Case 1:13-cv-01110-GMS Document 304 Filed 04/20/16 Page 1 of 19 PageID #: 3052
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`PFIZER INC. and UCB PHARMA GMBH,
`
`Plaintiffs,
`
`v.
`
`SANDOZ INC., et al.,
`
`Defendants.
`
`)
`)
`)
`)
`)
`)
`)
`)
`)
`)
`
`C.A. No. 13-1110-GMS
`CONSOLIDATED
`
`I.
`
`INTRODUCTION
`
`MEMORANDUM
`
`In this consolidated patent infringement action, Pfizer Inc. and UCB Pharma GmbH
`
`(collectively, "the Plaintiffs") allege that Accord Healthcare Inc., USA, Amerigen Pharmaceuticals
`
`Ltd., Amerigen Pharmaceuticals, Inc., Amneal Pharmaceuticals, LLC, and Sandoz Inc.
`
`(collectively, "the Defendants") infringe the asserted claims of the patents-in-suit. The court held a
`
`four:day bench trial in this matter on July 13 through July 16, 2015. Presently before the court are
`
`the parties' post-trial proposed findings of fact and conclusions of law concerning the validity of
`
`the patents-in-suit, specifically whether the asserted claims are invalid as obvious under 35 U.S.C.
`
`§ 103. (D.I. 292; D.I. 297.)
`
`Pursuant to Federal Rule of Civil Procedure 52(a), having considered the entire record in
`
`this case and the applicable law, the court concludes that none asserted claims of the patents-in-suit
`
`are invalid due to obviousness. These findings of fact and conclusions oflaw are set forth in further
`
`detail below.
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2001 - 0001
`
`

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`Case 1:13-cv-01110-GMS Document 304 Filed 04/20/16 Page 2 of 19 PageID #: 3053
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`II.
`
`FINDINGS OF FACT 1
`
`A.
`
`The Parties
`
`Plaintiff Pfizer Inc. ("Pfizer") is a corporation organized and existing under the laws of
`1.
`Delaware and has a place of business at 235 East 42nd Street, New York, New York.
`
`Plaintiff UCB Pharma GmbH is an entity organized and existing under the laws of Germany,
`2.
`and has a place of business at Alfred-Nobel-Strasse 10, Monheim, Germany.
`
`Defendant Accord Healthcare Inc., USA ("Accord") is a company organized and existing
`3.
`under the laws of North Carolina and has a principal place of business at 1009 Slater Road, Suite
`210-B, Durham, North Carolina.
`
`Defendant Amerigen Pharmaceuticals Ltd. is a corporation organized and existing under the
`4.
`laws of the Cayman Islands and has a registered office at C/O Codan Trust Company (Cayman)
`Limited, Cricket Square, Hutchins Drive, P.O. Box 2681, Grand Cayman, KYl-1111 Cayman.
`
`Defendant Amerigen Pharmaceuticals, Inc. is a company organized and existing under the
`5.
`laws of Delaware and has a principal place ofbusiness at 9 Polito Ave., Suite 900, Lyndhurst, New
`Jersey. Amerigen Pharmaceuticals, Inc. is the U.S. agent for Amerigen Pharmaceuticals Ltd
`(collectively, "Amerigen").
`
`Defendant Amneal Pharmaceuticals, LLC ("Amneal") is a company organized and existing
`6.
`under the laws of Delaware and has a principal place of business at 440 US Highway 22 East, Suite
`104, Bridgewater, New Jersey.
`
`Defendant Sandoz Inc. ("Sandoz") is a company organized and existing under the laws of
`· 7.
`Colorado and has a place of business at 100 College Road West, Princeton, New Jersey.
`
`8.
`
`The court has subject matter jurisdiction and personal jurisdiction over all parties.
`
`B.
`
`Background
`
`Pfizer holds approved New Drug Application ("NDA") No. 02-2030 for fesoterodine
`9.
`fumarate extended-release tablets, in 4 and 8 mg dosage strengths, which Pfizer sells under the trade
`name Toviaz®.
`
`1. Prior to trial, the parties submitted an exhibit of uncontested facts in conjunction with their Pretrial Order.
`(D.I. 256, Ex. 1.) The court takes most of its findings of fact from the parties' uncontested facts. The court has also
`reordered and renumbered some paragraphs and made minor edits for the purpose of concision and clarity that it does
`not believe alters the meaning of the paragraphs from the Pretrial Order. Otherwise, any differences between this section
`and the parties' statement of uncontested facts are unintentional.
