxyl group at the 2-position of the methylated
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`phenolic ring, whereas 5-HMT bears a second hydroxyl moiety on the
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`5-position methyl group of that ring.
`
`C.
`
`Challenged Claims
`
`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;
`
`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; Prelim. Resp. 1–2, 7; Ex. 1024, 8, 19.
`
`5
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`Case IPR2016-00517
`Patent 7,985,772 B2
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`D.
`
`The Asserted Grounds of Unpatentability
`
`Petitioner challenges claims 1, 3, 4, and 6–8 of the ’772 patent on two
`
`grounds (Pet. 3, 32–40):
`
`References
`
`Postlind,2 “Bundgaard
`publications,”3,4,5 Detrol
`Label,6 and Berge7
`Brynne,8 Bundgaard, and
`Johansson9
`
`
`Basis
`
`§ 103
`
`Claims Challenged
`
`1, 3, 4, and 6–8
`
`§ 103
`
`1, 3, 4, and 6–8
`
`Petitioner relies also on the Declaration of its technical expert Steven
`
`E. Patterson, Ph.D. (Ex. 1003) and the Declaration of DeForest McDuff,
`
`
`
`2 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”).
`3 We interpret Petitioner’s reference to “Bundgaard publications” as
`referring to Exhibits 1012 and 1020. See Pet. iv, 3, 28,
`4 Bundgaard, Design of Prodrugs Elsevier (1985). Ex. 1012
`(“Bundgaard”).
`5 WO 92/08459, published May 29, 1992. Ex. 1020 (“Bundgaard
`PCT”).
`6 Detrol™ (tolterodine tartrate tablets) prescribing information (1998).
`Ex. 1009 (“Detrol Label”).
`7 Berge et al., Pharmaceutical Salts, 66(1) J. Pharm. Sci. 1–19 (1977).
`Ex. 1013 (“Berge”).
`8 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”).
`9 Johansson et al., WO 94/11337, published May 26, 1994. Ex. 1005
`(“Johansson”).
`
`6
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`Case IPR2016-00517
`Patent 7,985,772 B2
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`Ph.D. (Ex. 1033) with respect to lack of commercial success.10 Patent
`
`Owner relies on the Declaration of William R. Roush, Ph.D. (Ex. 2002).
`
`A.
`
`Claim Construction
`
`
`
`ANALYSIS
`
`In an inter partes review, claim terms in an unexpired patent are
`
`interpreted according to their broadest reasonable constructions in light of
`
`the Specification of the patent in which they appear. See 37 C.F.R.
`
`§ 42.100(b); Cuozzo Speed Techs., LLC v. Lee, No. 15–446, 2016
`
`WL 3369425, at *12 (U.S. June 20, 2016) (upholding the use of the broadest
`
`reasonable interpretation standard). Under the broadest reasonable
`
`construction standard, claim terms are presumed to have their ordinary and
`
`customary meaning, as would be understood by one of ordinary skill in the
`
`art in the context of the entire disclosure. In re Translogic Tech., Inc., 504
`
`F.3d 1249, 1257 (Fed. Cir. 2007).
`
`In the present case, neither party contests the meaning of any claim
`
`term. See Pet. 6; Prelim. Resp. 9. Only those terms that are in controversy
`
`need 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). For purposes of this decision, we determine that no
`
`claim term requires express construction.
`
`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
`
`
`
`10 Patent Owner does not assert commercial success in the Preliminary
`Response.
`
`7
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`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
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`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.
`
`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. The level of ordinary skill in the art is further demonstrated
`
`8
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`Case IPR2016-00517
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`by the prior art asserted in the Petition. See Okajima v. Bourdeau, 261 F.3d
`
`1350, 1355 (Fed. Cir. 2001).
`
`C. Overview of the Asserted References
`
`We begin our discussion with a brief summary of the references
`
`asserted.
`
`i. Postlind (Ex. 1010)
`
`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”).
