Pfizer Inc. et al v. Mylan Pharmaceuticals Inc.

Filing 89

MEMORANDUM OPINION re Trial. Signed by Judge Gregory M. Sleet on 8/9/2017. (asw)

IN THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF DELAWARE

PFIZER INC. and UCB PHARMA GMBH,
Plaintiffs,
v.
MYLAN PHARMACEUTICALS INC.,
Defendant.

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C.A. No. 15-79-GMS

MEMORANDUM
I.

INTRODUCTION
In this Hatch-Waxman-patent infringement action, plaintiffs Pfizer Inc. and UCB Pharma

GmbH (collectively, "Pfizer" or "Plaintiffs") allege that Mylan Pharmaceuticals Inc. ("Mylan" or
"Defendant") infringes the asserted claims of the patents-in-suit. The court held a three-day bench
trial in this matter beginning on January 23, 2017. Presently before the court are the parties' posttrial proposed findings of fact and conclusions of law concerning the validity of the patents-insuit, specifically whether the asserted claims are invalid as obvious under 35 U.S.C. § 103. (D.I.
80; D.I. 81.)
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 of asserted claims of the patents-insuit are invalid due to obviousness. These findings of fact and conclusions of law are set forth in
further detail below.

II.

FINDINGS OF FACT 1
A.

The Parties

1.
Plaintiff Pfizer Inc. is a corporation organized and existing under the laws of Delaware,
having a place of business at 235 East 42nd Street, New York, New York.
2.
Plaintiff UCB Pharma GmbH is .an entity organized and existing under the laws of
Germany, having a place ofbusiness at Al:fred-Nobel-Strasse 10, Manheim, Germany.
3.
Defendant Mylan Pharmaceuticals Inc.") is a corporation organized.and existing under the
law of West Virginia, having principal place of business at 781 Chestnut Ridge Road,
Morgantown, West Virginia 26505-4310.
4.

. The court has subject matter jurisdiction and personal jurisdiction over all parties.

B.

Background

5.
Pfizer Inc. holds an approved New Drug Application ("NDA") No. 02-2030 under Section
505(a) of the Federal Food, Drug and Cosmetic Act ("FFDCA"), 21 U.S.C. § 355(a), for
fesoterodine fumarate extended-release tablets, in 4 ap.d 8 mg dosage strengths, which Pfizer sells
under the trade name Toviaz®.
6.
Toviaz® was approved by the United States Food and Drug Administration ("FDA") in
October 2008 for the treatment of overactive bladder with symptoms of urge urinary incontinence,
urgency, and urinary frequency.
7.
Pursuant to 21 U.S.C. § 355(b)(l), and attendant FDA regulations, U.S. Patent Nos.
6,858,650 (the '"650 patent"), 7,384,980 (the '"980 patent"), 7,855,230 (the '"230 patent"),
7,985,772 (the "'772 patent), and 8,338,478 (the '"478 patent") (collectively, the "patents-in-suit")
are listed in the FDA publication, "Approved Drug Products with Therapeutic Equivalence
Evaluations" (the "Orange Book"), with respect to Toviaz®.
8.
Mylan filed Abbreviated New Drug Application No. 20-6701 ("Mylan's ANDA") to the
FDA, pursuant to 21 U.S.C. §§ 355G), seeking approvalto market a generic version offesoterodine
fumarate extended release tablets in 4 and 8 mg dosage strengths.
9.

Chemical names for fesoterodine fumarate include:

1

Prior to trial, the parties submitted an exhibit of uncontested facts in conjunction with their Pretrial Order.
(D.I. 75, 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

a. Isobutyricacicl2-( (R)-3-diisopropylammonium-1-phenylpropyl)-4hydroxymethylphenyl ester hydrogen fumarate;
b. R-(+ )-2-(3-diisopropylamino-1-phenyl-propyl)-4-hydroxymethylphenylisobutyrate
ester hydrogen fumarate;
c. R-(+ )-2-(3-diisopropylamino-1-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.
10.

The structural formula of fesoterodine fumarate is:

The asreriSk (~) indicates'the chiral carbon.

C.

The Patents-in-Suit

11.
Collectively, the '980, '230, '772, and '478 patents may be refen-ed to as the "Compound
Patents."
12.
The Compound Patents each issued from common parent applications, each of which
ultimately claim priority to European Application No. 98108608.5, filed May 12, 1998.
13.
The '980 patent issued on June 10, 2008 and is entitled "Derivatives of 3,3Diphenylpropylamines." The '980 patent names Claus Meese and Bengt Sparf as inventors.
14.
The '230 patent issued on December 21, 2010 and is entitled "Derivatives of 3,3Diphenylpropylamines." The '230 patent names Claus Meese and Bengt Sparf as inventors.
15.
The '772 patent issued on July 26, 2011 and is entitled "Derivatives of 3,3Diphenylpropylamines." The '772 patent names Claus Meese and Bengt Sparf as inventors.
16.
The '478 patent issued on December 25, 2012 and is entitled "Derivatives of 3,3Diphenylpropylamines." The '478 patent names Claus Meese and Bengt Sparf as inventors.
17.
The '650 patent issued on February 22, 2005 and is entitled "Stable Salts of Novel
Derivatives of 3,3-Diphenylpropylamines." The parties refer to the '650 patent as the "Salt
3

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. Schwarz Pharma AG holds title to the
'650 patent, and has granted Pfizer Inc. an exclusive license to the patent.
(1)

The Asserted Claims

18.

Pfizer bas asserted infringement of claims 1-=5, and 21-24 of the '650 patent against Mylan.

19.

Pfizer has asserted infringement of claims 1-16 of the '980 patent against Mylan.

20.

Pfizer has asserted infringement of claims 1-5 of the '230 patent against Mylan.

21.

Pfizer has asserted infringement of claims 1, 3, 4, 6-8 of the '772 patent against Mylan.

22.

Pfizer has asserted infringement of claims 1-3, 5-8, 10-12 of the '478 patent against Mylan.
i.

23.

'650 Patent, Claim 1

Claim 1 of the '650 patent claims: Compounds of general formula I

in which R denotes C1-C6-alkyl, C3-C10-cycloaklkyl, substituted or unsubstituted phenyl andX- is
the acid residue of a physiologically compatible inorganic or organic acid" of claim 1 has its plain
and ordinary meaning.
24.
The term "[c]ompounds of general formula I in which R denotes C1-C6-alkyl, C3-C10cycloaklkyl, substituted or unsubstituted phenyl and X- is the acid residue of a physiologically
compatible inorganic or organic acid" of claim 1 has its plain and ordinary meaning. Pfizer Inc.
and UCB Pharma GmbH v. Alkem Labs. Ltd., et al., Civil Action No. 13-111-GMS (D.I. 168.)
ii.