`The court's findings of fact with respect to matters that were the subject of dispute between the parties are
`included in Part III this opinion ("Discussion and Conclusions of Law"), preceded by the phrase "the court finds" or
`"the court concludes."
`
`2
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2001 - 0002
`
`

`
`Case 1:13-cv-01110-GMS Document 304 Filed 04/20/16 Page 3 of 19 PageID #: 3054
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`Toviaz® is a FDA-approved treatment of overactive bladder with symptoms of urge urinary
`10.
`incontinence, urgency, and urinary frequency. The FDA first approved the NDA for Toviaz® on
`October 31, 2008.
`·
`
`Pursuant to 21 U.S.C. § 335(b)(l) and attendant FDA regulations, U.S. Patent Nos.
`11.
`7,384,980 (''the '980 patent"), 7,855,230 ("the '230 patent"), 7,985,772 ("the '772 patent"),
`8,338,478 ("the '478 patent"), and 6,858,650 ("the '650 patent") are among the patents listed in the
`FDA publication, "Approved Drug Products with Therapeutic Equivalence Evaluations" (the
`"Orange Book") with respect to Toviaz®.
`
`12.
`
`13.
`
`Fesoterodine fumarate is the active pharmaceutical ingredient in Toviaz®.
`
`Chemical names for fesoterodine fumarate include:
`a.
`isobutyric acid 2-((R)-3-diisopropylammonium-1-phenylpropyl)-4-
`hydroxymethylphenyl ester hydrogen fumarate;
`b. R~( + )-2-(3-diisopropylamino-1-phenyl-propyl)-4-hydroxymethylphenylisobutyrate
`ester hydrogen fumarate;
`c. R-( + )-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethylphenylisobutyrate
`ester hydrogen fumarate;
`d. R-( + )-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutyrate
`ester hydrogen fumarate; and
`e. R-( + )-isobutyric acid 2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethylphenyl
`ester hydrogen fumarate.
`
`14.
`
`The structural formula of fesoterodine fumarate is:
`
`HO
`
`.
`i
`' The asterisk(":) indic'ate_s tl~f: chiral carbon. ·
`
`C.
`
`The Patents-in-Suit
`
`Collectively, the '980, '230, '772, and '478 patents may be referred to as the "Compound
`15.
`Patents."
`
`The Compound Patents each issued from common parent applications, each of which
`16.
`ultimately claim priority to European Application No. 98108608.5, filed May 12, 1998.
`
`'980 patent issued on June 10, 2008 and is entitled "Derivatives of 3,3-
`The
`17.
`Diphenylpropylamines." The '980 patent names Claus Meese and Bengt Sparf as inventors.
`
`3
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2001 - 0003
`
`

`
`Case 1:13-cv-01110-GMS Document 304 Filed 04/20/16 Page 4 of 19 PageID #: 3055
`
`The '230 patent issued on December 21, 2010 and is entitled "Derivatives of 3,3-
`18.
`Diphenylpropylamines." The '230 patent names Claus Meese and Bengt Sparf as inventors.
`
`'772 patent issued on July 26, 2011 and is entitled "Derivatives of 3,3-
`The
`19.
`Diphenylpropylamines." The '772 patent names Claus Meese and Bengt Sparf as inventors.
`
`The '478 patent issued on December 25, 2012 and is entitled "Derivatives of 3,3-
`20.
`Diphenylpropylamines." The '4 78 patent names Claus Meese and Bengt Sparf as inventors.
`
`The '650 patent issued on February 22, 2005 and is entitled "Stable Salts of Novel
`21.
`Derivatives of3,3-Diphenylpropylamines." The parties refer to the '650 patent as the "Salt Patent."
`It claims priority to German Patent Application No. DE 199 55 190 filed November 16, 1999. The
`'650 patent names Claus Meese as the inventor.
`
`(1)
`
`The Asserted Claims
`
`The Plaintiffs have asserted infringement of claims 1, 2, 3 and 7 of the '980 patent against
`22.
`each defendant.
`
`The Plaintiffs have asserted infringement of claims 3 and 5. of the '230 patent against each
`23.
`defendant.
`
`The Plaintiffs have asserted infringement of claim 3 of the '772 patent against each
`24.
`defendant.
`
`The Plaintiffs have asserted infringement of claim 3 of ·the '4 78 patent against each
`25.
`defendant.
`
`The Plaintiffs have asserted infringement of claims 3, 5, 23 and 24 of the '650 patent against
`26.
`each defendant.
`
`1.
