Endo Pharmaceuticals Inc. v. Mylan Pharmaceuticals Inc. et al
Filing
226
OPINION (re bench trial). Signed by Judge Renee Marie Bumb on 1/28/2014. (bkb)
IN THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF DELAWARE
ENDO PHARMACEUTICALS INC.,
Plaintiff,
Civil No. 11-CV-00717 (RMB/KW)
v.
OPINION
MYLAN PHARMACEUTICALS INC., et
al.,
Defendants.
Appearances
Jack B. Blumenfeld
Jeremy A. Tigan
Julia Heaney
Morris, Nichols, Arsht & Tunnell LLP
1201 North Market Street
P.O. Box 1347
Wilmington, DE 19899
Attorneys for Plaintiff
Jeffrey I.D. Lewis
Richard Maidman
Sean Marshall
Edward R. Tempesta
Patterson Belknap Webb & Tyler LLP
1133 Avenue of the Americas
New York, NY 10036
Of Counsel for Plaintiff
Richard L. Horwitz
Bindu Ann George Palapura
David Ellis Moore
Potter Anderson & Corroon, LLP
1313 N. Market St.
Hercules Plaza, 6th Floor
Wilmington, DE 19899
Attorneys for Defendants
1
Douglas Carsten
Katherine Van Gunst
Elham F. Steiner
Matthew J. Bresnahan
Wilson Sonsini Goodrich & Rosati PC
12235 El Camino Real, Suite 200
San Diego, CA 92130
T.O. Kong
Wilson Sonsini Goodrich & Rosati PC
One Market Street
Spear Tower, Suite 3300
San Francisco, CA 94105
Of Counsel for Defendants
BUMB, United States District Judge:
INTRODUCTION
This is an action for patent infringement brought by
Plaintiff Endo Pharmaceuticals Inc. (“Endo” or “Plaintiff”)
against Defendants Mylan Pharmaceuticals Inc. and Mylan, Inc.
(collectively, “Mylan” or “Defendants”) pursuant to 35 U.S.C.
§ 271(e)(2)(A), and §§ 271(a), (b), and (c). Specifically, Endo
alleges that Mylan has infringed and/or will infringe U.S.
Patent Nos. 5,464,864 (filed Nov. 7, 1995) (the “‘864 Patent”),
5,637,611 (filed June 10, 1997) (the “‘611 Patent”), and
5,827,871 (filed Oct. 27, 1998) (the “‘871 Patent”)
(collectively, the “King Patents”) in connection with Mylan’s
submission of Abbreviated New Drug Application (“ANDA”) number
202931 seeking the approval of the U.S. Food & Drug
Administration (“FDA”) to market its generic ANDA Product prior
to the expiration of the King Patents.
2
On July 18, 2013, the Honorable Joseph E. Irenas held a
hearing pursuant to Markman v. Westview Instruments, Inc., 517
U.S. 370 (1996), and subsequently issued a claim construction
opinion addressing three disputed claim terms of the King
Patents (the “Claim Construction Opinion”). (Dkt. Ent. 167.)
Although Mylan disputes the claim construction adopted by the
Court, it conceded prior to trial that, under the Court’s claim
construction, Mylan infringes or will infringe the asserted
claims of the King Patents. (Notice of Concession of
Infringement, Dkt. Ent. 182.) However, Mylan maintained that the
King Patents are invalid under the doctrines of anticipation,
obviousness, written description, and enablement. The Court held
a bench trial from November 12 through November 21, 2013, after
which it permitted the parties to submit proposed findings of
fact and conclusions of law. 1
After consideration of the evidence and the parties’ posttrial submissions, and for the reasons set forth below, the
Court finds that (1) Endo has waived and is now judicially
estopped here from pursuing claims against Mylan related to the
1
Mylan subsequently filed a letter requesting that the
Court strike certain portions of Endo’s opening brief and
proposed findings of fact, which included inter alia certain
irrelevant or confidential information. (See Dkt. Ent. 201.)
Mylan’s request is moot in light of the decision set forth
herein and for the further reason that Endo’s materials were
filed under seal.
3
‘871 and ‘611 Patents in this litigation, and (2) the asserted
claims of the ‘864 Patent are valid. Accordingly, the Court
enters judgment against Mylan and in favor of Endo. This Opinion
constitutes the Court’s findings of fact and conclusions of law
pursuant to Federal Rule of Civil Procedure 52(a). 2
I.
BACKGROUND
A. The Drug Approval Process
Under the Federal Food, Drug, and Cosmetic Act, 21 U.S.C.
§ 301 et seq., the FDA must approve all new drugs before they
may be distributed in interstate commerce. 21 U.S.C. § 355(a).
To secure approval for a new drug, an applicant may file a New
Drug Application (“NDA”) that includes, inter alia, the number
and expiration date of any patents which claim the drug or a
method of using the drug if a claim of patent infringement could
reasonably be asserted. Id. § 355(b)(2). “The FDA publishes the
names of approved drugs and their associated patent information
in the Approved Drug Products with Therapeutic Equivalence
Evaluations list, commonly referred to as the ‘Orange Book.’”