'650 patent, Claim 2

25.
Claim 2 of the '650 patent claims: Compounds in accordance with Claim 1, characterized
in that X- in each case is an acid ester of hydrochloric acid, hydrobromic acid, phosphoric acid,
sulphuric acid, nitric acid, acetic acid, propionic acid, palmitic acid, stearic acid, maleic acid,
fumaric acid, oxalic acid, succinic acid, DL-malic acid, L-(-)-malic acid, D-(+)-malic acid, DLtartaric acid, L-(+) -tartaric acid, D-(-)-tartaric acid, citric acid, L-aspartic acid, L-(+)-ascorbic
acid, D-(+)- glucuronic acid, 2-oxopropionic acid (pyruvic acid), furan-2-carboxylic acid (mucic
acid), benzoic acid, 4-hydroxybenzoic acid, salicyclic acid, vanillic acid,4-hydroxycinammic acid,

4

gallic acid, hippuric acid (N - benzqyl-glycine), aceturic acid (Naectylglycine), phloretinic acid
(3-(4-hydroxyphenyl)-propionic acid), phthalic acid, methanesulfonic acid or orotic acid.

iii.

'650 Patent, Claim 3

26.
Claim 3 of the '650 Patent claims: Compounds m accordance with claims [sic] 1,
characterized in that they have general formula 2

HO

0

OAR
---

l~l-I,(
A x-

in which R denotes Cl-C6-alkyl, C3-Cl0-cycloalkyl, substituted or unsubstituted phenyl and Xis the acid residue of a physiologically compatible inorganic or organic acid.

iv.

'650 Patent, Claini 4

27.
Claim 4 of the '650 Patent claims: Compounds 26. in accordance with Claim 3,
characterized in that X- in each case is an acid ester of hydrochloric acid, hydrobromic acid,
phosphoric acid, sulphuric acid, nitric acid, acetic acid, propionic acid, palmitic acid, stearic acid,
maleic acid, fumaric acid, oxalic acid, succinic acid, DL-malic acid, L-(-)-malic acid, D-(+)-malic
acid, D L-tartaric acid, L-(+) -tartaric acid, D-(-)-tartaric acid, citric acid, L-aspartic acid, L-(+)ascorbic acid, D-(+)- glucuronic acid, 2-oxopropionic acid (pyruvic acid), furan-2-carboxylic acid
(mucic acid), benzoic acid, 4-hydroxybenzoic acid, salicyclic acid, vanillic acid, 4hydroxycinammic acid, gallic acid, hippuric acid (N -benzoyl-glycine), aceturic acid
(Naectylglycine), phloretinic acid (3-(4-hydroxyphenyl)-propionic acid), phthalic acid,
methanesulfonic acid or orotic acid.

v.

'650 Patent, Claim 5

28.
Claim 5 of the '650 Patent claims: Compounds in accordance with claims [sic] 3,
characterized
in
that
they
are
R-(+)-2-(3-(diisopropylamino-1-phenylpropyl)-4hydroxymethylphenylisobutyrate ester hydrogen fumarate, R-(+ )-2-(3-( diisopropylamino-lphenylpropyl)-4-hydroxymethylphenylisobutyrate ester-hydrochloride hydrate.

vi_

'650 Patent, Claim 21

29.
Claim 5 of the '650 Patent claims: Compounds in accordance with claims [sic] 3,
characterized
in
that
they
are
R-(+)-2-(3-(diisopropylamino-1-phenylpropyl)-4
hydroxymethylphenyliso butyrate ester hydro gen fumarate, R-(+)-2-(3-( diisopropylamino- lphenylpropyl)-4-hydroxymethylphenylisobutyrate ester-hydrochloride hydrate.
5

30.
Claim 21 ofthe '650 Patent claims: A method of treafi!lg a patient suffering from urinary
incontinence, which method comprises the step of administering to said patient an effective
.amount of a compound according to .claim 1.

vii.

'650 Patent, Claim 22

31.
Claim 22·ofthe '650 Patent claims: A method of treating a patient suffering from urinary
jncontinence, which method comprises the step of administering to said patient an effective
amount of a compound according to claim 3.

viii.

'650 Patent, Claim 23

32.
Claim 23 of the '650 Patent claims: A method of treating a patient suffering from urinary
incontinence, which method .comprises the step of administering to said patient an effective
amount of a.compound according to claim 5.

ix.

'650 Patent, Claim 24

33.
Claim 24 of the '650 Patent claims: The method of any one of claims 21-23, wherein the
urinary incontinence disorder is urge incontinence."

x.

'980 Patent, Claim 1

34.
Claim 1 of the '980patentclaims: R-(+)-isobutyric acid2-(3-diisopropylamino-1phenylpropyl)-4-hydroxymethylphenyl ester.
xi. ·'980 Patent, Claim 2

·35_
.Claim 2 of the '980 patent Claims: A salt ofR-(+)-isobutyric acid 2-(3-diisopropylaminol-phenyl propyl)-4-'hydroxymethylphenyl ester with a physiologically acceptable acid.

xii. '980 Patent, Claim 3
36.
Claim 3 of the '980 patent claims: A pharmaceutical composition comprising an effective
amount ofR-(+ )-isobutyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl
ester, or a salt thereof with a physiologically acceptable acid and a pharmaceutically acceptable
carrier.

xiii.

'980 Patent, Claim -4

37.
Claim 4 of the '980 Patent claims: A method of antagonizing a muscarinic receptor in a
patient in need thereof, the method comprising administering to the patient R-(+)-isobutYric acid
2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester or a salt thereof with a
physiologically acceptable acid so as to result in contact of the muscarinic receptor with an
effective amount of R -(+ )-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenol.

6

xiv.

'980 Patent, Claim 5

38.
Claim 5 of the '980 Patent Claims: 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-1-phenylpropyl)-4-hydroxymethylphenyl
ester or a salt thereof with a physiologically acceptable acid.

xv.

'980 Patent, Claim 6

39.
Claim 6 of the '980 Patent claims: The method according to claim 5 wherein the disease is
urinary incontinence.

xvi.

'980 Patent, Claim 7

40.
Claim 7 of the '980 Patent claims: The method according to claim 6 wherein the mammal
is a human.

xvii.

