Valeant Intern. (Barbados) SRL v. Watson Pharmaceuticals, Inc., Not Reported in...
`
`2011 WL 6792653
`Only the Westlaw citation is currently available.
`United States District Court,
`S.D. Florida.
`
`VALEANT INTERNATIONAL
`(BARBADOS) SRL, Plaintiff,
`v.
`WATSON PHARMACEUTICALS, INC.,
`Watson Laboratories, Inc.—Florida,
`and Watson Pharma, Inc., Defendants.
`
`No. 10–20526–CIV.
`|
`Nov. 8, 2011.
`
`Attorneys and Law Firms
`
`Clinton H. Brannon, Mayer Brown, LLP, Washington, DC,
`Gail Ann McQuilkin, Harley Shepard Tropin, Kozyak Tropin
`& Throckmorton, Coral Gables, FL, Theresa M. Gillis, Mayer
`Brown, LLP, New York, NY, Thomas W. Jenkins, Mayer
`Brown, LLP, Chicago, IL, for Plaintiff.
`
`Darcy L. Jones, Jeffrey J. Toney, John L. North, Meghan
`M. Rachford, Kasowitz, Benson, Torres & Friedman, LLP,
`Atlanta, GA, Norman E. B. Minnear, Kasowitz, Benson,
`Torres & Friedman, LLP, New York, NY, Janet T. Munn,
`Rasco Klock Reininger Perez Esquenazi Vigil & Nieto, Coral
`Gables, FL, for Defendants.
`
`Aplenzin® is an antidepressant that contains bupropion
`hydrobromide as the active ingredient. Valeant owns four
`patents related to Aplenzin®: U.S. Patent Nos. 7,569,610,
`7,563,823, 7,649,019, and 7,553,992 (collectively, “the
`patents-in-suit”). Each of the patents-in-suit contains several
`claims. In order to streamline the issues for trial, the
`parties agreed to try this case only with respect to five
`representative claims in the patents, with the resolution of
`the issues concerning those claims being dispositive as to all
`of the previously asserted claims as between the parties. The
`representative claims of the patents-in-suit are: (1) Claim 3
`of the ′ 610 patent; (2) Claim 9 of the ′823 patent; (3) Claim
`10 of the ′823 patent; (4) Claim 2 of the ′019 patent; and (5)
`Claim 1 of the ′992 patent. The representative claims relate to
`controlled release and once-a-day formulations of bupropion
`hydrobromide, methods of treating depression with those
`formulations, and a specific crystalline form of bupropion
`hydrobromide.
`
`The Court has jurisdiction over the parties and the subject
`matter pursuant to 28 U.S.C. § 1338(a). Additionally, venue
`is appropriate under 28 U.S.C. §§ 1391 and 1400(b). Neither
`jurisdiction nor venue is contested by the parties. The Court
`conducted a bench trial from June 21, 2011 to June 28, 2011.
`This Memorandum Opinion constitutes the Court's findings
`of fact and conclusions of law on the issues raised during trial.
`Ultimately, the Court finds that Watson has failed to prove by
`clear and convincing evidence that Valeant's asserted patent
`claims are invalid, and accordingly, grants judgment in favor
`of Valeant.
`
`AMENDED MEMORANDUM OPINION
`
`I. BACKGROUND
`
`FEDERICO A. MORENO, Chief Judge.
`
`*1 The prior opinion was incomplete and is thus stricken
`and replaced with the following Order:
`This action was filed by Valeant International (Barbados)
`SRL (“Valeant”) against Watson Pharmaceuticals, Inc.,
`Watson Laboratories, Inc.—Florida, and Watson Pharma,
`Inc. (collectively, “Watson”), alleging patent infringement.
`Valeant is the owner of several patents related to the drug
`known as Aplenzin®. Watson seeks to market the generic
`equivalent of that drug. Watson has conceded infringement
`but asserts as an affirmative defense that Valeant's asserted
`patents are invalid.
`
`Bupropion was invented by Nariman Mehta in 1969 as a
`method of treating depression and was subsequently patented
`by Mehta in 1974 in U.S. Patent No. 3,819,706 (the “Mehta
`patent”). (Def.Ex. 135.) While the Mehta patent mentions a
`number of bupropion salts, it does not specifically mention
`bupropion hydrobromide. (Pl.Ex. 96 ¶¶ 53–54; Trial Tr.