AstraZeneca LP v. Apotex, Inc., 633 F.3d 1042, 1045 (Fed. Cir.
2010). An applicant seeking approval to market a generic version
2
Endo’s oral motion made during trial, for judgment on
partial findings pursuant to Rule 52(c), is DISMISSED as moot.
Rule 52(c) permits such motions after “a party has been fully
heard on an issue during a nonjury trial.” As permitted under
the rule, the Court exercised its discretion to reserve on the
motion when it was made during trial. (Tr. 1176:11-12.)
4
of a drug that has already been approved may file an ANDA, which
“allows an applicant to rely on the safety and efficacy
information for the listed drug if the applicant can show that
the generic drug is ‘bioequivalent’ to the listed drug.” Id.
(citing 21 U.S.C. § 355(b)(2), (j)).
“[F]or each patent listed in the Orange Book that claims
either the listed drug or a use of the listed drug for which the
applicant is requesting approval, an ANDA must include either
one of four certifications or a ‘section viii statement.’”
AstraZeneca LP, 633 F.3d at 1046. If an applicant submits a
certification, the applicant must certify “(I) that . . . patent
information has not been filed, (II) that such patent has
expired, (III) . . . the date on which such patent will expire,
or (IV) that such patent is invalid or will not be infringed by
the manufacture, use, or sale of the new drug.” 21 U.S.C.
§ 355(j)(2)(A)(vii)(I)-(IV). The last of these is known as a
“paragraph IV certification”. If an ANDA applicant submits a
paragraph IV certification and a patent infringement suit is
commenced within 45 days, then the FDA may not approve the ANDA
application until expiration of a 30-month statutory period. Id.
§ 355(c)(3)(C).
B. Frova
On November 8, 2001, the FDA approved NDA No. 21-006 for
Frova (frovatriptan succinate) oral tablets. (Stipulated Facts
5
(“SF”), Dkt. Ent. 172 ¶ 8.) Frova is indicated for the acute
treatment of migraine attacks with or without aura in adults.
(Id. ¶ 10; see also John Campbell (“Campbell”) Tr. 29:8-20,
29:25-30:10.) 3 Physicians also prescribe Frova “off-label” for
the treatment of menstrual migraine. 4 (Dr. Brian Grosberg
(“Grosberg”) Tr. 1374:12-1376:2; see also Campbell Tr. 46:2247:6.) The Orange Book associates the King Patents with
frovatriptan succinate. 5 (Answer, Dkt. Ent. 9 ¶ 36.)
Endo commercially markets Frova, which contains a compound
chemically designated as (R)-(+)-3-methylamino-6-carboxamido1,2,3,4-tetrahydrocarbazole monosuccinate monohydrate, known as
frovatriptan monosuccinate monohydrate, as the active
pharmaceutical ingredient (“API”). (SF ¶ 5; Dr. Vincent Rocco
(“Rocco”) Tr. 126:8-10; see also Dr. Graham Johnson (“Johnson”)
Tr. 1024:4-6.) The label for Frova refers to the API as
3
“Tr.” refers to the trial transcripts, and is preceded by
the name of the testifying witness.
4
An “off-label” use means a use beyond those specifically
approved of by the FDA. (Grosberg Tr. 1375:19-1376:2; Campbell
Tr. 46:22-47:6.)
5
The Orange Book also lists U.S. Patent Nos. 5,616,603 (the
“‘603 Patent”) (DTX-1399) and 5,962,501 (the “‘501 Patent”)
(collectively, the “Borrett Patents”). (Plaintiff’s Answer to
the Counterclaims of Defendants (“Answer to Counterclaims”),
Dkt. Ent. 17 ¶ 9.) However, the parties entered into a covenantnot-to-sue with respect to these patents. (Stipulation of
Dismissal, Dkt. Ent. 18 (stipulating to dismissal of
counterclaim related to these patents).)
6
frovatriptan succinate. (Rocco Tr. 125:8-10; Campbell Tr. 28:1012; PX-0008; PX-0009; PX-0059.)
The empirical formula for frovatriptan monosuccinate
monohydrate is C14H17N3O·C4H6O4·H2O, and it has a molecular weight
of 379.4. (SF ¶ 6; PX-0008; PX-0059.) Frova tablets contain 3.91
mg frovatriptan monosuccinate monohydrate, equivalent to 2.5 mg
of frovatriptan free base. (SF ¶ 9; PX-0008; PX-0009.) This
difference in weight is accounted for by the weight of the
succinate and water molecules added to the free base. (Rocco Tr.
128:3-15.)
Chemical compounds may exist in a variety of forms,
including free base forms, salts, solvates, hydrates, salthydrates, and salt-solvates. Frovatriptan monosuccinate
monohydrate is a hydrated salt form of frovatriptan. (Rocco Tr.