'980 Patent, Claim 8

41.
Claim 8 ofthe '980 Patent claims: A compound sel.ected from the
group consisting of: acetic acid 4-acetoxy-3-(3-diisopropylamino- 1-phenylpropyl)-benzyl ester,
n-butyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, isobutyric
acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, isobutyric acid 2-(3diisopropylamino-1-phenylpropyl )-4-isobutyryloxymethylphenyl ester, n-butyric acid 4nbutyryloxymethyl-2-(3-diisopropylamino-1-phenylpropyl)-phenyl ester, propionic acid 2-(3diisopropylamino-1-phenylpropyl)-4-propionyloxymethylphenyl ester, propionic acid 2-(3diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, and acetic acid 2-(3diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, including racemic mixtures and
individual enantiomers of said compounds, and salts of said compounds with a physiologically
acceptable acid.

xviii.

'980 Patent, Claim 9

42.
Claim 9 of the '980 Patent claims: The compound of claim 8 where the compound is
selected from the group consisting of: n-butyric acid 2-(3-diisopropylamino-l-phenylpropyl)-4hydroxymethylphenyl ester, isobutyric acid 2-(3-diisopropylamino-1-phenylpropy 1)-4hydroxymethylphenyl ester, prop10mc acid 2-(3-diisopropylamino-1-phenyl-propyl)-4hydroxymethylphenyl ester, and acetic acid 2-(3-diisopropylamino-l-phenylpropyl)-4hydroxymethylphenyl ester, including racemic mixtures and individual enantiomers of said
compounds, and salts of said compounds with a physiologically acceptable acid.

xix.

'980 Patent, Claim 10

43.
Claim 10 of the '980 Patent claims: A pharmaceutical composition comprising an effective
amount of a compound selected from the group consisting of: acetic acid 4-acetoxy-3-(37

diisopropylamino-1-phenylpropyl)-benzyl ester, n-butyric acid 2-(3-diisopropylamino-1phenylpropyl)-4-hydroxymethylphenyl ester, isobutyric acid 2-(3-diisopropylamino-lphenylpropyl)-4-hydroxymethylphenyl ester, isobutyric acid 2-(3-diisopropylamino-lphenylpropyl )-4-isobutyryloxymethylphenyl ester, n-butyric acid 4-nbutyryloxymethyl-2-(3diisopropylamino-1-phenylpropyl)-phenyl ester, propionic acid 2-(3-diisopropylamino-1phenylpropyl)-4-propionyloxymethylphenyl ester, propionic acid 2-(3-diisopropylamino-1phenylpropyl)-4-hydroxymethylphenyl ester, and acetic acid 2-(3-diisopropylamino-1phenylpropyl)-4-hydroxymethylphenyl ester, including racemic mixtures and individual
enantiomers of said compounds, and salts of said compounds with a physiologically acceptable
acid, and a pharmaceutically acceptable carrier.

xx.

'980 Patent, Claim 11

44.
Claim 11 of·the '980 Patent claims: The pharmaceutical composition of claim 10 where
the compound is selected from the group consisting of: n-butyric acid 2-(3-diisopropylamino1aphenylpropyl)-4-hydroxymethylphenyl ester, isobutyric acid 2-(3-diisopropylamino-1phenylpropyl)-4-hydroxymethylphenyl ester, prop10mc acid 2-(3-diisopropylamino-1phenylpropyl)-4-hydroxymethylphenyl ester, and acetic acid 2-(3-diisopropylamino-1phenylpropyl)-4-hydroxymethylphenyl ester, including racemic mixtures and individual
enantiomers of said compounds, and salts of said compounds with a physiologically acceptable
acid.
-

xxi.

'980 Patent, Claim 12

45.
Claim 12 of the '980 Patent claims: A method of treating a disease or condition 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 a compound selected from the group consisting of: acetic acid 4-acetoxy-3(3-diisopropylamino-1-phenylpropyl)-benzyl ester, nbutyric acid 2-(3-diisopropylamino-1phenylpropyl)-4-hydroxymethylphenyl ester, isobutyric acid 2-(3-diisopropylamino-1phenylpropyl)-4-hydroxyinethylphenyl ester, isobutyric acid 2-(3-diisopropylamino-1phenylpropyl)-4-isobutyryloxymethylphenyl ester, n-butyric acid 4-nbutyryloxymethyl-2-(3diisopropylamino-1-phenylpropyl)-phenyl ester, propionic acid 2-(3-diisopropylamino-1phenylpropyl)-4-propionyloxyniethylphenyl ester, propionic acid 2-(3-diisopropylamino-lphenylpropyl)-4-hydroxymethylphenyl ester, and acetic acid 2-(3-diisopropylamino-1phenylpropyl)-4-hydroxymethylphenyl ester, including racemic mixtures . and individual
enantiomers of said compounds, and salts of said compounds with a physiologically acceptable
acid.

xxii.

'980 Patent, Claim 13

46.
Claim 13 of the '980 Patent claims: The method of claim 12 where the compound is
selected from the group consisting of: n-butyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4hydroxymethylphenyl ester, isobutyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4hydroxymethylphenyl ester, propionic acid 2-(3-diisopropylamino-1-phenylpropyl)-4hydroxymethylphenyl ester, and acetic acid 2-(3-diisopropylamino-1-phenylpropyl)-48

hydroxymethylphenyl ester, including racemic mixtures and individual enantiomers of said
compounds, and salts of said compounds with a physiologically acceptable acid.

xxiii.

'980 Patent, Claim 14

47.
Claim 14 of the '980 Patent claims: The method of claim 12 or 13 where the disease or
condition is a spasmogenic condition that is caused by a muscarinic mechanism.

xxiv.

'980 Patent, Claim 15

48.
Claim 15 of the '980 Patent claims: The method 9f claim 12 or 13 where the disease or
condition is urinary incontinence.

xxv.

'980 Patent, Claim 16

49.
Claim 16 of the '980 Patent claims: The method of claim 15 where the mammal is a
human.

xxvi.

'230 Patent, Claim 1

50..
Claim 1 of the '230 Patent claims: A method of treating 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-1phenylpropyl)-4-hydroxymethylphenyl ester, isobutyric acid 2-(3-diisopropylamino-1phenylpropyl)-4-hydroxymethylphenyl ester, prop10mc acid 2-(3-diisopropylamino-1phenylpropyl)-4-hydroxymethylphenyl ester, and acetic acid 2-(3-diisopropylamino-1phenylpropyl)-4-hydroxymethylphenyl ester, including the racemic mixtures and individual
enantiomers of said compounds, and a salt of said compounds with a physiologically acceptable
acid.
xxvii. '230 Patent, Claim 2
51.
Claim 2 of the '230 Patent claims: The method according to claim 1, wherein the compound
is · isobutyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,
including the racemic mixture and individual enantiomers of said compound, and a salt of said
compound with a physiologically acceptable acid.

xxviii.