`437:25–438:11.) Bupropion has been sold since the 1980s
`as the bupropion hydrochloride salt, under the brand name
`Wellbutrin®. (Pl.Ex. 98 ¶ 18; Def. Ex. 602 at 10.) Today, both
`branded and generic versions of bupropion hydrochloride are
`on the market, including generic versions sold by Watson.
`(Pl.Ex. 94 at 86.)
`
`Since the early 1980s, however, it was known that bupropion
`hydrochloride had stability problems when combined with
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`Valeant Intern. (Barbados) SRL v. Watson Pharmaceuticals, Inc., Not Reported in...
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`pharmaceutical excipients. (Def. Ex. 128 at 20556–57;
`Def. Ex. 602 at 18–19.) Between 1984 and 2004 many
`attempts were made to improve the stability of bupropion
`hydrochloride formulations. (Trial Tr. 66:18–68:25; 301:10–
`303:16; Pl.Ex. 94 at 38.) One of the first such attempts was
`a 1984 patent application by Billinghurst where he tested
`several different bupropion salts to see if any had improved
`stability relative to the hydrochloride salt. (Def. Ex. 128;
`Pl.Ex. 94 at 38; Def. Ex. 379 at 40832.) Among the salts
`Billinghurst tested were a number of mineral acids 1 , all of
`which were found to be unstable. (Trial Tr. 473:22–474:11.)
`As was the case in the Mehta patent, the hydrobromide salt
`was neither mentioned nor tested. (Trial Tr. 66:18–67:15.)
`Only the maleate salt, which is an organic carboxylic acid
`salt, was found to have improved stability. (Def. Ex. 602 at
`18–19; Trial Tr. 434:21–436:10.) Due to toxicology concerns,
`however, it could never be formulated into a commercial
`product. (Def. Ex. 128 at 20557; Trial Tr. 435:10–23; Maes
`Dep. 130:20–131:24.) During the twenty years following
`Billinghurst's failed attempt to find an alternative salt
`with improved stability over bupropion hydrochloride, no
`new efforts were made to find a different bupropion salt;
`instead, other means were explored to improve stability of
`bupropion hydrochloride formulations, several of which were
`subsequently patented. (Trial Tr. 66:18–68:25; Def. Ex. 602
`at 18–19.)
`
`*2 Despite the various attempts to improve the stability
`of bupropion hydrochloride formulations, the shelf life of
`commercial bupropion hydrochloride tablets has remained
`short, with once-a-day formulations having never achieved
`a shelf life longer than eighteen months. (Trial Tr.
`299:23–300:4.) Thus, in 2003, Valeant (then Biovail)
`set out to address the longstanding stability issues with
`bupropion hydrochloride formulations. (Trial Tr. 298:20–
`299:20; 303:17–22; 380:16–21.) While Valeant tried a
`number of different approaches, it ultimately decided to
`revisit what Billinghurst had attempted but failed to discover
`in 1984—a new bupropion salt that could be formulated into
`a commercial product with an extended shelf life. (Trial Tr.
`303:14–22.) The goal of this new salt project was to extend
`the shelf life of Wellbutrin® without negatively impacting
`any of its other properties. (Trial Tr. 307:5–8.)
`
`The first step in the project was to figure out what salts of
`bupropion could even be made. (Maes Dep. Tr. 64:15–16.)
`Because Valeant was not specialized in manufacturing new
`salts, it sought the assistance of an Italian chemical company
`known as Chemi S.p.A. (“Chemi”). (Maes Dep. Tr. 64:15–
`
`65:6.) Valeant and Chemi spent several months attempting to
`make new salts, many of which failed to result in a testable
`product. (Def. Ex. 95; Def. Ex. 98.) Their selection of salts
`was largely an empirical process, because it was difficult to
`predict exactly which salt would be the best. (Maes Dep.
`84:2–6; 170:23–171:13.)
`
`In 2004 the inventors from Valeant and Chemi made
`bupropion hydrobromide. They discovered that bupropion
`hydrobromide exists in many forms, both amorphous
`and crystalline. (Def. Ex. 604 at 10; Pl.Ex. 96 at 15;
`Trial Tr. 643:16–25; 671:2–15.) Among these forms was
`the very stable crystalline compound—Form I bupropion
`hydrobromide—covered by Claim 1 of the ′992 patent.
