Trials@uspto.gov
`571.272.7822
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`
`
`
`
` Paper No. 12
`
` 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 IPR2016-00510
`Patent 6,858,650 B1
`____________
`
`
`Before KRISTINA M. KALAN, ROBERT A. POLLOCK, and
`MICHELLE N. ANKENBRAND, Administrative Patent Judges.
`
`ANKENBRAND, Administrative Patent Judge.
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`

`

`Case IPR2016-00510
`Patent 6,858,650 B1
`
`
`
`
`INTRODUCTION
`
`Mylan Pharmaceuticals Inc. and Mylan Laboratories Limited,
`
`(collectively, “Petitioner”) filed a Corrected Petition requesting an inter
`
`partes review of claims 1–5 and 21–24 of U.S. Patent No. 6,858,650 B1
`
`(Ex. 1001, “the ’650 patent”). Paper 5 (“Pet.”). UCB Pharma GmbH,
`
`(“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.” Applying that standard, and upon
`
`considering the information presented in the Petition and the Preliminary
`
`Response, we institute an inter partes review of claims 1–5 and 21–24.
`
`A.
`
`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.),1 and was asserted in the now-dismissed
`
`
`
`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; see Prelim. Resp. 7–8. The district court
`
`2
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`Case IPR2016-00510
`Patent 6,858,650 B1
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`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, Petitioner requested institution of
`
`inter partes review in the following matters involving patents generally
`
`directed to 3,3-diphenylpropylamine compounds: Case No. IPR2016-00512
`
`(U.S. Patent No. 7,384,980 B2); Case No. IPR2016-00514 (U.S. Patent No.
`
`7,855,230 B2); Case No. IPR2016-00516 (U.S. Patent No. 8,338,478 B2),
`
`and Case No. IPR2016-00517 (U.S. Patent No. 7,985,772 B2).
`
`B.
`
`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 is generally 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
`
`unfavourable metabolism of [the active substance].” Id. at 1:20–22.
`
`According to the specification, the compounds also “have improved
`
`
`
`reached that determination on a different record and applying different
`standards, but the arguments and references applied overlap with those
`before us. See Ex. 2001; Prelim. Resp. 1–2, 15–17, 21, 25, 33.
`Accordingly, although we are not bound by those findings, we find the
`district court’s analysis informative.
`
`3
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`Patent 6,858,650 B1
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`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, 3; Ex. 1014, 528.
`
`C.
`
`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 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 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
`
`4
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`24 recites the method of any one 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-hydroxymethl-
`
`phenylisobutyrate ester hydrogen fumarate)) distributed by Pfizer Labs
`
`under the brand TOVIAZ. See Pet. 5; Prelim. Resp. 1–2, 7; Ex. 1024, 8, 19.
`
`D.
`
`The Asserted Grounds of Unpatentability
`
`The Petition asserts the following grounds of unpatentability:
`
`References
`
`Postlind,2 “Bundgaard
`publications,”3,4,5 Detrol
`Label,6 and Berge7
`Brynne,8 Bundgaard
`publications, and Johansson9
`
`
`
`Basis
`
`§ 103
`
`Claims Challenged
`
`1–5 and 21–24
`
`§ 103
`
`1–5 and 21–24
`
`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, 19–20, 27, 29.
`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”).
`
`5
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`
`The Petition is supported by the Declarations of Steven E. Patterson,
`
`Ph.D. (Ex. 1003) and DeForest McDuff, Ph.D. (Ex. 1033). Patent Owner’s
`
`Preliminary Response is supported by the Declaration of William R. Roush,
`
`Ph.D. (Ex. 2002).
`
`
`
`ANALYSIS
`
`We address below whether the Petition meets the threshold showing
`
`for institution of an inter partes review under 35 U.S.C. § 314(a). We
`
`consider each ground of unpatentability in view of the understanding of a
`
`person of ordinary skill in the art.10
`
`A.