'230 Patent, Claim 3

52.
Claim 3 of the '230 Patent claims: The method according to claim 1, wherein the compound
is R-(+) isobutyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester.

xxix. '230 Patent, Claim 4
53.
Claim 4 of the '230 Patent claims: The method according to claim 1, wherein the compound
is a salt of R-(+) isobutyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl
ester.

9

xxx.

'230 Patent, Claim 5

54.
Claim 5 of the '230 Patent claims: The method according to any one of claims 1-4, wherein
the compound is administered to the patient in the form of a pharmaceutical composition
comprising a pharmaceutically acceptable carrier.
xx.xi.

'772 Patent, Claim 1

55.
Claim 1 of the '772 Patent claims: 3,3-Diphenylpropylamines of the
general formula:

wherein Rl is hydrogen and R2 is Cl-C6 alkylcarbonyl; or Rl is Cl-C6 alkylcarbonyl and R2 is
hydrogen; their salts with physiologically acceptable acids, their free bases and, when the 3,3Diphenylpropylamines are in the form of optical isomers, the racemic mixture and the individual
enantiomers.
xxxii.

'772 Patent, Claim 3

56.
Claim 3 of the '772 Patent claims: The 3,3-Diphenylpropylamine of claim 1 wherein Rl is
Cl-C6 alkylcarbonyl and R2 is hydrogen.
xxxiii.

'772 Patent, Claim 4

57.
Claim 4 of the '772 Patent claims: A method of treating urinary incontinence in a patient
in need thereof, the method comprising administering to the patient an effective amount of a 3,3Diphenylpropylamine of the general formula:
RI

I

0

wherein: Rl is hydrogen and R2 is Cl-C6 alkylcarbonyl; or Rl is Cl-C6 alkylcarbonyl and R2 is
hydrogen; or its salt with a physiologically acceptable acid, its free base or, when the 3,3
10

Diphenylpropylamine is in the form of optical isomers, the racemic mixture and the individual
enantiomers."
xxxiv.

'772 Patent, Claim 6

58.
Claim 6 of the '772 Patent claims: The method of claim 4 whereinRl is Cl-C6
alkylcarbonyl and R2 is hydrogen.
xx.xv.

'772 Patent, Claim 7

59.
Claim 7 of the '772 Patent claims: The method according to any one of claims 4-6, wherein
the 3,3-Diphenylpropylamine is administered to the patient in the form of a pharmaceutical
composition comprising a pharmaceutically acceptable carrier.
xxxvi.

'772 Patent, Claim 8

60.
Claim 8 of the '772 Patent claims: A pharmaceutical composition comprising an effective
amount of a 3,3-Diphenylpropylamine according to any one of claims 1-3 and a pharmaceutically
acceptable carrier.
xx.xvii.

61.

'478 Patent, Claim 1

Claim 1 of the '478 Patent claims: 3,3-Diphenylpropylamines of the formula

R2

_o

x

where: Rl is hydrogen and R2 is Cl-C6 alkylcarbonyl; or Rl is Cl-C6 alkylcarbonyl and R2
is hydrogen; and Xis a tertiary amino group of formula

where R8 and R9 are each independently Cl-C8 alkyl and together comprise at least three carbon
atoms; their salts with physiologically acceptable acids, their free bases and, when the 3,3Diphenylpropylamines are in the form of optical isomers, the racemic mixture and the individual
enantiomers.

11

xxxviii.

'478 Patent, Claim 2

62.
Claim 2 of the '478 Patent claims: The 3,3-Diphenylpropylamines of claim 1, where R8
and R9 are each independently Cl-C6 alkyl.

xxxix.

'478 Patent, Claim 3

63.
Claim 3 of the '478 Patent claims: The 3,3-Diphenylpropylamines of
claim 1, where X is selected from the group consisting of:

xi.

'478 Patent, Claim 5

64.
Claim5 of the '478 Patent claims: The 3,3-Diphenylpropylamines of claim 1 wherein Rl
is Cl-C6 alkylcarbonyl and R2 is hydrogen.

xii.

'478 Patent, Claim 6

65.
Claim 6 of the '478 Patent claims: A method of treating urinary incontinence in a patient
in need thereof, the method comprising administering to the patient an effective amount of a 3,3Diphenylpropylamine of the formula

R2

x

.o

::::::,...

where: Rl is hydrogen and R2 is Cl-C6 alkylcarbonyl; or Rl is Cl-C6 alkylcarbonyl and R2
is hydrogen; and Xis a tertiary amino group of formula

I

CH:::

-

-N

\

C(CII3)3~

where R8 and R9 are each independently Cl -C8 alkyl and together comprise at least three carbon
atoms; or its salt with a physiologically acceptable acid, its free base or, when the 3,3-

12

Diphenylpropylamine is in the form of optical isomers, the racemic mixture and the individual
enantiomers.

xiii.

'478 Patent, Claim 7

66.
Claim 7 of the '478 Patent claims: 96. The method of claim 6 wherein
R8 and R9 are each independently Cl-C6 alkyl.

xliii.

'478 Patent, Claim 8

67.
Claim 8 of the '4 78 Patent claims: The method of claim 6 where X is
selected from the group consisting of:

I CH~
-

I CH(CH~})
. ··-

-N

-1\

\

CII l,.c-r.,
.l 3)2~·
xliv.

\

C(Cll3b~

'478 Patent, Claim 10

68.
Claim 10 of the '478 Patent claims: The method of claim 6 where Rl 1s Cl-C6
alkylcarbonyl and R2 is hydrogen."

xlv.

'478 Patent, Claim 11

69.
Claim 11 of the '478 Patent claims: The method of claim 6, where the 3,3Diphenylpropylamine is administered .to the patient in the form of a pharmaceutical composition
comprising a pharmaceutically acceptable carrier.

xlvi.

'478 Patent, Claim 12

70.
Claim 12 of the '478 Patent claims: A pharmaceutical composition comprising an effective
amount of a 3,3-Diphenylpropylamine according to any one of claims 1-5 and a pharmaceutically
acceptable carrier.

(2)

The Accused Product

i.

ANDA No. 20-6701 Submitted by Mylan

71.
Mylan submitted Abbreviated New Drug Application No. 20-6701 ("Mylan's ANDA") to
the FDA, pursuant to 21 U.S.C. §§ 355G), seeking approval to market a generic version of
fesoterodine fumarate extended release tablets in 4 and 8 mg dosage strengths ("Mylan's
Product").