`
`'980 Patent, Claim 1
`
`Claim 1 of the '980 patent claims: R-(+)-isobutyric acid 2-(3-diisopropylamino-1-
`27.
`phenylpropyl)-4-hydroxymethylphenyl ester.
`
`11.
`
`'980 Patent, Claim 2
`
`Claim 2 of the '980 patent claims: A salt ofR-(+)-isobutyric acid 2-(3-diisopropylamino-1-
`28.
`phenyl propyl)-4-hydroxymethylphenyl ester with a physiologically acceptable acid.
`
`m.
`
`'980 Patent, Claim 3
`
`Claim 3 of the '980 patent claims: A pharmaceutical composition comprising an effective
`29.
`amount of R-(+ )-isobutyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl
`
`4
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2001 - 0004
`
`

`
`Case 1:13-cv-01110-GMS Document 304 Filed 04/20/16 Page 5 of 19 PageID #: 3056
`
`ester, or a salt thereof with a physiologically acceptable acid and a pharmaceutically acceptable
`earner.
`
`1v.
`
`'980 Patent, Claim 7
`
`Claim 7 of the '980 patent claims: The method according to claim 6 [a method according
`30.
`to claim 5 {a method of treating a disease in a mammal that is amenable to treatment by
`antagonizing muscarinic receptors in the mammal, the method comprising administering to the
`mammal a pharmaceutical composition comprising an effective amount of R-( + )-isobutyric acid 2-
`(3-diisopropylamino-I -phenylpropyl)-4-hydroxymethylphenyl ester or a salt thereof with a
`physiologically acceptable acid} wherein the disease is urinary incontinence] wherein the mammal
`is a human.
`
`v.
`
`'230 Patent, Claim 3
`
`Claim 3 of the '230 patent claims: The method according to claim 1 [a method of treating
`31.
`urinary incontinence in a patient in need thereof, the method comprising administering to the
`patient an effective amount of a compound selected from the group consisting of n-butyric acid 2-
`(3-diisopropylamino-I-phenylpropyl)-4-hydroxymethylphenyl
`ester,
`isobutyric acid 2-(3-
`diisopropylamino-I-phenylpropyl)-4-hydroxymethylphenyl
`ester,
`propionic
`acid
`2-(3-
`diisopropylamino-I-phenylpropyl)-4-hydroxymethylphenyl
`ester,
`and acetic acid 2-(3-
`diisopropylamino-I-phenylpropyl)-4-hydroxymethylphenyl ester, including the racemic mixtures
`and individual enantiomers of said compounds, and a salt of said compounds with a physiologically
`acceptable acid], wherein the compound is R-(+) isobutyric acid 2-(3-diisopropylamino-1-
`phenylpropyl)-4-hydroxymethylphenyl ester.
`
`vi.
`
`'230 Patent, Claim 5
`
`Claim 5 of the '230 patent claim.s: The method according to any one of claims 1-4, wherein
`32.
`the compound is administered to the patient in the form of a pharmaceutical composition
`comprising a pharmaceutically acceptable carrier.
`
`VIL
`
`'772 Patent, Claim 3
`
`Claim 3 of the '772 patent claims: The 3,3-Diphenylpropylamine of claim 1 [3,3-
`33.
`Diphenylpropylamines of the general formula:
`R'
`I
`
`"""'
`
`!)
`
`""'-.
`wherein RI is hydrogen and R2 is CI-C6 alkylcarbonyl; or RI is CI-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] wherein RI is Cl-C6 alkylcarbonyl and R2 is hydrogen.
`
`5
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2001 - 0005
`
`

`
`Case 1:13-cv-01110-GMS Document 304 Filed 04/20/16 Page 6 of 19 PageID #: 3057
`
`vm.
`
`'47B Patent, Claim 3
`
`Claim 3 of the '478 patent claims: The 3,3-Diphenylpropylamines of claim 1 [3,3-
`34.
`Diphenylpropylamines of the formula
`R1
`I
`0
`
`x
`
`=::::,,...
`where: RI is hydrogen and R2 is Cl-C6 alkylcarbonyl; or RI is Cl-C6 alkylcarbonyl and R2 is
`hydrogen; and Xis a tertiary amino group of formula
`RSl
`I
`-.!\
`-\
`---
`-- Rile -
`where RB and R9 are each independently Cl-CB alkyl and together comprise at least three
`carbon atoms; 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], where Xis selected from the group consisting of:
`CH,
`CH
`CH(CH·1,
`I
`-
`·'·'·
`I
`-
`I
`3
`-N
`-N
`·-"!\"
`\
`\
`\
`cmcn,)2,.