`(Trial Tr. 224:16–225:8.) The inventors also tested bupropion
`hydrobromide and discovered that bupropion hydrobromide
`in a controlled-release formulation produces a much
`more stable product relative to corresponding bupropion
`hydrochloride formulations. (Trial Tr. 311:18–312:8; Pl.Ex.
`95 at 015319, 154331.) They also discovered that bupropion
`hydrobromide once-a-day tablets can be formulated at all the
`recommended daily dosages, even the highest dosage, which
`had never been accomplished with bupropion hydrochloride.
`(Trial Tr. 312:25–316:13; Pl.Ex. 98 ¶ 34.)
`
`As a result of this research project, Valeant was able to
`develop Aplenzin®, a once-a-day bupropion hydrobromide
`tablet covered by the patents-in-suit. The effective filing
`date of the patents-in-suit is June 27, 2005. Valeant
`launched Aplenzin® in April 2009. Less than a year later
`Watson sought FDA approval to market a generic version
`of Aplenzin®, which Watson has conceded infringes the
`patents-in-suit. Therefore, the sole issue for trial was whether
`each of the asserted claims in the four patents-in-suit is
`invalid.
`
`II. DISCUSSION
`
`*3 “A patent shall be presumed valid.” 35 U.S.C. § 282.
`By statute, the patents-in-suit “have a strong presumption
`of validity in infringement proceedings.” Al–Site Corp. v.
`VSI Int'l, Inc., 174 F.3d 1308, 1323 (Fed.Cir.1999). This
`presumption of validity applies independently to each claim
`within a patent, even if other claims within the patent are held
`invalid. 35 U.S.C. § 282. Accordingly, Watson must prove
`invalidity for each asserted claim.
`
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`To overcome the presumption of validity, the challenger has
`the burden of proving by clear and convincing evidence that
`the patent is invalid. Microsoft Corp. v. i4i Ltd. Partnership,
`––– U.S. ––––, ––––, 131 S.Ct. 2238, 2242, 180 L.Ed.2d
`131 (2011). Clear and convincing evidence is evidence that
`places in the fact finder “an abiding conviction that the truth
`of [the] factual contentions [is] highly probable.” Colorado
`v. New Mexico, 467 U.S. 310, 316, 104 S.Ct. 2433, 81
`L.Ed.2d 247 (1984) (internal quotations omitted). “[I]f the
`fact trier of the issue is left uncertain, the party with the
`burden loses.” Tech. Licensing Corp. v. Videotek, Inc., 545
`F.3d 1316, 1327 (Fed.Cir.2008). This burden “is constant
`and remains throughout the suit on the challenger” and “does
`not shift at any time to the patent owner.” TP Labs., Inc. v.
`Prof'l Positioners, Inc., 724 F.2d 965. 971 (Fed.Cir.1984).
`Moreover, when the Patent Office has considered the prior
`art during prosecution of the patents, the burden on the
`challenger to establish invalidity is even heavier. Glaxo Ltd.
`v. Apotex, Inc., 376 F.3d 1339, 1348 (Fed.Cir.2004); Impax
`Labs., Inc. v. Aventis Pharms., Inc., 468 F.3d 1366, 1378
`(Fed.Cir.2006).
`
`Here, Watson challenges the validity of the five representative
`patent claims on the basis that they are (1) anticipated by the
`prior art; and/or (2) obvious in view of the prior art. The Court
`will address each argument in turn.
`
`A. Anticipation
`
`Watson contends that Claim 3 of the ′610 patent and Claim 1
`of the ′992 patent are invalid for anticipation under 35 U.S.C.
`§ 102(b). 2 Generally speaking, “[a]nticipation means that
`the claimed invention was previously known, and that all of
`the elements and limitations of the claims are described in a
`single prior art reference.” Hakim v. Cannon Avent Group,
`PLC, 479 F.3d 1313, 1319 (Fed.Cir.2007). “[Anticipation]
`requires a finding that ‘each and every limitation is found
`either expressly or inherently in a single prior art reference.’
`” Sanofi, 470 F.3d at 1375 (quoting Celeritas Techs. Ltd. v.