13

72.
Mylan's ANDA refers to and relies upon the Toviaz® NDA and contains data that,
according to Mylan, demonstrates that Mylari's Product is bioequivalent to Toviaz®.
73.
Mylan included certifications in its ANDA, pursuant to 21 U.S.C. § 355(i)(2)(A)(vii)(IV),
thatthe '650, '980, '230, '772, and '478 patents are invalid, unenforceable, or will not be infringed
by the commercial manufacture, use, or sale ofMylan's Product.
74.
On December 11, 2014, Mylan sent Notice of its Paragraph IV certifications to Plaintiffs,
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.
75.
In response to Mylan' s Notice, on January 23, 2015, Plaintiffs sued Mylan for infringement
of the '650, '980, '230, '772, and '478 patents, pursuant to 35 U.S.C. § 271(e)(2)(A).
D.

Procedural History

On January 23, 2015, Plaintiffs sued Mylan for patent infringement related to ANDA No.
76.
20-6701 under Civil Action No. 15-79.
77.
The court held a bench trial on January 23, January 25, and January 26, 2017. Mylan
argued that all asserted claims are invalid as obvious under 35 U.S.C. § 103. Mylan stipulated to
infringement on all asserted claims of all asserted patents.
78.
At the close of Plaintiffs' prima facie case for invalidity of the asserted patents, Mylan
moved pursuant to Federal Rule of Civil Procedure 52( c) for judgment on partial findings on the
issue of obviousness. (Tr. 408:1-5.) The court denied Pfizer's motion. (Tr. 408:6-8.)

III.

DISCUSSION AND CONCLUSIONS OF LAW
The court has subject matterjurisdiction over this matter pursuant to 28 U.S.C. §§ 1331

and 1338(a). Venue is proper in this court under 28 U.S.C. §§ 1391 and 1400(b). Mylan
challenges the validity of each of the asserted claims of the patents-in-suit as obvious in light of
the prior art. After having considered the entire record inthis case, the substantial evidence in the
record, the parties' post-trial submissions, and the applicable law, the court concludes that the
defendant has failed to establish by clear and convincing evidence that the asserted claims of the
asserted patents would have been obvious to a person of ordinary skill in the art. Pfizer's Rule
52(c) motion is granted and Mylan's Rule 52(c) motion is denied. The court's reasoning follows.

14

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." Obviousness is a question
oflaw 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 nonobviousness, 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'! 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, the Supreme Court rejected the rigid application of the principle that there should be an
explicit teaching, suggestion, or motivation in the prior art, the "TSM test;" in order to find
obviousness.

See id. at 415.

The KSR Court acknowledged, however, the importance of

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)).

15

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." Id. at 418.
"Obviousness does not require absolute predictability of success," but rather, requires "a
reasonable expectation of success." See Medichem, S.A. v. Rolado, S.L., 437 F.3d 1157, 1165
(Fed. 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
so long as there was a reasonable probability of success." Pfizer, Inc. v. Apotex, Inc., 480 F.3d
1348, 1364 (Fed. Cir. 2007). Moreover, while the Federal Circuit has noted that pharmaceuticals
can be. an "unpredictable art" to the extent that results may be unexpected, it also recognizes that,
per KSR, evidence of a "finite number of identified, predictable solutions" or alternatives "might
support an inference of obviousness." See Eisai Co. Ltd. v. Dr. Reddy's Labs. Ltd., 533F.3d1353,
1359 (Fed. Cir. 2008).

B.

The Level of Ordinary Skill in the Art

A person of ordinary skill in the art ("POSA") with respect to the patents-in-suit would
have a Ph.D. in chemistry, medicinal chemistry, pharmacology, or a related field. 3 Additional
experience in drug discovery, drug synthesis, and structure-activity work could substitute for the
advanced degree. A POSA would further have knowledge of bladder physiology and overactive
bladder. The court concludes that the parties' definitions of a person of ordinary skill in the art do
not differ in a meaningful way.

3

Plaintiffs' identification of a person of ordinary skill in the art is derived from Dr. Maag and Dr. Roush.
(Tr. 415:18-24 (Maag); Tr. 531:4-15 (Roush).) Defendant's identification ofa person of skill in the art is derived
from Dr. Janero. (Tr. 259:10-260:2 (Janero).)

16

C.

The Scope and Content of the Prior Art and Differences Between the Cla:imed
Subject Matter and the Prior Art

Mylan argues a POSA would have found it obvious to synthesize fesoterodine as an
improved overactive bladder treatment.

Mylan bases its theory on the prior art molecule

tolterodine and its metabolite, 5-Hydroxymethyl Tolterodine ("5-HMT"). To determine whether
the Defendant has established a prima facie case of obviousness, the court must determine (1)
"whether a chemist'of ordinary skill would have selected the asserted prior art compounds as lead
compounds, or starting points, for future development efforts"; and (2) whether the prior art would
have supplied_ one of ordinary skill in the art with a reason or motivation to modify a lead
'.!.'.

compound to make the claimed compound with a reasonable expectation of success." Otsuka
Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1291-92 (Fed. Cir. 2012).

(1)

5-HMT as a Lead Compound

Mylan argues a POSA would have selected 5-HMT as a lead compound for an improved
overactive bladder treatment. (D.I. 80 at 8.) As of the May 12, 1998 priority date, overactive
bladder treatments included negative limitations such as urinary retention, dry mouth, constipation,
and central nervous system effects. (D.I. 81 at 5-6.) According to Mylan, a POSA seeking to
create an improved overactive bladder drug would have focused on antimuscarinic compounds.
Antimuscarninc compounds block the neurotransmitter acetylcholine from binding to one or more
of the five types of muscarinic receptors found in the body. Both parties agree that antimuscarinics
were a popular treatment for overactive bladder at that time.

(D.I. 80 at 7; D.I. 81 at 5.)

Oxybutynin and tolterodine were the primary antimuscarinic compounds approved to treat
overactive bladder in the United States. (Tr. at 112:4-17, 116:4-7 (Carson).) Mylan contends that
because the prior art detailed the efficacy and safety of 5-HMT as associated with tolterodine
administration, a person of skill in the art would have been motivated to choose 5-HMT for further