99:15-101:22.) A salt is formed through a reaction between an
acid and a free base (Rocco Tr. 99:15-17; Dr. Albert Lee (“Lee”)
Tr. 389:4-23); here, succinic acid reacts with the frovatriptan
free base to form the salt (Rocco Tr. 99:18-100:8). A salt may
be hydrous or anhydrous, depending on whether the molecule has
water associated with it. (Rocco Tr. 101:3-12.) Frovatriptan
monosuccinate monohydrate is a hydrate, which means that it is a
crystalline form of a compound in which water is part of the
crystal lattice. (Lee Tr. 390:4-6; Rocco Tr. 100:24-101:6.) Like
a hydrate, a solvate is a crystalline form of a compound with
7
solvent molecules that form part of the crystal lattice. (Lee
Tr. 390:12-13; see also Rocco Tr. 102:13-15.) As such, a hydrate
can be considered a solvate in which water is the specific
solvent. (Lee Tr. 390:13-15; see also Rocco 102:18-20.)
Certain molecules may exist in different orientations in
three-dimensional space. (SF ¶ 30.) A molecule’s threedimensional configuration is referred to as its stereochemistry.
(See Rocco Tr. 94:14-23.) Compounds may have the same molecular
formula but different three-dimensional configurations, or
stereoisomers. (See Rocco Tr. 94:19-23.) Where the stereoisomers
are related to each other, and form non-superimposable mirror
images of one another, they are known as enantiomers. (Rocco Tr.
94:24-95:25.)
A molecule’s stereochemistry is indicated by certain naming
conventions, such as inclusion of an (R) or (S) before the
molecular formula, and may also be reflected in a diagram of the
chemical structure. (SF ¶¶ 32-33; see also Rocco Tr. 96:4-97:9.)
In a diagram, a line connecting two atoms represents a chemical
bond located on the plane of the paper. A solid triangle
represents a bond extending out in front of the paper (i.e.,
towards the reader), and a hatched triangle represents a bond
extending behind the paper (i.e., away from the reader). (SF
¶ 33; Rocco Tr. 96:4-97:9.)
8
There are two enantiomers for frovatriptan, based upon
whether the “NHCH3” component at the 3-position is extending
towards or away from the reader. (Rocco Tr. 96:4-97:9.) The
specific frovatriptan enantiomer used as the API in Frova is the
(R)-(+) enantiomer, which has the following chemical structure:
(PX-0008 at 1 (Frova product label); see also SF ¶¶ 5, 20.)
C. Migraine and Migraine Treatment
Frova is indicated for the acute treatment of migraine.
Migraines are a neurologic (i.e., central nervous system)
syndrome characterized by episodes of severe cephalic (head)
pain, which may be associated with neurological, autonomic,
and/or gastrointestinal symptoms and which are frequently
accompanied by nausea, vomiting, and/or sensitivity to light or
sound. (SF ¶¶ 15-16; see also Dr. Stephen Peroutka (“Peroutka”)
Tr. 534:9-536:1; Grosberg Tr. 1336: 14-22; Johnson Tr. 659:7661:21.) The art had a similar understanding as of the priority
date. If untreated or unsuccessfully treated, a migraine attack
typically lasts from 4 to 72 hours, with a median duration of 24
hours. (Grosberg Tr. 1336:15-22.) The causes of migraine are
unknown. (Grosberg Tr. 1338:9-10.)
9
Medication used to treat acute migraine attacks include
both specific and nonspecific treatments. A nonspecific
treatment for migraine is a treatment that addresses the
symptoms of migraine, and includes acetaminophen or Tylenol,
aspirin, non-steroidal anti-inflammatory drugs like ibuprofen,
and combination analgesics. (Grosberg Tr. 1339:15-19.)
Nonspecific treatments are sometimes available without
prescription and may be effective in less severe attacks, but
they are susceptible to overuse and have potential side effects.
(Grosberg Tr. 1339:25-1340:5.) A specific treatment for migraine
refers to a treatment that addresses the mechanism of migraine,
and includes ergotamines and triptans. (Grosberg Tr. 1339:191340:14.) Specific treatments are generally prescription
medications that are more efficacious but have lower recurrence 6
and potential for overuse. (Id.)
Ergotamines, or ergots, were an early form of specific
treatment for migraine that became available in the 1920s. (SF
¶ 18; Peroutka Tr. 537:5-9.) Ergots were non-selective, 7 and had
6
Recurrence refers to “the reappearance of the migraine
headache after the initial treatment was successful in
alleviating the pain.” (Grosberg Tr. 1340:18-21.)
7
Selectivity refers to the degree to which a compound
“differentiates between different receptors subtypes.” (Dr.
David Nelson (“Nelson”) Tr. 1185:5-21; see also Rocco Tr.
1645:7-9.) A “selective” drug reacts primarily with desired
receptors, whereas a “non-selective” drug also interacts with
other receptors. (See Rocco Tr. 116:23-117:12; Nelson Tr.
10
low tolerability and notable side effects, such as the
contraction of blood vessels in the leg leading in some cases to
gangrene. (Peroutka Tr. 553:21-554:12; Johnson Tr. 662:5-663:13;
Grosberg Tr. 1340:14-17.) Compounds in the ergot family include
dihydroergotamine (“DHE”), ergotamine, and methysergide. (Rocco
Tr. 1687:24-1688:20 (referring to Slide 3).)