`
`Claim Construction
`
`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
`
`
`
`10 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
`Prelim. Resp. 9 (Patent Owner “does not dispute Petitioner’s definition of a
`person of ordinary skill in the art.”).
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`art in the context of the entire disclosure. In re Translogic Tech., Inc., 504
`
`F.3d 1249, 1257 (Fed. Cir. 2007).
`
`At this stage of the proceeding, the parties do not propose any claim
`
`term for construction. 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. Overview of the Asserted References
`
`We begin our discussion with a brief summary of the asserted
`
`references.
`
`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.
`
`
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`Figure 1 illustrates that, “[m]etabolites are formed via two pathways:
`
`oxidation of the 5-methyl group to a 5-hydroxymethyl derivative [5-HMT]”
`
`by cytochrome P450 2D6 (“CYP2D6” or “2D6”) “and dealkylation of the
`
`nitrogen” by cytochrome P450 CYP3A4 (“CYP3A4”).11 Id. at 289; see also
`
`id. at 292 (concluding that the dealkylation reaction “is predominantly
`
`catalyzed by CYP3A4 in human liver microsomes.”)12
`
`
`
`Postlind explains “[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
`
`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
`
`
`
`11 Postlind’s Figure 1 depicts the chemical structures of, inter alia,
`tolterodine, and its active metabolite, the 5-hydroxymethyl derivative of
`tolterodine (“5-HMT”). As illustrated, tolterodine has a single hydroxyl
`group at the 2-position of the methylated phenolic ring, whereas 5-HMT
`bears a second hydroxyl moiety on the 5-position methyl group of that ring.
`12 Petitioner’s technical expert, Dr. Patterson, emphasizes that 5-HMT
`is also N-dealkylated by CYP3A4. See Ex. 1003 ¶¶ 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, 291, Fig. 2 (1997) (Ex. 1007)).
`
`8
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`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
`
`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
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`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. at Abstract. Brynne suggests that “the
`
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`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
`
`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. at 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
`
`discloses 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
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`
`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, explains 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.
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`
`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,
`
`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 frequently are 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
`
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`preparations suitable for parenteral administration.” Id. at 7. This approach
`
`makes it “feasible to obtain derivatives with almost any desirable
`
`hydrophilicity or hydrophobicity 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 acids
`
`esters.” Id. at 8.
`
`v. Bundgaard PCT (Ex. 1020)
`
`Bundgaard PCT describes ester and diester prodrug derivatives of
`
`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
`
`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.
`
`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.
`
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`Ex. 1013, 1. Berge Table I provides 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 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,
`
`
`
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`and the like.” Id. at 2:5–10. According to Dr. Patterson, Johansson’s
`
`general formula encompasses 5-HMT. Ex. 1003 ¶¶ 133–136.
`
`C. Obviousness Analysis
`
`Petitioner challenges claims 1–5 and 21–24 of the ’650 patent on two
`
`grounds. Pet. 3. Patent Owner argues that Petitioner has not presented
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`sufficient data or objective evidence to show a reasonable likelihood that it
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`would prevail in showing the unpatentability of claims 1–5 and 21–24.
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`Prelim. Resp. 11–43. We present an overview of the parties’ positions
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`below.
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`i. Ground I: Obviousness over Postlind, Bundgaard Publications,
`Detrol Label, and Berge
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`Petitioner asserts that claims 1–5 and 21–24 would have been obvious
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`over the combination of Postlind, Bundgaard, Bundgaard PCT, Detrol Label,
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`and Berge. See Pet. 3, 21–43. In particular, with regard to claims 1, 2, 21,
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`and 24, Petitioner argues that it would have been obvious for one of ordinary
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`skill in the art to (1) identify 5-HMT as a lead compound for drug
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`development; (2) recognize that 5-HMT would have poor oral bioavailability
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`due to its lipophilicity profile; (3) address these concerns regarding poor oral
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`bioavailability by esterifying 5-HMT to create a prodrug (i.e., fesoterodine)
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`having increased lipophilicity and subsequently optimizing the ester moiety
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`to arrive at a compound having a short-chain mono-ester derivative at only
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`the 5-hydroxyl position; and (4) select an acid-addition salt that provides the
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`desired product stability. Id. at 21–38. Further, with regard to claims 3–5,
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`22, and 23,13 which require specific chirality, Petitioner argues that the
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`
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`13 Claim 24 alternatively depends from any one of claims 21–23 and,
`therefore, does not require a specific chirality.