17

development. (D.I. 80 at 8.) Lead compound analysis "requires the challenger to demonstrate ..
. that one of ordinary skill in the art would have had a reason to select a proposed lead compound
or compounds over other compounds in the prior art." Daiichi Sankyo Co. v. Matrix Labs., Ltd,
619 F.3d 1346, 1354 (Fed. Cir. 2010).
Mylan's lead compound theory is flawed for several reasons. First, Mylan failed to justify
its expert's narrow focus on tolterodine and 5-HMT. Pfizer's expert, Dr. Maag, testified that
researchers eschewed nonselective antimuscarinic compounds and were actively pursumg a
number of different strategies in search of improved overactive bladder treatments. (Tr. 417:9421:5, 422:10-25 (Maag)) In contrast, Mylan's expert, Dr. Carson, posited that 5-HMT seemed
to be "at the forefront" of overactive bladder compounds, which made it prime for further
investigation. (Tr. 146:15-23 (Carson).) Dr. Carson's lead compound analysis strikes the court as
somewhat constrained. For example, Dr. Maag testified that the state of the art design approaches
were directed to (1) receptor subtype-selective antimuscarinics (PTX-510; PTX- 271; PTX-666)
and (2) alternative mechanisms of action (PTX-666; PTX-104). (Tr. 417:9-412:5 (Maag).)4 In
addition, Dr. Carson acknowledged that nothing in the prior art suggested administering 5-HMT
to patients, which contradicts focusing on 5-HMT as a lead compound. (Tr. 155:8-15 (Carson).)
The court finds Dr. Maag's testimony more persuasive because it is consistent with the field of
overactive bladder treatment as of the priority date. The court therefore concludes that a POSA
would have considered tolterodine and 5-HMT in addition to several other lead compounds.
Second, even if a person of skill in the art would have focused on tolterodine and 5-HMT,
tolterodine did not have problems that would have caused a POSA to develop 5-HMT. Mylan

4

The court notes that Dr. Maag identified specific M3 receptor-selective compounds-darifenacin (PTX271) and solifenacin (PTX-48). (D.I. 81 at 7.) He also delineated the alternative mechanisms of action as: (1)
compounds having both antimuscarinic and calcium antagonistic activity; (2) potassium channel agonists; and (3)
compounds acting on adrenoceptors. (Tr. 420:3-8 (Maag).)

18

contends that the metabolism of tolterodine to arrive at 5-HMT presented a concern. (D.I. 80 at
9.) Mylan relies on the Nilvebrant (DTX-50) and Postlind (DTX-35) prior art publications to
support this ?-Ssertion. Nilvebrant disclosed that the activity profile of 5-HMT was identical to
tolterodine and reported 5-HMT was significantly more potent at inhibiting bladder contractions
in an in vivo analysis. (Tr. 247:7-22 (Janero).) Postlind confirms that the most common metabolic
pathway utilizes CYP2D6 to convert tolterodine to 5-HMT. (Tr. 250:15-251 :4 (Janero).) Dr.
Janero explained that patients known as extensive metabolizers utilize this metabolic pathway.
(Tr. 251:5-8 (Janero).) Further, the evidence showed that tolterodine is also metabolized via an
alternative metabolic pathway that is mediated by a CYP3A4. (DTX-35) Patients that are poor
metabolizers utilize this second pathway. (Tr. 251:23-252:17 (Janero).) According to Dr. Janero,
because tolterodine is metabolized via the CYP2D6 pathway and CYP2D6 polymorphism can
adversely affect the metabolism of a given drug, a POSA would have sought to dose "a potent
muscarinic antagonist without the involvement of CYP2D6." (Tr. 252:18-253:18 (Janero).)
In response, Pfizer argues that a POSA would not have ignored the prior art references that
taught polymorphism was not a problem for tolterodine because poor and extensive metabolizers
experienced nearly identical effects from the drug.

(Tr. 423:13-17 (Maa:g); Tr. 589:3-14

(MacDiarmid).) Particularly, Pfizer points to the teachings of the Detrol Label (DTX-34), Brynne
reference (DTX-39), and Nilvebrant reference (DTX-50). The Detrol Label taught that "the net
activity ofDETROL Tablets is expected to be similar in extensive and poormetabolizers." (DTX34 at 2.) The Brynne reference (DTX-39) disclosed that "[d]espite the influence of CYP2D6
polymorphism on the pharmacokinetics of tolterodine, this does not appear to be of great
pharmacodynamics importance." (DTX-39 at 10.) The Nilvebrant reference concluded that "the
pharmacological in vitro and in vivo profiles of [5-HMT] are almost identical to those of

19

tolterodine, the parent compound." (DTX-50 at 4.) Mylan's expert, Dr. Janero, supported the
conclusion that there is no evidence that any POSA would have disregarded these conclusions,
undermining the weight of Mylan's assertions. (Tr. 361 :6..:12 (Janero).) The court believes that a
POSA would not have disregarded these conclusions.

Thus, the court concludes that

polymorphism would not have motivated a POSA to shift focus from tolterodine to its metabolite,
5-HMT.
Third, Mylan argues that a POSA would have focused on 5-HMT instead of tolterodine
because tolterodine was associated with certain side effects not attributable to 5-HMT. (D.I. 80 at
10.) In support of this contention, Mylan relied on the Brynne reference. (DTX-39.) According
to this reference, tolterodine likely caused heart rate issues; visual accommodation; and was ten
times more lipophilic than 5-HMT. (D .I. 80 at· 11.) Mylan contends that a POSA would have
recognized thatthe lipophilic profile would have likely permitted tolterodine to cross the bloodbrain barrier leading to adverse side effects, such as headache, paresthesia, dizziness, and
nervousness, which are identified as treatment related side effects in clinical reports and the FDA
labelfortolterodine. (Id.; Tr.130:3-18 (Carson).)
The court is not persuaded. Dr. Carson's testimony undermines the credibility ofMylan's
assertions. Dr. Carson admitted that the clinical data considered tolterodine and5-HMT together
and, as a clinician, he knew of no differences between the two compounds. (Tr. 132:24-133:6
(Carson).) Moreover, Dr. Maag testified that a POSA would have expected the benefits and
limitations associated with tolterodine to also be associated with 5-HMT. (Tr. 449:10-14 (Maag).)
At minimum, given the state of the art, a POSA could not have drawn inferences about whether
tolterodine or 5-HMT was driving any one of the side effects. (Tr. 358:19-359:8 (Janero).)

20

Finally, Mylan suggests that tolterodine's metabolism via the CYP3A4 pathway in poor
metabolizers was a potential problem to solve. (D.I. 80 at 12.) Mylan relies on the Detrol® label,
which discloses that "[p]atients receiving cytochrome P450 3A4 inhibitors should not receive
doses of DETROL greater than 1 mg twice daily." (DTX-34 at 5.) Mylari's expert, Dr. Carson,
points out that the Appell reference (DTX-238) teaches that 1 mg twice daily is statistically less
effective than the higher dosage oftolterodine. (Tr. 125:21-126:6 (Carson).) In light ofthis prior
art, Mylan asserts that a POSA would have been motivated to eliminate dosing a compound such

as tolterodine from the metabolic pathway responsible for delivering 5-HMTto the body. (D.I. 80
at 12.) The evidence adduced at trial established that if a patient takes multiple CYP3A4 drugs,
including tolterodine, there may be a reduction in the metabolism of tolterodine. (D .I. 81 at 11.)
This reduced metabolism of tolterodine may lead to an accumulation of tolterodine in the system,
in addition to other drugs a patient is taking, resulting in adverse effects. (Id.) Mylan:'s own
experts concede, however, that if CYP3A4 metabolism had been a real concern, a POSA would
have also rejected 5-HMT since 5-HMT is also metabolized via the CYP3A4 pathway. (Tr.
165:14-25 (Carson); Tr. 359:16-23 (Janero).) Put simply, if 3A4 metabolism was a concern.for
tolterodine, it also would have been for 5-HMT.