`
`
`
`9
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`Case IPR2016-00517
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`Id. at 289; see also id. at 292 (concluding that the dealkylation reaction “is
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`predominantly catalyzed by CYP3A4 in human liver microsomes.”)11
`
`
`
`Postlind notes that “[c]linical studies have demonstrated that
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`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
`
`poor 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.
`
`ii. 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
`
`
`
`11 Petitioner’s technical expert, Dr. Patterson, emphasizes that 5-HMT
`is also N-dealkylated by CYP3A4. See Ex. 1003 ¶¶ 111, 45–46 (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). See Ex. 1007
`(“Brynne 1997”), 291 Fig. 2.
`
`10
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`Case IPR2016-00517
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`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 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. The authors posit that “the most likely explanation is the
`
`11
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`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 pharmacodynamics 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., Abstract.
`
`iii. 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 overactive bladder with symptoms of urinary
`
`frequency, urgency, or urge incontinence.” Ex. 1009, 5. The reference
`
`states that:
`
`Tolterodine is extensively metabolized in 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
`
`12
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`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, a
`
`potent inhibitor of cytochrome P450 2D6 activity, 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 dosage
`
`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.
`
`iv. Bundgaard (Ex. 1012)
`
`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.” Ex. 1012,
`
`13
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`v. 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 when 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 drugs containing a hydroxyl moiety, exemplary prodrugs have employed,
`
`for example, carboxylate, carbonate, phosphate, diacetyl, amino acid,
`
`ditoluluyl, 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
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`makes it “feasible to obtain derivatives with almost any desirable
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`hydrophilicity or hydrophobicity as well as in vivo lability.” Id. at 4. “The
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`most commonly used esters for increasing aqueous solubility of alcoholic
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`14
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`Patent 7,985,772 B2
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`drugs are hemisuccinates, phosphates, dialkylaminoacetates and amino acids
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`esters.” Id. at 8.
`
`v. Bundgaard PCT (Ex. 1020)12
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`Bundgaard PCT describes ester and diester prodrug derivatives of
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`morphine for transdermal delivery. Ex. 1020, 2–5, 7–8, 10, 15. In contrast
`
`to morphine, “the morphine esters [were] more lipophilic than the parent
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`drug in terms of octanol-aqueous buffer partition coefficients” and “the
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`3-hexanoyl, 3,6-dihexanoyl and other 3,6-dipropionyl morphine esters
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`readily penetrated human skin.” Id. at 9–10.
`
`vi. 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.
`
`
`
`12 Petitioner variously refers to Exhibit 1020 as “Bundgaard PCT,”
`“Bundgaard Patent,” and, collectively with Ex. 1012, “Bundgaard
`publications.” See Pet. iv, 3, 28,
`
`15
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`Case IPR2016-00517
`Patent 7,985,772 B2
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`Ex. 1013, 1. Berge Table I is a list of FDA-approved, commercially
`
`marketed salts, along with an indication of how frequently those salts are
`
`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.
`
`vii. 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, hydroxyl, 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 salt
`
`forms 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.
`
`16
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`Case IPR2016-00517
`Patent 7,985,772 B2
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`D. Obviousness Analysis
`
`Petitioner challenges claims 1, 3, 4, and 6–8 of the ’772 patent on two
`
`grounds. Pet. 3. Patent Owner argues that Petitioner has not presented
`
`sufficient data or objective evidence to show a reasonable likelihood that it
`
`would prevail in showing the unpatentability of claims 1, 3, 4, and 6–8.
`
`Prelim. Resp. 11–41. We present an overview of the parties’ positions
`
`below.
`
`i. Ground I: Obviousness over Postlind, Bundgaard Publications,
`Detrol Label, and Berge
`
`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. To briefly summarize
`
`Petitioner’s argument, 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 would have poor oral
`
`bioavailability due to its lipophilicity profile; (3) address these concerns
`
`regarding 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.
`
`1. Identification of 5-HMT
`
`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, 99, 101. Petitioner argues
`
`17
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`Case IPR2016-00517
`Patent 7,985,772 B2
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`that because these references disclose that tolterodine is metabolized to
`
`5-HMT by cytochrome P450 2D6, 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 this 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 metabolizer phenotype.” Id.