The “triptan” family of compounds, a class of tryptamine
derivative compounds used to treat migraine, were an improvement
over ergotamines. (SF ¶¶ 19-20; PX-0219 at 83.) Frovatriptan is
a member of the triptan family, and is one of seven triptans
currently on the market. (SF ¶ 20; Campbell Tr. 29:15-24.)
Sumatriptan was a prior art triptan. (SF ¶ 22.) The others are
listed below with the chemical structure, year of FDA approval,
marketing company, and trade name.
Sumatriptan (1993),
Glaxo SmithKline,
"Imitrex"
Zolmitriptan (1997),
AstraZeneca, "Zomig"
Rizatriptan
(1998), Merck,
"Maxalt"
1185:8-1186:5.) A drug’s selectivity impacts the potential side
effects of that drug. (Rocco Tr. 115:17-21, 116:23-117:12.)
11
Naratriptan (1998),
Glaxo SmithKline,
"Amerge"
Almotriptan (2001),
Janssen, "Axert"
Eletriptan
(2002), Pfizer,
"Relpax"
(SF ¶¶ 22, 25-29; Campbell Tr. 25:21-22; PX-0121 8 at 62.)
Frovatriptan is the only FDA-approved triptan with a fused
three-ring or tricyclic core structure, known as a 1,2,3,4tetrahydrocarbazole. (Rocco Tr. 123:15-17, 1696:3-11.) The other
triptans have only a 2-ring core structure. (Id.) In addition,
frovatriptan is the only FDA-approved triptan with an
unsubstituted carboxamido substituent at its 6-position and a
methylamino in its 3-position. (See Rocco Tr. 1697:8-1699:17.)
Serotonin is a member of the tryptamine class of compounds
that, as of the priority date, was believed to affect migraine
treatment. (SF ¶ 14; Rocco Tr. 110:10-25.) Serotonin is a
naturally-occurring molecule that can function as a
neurotransmitter; its chemical name is 5-hydroxytryptamine or
“5-HT” and it bears the following chemical structure:
8
Peter De Vries et al., Review: Pharmacological aspects of
experimental headache models in relation to acute antimigraine
therapy, 375 Eur. J. Pharm. 61 (1999).
12
(Id.; see also SF ¶¶ 11-13; Peroutka Tr. 536:2-14.) By 1991,
there was a lot of general interest in serotonin because of its
numerous biologic effects and research into serotonin was
“extremely active”. (DTX-1196 9 at 1; Peroutka Tr. 517:14-25; see
also Johnson Tr. 938:21-939:6 (explaining that Glennon 1987 was
a “very significant paper in the field of serotonin research”).)
Serotonin interacts with numerous receptors throughout the
body, known as 5-HT or serotonin receptors, and causes a
physiological response. (See Nelson Tr. 1198:3-7; Rocco Tr.
110:23-111:9.) A chemical compound that binds to a receptor can
be referred to as a “ligand.” (Peroutka Tr. 614:25-615:2.) If
the ligand binds to the receptor and causes a physiological or
biological response, then the ligand is called an “agonist.”
(Rocco Tr. 111:1-9.) If the ligand binds to the receptor but
does not cause a physiological or biological response, then it
is called an “antagonist.” (Rocco Tr. 111:10-22.) Serotonin
treats migraine by interacting with certain 5-HT receptors.
(Rocco Tr. 110:23-111:9.)
9
Richard A. Glennon, Central Serotonin Receptors as Targets
for Drug Research, J. Med. Chem., Vol. 30, No.1 (Jan. 1987)
(“Glennon 1987”).
13
Serotonin receptors are categorized into general families,
indicated by subscripts after 5-HT, such as the “5-HT1 family”.
(Rocco Tr. 112:23-113:4.) Some families are further subdivided
as indicated by subscript letters that follow the numerical
designation, such as 5-HT-1B and 5-HT-1D. (Rocco Tr. 112:23113:4.) As of 1991, identification of serotonin receptor
subtypes was ongoing and designations changed as research
regarding the subtype structure advanced. (See Peroutka Tr.
546:9-547:19, 545:4-546:8.) By the beginning of the 1990s, a
person of ordinary skill in the art knew that migraine drugs
interacted with the 5-HT1 receptor family. (Peroutka Tr. 546:917; Rocco Tr. 112:2-4.)
D. The King Patents
1. '864 Patent
On November 7, 1995, the United States Patent and Trademark
Office (the “PTO”) issued the ‘864 Patent, entitled “Use of
Tetrahydrocarbazole Derivatives As 5HT1 Receptor Agonists.” (PX0001.) The ‘864 Patent issued from U.S. Patent Application No.
08/167,846, filed June 17, 1992, and lists a foreign application
priority date of June 26, 1991. (Id.) The named inventors are
Francis D. King, Laramie M. Gaster, Alberto J. Kaumann, and
Rodney C. Young. The ‘864 Patent was granted a Patent Term
Extension under 35 U.S.C. § 156 on February 10, 2006, which on
its face extends the patent term to November 7, 2015. (SF ¶ 39.)