`C(CII:;)3,
`C(CII3)2C'II2CII3.
`
`1x.
`
`'650 Patent, Claim 3
`
`Claim 3 of the '650 patent claims: "Compounds in accordance with claim 1, characterized
`35.
`in that they have general formula 2
`
`110
`
`x-
`
`in which R denotes Cl-C6-alkyl, C3-C10-cycloalkyl, substituted or unsubstituted phenyl and X(cid:173)
`is the acid residue of a physiologically compatible inorganic or organic acid.
`
`x.
`
`'650 Patent, Claim 5
`
`Claim 5 of the '650 patent claims: Compounds in accordance with claim 3, characterized
`36.
`in that they are R-(+)-2-(3-(diisopropylamino-1-phenylpropyl)-4-
`hydroxymethylphenylisobutyrate ester hydrogen fumarate, R-( + )-2-(3-( diisopropylamino-l(cid:173)
`phenylpropyl)-4-hydroxymethylphenylisobutyrate ester-hydrochloride hydrate.
`
`6
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2001 - 0006
`
`

`
`Case 1:13-cv-01110-GMS Document 304 Filed 04/20/16 Page 7 of 19 PageID #: 3058
`
`xi.
`
`~650 Patent, Claim 23
`
`Claim 23 of the '650 patent claims: A method of treating a patient suffering from urinary
`37.
`incontinence, which method comprises the step of administering to said patient an effective
`amount of a compound according to claim 5.
`
`xn.
`
`· '650 Patent, Claim 24
`
`Claim 24 of the '650_patent claims: The method of any one of claims 21-23, wherein the
`38.
`urinary incontinence disorder is urge incontinence.
`
`(2)
`
`The Accused Products
`
`i.
`
`ANDA No. 205012 Submitted by Accord
`
`Accord submitted Abbreviated New Drug Application ("ANDA") No. 205012 to the FDA
`39.
`pursuant to 21 U.S.C. §§ 355G), seeking approval to market fesoterodine fumarate extended-release
`tablets in 4 and 8 mg dosage strengths ("Accord's Product")
`
`Accord's ANDA refers to and relies upon the Toviaz® NDA and contains data that,
`40.
`according to Accord, demonstrates that Accord's Product is bioequivalent to Toviaz®.
`
`Accord included certifications in its ANDA, pursuant to 21 U.S.C. § 355G)(2)(A)(vii)(IV),
`41.
`that the '650, '980, '230, '772, and '478 patents are invalid, unenforceable, or will not be infringed
`by the commercial manufacture, use, or sale of Accord's Product.
`
`On June 7, 2013, Accord sent Notice of its Paragraph IV certifications to the Plaintiffs,
`42.
`providing its asserted factual and legal bases for its contentions that the '650, '980, '230, '772, and
`'478 patents.are not infringed, invalid or unenforceable.
`
`In response to Accord's Notice, on August 21, 2013, the Plaintiffs sued Accord for
`43.
`infringement of the '650, '980, '230, '772, and '478 patents, pursuant to 35 U.S.C. § 271(e)(2)(A).
`
`11.
`
`ANDA No. 204504 Submitted by Amerigen
`
`Amerigen submitted ANDA No. 204504 to the FDA, pursuant to 21 U.S.C. §§ 355G),
`44.
`seeking approval to market fesoterodine fumarate extended-release tablets in 4 and 8 mg dosage
`strengths ("Amerigen's Product").
`
`Amerigen's ANDA refers to and relies upon the Toviaz® NDA and contains data that,
`45.
`according to Amerigen, demonstrates that Amerigen's Product is bioequivalent to Toviaz®.
`
`to 21 U.S.C. §
`its ANDA, pursuant
`in
`included certifications
`Amerigen
`46.
`355G)(2)(A)(vii)(IV), that the '650, '980, '230, '772, and '478 patents are invalid, unenforceable,
`or will not be infringed by the commercial manufacture, use, or sale of Amerigen's Product.
`
`7
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2001 - 0007
`
`

`
`Case 1:13-cv-01110-GMS Document 304 Filed 04/20/16 Page 8 of 19 PageID #: 3059
`
`On May 31, 2013, Amerigen sent Notice of its Paragraph IV certifications to tht'. Plaintiffs,
`47.
`providing its asserted factual and legal bases for its contentions that the '650, '980, '230, '772, and
`'4 78 patents are not infringed, invalid or unenforceable.