`Rockwell Int'l Corp., 150 F.3d 1354, 1361 (Fed.Cir.1998).
`Anticipation is a question of fact. Eli Lilly & Co. v. Zenith
`Goldline Pharms., Inc., 471 F.3d 1369, 1375 (Fed.Cir.2006).
`
`For a prior art reference to anticipate a claimed invention,
`the reference “must not only disclose all elements of the
`claim within the four corners of the document, but must
`also disclose those elements arranged as in the claim.”
`Net MoneyIN, Inc. v. Verisign, Inc., 545 F.3d 1359,
`
`1369 (Fed.Cir.2008) (internal quotations omitted). “[T]he
`reference must clearly and unequivocally disclose the claimed
`[invention] or direct those skilled in the art to the [invention]
`without any need for picking, choosing, and combining
`various disclosures not directly related to each other by the
`teachings of the cited reference.” In re Arkley, 59 C.C.P.A.
`804, 455 F.2d 586, 587 (C.C.P.A.1972). Any difference
`between the prior art reference and the claimed invention,
`no matter how slight, defeats an anticipation challenge to
`validity. NetMoneyIN, 545 F.3d at 1371. As explained by the
`Federal Circuit in Net MoneyIN:
`
`*4 Thus, it is not enough that the
`prior art reference discloses part of the
`claimed invention, which an ordinary
`artisan might supplement to make the
`whole, or that it includes multiple,
`distinct teachings that the artisan might
`somehow combine to achieve the
`claimed invention.
`
`Id.
`
`In other words, elements of a claim that are not present
`in the single piece of prior art on which the anticipation
`defense is based may not be supplied by the knowledge of one
`skilled in the art or the disclosure of another reference. See
`Structural Rubber Prods. Co. v. Park Rubber Co., 749 F.2d
`707, 716 (Fed.Cir.1984); see also Eli Lilly and Co. v. Sicor
`Pharms., Inc., 705 F.Supp.2d 971, 992 (S.D.Ind.2010) (“In
`showing that all elements of an invention were anticipated,
`the challenging party may not rely upon the knowledge of
`one skilled in the art or the disclosure of another reference to
`supply missing elements.”).
`
`Here, Watson contends that the 1974 Mehta patent (Def.Ex.
`135.) anticipates both Claim 3 of the ′610 patent and Claim
`1 of the ′992 patent, the former expressly and the latter
`inherently. The Court finds that Watson has not met the
`exacting standard for anticipation with respect to either patent
`claim.
`
`I. Claim 3 of the #610 patent is not expressly anticipated
`
`Claim 3 of the ′610 patent is a dependant claim which
`incorporates by reference the elements of Claim 1 of the ′610
`patent. When the two claims are integrated Claim 3 reads as
`follows:
`
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`A method of treating depression,
`comprising administering an effective
`amount of bupropion hydrobromide in
`a once-daily dosage to treat depression
`to a subject in need thereof.
`
`(Def. Ex. 003 at 786051.) Thus, Claim 3 requires that
`the bupropion hydrobromide comprise a once-daily dosage
`form. Yet it is undisputed that the Mehta patent contains
`no disclosure of any once-daily dosage form. (Def.Ex. 135.)
`Indeed. Watson has admitted as such in its post-trial filings.
`(Dkt. No. 141 at 6.) This alone precludes a finding that Claim
`3 of the ′610 patent is expressly anticipated by the Mehta
`patent, as the claimed invention must be identically disclosed
`in the cited prior art reference. NetMoneyIN, 545 F.3d at 1371.
`
`Watson argues that Claim 3 is nevertheless expressly
`anticipated because once-daily dosing of bupropion was well
`known in the prior art by 2004 and thus would “immediately
`have been envisaged by a person of ordinary skill in the art
`in 2004 reading the Mehta ′706 patent.” (Dkt. No. 141 at 5.)
`This argument, however, is exactly the kind of argument that
`has been rejected by the Federal Circuit. See, e.g., Structural
`Rubber, 749 F.2d at 716; NetMoneyIN, 545 F.3d at 1371.
`Accordingly, the Court finds that the Mehta patent does not
`expressly anticipate Claim 3 of the ′610 patent.