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`ordinarily skilled artisan would have been led to the (R) enantiomer of
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`fesoterodine. Id. at 37, 38, 41, 42. Petitioner also argues that it would have
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`been obvious for one of ordinary skill in the art to treat a patient suffering
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`from urinary incontinence, such as urge incontinence, with fesoterodine
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`fumarate as recited in claims 21–24. Id. at 38–43.
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`1. Identification of 5-HMT
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`Petitioner begins with the proposition that, in light of Postlind and the
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`pharmacodynamic information in the Detrol Label, one of ordinary skill in
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`the art would recognize that tolterodine was metabolized to 5-HMT and that
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`5-HMT possesses beneficial properties as compared to the parent compound.
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`Pet. 22–24; see Ex. 1003 ¶¶ 40–43, 99, 101. Petitioner argues that because
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`those references disclose that tolterodine is metabolized to 5-HMT by
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`cytochrome P450 2D6, one of ordinary skill in the art would have elected to
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`begin with the 5-HMT metabolite in order to avoid the potential for 2D6
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`drug-drug interactions or the propensity of 2D6 poor metabolizers to
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`develop adverse side effects when using drugs subject to this pathway.
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`Pet. 23–24.
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`In particular, Petitioner relies on Postlind, which provides the general
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`caution that “[c]linical studies have demonstrated that individuals with
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`reduced CYP2D6-mediated metabolism represent a high-risk group in the
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`population with a propensity to develop adverse drug effects” and states that
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`a “number of drugs have been identified as being affected by CYP2D6
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`polymorphism.” Ex. 1010, 292. In light of that experience with other drugs
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`metabolized via the 2D6 pathway, Postlind suggests that, for tolterodine,
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`“[t]he possibility of clinical drug interaction at the enzyme level [] exists,
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`especially if tolterodine is administered at the same time as a compound that
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`is preferentially metabolized by CYP2D6 or to individuals associated with
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`the poor CYP2D6 poor metabolizer phenotype.” Id.
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`Patent Owner responds that Postlind’s caution regarding the
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`possibility of clinical drug interactions related to 2D6 metabolism was
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`superseded by, e.g., the teachings of the Detrol Label, Brynne, and
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`Nilvebrandt 1997,14 which collectively teach that (1) tolterodine and 5-HMT
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`have “almost identical” pharmacological profiles; (2) “[d]espite the
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`influence of CYP2D6 polymorphism on the pharmacokinetics of tolterodine,
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`this does not appear to be of great pharmacodynamics importance”;
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`(3) “[t]olterodine is not expected to influence the pharmacokinetics of drugs
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`that are metabolized by cytochrome p450 2D6”; and (4) no dose adjustment
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`is required when tolterodine is co-administered with the potent 2D6 inhibitor
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`fluoxetine. See Prelim. Resp. 14–17; Ex. 1015, 172; Ex. 1011, 538;
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`Ex. 1009, 2. Thus, Patent Owner argues, “[i]n view of the prior art as a
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`whole, a person of skill in the art would have had no reason to avoid
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`tolterodine’s CYP2D6 polymorphism and would have had no reason to turn
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`to 5-HMT.” Prelim. Resp. 14 (citation omitted).
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`Although we find Patent Owner’s arguments reasonable, Patent
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`Owner’s “supporting evidence concerning disputed material facts will be
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`viewed in the light most favorable to the petitioner for purposes of deciding
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`whether to institute an inter partes review.” 37 C.F.R. § 42.108(c).