14
At issue in this case are claims 1, 2, 3, and 6 of the ‘864
Patent.
2. '611 Patent
On June 10, 1997, the United States Patent and Trademark
Office issued the ‘611 Patent, entitled “Medicaments.” (PX0003.) The ‘611 Patent issued from U.S. Patent Application No.
08/442,719, filed May 15, 1995, and is a continuation of the
application which led to the ‘864 Patent. The ‘611 Patent
originally expired on June 10, 2014. (SF ¶ 46.) However, on
October 30, 2013, Endo filed a terminal disclaimer with respect
to the ‘611 Patent, which effectively disclaimed that portion of
its term that extends beyond the term of the ‘864 Patent. (See
Dkt. Ent. 178.) The PTO accepted the terminal disclaimer on
November 27, 2013. (Dkt. Ent. 188.)
The asserted claims are 1, 2, 3, 8, 9, and 10 of the ‘611
patent.
3. '871 Patent
On October 27, 1998, the United States Patent and Trademark
Office issued the ‘871 Patent, entitled “Medicaments 1,2,3,4,Tetrahydrocarbazoles and 5-HT1 Agonist Use Thereof.” (PX-0002.)
The ‘871 patent issued from U.S. Patent Application No.
08/442,720, filed May 15, 1995, and is a continuation-in-part of
the application leading to the ‘864 Patent. The ‘871 Patent
originally expired on October 27, 2015. (SF ¶ 53.) However, Endo
15
filed a terminal disclaimer, which disclaims that portion of its
term that extends beyond the '611 and '864 Patents. (See Dkt.
Ent. 178.) The PTO accepted the terminal disclaimer on November
27, 2013. (Dkt. Ent. 188.)
The asserted claims are 1, 2, 3, 4, 5, 6 and 7 of the ‘871
patent.
E. Ownership of Frova and the King Patents
The King Patents identify SmithKline Beecham P.L.C. (“SKB”)
as the assignee. (SF ¶ 56.) SKB licensed certain rights to Frova
to Vernalis Ltd. (f/k/a Vanguard Medica, and referred to herein
as “Vernalis”). (Philip Green (“Green”) Tr. 2011:23-2012:4; see
also SF ¶ 57.) In 1999, Vernalis submitted to the FDA NDA 21-006
for frovatriptan tablets, which the FDA approved on November 8,
2001. (SF ¶¶ 58, 60.) However, in 1998, while Frova was still in
development, Vernalis licensed North American sales and
distribution rights to Elan Corporation P.L.C. (“Elan”). (SF
¶ 59.)
In 2000, SKB and Glaxo Wellcome P.L.C. merged. (PX-0378 at
3.) However, because the merged entity would have owned three of
the seven triptans, the United States Federal Trade Commission
entered into a Consent Agreement with the merging entities
pursuant to which SKB agreed to “transfer and surrender,
absolutely and in good faith, all Frovatriptan Assets . . . to
Vernalis . . . .” (Id. at 37.) As a result, SKB transferred all
16
of the rights to the Frova product and assigned the King Patents
to Vernalis. (Green Tr. 2012:4-12.)
Pursuant to an agreement with Vernalis, and in conjunction
with UCB Pharma Inc., Elan launched the Frova product in the
United States in 2002. (See Campbell Tr. 30:11-14; Green Tr.
2004:6-15; DTX-1153 at 9.) Two years later, Vernalis reacquired
from Elan the commercialization rights for the Frova product in
North America. (Green Tr. 2012:13-16.) Vernalis subsequently
licensed the U.S. rights to Endo in 2004 (DTX-1003; Green Tr.
2012:17-18) and ultimately assigned the King Patents to Endo in
2011 (SF ¶ 61; DTX-1059).
F. This Court's Claim Construction Opinion
On August 7, 2013, the Honorable Joseph E. Irenas issued a
Claim Construction Opinion that addressed three disputed claim
terms of the King Patents. First, the Court construed the term
“compound of (general) formula (I),” which appears in claim 1 of
each of the King Patents. (See Claim Constr. Op. 8-10.) After
noting that the parties agreed that the compound includes “all R
[enantiomers] and no S to all S and no R, and every ratio in
between,” the Court determined that this term refers to “the
formula without regard to its stereochemistry.” (Id. at 9.)
Second, the Court construed the term “or a salt, solvate or
hydrate thereof,” which appears in claim 1 of the ‘864 Patent,
as meaning “or one or more of salt, solvate or hydrate thereof.”
17
(Id. at 11-14.) The Court saw “no basis for finding that ‘salt’
does not also include a salt that is also a hydrate or also a
solvent.” (Id. at 12.) The parties agreed that salt should be
similarly construed in claim 6, which refers to “a
physiologically acceptable salt thereof.” (Id. at 11.) 10
Third, the Court construed the term “treatment of a
condition wherein a 5-HT1-like agonist is indicated,” which
appears in claim 2 of the ‘864 Patent, 11 claim 1 of the ‘871
Patent, and claim 10 of the ‘611 Patent, as meaning “treatment
without prophylaxis.” (Id. at 20.)