`
`2. Claim 1 of the #992 patent is not inherently anticipated
`
`Claim 1 of the ′992 patent is directed to a specific and highly
`stable crystalline compound of bupropion hydrobromide—
`Form I bupropion hydrobromide. Watson does not contend
`that Claim 1 of the ′992 patent is expressly anticipated.
`Rather, Watson's sole challenge to Claim 1 of the ′ 992 patent
`is that it is “inherently” anticipated by the Mehta patent.
`
`*5 Under the doctrine of inherent anticipation, a prior art
`reference that does not expressly disclose a particular element
`of a claimed invention may nevertheless anticipate “if that
`missing characteristic is necessarily present, or inherent, in
`the single anticipating reference.” Schering Corp. v. Geneva
`Pharm., 339 F.3d 1373, 1377 (Fed.Cir.2003). “In general, a
`limitation or the entire invention is inherent and in the public
`domain if it is the natural result flowing from the explicit
`disclosure of the prior art.” Id. at 1379 (internal quotations
`omitted) (emphasis added).
`
`Moreover, the result flowing from the explicit disclosure
`must invariably happen. As the Federal Circuit has stated,
`“[i]nherency ... may not be established by probabilities or
`possibilities. The mere fact that a certain thing may result
`from a given set of circumstances is not sufficient.” In
`re Robertson, 169 F.3d 743, 745 (Fed.Cir.1999) (internal
`quotations omitted) (emphasis added). Cases dealing with
`inherent anticipation look to whether the purported inherent
`production of the claimed compound “faithfully followed”
`the prior art example being relied upon. Glaxo, Inc. v.
`Novopharm Ltd., 830 F.Supp. 871, 876 (E.D.N.C.1993),
`aff'd, 53 F.3d 1043 (Fed.Cir.1995). A prior art example
`inherently anticipates a claimed compound only if the claimed
`compound is “invariably” produced when one follows the
`example. Id. at 874.
`
`In this case, Watson contends that following Example 1
`of the Mehta patent invariably results in Form I bupropion
`hydrobromide and therefore that Claim 1 of the ′992 patent
`is inherently anticipated. In support of this argument, Watson
`relies on the “blinded” opinion of its synthetic chemist
`expert, Dr. Robert Adlington, who synthesized bupropion
`hydrobromide—the result of which was Form I—using
`Example 1 of the Mehta patent. Dr. Adlington concluded that
`following Example 1 invariably results in Form I bupropion
`hydrobromide.
`
`It is undisputed, however, that the explicit disclosure of
`Example 1 of the Mehta patent produces only bupropion
`hydrochloride, not bupropion hydrobromide. (Trial Tr.
`141:13–142:6; 231:5–10; 234:13–16; 639:13–18; Pl.Ex. 96
`at 24 ¶ 73.) Indeed, Dr. Adlington admitted at trial that
`Watson instructed him to modify Example 1 to produce
`bupropion hydrobromide by using hydrobromic acid instead
`of hydrochloric acid. (Trial Tr. 142:7–11.) Thus, because Dr.
`Adlington did not follow the explicit disclosure of Example
`1 of the Mehta patent, his experiment is simply not probative
`of the issue of inherent anticipation, as it clearly does not
`demonstrate that Form I bupropion hydrobromide is the
`“natural result flowing from the explicit disclosure of the prior
`art.” Schering Corp., 339 F.3d at 1379. Accordingly, on this
`basis alone, the Court finds that the Mehta patent does not
`inherently anticipate Claim 1 of the ′992 patent.
`
`Watson argues that Claim 1 is nevertheless inherently
`anticipated because a person of ordinary skill in the art would
`have known that the hydrochloric acid used in Example 1 of
`the Mehta patent could be replaced by hydrobromic acid to
`form bupropion hydrobromide. The Court again finds this line
`
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`of reasoning unpersuasive, as the law of anticipation is clear
`that the challenging party may not rely upon the knowledge
`of one skilled in the art to supply missing elements from the
`claimed invention. See Structural Rubber, 749 F.2d at 716;
`Eli Lilly, 705 F.Supp.2d at 992.
`
`B. Obviousness
`
`*6 Watson also contends that Claims 9 and 10 of the ′823
`patent, Claim 2 of the ′019 patent, and Claim 3 of the ′610
`patent are invalid for obviousness. 3 A patent may not be
`obtained “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.” 35 U.S.C. § 103(a).