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`Accordingly, on the present record, we find that Petitioner has demonstrated
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`
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`14 Nilvebrant et al., Antimuscarinic Potency and Bladder Selectivity of
`PNU-200577, a Major Metabolite of Tolterodine, 81 PHARMACOLOGY &
`TOXICOLOGY 169–172 (1997) (Ex. 1015).
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`a reasonable likelihood that one of ordinary skill in the art would have
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`selected 5-HMT over tolterodine for further development.
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`2. Reason to modify 5-HMT
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`With respect to a reason to modify 5-HMT, Petitioner first argues that
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`Postlind “would have motivated a person of ordinary skill to modify 5-HMT
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`to a compound that avoided CYP2D6 metabolism as known to occur with
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`tolterodine.” Pet. 23. Insofar as 5-HMT is the result of CYP2D6
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`metabolism of tolterodine (i.e., there is no evidence that 5-HMT undergoes
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`CYP2D6 metabolism, Ex. 1003 ¶ 111), we do not find Petitioner’s argument
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`persuasive.
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`Petitioner next focuses on Detrol Label’s dose reduction
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`recommendation for “patients with significantly reduced hepatic function or
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`who are currently taking drugs that are inhibitors of cytochrome P450 3A4.”
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`Pet. 24. As noted in section II(C)(i), tolterodine and 5-HMT are both P450
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`3A4 substrates, and Petitioner does not explain adequately how Detrol
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`Label’s concerns relating to the P450 3A4 substrate profile would have led
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`the ordinarily skilled artisan to modify either compound.
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`Petitioner also relies on paragraphs 116 and 118 of Dr. Patterson’s
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`report in asserting that “a person of ordinary skill in the art would have
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`appreciated that 5-HMT was too lipophilic and needed to be modified in a
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`way to improve bioavailability.” Pet. 26. We presume Petitioner’s assertion
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`that 5-HMT was “too lipophilic” is intended as an argument that 5-HMT
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`was not lipophilic enough. See id. at 10 (asserting it was known that 5-HMT
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`had “poor lipophilicity”). Relevant to Ground I, Dr. Patterson testifies:
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`[w]hen the skilled artisan would have looked at 5-HMT, it
`would have seen that the presence of two hydroxyl groups around
`the left most aromatic ring . . . would have created a product
`likely to have decreased oral bioavailability compared to
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`tolterodine because of its hydrophilicity and thus lower than
`acceptable lipophilicity.
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`Ex. 1003 ¶ 112; see also id. ¶ 115 (“[E]xamination of the structure of
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`5-HMT would have suggested that 5-HMT could have significantly less
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`bioavailability than its parent, tolterodine. Confirming this would be a
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`matter of routine experimentation.”).
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`Regarding the lipophilicity and bioavailability of 5-HMT, we note that
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`Dr. Patterson testifies that Brynne (asserted in the Petition with respect to
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`Ground II) “specifically informed the field that tolterodine ‘is tenfold more
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`lipophilic than 5-HM[T], and consequently tolterodine penetrates
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`membranes more rapidly.’” Ex. 1003 ¶ 116 (quoting Ex. 1011, 538).
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`Accordingly, Petitioner argues that a person of ordinary skill in the art would
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`have appreciated 5-HMT’s lipophilicity issues and “modified 5-HMT in a
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`way to improve bioavailability.” Pet. 26 (citing Ex. 1003 ¶¶ 116, 118). As
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`to the type of modification, Petitioner asserts that “preparing an ester
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`prodrug would have been an obvious choice.” Id.
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`Patent Owner argues that Petitioner has failed to establish that one of
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`ordinary skill in the art would have considered 5-HMT to be “too
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`lipophilic,” not lipophilic enough, or have oral bioavailability or absorption
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`problems. Prelim. Resp. 3, 17–20. Patent Owner contends that
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`(1) Petitioner fails to cite any prior art discussing the bioavailability of
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`5-HMT (id. at 18); (2) “5-HMT had never been directly adminis