`
`In response to Amerigen's Notice, on June 28, 2013, the Plaintiffs sued Amerigen for
`48.
`infringement of the '650, '980, '230, '772, and '478 patents, pursuant to 35 U.S.C. § 271(e)(2)(A).
`
`111.
`
`ANDA No. 205002 Submitted by Amneal
`
`Amneal submitted ANDA No. 205002 to the FDA, pursuant to 21 U.S.C. §§ 355(j), seeking
`49.
`approval to market fesoterodine fumarate extended-r~lease tablets in 4 and 8 mg dosage strengths
`("Amneal' s Product").
`
`50.
`Amneal's ANDA refers to and relies upon the Toviaz® NDA and contains data that,
`according to Amneal, demonstrates that Amneal's Product is bioequivalent to Toviaz®.
`
`Amneal included certifications in its ANDA, pursuant to 21 U.S.C. § 355(j)(2)(A)(vii)(IV),
`51.
`that the '650, '980, '230, '772, and '4 78 patents are invalid, unenforceable, or will not be infringed
`by the commercial manufacture, use, or sale of Amneal's Product.
`
`On May 24, 2013, Amneal sent Notice of its Paragraph IV certifications to the Plaintiffs,
`52.
`providing its asserted factual and legal bases for its contentions that the '650, '980, '230, '772, and
`'4 78 patents are not infringed, invalid or unenforceable.
`
`In response to Amneal's Notice, on June 28, 2013, the Plaintiffs sued Amneal for
`53.
`infringement of the '650, '980, '230, '772, and '478 patents, pursuant to 35 U.S.C. § 271(e)(2)(A).
`
`1v.
`
`ANDA No. 204844 Submitted by Sandoz
`
`Sandoz submitted ANDA No. 204844 to the FDA, pursuant to 21 U.S.C. §§ 355(j), seeking
`54.
`approval to engage in the commercial manufacture, use, sale, offers for sale and importation of
`fesoterodine fumarate extended-release tablets in 4 and 8 mg dosage strengths ("Sandoz's
`Product").
`
`Sandoz's ANDA refers to and relies upon the Toviaz® NDA and contains data that,
`55.
`according to Sandoz, demonstrates that Sandoz's Product is bioequivalent to Toviaz®.
`
`Sandoz included certifications in its ANDA, pursuant to 21 U.S.C. § 355(j)(2)(A)(vii)(IV),
`56.
`thatthe '650, '980, '230, '772, '478, '715, '398, and '723 patents are invalid, unenforceable, or will
`not be infringed by the commercial nianufacture, use, offer for sale, sale or importation of Sandoz' s
`Product.
`
`57.
`On May 9, 2013 and September 19, 2013, Sandoz sent Notices of its Paragraph IV
`certifications to the Plaintiffs, providing its asserted factual and legal bases for its contentions that
`the '650, '980, '230, '772, '478, '715, '398, and '723 patents are not infringed, invalid or
`unenforceable.
`
`8
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2001 - 0008
`
`

`
`Case 1:13-cv-01110-GMS Document 304 Filed 04/20/16 Page 9 of 19 PageID #: 3060
`
`In response to Sandoz's Notice, on June 21, 2013, the Plaintiffs sued Alkem for
`58.
`infringement of the "650, '980, '230, '772, and '478 patents, pursuant to 35 U.S.C. § 271(e)(2)(A).
`
`Sandoz answered the complaint on August 14, 2013, denying infringement, raising
`59.
`affirmative defenses of invalidity, no direct infringement, no inducement of infringement, and no
`contributory infringement. At that time, Sandoz asserted counterclaims seeking declaratory
`judgment ofinvalidity and non-infringement of the '650, '980, '230, '772, and '478 patents, as well
`as the '715 and '398 patents.
`
`D.
`
`Procedural History
`
`The Plaintiffs' patent infringement claims against Accord, Amerigen, Amneal, and Sandoz
`60.
`were consolidated under Civil Action No. 13-1110 on November 6, 2013.
`
`--
`The court held a bench trial on July 13 through July 16, 2015. The Defendants argued that
`61.
`all asserted claims are invalid as obvious under 35 U.S.C. § 103. The Defendants also argued that
`claims 5, 23, and 24 of the '650 patent are invalid as anticipated under 35 U.S.C. § 102, and that
`claim 5 of the '650 patent is invalid as indefinite under 35 U.S.C. § 112(b). All defendants except
`for Sandoz stipulated to infringement of all asserted claims. Sandoz denied that it infringed claim
`1 of the '980 patent and claim 3 of the '230 patent.