Mylan's argument is to the contrary is

unconvincing. Thus, the court rejects Mylan's arguments as to the selection of a lead compound,
and concludes that Mylan has failed to meet its burden in this regard.
(2)

Modification of 5-HMT

Even accepting Mylan's selection of 5-HMT as lead compound, the court finds that Mylan
has not established by clear and convincing evidence that modifying the lead to yield fesoterodine
would have been obvious to a POSA. See Daiichi, 619 F.3d 1346 at1352 ("Proof of obviousness
based on structural similarity requires clear and convincing evidence that a medicinal chemist of

21

ordinary.skill would have been motivated to select and then to modify a prior art compound (e.g.,
a lead compound) to arrive at a claimed compound with a reasonable expectation that the new
compound would have similar or improved properties compared with the old.").
Mylan argues that a POSA would have sought to develop a new prodrug5 of 5-HMT that
would have similar absorption to tolterodine, but that had less CNS penetration, and did not exhibit
variable bioavailability. (Tr. 284:12-285:12 (Janero).) Prodrug strategies were known options for
modifying the lipophilicity, hydrophilicity, and solubility of drug compounds. (Tr. 288:1-12
(Janero).) Mylan therefore argues that a POSA would have expected that creating a new prodrug
of 5-HMT would yield a compound with similar, but improved properties over tolterodine and 5HMT.
In contrast, Pfizer offered evidence that 5-HMT's oral absorption propei:ties were, and still
are, unknown.

(Tr. 421:18-422:1, (Maag); Tr. 536:10-20 (Roush); Tr. 155:8-15, 162:10-12

(Carson).) Nonetheless, Pfizer contends that, based on 5-HMT's properties, a POSA would have
expected 5-HMT to be well absorbed. (D.I. 81 at 12.) The evidence adduced at trial established
that 5-HMT is "bracketed" by many other compounds that are significantly more and significantly
less lipophilic, but which are well absorbed orally.

(Tr. 510:7-511:22 (Roush).) Dr. Roush

testified that a POSA would have observed .5-HMT amongst the previously noted compounds that
are sufficiently bioavailable and would have identified no reason to assume poor oral absorption
associated with 5-HMT. (Tr. 511 :19-22 (Roush).) Dr. Roush also testified that the Lipinski Rule
of Five6 shows 5-HMT is safely within each of the Rule's four criteria, indicating that nothing

5
"Prodrug design comprises an area of drug research that is concerned with the optimization of drug delivery.
A prodrug is a pharmaceutically inactive derivative of a parent 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." (DTX-41 at 5.)
6
The Lipinski Rule of Five, designed and published in 1997 to identify candidate compounds with the
potential for poor absorption, is derived from a seminal paper in the field of medicinal chemistry. (D.I. 81 at 12.)

22

about its structure suggests that 5-HMT would have oral absorption problems. (Tr. 513:9-515:8
(Roush).) Given that 5-HMT was "bracketed" by other well-absorbed compounds, satisfied the
Rule of Five, and in the absence of data to the contrary, a POSA would have expected 5-HMT to
be well-absorbed orally and would not have seen a reason to modify the compound to alter its
absorption properties.
Pfizer also adduced evidence that POSAs viewed prodrug design as a complex "last resort"
approach to drug development because of: (1) stability concerns in drug manufacture, in
formulation, and in the body, (Tr. 431:6-13 (Maag)); (2) higher potential for negative side effects
due to multiple chemical entities/moieties, (Tr. 432:8-17 (Maag)); .and (3) risk of premature
metabolism, (Tr.

431:17~25

(Maag). Drs. Roush and Maag testified that POSAs would have

considered developing a prodrug only after satisfaption of the following conditions: (1) a clearly
defined and understood problem requiring use of a prodrug, (Tr. 441 :14-22 (Maag); Tr. 508:7-14
(Roush); PTX-623 at 14); (2) well-understood pharmacokinetics of the active compound, (Tr.
439:21-440:3 (Maag); Tr. 508:7-14 (Roush); PTX-616 at 7); and (3) a meaningful clinical
advantage presented by the prodrug, (Tr. 440:9-13 (Maag); PTX-616 at 7). Pfizer argues that the
prior art depicted 5-HMT as an unattractive prodrug candidate, as it failed to meet any of the
requirements outlined by Drs. Maag and Roush. {Tr. 430:6-15 (Maag) (no known issue with 5HMT); Tr. 439:21-440:3 (Maag) (pharmacokinetics not well understood); (Tr. 423:2-10 (Maag)
(no meaningful clinical advantage because most patients already exposed to 5-HMT).)
Lastly, Pfizer contends that a POSA would have first pursued non-prodrug development
approaches, such as performing structural modifications to create an analog of tolterodine, or
experimenting with the formulation of 5-HMT. (Tr. 503:17-504:14 (Roush) (describing structural

(PTX-252). Specifically, the Lipinski Rule of Five entails analyzing four different physical properties of a compound
to evaluate its potential to be orally available. (Tr. 512:7-513:3 (Roush).)

23

analogs as the "bread and butter of the activities of medicinal chemist everywhere"); Tr. 506:7507:23 (Roush) (describing formulation approaches)). The court agrees with Pfizer. The dearth
of information about 5-HMT's properties, the inherent risk associated with prodrug development,
and the existence of more straightforward optimization techniques all suggest that a prodrug
approach would not have been obvious.