`
`Patent Owner responds that Postlind’s caution regarding the
`
`possibility of clinical drug interactions related to 2D6 metabolism is
`
`superseded by, e.g., the teachings of the Detrol Label, Brynne, and
`
`Nilvebrandt 1997,13 which collectively teach that tolterodine and 5-HMT
`
`have “almost identical” pharmacological profiles; that “[d]espite the
`
`influence of CYP2D6 polymorphism on the pharmacokinetics of tolterodine,
`
`
`
`13 Nilvebrant et al., Antimuscarinic Potency and Bladder Selectivity of
`PNU-200577, a Major Metabolite of Tolterodine, 81 PHARMACOLOGY &
`TOXICOLOGY 169–172 (1997). Ex. 1015.
`
`18
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`Case IPR2016-00517
`Patent 7,985,772 B2
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`this does not appear to be of great pharmacodynamics importance”; that
`
`“[t]olterodine is not expected to influence the pharmacokinetics of drugs that
`
`are metabolized by cytochrome p450 2D6”; and that no dose adjustment is
`
`required when tolterodine is co-administered with the potent 2D6 inhibitor
`
`fluoxetine. See Prelim. Resp. 12–16; Ex. 1015, 172; Ex. 1011, 538;
`
`Ex. 1009, 2. Thus, Patent Owner argues, “[i]n view of the prior art as a
`
`whole, a person of skill in the art would have had no reason to avoid
`
`tolterodine’s CYP2D6 polymorphism and would have had no reason to turn
`
`to 5-HMT.” Prelim. Resp. 12–13 (citation omitted).
`
`Although we find Patent Owner’s arguments reasonable, Patent
`
`Owner’s “supporting evidence concerning disputed material facts will be
`
`viewed in the light most favorable to the petitioner for purposes of deciding
`
`whether to institute an inter partes review.” 37 C.F.R. § 42.108(b).
`
`Accordingly, on the present record, we find that Petitioner has demonstrated
`
`a reasonable likelihood that one of ordinary skill in the art would have
`
`selected 5-HMT over tolterodine for further development.
`
`2. Reason to Modify 5-HMT
`
`With respect to a reason to modify 5-HMT, Petitioner first states that
`
`Postlind “would have motivated a person of ordinary skill to modify 5-HMT
`
`to a compound that avoided CYP2D6 metabolism as known to occur with
`
`tolterodine.” Pet. 23. Insofar as 5-HMT is the result of CYP2D6
`
`metabolism of tolterodine (i.e., there is no evidence that 5-HMT undergoes
`
`CYP2D6 metabolism), we do not find this statement persuasive.
`
`Petitioner also focuses on the Detrol Label’s dose reduction
`
`recommendation for “patients with significantly reduced hepatic function or
`
`who are currently taking drugs that are inhibitors of cytochrome P450 3A4”
`
`but, as noted in section II(C)(i), tolterodine and 5-HMT are both P450 3A4
`
`19
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`Case IPR2016-00517
`Patent 7,985,772 B2
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`substrates. See Pet. 24–25. Petitioner has not explained adequately how
`
`Detrol Label’s concerns relating the P450 3A4 substrate profile of
`
`tolterodine would have motivated one of ordinary skill in the art to modify
`
`either compound.
`
`Petitioner also relies on paragraphs 116 and 118 of Dr. Patterson’s
`
`report in asserting that “a person of ordinary skill in the art would have
`
`appreciated that 5-HMT was too lipophilic and needed to be modified in a
`
`way to improve bioavailability.” Pet. 27. We presume that Petitioner’s
`
`assertion that 5-HMT was “too lipophilic” is intended as an argument that 5-
`
`HMT is not lipophilic enough. See id. at 10 (asserting that 5-HMT was
`
`known to have “poor lipophilicity”). Relevant to Ground I, Dr. Patterson
`
`asserts in paragraph 112 of his report that
`
`[w]hen the skilled artisan would have looked at 5-HMT, it
`would have seen that the presence of two hydroxyl groups around
`th
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