`
`At the close of the Plaintiffs' production of evidence concerning infringement, Sandoz and
`62.
`the Plaintiffs moved pursuant to Federal Rule of Civil Procedure 52(c) for judgment on partial
`findings on the issue of infringement. (D.I. 272; D.I. 273.) The court ruled in favor of the Plaintiffs,
`finding that to the extent that the asserted claims are valid, Sandoz infringes the claims. (D.I. 276.)
`
`At the close of the Defendants' prima facie case for invalidity of the asserted patents, the
`63.
`Plaintiffs moved pursuant to Federal Rule of Civil Procedure 52( c) for judgment on partial findings
`on the issues of obviousness, anticipation, and indefiniteness. (Tr. at 452:4-457:20.) The court
`denied the Plaintiff's motion on obviousness (Tr. at 457:23-25), and granted the Plaintiffs' motion
`on anticipation (Tr. at 660:16-662:25) and indefiniteness (D.I. 278).
`
`III. DISCUSSION AND CONCLUSIONS OF LAW
`
`The court has subject matter jurisdiction over this matter pursuant to 28 U.S.C. §§ 1331,
`
`1338, and 2201. Venue is proper in this court under 28 U.S.C. §§ 1391 and 1400(b). The only
`
`remaining issue is whether the asserted claims of the patents-in-suit are invalid due to obviousness.
`
`The Defendants challenge the validity of each of the asserted claims, arguing that they are obvious
`
`in light of the prior art. The court finds that, for the reasons that follow, the Defendants have failed
`
`to establish by clear and convincing evidence that the patents-in-suit are obvious.
`
`9
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2001 - 0009
`
`

`
`Case 1:13-cv-01110-GMS Document 304 Filed 04/20/16 Page 10 of 19 PageID #: 3061
`
`A.
`
`The Legal Standard
`
`35 U.S.C. § 103(a) provides that 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 to a person having ordinary skill in the art." 35 U.S.C. § 103(a).
`
`Obviousness is a question of law that is predicated on several factual inquires. See Richardson-
`
`Vicks v. Upjohn Co., 122 F.3d 1476, 1479 (Fed. Cir. 1997). The trier of fact is directed to assess
`
`four considerations: (1) the scope and content of the prior art; (2) the level of ordinary skill in the
`
`art; (3) the differences between the claimed subject matter and the prior art; and (4) secondary
`
`considerations of non-obviousness, such as commercial success, long felt but unsolved need, failure
`
`of others, acquiescence of others in the industry that the patent is valid, and unexpected results. See
`
`Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966).
`
`"A patent shall be presumed valid." 35 U.S.C. § 282. A party seeking to challenge the
`
`validity of a patent based on obviousness must demonstrate by clear and convincing evidence2 that
`
`the invention described in the patent would have been obvious to a person of ordinary skill in the
`
`art at the time the invention was made. Importantly, in determining what would have been obvious
`
`to one of ordinary skill in the art, the use of hindsight is not permitted. See KSR Int 'l Co. v. Teleflex,
`
`Inc., 550 U.S. 398, 421 (2007) (cautioning the trier of fact against "the distortion caused by
`
`hindsight bias" and "arguments reliant upon ex post reasoning" in determining obviousness). In
`
`KSR, th.e Supreme Court rejected the rigid application of the principle that there should be an
`
`explicit "teaching, suggestion, or motivation" in the prior art, the nature of the problem, or the
`
`knowledge of a person having ordinary skill in the art, in order to find obviousness. See id. at 415.
`
`2 "Clear and convincing evidence is evidence that places in the fact finder an abiding conviction that the truth
`of [the] factual contentions are highly probable." Alza Corp v. Andrx Phanns., LLC, 607 F. Supp. 2d 614, 631 (D. Del.
`2009) (internal quotations omitted) (quoting Colorado v. New Mexico, 467 U.S. 310, 316 (1984)).
`
`10
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`Patent Owner, UCB Pharma GmbH – Exhibit 2001 - 0010
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`Case 1:13-cv-01110-GMS Document 304 Filed 04/20/16 Page 11 of 19 PageID #: 3062
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`TheKSR Court acknowledged, however, the importance of identifying '"a reason that would have
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`prompted a person of ordinary skill in the relevant field to combine the elements in the way the
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`claimed new invention does' in an obviousness determination." Takeda Chem. Indus. v.
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`Alphapharm Pty. Ltd., 492 F.3d 1350, 1356-57 (Fed. Cir. 2007) (quotingKSR, 550 U.S. at 418).