LEGAL ANALYSIS
A patent and each of its claims are presumed to be valid,
even where those claims may be dependent upon other invalid
claims in the patent. 35 U.S.C. § 282(a). A party may rebut this
presumption of validity with clear and convincing evidence of
invalidity. Sciele Pharma Inc. v. Lupin Ltd., 684 F.3d 1253,
1260 (Fed. Cir. 2012) (citing 35 U.S.C. § 282 and Microsoft
Corp. v. i4i Ltd. P’ship, -- U.S. --, 131 S. Ct. 2238, 2245
(2011)). “The ‘clear and convincing’ standard of proof of facts
10
The Court’s Claim Construction Opinion addressed similar
terms appearing in other asserted claims of the ‘611 and ‘871
Patents (id.), which are no longer relevant in light of Endo’s
waiver of its rights and the Court’s decision to estop Endo from
proceeding under these Patents in this litigation.
11
This term also affects claim 3 of the ‘864 Patent, which
refers to the method in claim 2.
18
is an intermediate standard which lies somewhere between ‘beyond
a reasonable doubt’ and a ‘preponderance of the evidence’ . . .
[and] has been described as evidence which produces in the mind
of the trier of fact ‘an abiding conviction that the truth of
[the] factual contentions are highly probable.’” Buildex Inc. v.
Kason Indus., Inc., 849 F.2d 1461, 1463 (Fed. Cir. 1988)
(citations omitted).
Where an invalidity challenge is based upon prior art that
was considered by the PTO during the patent prosecution, and
where a patent was issued notwithstanding the prior art, “a
court owes some deference to the PTO’s decision.” Minnesota
Mining & Mfg. Co. v. Johnson & Johnson Orthopaedics, Inc., 976
F.2d 1559, 1572 (Fed. Cir. 1992) (citations omitted)). Although
Defendants’ burden does not change, evidence considered by the
PTO may not be given the same weight as new evidence. See Sciele
Pharma Inc., 684 F.3d at 1260 (“[N]ew evidence not considered by
the PTO ‘may carry more weight . . . than evidence previously
considered by the PTO,’ and may ‘go further toward sustaining
the attacker's unchanging burden.’” (citing Microsoft Corp., 131
S. Ct. at 2251)).
I.
Endo Abandoned Its Claims Related to the ‘871 and ‘611
Patents
During the trial, Endo abandoned its claims related to the
‘871 and ‘611 Patents. As a result, this Court ruled that Endo
19
would be estopped from resurrecting those claims at a later date
in this litigation. 12 Endo’s abandonment of those claims occurred
in the midst of trial after some evidence relating to those
patents already had been presented. Endo stated that “with this
[terminal] disclaimer everything rises and falls on the ‘864
patent, we can litigate the ‘864 patent and that will govern
what occurs in the case.” 13 (Tr. 268:22-269:19.) Hence, it was
the Court’s view that any further effort to pursue claims
against Mylan related to the ‘871 and ‘611 patents, in this
litigation, would be judicially estopped. Endo had asserted
claims against Mylan relating to the ‘871 and ‘611 Patents in
the current litigation but midway chose instead to abandon them
in favor of the ‘864 Patent. Permitting Endo to reassert the
abandoned claims against Mylan later in this litigation (or even
12
It is clear Endo would also be estopped in subsequent
litigation.
13
On the eve of trial, Endo filed a terminal disclaimer,
which disclaims:
(i) the terminal part of the term of the ‘871 patent
which would extend beyond the expiration dates of the
full terms of the ‘611 patent and . . . [the ‘864
patent], and (ii) the terminal part of the term of the
‘611 patent which would extend beyond the expiration
date of the full term of the ‘864 patent.
(Dkt. Ent. 178-1.) In addition, the disclaimer provides that the
‘871 and ‘611 Patents “shall be enforceable only for and during
such period that they and the ‘864 patent are commonly owned.”
(Id.) The terminal disclaimer was later approved by the PTO.
(See Dkt. Ent. 188.)
20
in the future) would be manifestly unjust to Defendants and,
therefore, judicial estoppel is an appropriate remedy. Cf. Van
Blunk v. McAllister Towing of Phila., Inc., No. 10-00686, 2012
WL 832997, at *5 (D.N.J. Mar. 12, 2012) (judicially estopping
plaintiff from presenting inconsistent position in order to
“prevent manifest injustice” and prejudice to defendant); Haines
& Kibblehouse, Inc. v. Balfour Beatty Constr., Inc., 789 F.
Supp. 2d 622, 636 (E.D. Pa. 2011) (same).
Endo now argues that the Court erred because Endo was
permitted to file the terminal disclaimer at any point in this
litigation and that filing could not be deemed an admission of
the merits of the double-patenting allegation. Although Endo is
correct as to the legal effect of the terminal disclaimer, its
arguments miss the point: the Court based its decision not on
the terminal disclaimer, but on the unequivocal statements of
counsel signifying Endo’s intent to abandon its claims here.