`“Obviousness is a question of law based on underlying facts.”
`Group One, Ltd. v. Hallmark Cards, Inc., 407 F.3d 1297,
`1303 (Fed.Cir.2005). Obviousness is determined with respect
`to the subject matter as a whole, not separate pieces of the
`claim. Sanofi–Syntehelabo v. Apotex, Inc., 550 F.3d 1075,
`1086 (Fed.Cir.2008).
`
`1. Legal Standard
`
`To establish a prima facie case of obviousness, the party
`challenging the patent must prove by clear and convincing
`evidence that a person of ordinary skill in the art would
`have been motivated to combine the teachings of the prior
`art references to achieve the claimed invention, and that
`said artisan would have had a reasonable expectation of
`success in doing so. Procter & Gamble Co. v. Teva Pharm.
`USA, Inc., 566 F.3d 989, 994 (Fed.Cir.2009). Underpinning
`this legal inquiry are four groups of factual findings: (a)
`the scope and content of the prior art; (b) the level of
`ordinary skill in the art; (c) the differences between the
`claimed subject matter and the prior art; and (d) secondary
`considerations of non-obviousness, such as commercial
`success, long-felt but unsolved needs, and failure of others. 4
`DyStarTextilfarben GmbH v. C.H. Patrick Co., 464 F.3d
`1356, 1360 (Fed.Cir.2006); Graham v. John Deere Co.,
`383 U.S. 1, 17–18, 86 S.Ct. 684, 15 L.Ed.2d 545 (1966).
`“If a patent challenger makes a prima facie showing of
`obviousness, the owner may rebut based on ‘unexpected
`results' by demonstrating ‘that the claimed invention exhibits
`some superior property or advantage that a person of ordinary
`
`skill in the relevant art would have found surprising or
`unexpected.’ ” Procter & Gamble Co., 566 F.3d at 994
`(quoting In re Soni, 54 F.3d 746, 750 (Fed.Cir.1995).
`
`In KSR Int'l Co. v. Teleflex, Inc., 550 U.S. 398, 407, 127 S.Ct.
`1727, 167 L.Ed.2d 705 (2007), the Supreme Court rejected
`a rigid application of the teaching, suggestion, or motivation
`test, and reaffirmed that the Graham factors “continue to
`define the inquiry that controls” an obviousness analysis.
`Nevertheless, the Court acknowledged the importance of
`identifying “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.” Therefore, “it
`remains necessary to identify some reason that would have
`led a chemist to modify a known compound in a particular
`manner to establish prima facie obviousness of a new claimed
`compound.” Takeda Chem. Indus., Ltd. v. Alphapharm Pty.,
`492 F.3d 1350, 1357 (Fed.Cir.2007). In addition, the KSR
`Court held that an invention may be found obvious if it
`would have been “obvious to try.” KSR, 550 U.S. at 421.
`A patent claim is obvious to try if “there is a design need
`or market pressure to solve a problem and there are a finite
`number of identified, predictable solutions” and pursuit of
`those solutions “leads to the anticipated success.” Id.
`
`*7 Thus, since KSR, the Federal Circuit has emphasized
`that “predictability is the touchstone of obviousness.” DePuy
`Spine, Inc. v. Medtronic Sofamar Danek, Inc., 567 F.3d 1314,
`1326 (Fed.Cir.2009). “[T]he ‘predictable result’ discussed
`in KSR refers not only to the expectation that prior art
`elements are capable of being physically combined, but also
`that the combination would have worked for its intended
`purpose.” Id. (internal citation omitted). In the instant case,
`the intended purpose of the claimed inventions was to create
`a bupropion formulation with improved stability over the
`prior art bupropion hydrochloride formulations. Therefore,
`for Watson to establish that the asserted patent claims
`are obvious, Watson must prove by clear and convincing
`evidence that an ordinarily skilled artisan in 2004 would have
`been motivated to combine the prior art references to achieve
`the claimed inventions—in this case a controlled release
`or once-a-day bupropion hydrobromide formulation—and
`that said artisan would have had a reasonable expectation
`that a bupropion hydrobromide formulation would achieve
`the anticipated success—in this case greater stability over
`bupropion hydrochloride formulations.