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`"Obviousness does not require absolute predictability of success," but rather, requires "a
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`reasonable expectation of success." See Medichem, S.A. v. Rolado, S.L., 437 F.3d 1157, 1165 (Fed.
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`Cir. 2006) (quoting In re O'Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988)). To this end,
`obviousness "cannot be avoided simply by a showing of some degree of unpredictability in the art
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`so long as there was a reasonable probability of success." Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348,
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`1364 (Fed. Cir. 2007). Moreover, while the Federal Circuit has noted that pharmaceuticals can be
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`an "unpredictable art" to the extent that results may be unexpected, it also recognizes that, per KSR,
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`evidence of a "finite number of identified, predictable solutions" or alternatives "might support an
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`inference of obviousness." See Eisai Co. Ltd. v. Dr. Reddy's Labs. Ltd., 533 F.3d 1353, 1359 (Fed.
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`Cir. 2008).
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`B.
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`The Level of Ordinary Skill in the Art
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`A person of ordinary skill in the art with respect to the patents-in-suit would have: (1) a
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`Ph:D. in chemistry, medicinal chemistry, pharmacology, or a related field; 3 or (2) a Ph.D. in organic
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`chemistry, medicinal chemistry, pharmacology, biochemistry or a related discipline with two or
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`more years of industrial experience in organic synthetic chemistry or drug formulation, and would
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`collaborate with others having more biological experience in pertinent disciplines such as urology,
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`medicine, and pharmacology.4 Additional experience could substitute for the advanced degree. The
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`3 The Plaintiffs' identification of a person of ordinary skill in the art is derived from Dr. Roush and Dr. Maag.
`(Tr. at 605:9-18 (Roush); Tr. at 531:20-532:6 (Maag).)
`4 Defendants' description of a personal of ordinary skill in the art is derived from Dr. Sloan. (Tr. at 301:3-23
`(Sloan).)
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`11
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`Patent Owner, UCB Pharma GmbH – Exhibit 2001 - 0011
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`Case 1:13-cv-01110-GMS Document 304 Filed 04/20/16 Page 12 of 19 PageID #: 3063
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`court concludes that the parties' definitions of a person of ordinary skill in the art do not differ in a
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`meaningful way.
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`C.
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`The Scope and Content of the Prior Art and Differences Between the Claimed
`Subject Matter and the Prior Art
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`The Defendants argue a person of ordinary skill in the art would have found it obvious to
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`synthesize fesoterodine as an improved overactive bladder treatment. The Defendants base their
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`theory on the prior art molecule tolterodine and its metabolite, 5-HMT. To determine whether the
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`Defendants have _established a prima facie case of obviousness, the court must determine 1)
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`"whether a chemist of ordinary skill would have selected the asserted prior art compounds as lead
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`compounds, or starting points, for future development efforts"; and 2) whether the prior art would
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`have supplied one of ordinary skill in the art with a reason or motivation to modify a lead compound
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`to make the claimed compound with a reasonable expectation of success." Otsuka Pharm. Co. v.
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`Sandoz, Inc., 678 F.3d 1280, 1291-92 (Fed. Cir. 2012).
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`(1)
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`5-HMT as a Lead Compound
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`The Defendants argue a person of ordinary skill would have chosen 5-HMT as a lead
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`compound for an improved overactive bladder treatment. As of the May 12, 1998 priority date,
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`overactive bladder treatments included negative limitations such as urinary retention, dry mouth,
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`and cardiac side effects. (D.I. 292 at 5.) The Defendants argue that a person of ordinary skill seeking
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`to create an improved overactive bladder drug would only focus on antimuscarinic compounds.
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`Antimuscarinic compounds block the neurotransmitter acetylcholine from binding to one of five
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`types of muscarinic receptors in the body. Both parties agree that antimuscarinics were a popular
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`treatment for overactive bladder at that time. (D.I. 292 at 5; D.I. 297 at 3.) Tolterodine and
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`oxybutynin were the antimuscarinic compounds approved to treat overactive bladder in the United
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`States. (Tr. at 760:7-18 (Serels).) Unlike oxybutynin, tolterodine and its metabolite 5-HMT were
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`12
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`Patent Owner, UCB Pharma GmbH – Exhibit 2001 - 0012
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`Case 1:13-cv-01110-GMS Document 304 Filed 04/20/16 Page 13 of 19 PageID #: 3064
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`selective for the urinary bladder over salivary glands, which reduced the adverse side effect of dry
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`mouth. (Tr. at 213:7-19 (Mayersohn).) The Defendants claim that tolterodine's bladder selectivity
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`would have motivated a person of ordinary skill to focus on developing 5-HMT.