See, e.g., Boehringer Ingelheim Int’l GmbH v. Barr Labs., Inc.,
592 F.3d 1340, 1347 (Fed. Cir. 2010) (terminal disclaimer may be
filed lawfully at any time “after issuance of the challenged
patent or during litigation, [or] even after a finding that the
challenged patent is invalid for obviousness-type double
patenting”) (citations omitted); Quad Envtl. Techs. Corp. v.
Union Sanitary Dist., 946 F.2d 870, 874 (Fed. Cir. 1991) (“It is
improper to convert this simple expedient of “obviation” [of a
21
rejection of double-patenting] into an admission or acquiescence
or estoppel on the merits.”); (see also Pl.’s Opening Post-Trial
Br. (“Pl.’s Br.”), Dkt. Ent. 191, at 36-37). When Endo advised
the Court that it had filed a terminal disclaimer with respect
to the ‘871 and ‘611 Patents, it stated that “[i]n preparing for
trial it has become clear that issues concerning Mylan’s
infringement of the ‘871 and ‘611 Patents are consistent with
those for infringement of the ‘864 Patent,” and Endo wished to
“simplif[y] the issues for the upcoming trial” by mooting
Mylan’s double-patenting defense. 14 (Letter, Dkt. Ent. 178 at 2.)
The Court understood from this letter, together with the
voluntary filing of the terminal disclaimer, that, contrary to
the Final Pretrial Order, Endo no longer wished to proceed with
its claims against Mylan as to these two patents. Endo treated
the terminal disclaimer, in essence, as a withdrawal of Endo’s
claims. (See, e.g., Tr. 254:24-255:18 (“THE COURT: . . . either
way you look at it Mylan is not threatened by those patents as a
result of the filing of the disclaimer . . . you no longer have
any threat of prosecution.”); Tr. 268:3-7 (“MS. STAFFORD: . . .
I think Endo is claiming if you allow their terminal claims to
14
Obviousness-type double patenting is a judicially created
doctrine intended “to prevent the extension of the term of a
patent . . . by prohibiting the issuance of the claims in a
second patent not patently distinct from the claims of the first
patent.” In re Longi, 759 F.2d 887, 892 (Fed. Cir. 1985).
22
moot our defense that their claims for those patents still
continue. THE COURT: But not as to Mylan.”).) 15
Endo’s counsel then repeatedly confirmed its intention to
abandon the claims related to the ‘871 and ‘611 Patents as set
forth in the Pretrial Order:
THE COURT: . . . Do I have it all wrong, Mr. Lewis?
Maybe I do. . . .
MR. LEWIS: Unfortunately, a lot of it wrong, but not
on that point.
THE COURT: I thought you were giving up your fight
against Mylan on the other two patents by filing the
disclaimer.
MR. LEWIS: What I’ve said, your Honor, is that with
this disclaimer everything rises and falls on the ‘864
patent, we can litigate the ‘864 patent and that will
govern what occurs in the case.
THE COURT: Okay. But just answer my question with a
yes or no, if you can. Do you agree that by filing the
disclaimer . . . that you no longer would have any
claims against Mylan on the remaining two patents?
MR. LEWIS: It is effective and the claim stops at the
date that those patents are terminally disclaimed on
those patents, but the ‘864 runs longer. And we
believe the ‘864 patent covers all of the issues in
the case and everything else [rises and falls] on that
in terms of the infringement.
15
See also Tr. 275:18-276:2 (“THE COURT: . . . So I
understand Endo’s position is that [the disclaimer is] effective
because that’s where Endo is, they no longer wish to pursue the
‘611 and ‘871, I get that, the issue for the Court is is it a
final order, so to speak. And, as of now, it isn’t. But it
really is a moot point at this juncture because I think
regardless the issue of going forward is this case will go
forward on the ‘864 . . . and Endo is estopped from further
pursuing any cause of action against Mylan for those two patents
on this ANDA.”).
23
(Tr. 268:22-269:19 (emphasis added); see also Tr. 271:23272:1.) 16 Indeed, counsel affirmed that “there is no risk to
Mylan separate that goes beyond the ‘864 patent” (Tr. 272:1011), and offered to stipulate that “the case [rises] and falls
with the ‘864 patent” (Tr. 277:19-21; Tr. 278:3-6). These
statements provided to the Court a clear indication of Endo’s
intent to abandon or withdraw its claims regarding the ‘871 and
‘611 Patents, and to proceed only with the ‘864 Patent
infringement action here.
Despite these concessions, Mylan remained concerned that
Endo would at some later point attempt to revive the claims it
had just waived. Thus, the Court stated:
But what I asked Mr. Lewis is why shouldn’t [you be]
judicially estopped from prosecuting under the ‘611
and ‘871 if I deem the terminal disclaimer to have the
effect you say I should deem it to have. And Mr.
Lewis’ response is that we should be judicially
estopped and I think that’s the right answer.