`
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`2. Watson has not established a
`prima facie case of obviousness
`
`Taking into account the Graham factors, the Court finds that
`Watson has not made the required showing. Specifically,
`Watson has not proved by clear and convincing evidence
`that a person of ordinary skill in the art in 2004 would
`have had a reasonable expectation that changing the salt in a
`bupropion formulation from hydrochloride to hydrobromide
`would result in increased stability.
`
`As a general rule, salt selection is an unpredictable art.
`Numerous prior art references produced at trial support this
`principle. (See Def. Ex. 132 at 20550 (“Berge”) (Selecting a
`salt form that exhibits the desired combination of properties
`is a difficult semiempirical choice.); Def. Ex. 173 at 20737
`(“Gould”) (same); Def. Ex. 166 at 3683048 (“Bighley”)
`(same); Def. Ex. 345 at 740703 (“Davies”) (“There is yet.
`no reliable way of predicting exactly what effect changing
`the salt form ... will have on its biological activity ....”); Def.
`Ex. 383 at 79314 (“Verbeek”) (“Unfortunately, there is no
`reliable way of predicting the influence of a particular salt
`species on the behavior of the parent compound.”); Pl.Ex. 82
`at 1 (“Black”) (“[T]he ability to predict which salt forms will
`have desirable properties is essentially nonexistent.”).)
`
`Watson has not cited to any witness testimony or prior art
`that contradicts this general rule, and while Watson has cited
`several prior art references that refer to bupropion-related
`compounds, none with the exception of Billinghurst address
`the issue of stability. Thus, Watson relies on the testimony
`of its pharmaceutics expert. Dr. Graham Buckton. At trial
`Dr. Buckton testified that the prior art suggested moving to
`a bupropion hydrobromide formulation as a way to solve
`the known stability problems with bupropion hydrobromide
`formulations. Dr. Buckton cited several prior art references in
`support of this conclusion.
`
`*8 The first is a 1986 publication by Philip L. Gould titled,
`“Salt Selection of Basic Drugs” (“Gould”). (Def.Ex. 173).
`Gould contains a chart with three suggestions for improving
`the stability of a salt. (Def. Ex. 173 at 20747.) Gould's
`first suggestion is to reduce hygroscopicity by increasing the
`acid's hydrophobicity and using a carboxylic acid instead of
`a sulphonic or mineral acid. It is undisputed, however, that
`hydrobromide is a mineral acid salt, not a carboxylic acid salt,
`so this teaching may have actually directed one away from
`the hydrobromide. (Trial Tr. 442:18–443:10.)
`
`Gould's second suggestion for improving stability is to use an
`acid with a higher pKa to reduce the acidity of the acqueous
`solution. It is undisputed, however, that hydrobromic acid is
`one of the few acids with a lower pKa than hydrochloric acid
`(and would thus increase acidity), so this teaching may also
`have directed one away from the hydrobromide. (Pl.Ex. 103
`at 103.349; Trial Tr. 443:16–444:13.)
`
`Gould's third suggestion is to raise the melting point of the
`salt. As one of three possibilities for doing so he suggests
`choosing a small counter ion, listing the chloride and the
`bromide as examples. In a 2003 version of the same chart
`reproduced by P. Heinrich Stahl, however, the bromide ion
`is no longer referenced as an example of a “small counter
`ion.” (Def. Ex. 130 at 20598.) At trial Dr. Buckton could offer
`no explanation for the subsequent omission of the bromide
`ion from the Gould chart, nor did he explain why he chose to
`rely on the outdated 1986 version of the Gould chart, rather
`than the 2003 Stahl version that was contemporaneous with
`the time of the invention. (Trial Tr. 74:19–76:17.)
`
`In addition, Gould's suggestion to raise the melting point of
`the salt would not lead to the selection of a hydrobromide
`as a means to improve the stability of a hydrochloride salt,
`because the relative melting points of chlorides and bromides
`are not possible to predict. For example, lithium bromide and
`sodium bromide have lower melting points than their chloride
`containing counterparts; conversely, ammonium bromide has
`a higher melting point than ammonium chloride. Moreover,
`bupropion hydrobromide actually has a lower melting point
`than bupropion hydrochloride. (Pl.Ex. 94 at 13.)