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`The fatal flaw in the Defendants' lead compound theory is that their experts did not analyze
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`the full field of overactive bladder treatments to determine what would qualify as a lead compound.
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`The Plaintiffs' expert Dr. Maag testified that a person of ordinary skill would also consider other
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`types of lead compounds, such as calcium channel antagonists, potassium channel antagonists, and
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`alpha adrenoreceptor antagonists. (Tr. at 524:20-525:13, 528:7-17 (Maag)). Meanwhile, the
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`Defendants' experts Dr. Mayersohn and Dr. Sloan narrowly considered tolterodine and 5-HMT and
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`did not address other possibilities. (Tr. at 220:24-222:5 (Mayersohn); Tr. at 300:~ 7 (Sloan).) Dr.
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`Mayersohn's and Dr. Sloan's myopic approach to the field of overactive bladder treatments
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`undermines their credibility. Based on Dr. Maag's testimony, the court concludes that a person of
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`ordinary skill would have considered tolterodine and 5-HMT along with several other lead
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`compounds.
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`(2) Modification of 5-HMT
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`After choosing tolterodine and 5-HMT as lead compounds, the Defendants argue that the
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`prior art would have motivated a person of ordinary skill to modify 5-HMT. The prior art taught
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`that tolterodine was metabolized differently across the patient population. Dr. Mayersohn and Dr.
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`Sloan testified that this led to huge variations in bioavailability, and therefore, the effectiveness of
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`the treatment. (Tr. at 163 :21-191 : 12 (Mayersohn).) The Defendants argue that this shortcoming of
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`tolterodine would motivate a person of ordinary skill to modify its metabolite, 5-HMT. In response,
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`the Plaintiffs assert that the differential metabolism was clinically insignificant. (Tr. at 533:22-
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`535:25 (Maag).) Dr. Maag discussed three prior art publications: the Brynne II reference (DTX
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`Patent Owner, UCB Pharma GmbH – Exhibit 2001 - 0013
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`Case 1:13-cv-01110-GMS Document 304 Filed 04/20/16 Page 14 of 19 PageID #: 3065
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`268), the Detrol® label (DTX 168), and the Nilvebrant article (DTX 57). These publications
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`conclude that the pharmacokinetics of tolterodine do not produce significant differences in patient
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`outcomes. (Tr. at 534:2-535:25 (Maag).) Dr. Mayersohn performed his own analysis of these
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`publications and concluded that the studies were flawed. (Tr. at 191:13-192:13, 259:15-260:10,
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`205:3-208:8 (Mayersohn).)
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`Even if his conclusions are accurate, Dr. Mayersohn's post hoc analysis of the references'
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`methodology does not persuade the court that a person of ordinary skill would have drawn the same
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`conclusion during the relevant time period. Dr. Mayersohn did not point to any contemporary prior
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`art contradicting the teaching of these references, and the references do not independently bear
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`evidence of unreliability. The court is not convinced that a person of ordinary skill would have
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`disregarded the Brynne II reference, the Detrol® label, and the Nilvebrant article. Therefore, the
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`court concludes that the prior art does not suggest that tolterodine had a bioavailability problem.
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`The Defendants next argue that the prior art would motivate a person a skill to develop a
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`new prodrug of 5-HMT. Tolterodine functions as a prodrug of 5-HMT. (Tr. at 321:1-14 (Sloan).)
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`Based on 5-HMT's structure and its low lipophilicity, the Defendants argue that a person of
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`ordinary skill would have understood that 5-HMT was too water soluble and would be poorly
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`absorbed if administered without modification. (Tr. at 193:22-194:8 (Mayersohn), 330:7-332:2
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`(Sloan). Prodrug strategies were known options for modifying the lipophilicity and solubility of
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`drug compounds. (Tr. at 194:9-19, 210:25-211:14 (Mayersohn); Tr. at 334:1-22 (Sloan); DTX283
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`at 1.) Therefore, the Defendants argue that a person of ordinary skill would have expected that
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`creating a new prodrug of 5-HMT would yield a compound with similar, but improved properties
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`over tolterodine and 5-HMT.
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`14
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`Patent Owner, UCB Pharma GmbH – Exhibit 2001 - 0014
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`Case 1:13-cv-01110-GMS Document 304 Filed 04/20/16 Page 15 of 19 PageID #: 3066
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`The Plaintiffs, however, off