(3)

Chemical Structure of Fesoterodine

Even accepting Mylan's proposal that it would have been obvious to create a new 5-HMT
prodrug, the court does not find it would have been obvious to obtain the final chemical structure
of fesoterodine. To prevail, Mylan must prove that a person of ordinary skill would have known
to (1) use an ester prodrug, (2) add the substituent to only the phenolic hydroxyl, and (3) use an
isobutyryl substituent, and (4) that a person of ordinary skill would have had a reasonable
expectation of success regarding the resulting compound's properties. (D .I. 80 at 14-21.)
Mylan argues that a POSA would have chosen to develop an alkyl ester prodrug because
esters were among the most commonly used prodrug moieties. (D.I. 80 at 15.) Dr. Janero testified
that a POSA would have recognized two possible options for developing an ester prodrug of 5HMT: the hydroxyl group at either the 2 position or on the methyl group of the 5-HMT phenyl
ring (at the 5 position), which could be esterified by standard medicinal chemistry. (Tr. 295:8296:10 (Janero).) Dr. Janero also noted that other types of prodrug groups would have been more
likely to carry different biological properties, biological activities, or chemical reactivities than the
desired activity of 5-HMT. (Tr. 293:16-294:15 (Janero).) Mylan therefore argues that a POSA,
using routine experimentation, would have focused on small hydrocarbon esters that would not be
prone to other reactivities and would be readily eliminated from the body to make 5-HMT

24

available. (Tr. 293:16-294:15 (Janero).) Thus, Mylan submits that a POSA would have had a
reasonable expectation of obtaining fesoterodine.
Mylan's analysis is unavailing for several reasons. First, Mylan improperly narrows the
field to ester prodrugs. A POSA would have considered a variety of prodrug types in the prior art,
including carboxylic esters, phosphate esters, carbamate esters, carbonate esters, ethers, and others,
in search of the right set of aggregate properties. (Tr. 515:16-516:11, 516:19-25, 517:7-518:24
(Roush); PTX-95 at Table 2). Mylan's expert, Dr. Janero, relied on one prior art reference
(Bundgaard, DTX-41) to support his argument that carboxylic ester prodrugs would have been
obvious. The doctor's focus seems unduly n·arrow. The Bundgaard reference discussed other
types of prodrug design that appear to have been overlooked in Dr. Janero's analysis. (Tr. 362:58 (Janero).) In addition, he conceded that a POSA would have considered other classes of
prodrugs. (Tr. 293: 18-25 (Janero ). )7 The court therefore believes a POSA would have not engaged
in a limited review of the prodrug field.
Second, while Mylan contends that a POSA would have to modify only one of the hydroxyl
groups, Pfizer points out that 5-HMT contains four possible substitutions: (1) single substitution
at the benzylic (or 5-position) hydroxyl, (2) a single substitution at the phenolic (or 2-position)
hydroxyl, (3) identical substitutions at both hydroxyls ("di-esters"), or (4) differ.ent substituents at
each hydroxyl ("mixed di-esters"). (Tr. 521:12-21 (Roush).) The court is persuaded by Dr.
Roush's testimony that pursuing one position to the exclusion of the others would be "like putting
on a straightjacket or tying a hand behind your back." (Tr. 521 :22-522:8 (Roush).) Indeed, the
prior art would have taught a POSA to try monoesters and di-esters, (Tr. 363:5-20 (Janero)), and

7

Notably, Dr. Janero failed to identify a known ester prodrug created using his allegedly obvious approach.
The evidence adduced at trial revealed that codeine is an ether, not an ester, (Tr. 366:9-18 (Janero )), and the approach
that would have rendered fesoterodine obvious failed with ampicillin, (Tr. 369: 10-17 (Janero).)

25

nothing taught that monoesters are preferred to diesters (Tr. 365: 16-22 (Janero)). Further, nothing
in the prior art directed a POSA to only use a conservative small hydrocarbon ester (as Mylan
suggests) and, if ease of conversion were the issue (as Mylan suggests), other types of esters would
also provide for a one-step conversion process. (Tr. 364: 12-17; 370:8-14; 371: 11-18 (Janero).)
Third, Mylan provided no evidence specifically teaching towards a phenolic isobutyryl
ester of 5-HMT. Instead, Mylan argues that a POSA would have only made conservative ester
modifications of no more than four carbons so as not to markedly increase the molecular weight
of the compound. (Tr. 307: 11-308:5, 310:7-312:8, 364: 18-24 (Janero).) Pfizer observes, however,
that even limiting potential options to those presented by Mylan---esters with two to six carbonsa POSA would have had over 7,000 options for modifying the 5-HMT molecule. (Tr. 523 :3-11
(Roush).) The sheer number of possible combinations seriously undermines Mylan's assertion
that the obvious pathway to solve the problem would have been ester-based prodrug design. The
prior art does not provide any suggestion or teaching that the isobutyrl prodrug group would be
compatible with 5-HMT, (Tr. 519:2-7 (Roush); Tr. 377:8-12 (Janero)), and Mylan identified no
reference that disclosed an isobutyryl derivative. (Tr. 371:24-372:6 (Janero).)
Finally, the process engaged by the inventors' demonstrates the highly unpredictable nature
of the prodrug development approach.

The inventors prepared 20 prodrug candidates and

evaluated their conversion rates and absorption rates.

Pfizer submitted evidence that their

experiments yielded unpredictable results. (Tr. 435:10-18, 436:18-19, 437:1-12 (Maag).) The
inventors' results, and Dr. Janero's ultimate admission that prodrugs are complicated, are powerful
evidence of the unpredictability inherent in prodrug design, a factor that weighs strongly against
an obviousness finding. Procter & Gamble Co. v. Teva Pharm USA, Inc., 566 F.3d 989, 996 (Fed.
Cir. 2009) (highlighting unpredictability seen with a class of compounds in finding

26

nonobviousness). This unpredictability militates against a finding that there was a reasonable
expectation of success in discovering fesoterodine. Accordingly, the court concludes that the
Composition Patents are not invalid for obviousness.
(4)

Salt Forms of Fesoterodine

Mylan argues it would have been obvious to make salt forms of fesoterodine as claimed in
the '650 patent. As fesoterodine is not prior art to the '650 patent, Mylan must prove fesoterodine
would have been obvious to invalidate its claims. Mylan has failed to do so. Preparation of salt
forms of a compound, like prodrugs, is a highly unpredictable exercise. (Tr. 372:7-373:8 (Janero);
Tr. 561:18-562:2, 571:1-7 (Chyall).) The inventor's (Dr. Meese) testimony illuminates this
unpredictability. Dr. Meese prepared more than 70 salts. All but the hydrogen fumarate salt of
fesoterodine initially resulted in oils, rather than the desired crystalline solids. (Tr. 182: 11-183 :6
(Meese).) Dr. Meese fortuitously discovered the hydrochloride hydrate of festoerodine, which
formed after the initial non-hydrate form was exposed to ambient moisture for some time. (Tr.
161:9-24, 182:4-10 (Meese).) The court finds that the asserted claims of the '650 patent are not
obvious.

*****
In sum, Mylan has failed to present a prima facie case that the asserted claims of the

patents-in-suit are invalid as obvious. 8
IV.

CONCLUSION

For the reasons stated above, the court concludes that none of the asserted claims of the
patents-in-suit are invalid due to obviousness.

8
Because Mylan has failed to establish a prima facie case of obviousness, the court does not address Pfizer's
secondary considerations. See Graham, 383 U.S. at 17-18.

27

Dated: August

_j_, 201 7

28