`
`Thus, none of the suggestions in Gould would have led an
`ordinarily skilled artisan in 2004 to reasonably expect that
`switching from a hydrochloride to a hydrobromide would
`improve salt stability. In fact, Gould's suggestions may have
`actually led one away from choosing a hydrobromide to solve
`the known stability problem with bupropion hydrochloride.
`
`The second prior art reference cited by Dr. Buckton
`is a 1996 publication by Lyle D. Bighley titled, “Salt
`Forms of Drugs and Absorption” (“Bighley”). (Def.Ex.
`166.) Although Bighley teaches that salt selection is a
`difficult choice (Def. Ex. 166 at 3683048), Dr. Buckton
`cited Bighley at trial as purportedly containing a reason
`to select bupropion hydrobromide to improve stability
`of bupropion hydrochloride formulations. (Trial Tr. 99:3–
`25.) In particular, Dr. Buckton pointed to the following
`
` © 2016 Thomson Reuters. No claim to original U.S. Government Works.
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`Valeant Intern. (Barbados) SRL v. Watson Pharmaceuticals, Inc., Not Reported in...
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`statement under the heading Preparation of Other Mineral
`Acids: “Mineral acids other than hydrochloric, such as
`sulfuric, phosphoric, and hydrobromic, have been employed
`principally to reduce hygroscopicity and perhaps the acidity
`of a resulting solution.” (Def. Ex. 166 at 3683080.)
`
`*9 This section, however, contains no discussion of stability.
`Rather, stability is addressed in the following section, and
`while that section mentions several possible options to
`improve stability, using a hydrobromide salt is not one
`of them. (Def. Ex. 166 at 3683080.) Furthermore, given
`that Billinghurst had already tested a number of bupropion
`mineral acids, albeit not the hydrobromide, and found all
`of them to be unstable, Bighley's statement about reducing
`hygroscopicity by using other mineral acids would provide
`little guidance to an ordinarily skilled artisan in 2004
`looking to solve the known stability problems with bupropion
`hydrochloride.
`
`Dr. Buckton also cited to a 2000 publication by Richard
`J. Bastin, but this prior art offers no guidance on how
`to improve the stability of a hydrochloride salt, let alone
`bupropion hydrochloride. (Def.Ex. 176.) The final prior art
`reference cited by Dr. Buckton as suggesting to try bupropion
`hydrobromide to solve the known stability problems with
`bupropion hydrochloride is U.S. Patent No. 6,110,940, filed
`May 17, 1995 (the “Harding patent”). (Def.Ex. 138.) In his
`expert report, Dr. Buckton cited Harding for its purported
`teaching that a hydrobromide salt of an indole compound
`was stable while the hydrochloride salt supposedly was not.
`(Def. Ex. 602 at 31.) At trial, however, Dr. Buckton was
`forced to concede that the Harding patent in fact taught that
`the indole hydrochloride salt was stable. (Trial Tr. 78:21–
`82:8.) In an effort to explain this apparent inconsistency, Dr.
`Buckton admitted that it is not possible to predict the stability
`of bupropion hydrobromide based on information about the
`stability of different drugs. (Trial Tr. 81:25–82:22.)
`
`Moreover, the relative hygroscopicity of chlorides and
`bromides is not predictable. In some cases bromides are
`more hygroscopic than chlorides; in other cases chlorides
`are more hygroscopic than bromides; and in still other
`cases, they are comparable. For example, potassium bromide
`is more hygroscopic than potassium chloride, while on
`the other hand lithium bromide is more hygroscopic than
`lithium chloride. (Def. Ex. 94 at 12.) And in the Harding
`and Bastin references cited by Dr. Buckton (and discussed
`more thoroughly below), hydrobromides and hydrochlorides
`are shown to be comparable, not different, in terms of
`hygroscopicity. (Trial Tr. 78:21–81:21.)
`
`*10 Dr. Buckton thus confirmed that one cannot predict how
`the stability of bupropion formulations will be affected by
`a change in salt based on teachings about the corresponding
`salts of other drugs. That admission is consistent with the
`many prior art references that teach that salt selection is
`inherently unpredictable and, in particular, with the statement
`made in the Davies reference: “There is, as yet, no reliable
`way of predicting exactly what effect changing the salt form
`of an acti