(Tr. 274:10-15.) Endo, however, clarified only that it believed
the terminal disclaimer to be effective. (Tr. 275:4-6.) But,
having decided to “litigate the ‘864 patent” only at such late
juncture, i.e., the second day of trial, Endo would not later be
16
Counsel’s statements imply that the asserted claims of
the ‘871 and ‘611 Patents may not be “patentably distinct” from
the asserted claims of the ‘864 Patent and, therefore, seemingly
bolster Defendants’ double-patenting argument. However, no
proofs were submitted on this issue, and the Court does not
decide it here.
24
permitted to resurrect claims against Mylan on the other two
patents. 17 (See Tr. 269:4-7.)
Endo also now argues that the requirements for judicial
estoppel are not met as there is no evidence of bad faith.
“Though there is no rigid test for judicial estoppel, three
factors inform a federal court’s decision whether to apply it:
there must be (1) ‘irreconcilably inconsistent positions;’ (2)
‘adopted . . . in bad faith;’ and (3) ‘a showing that . . .
estoppel . . . address[es] the harm and . . . no lesser sanction
[is] sufficient.’” Singer Mgmt. Consultants, Inc. v. Milgram,
650 F.3d 223, 239 (3d Cir. 2011) (quoting G–I Holdings, Inc. v.
17
Cf. Johnson v. Zerbst, 304 U.S. 458, 464 (1938) (“A
waiver is ordinarily an intentional relinquishment or
abandonment of a known right or privilege.”), overruled on other
grounds by Edwards v. Arizona, 451 U.S. 477 (1981); Boro
Constr., Inc. v. Lenape Reg’l High Sch. Dist. Bd. Of Educ., No.
05-4689, 2010 WL 5419035, at *6 (D.N.J. Dec. 23, 2010) (noting
waiver of contractual rights may be supported “by such conduct
as to stop the waiving party from denying the intent to waive”);
Singer Mgmt. Consultants, Inc. v. Milgram, 650 F.3d 223, 239 (3d
Cir. 2011) (“If the State were to assert again that the Truth in
Music Act does not recognize valid common law trademarks, it
would be asserting an inconsistent position in presumptive bad
faith after already having conceded the wrongfulness of such an
assertion. Judicial estoppel, therefore, would apply to prevent
the State from perpetuating a fraud on the court.”); see also
Holstein v. City of Chi., 803 F.Supp. 205, 211 (N.D. Ill. 1992)
(“If an individual intentionally relinquishes a known right,
either expressly or by conduct inconsistent with an intent to
enforce that right, he has waived it.”(citing J.H. Cohn & Co. v.
Am. Appraisal Assocs., Inc., 628 F.2d 994, 1000 (7th Cir.
1980))).
25
Reliance Ins. Co., 586 F.3d 247, 262 (3d Cir. 2009)). 18 Endo is
correct. Its change in position before this Court, i.e., that it
would pursue the ‘864 Patent only, did not evince bad faith at
the time. But, Endo’s current position - “that its infringement
claims against Mylan on the ‘611 and ‘871 Patents should have
remained a part of this case” – is directly contradicted by the
arguments made before this Court during trial (and summarized
above). (Pl.’s Br. at 37.) Moreover, its current assertion that
it has somehow maintained a consistent position all along
troubles the Court. Nonetheless, for the reasons stated, Endo
abandoned its claims, and is thus estopped from further pursuing
claims against Mylan related to the ‘871 and ‘611 Patents in
this matter.
II.
Invalidity of the '864 Patent
Turning to the ‘864 Patent, Endo asserts that Mylan’s ANDA
product will infringe claims 1, 2, 3, and 6. Claim 1, the only
independent claim, states: “A compound of formula(I) which is 3methylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole, or a
salt, solvate or hydrate thereof.” (PX-0001 col.20 ll.44-46.) 19
18
In a patent action, judicial estoppel “is applied in
accordance with the law of the regional circuit as opposed to
Federal Circuit law.” Novo Nordisk A/S v. Bio-Tech. Gen. Corp.,
Ltd., No. 02-332, 2003 WL 21383717, at *2 (D. Del. June 9, 2003)
(citations omitted).
19
Claim 2 claims “A method of treatment of a condition
wherein a 5-HT1-like agonist is indicated, which comprises
administering to a subject in need thereof an effective amount
26
Although Mylan disputes the Court’s claim construction, Mylan
filed a Notice of Concession of Infringement prior to the
commencement of trial whereby it conceded that, under the claim
construction, “the manufacture, use, sale, offer for sale, or
importation of Mylan’s ANDA Product infringes” and/or “will
constitute contributory infringement or induce infringement” of
each claim at issue. (Dkt. Ent. 182; see also Pretrial Order,
Dkt. Ent. 171, at 19.)
Mylan contends, however, that the ‘864 Patent is invalid on
four separate grounds: anticipation, obviousness, lack of
written description, and failure to enable. Before turning to
the merits of these arguments, the Court notes two things.
First, the parties agree that the difference in how they define
a person of ordinary skill in the art (“POSA”) with respect to
the patents is immaterial to the invalidity analysis. (See Tr.
of Oct. 24, 2013 H’rg 45:10-25 (acknowledging that experts would
render the same opinions regardless of which definition is
utilized); see also Johnson Tr. 658:24-659:3; Rocco Tr. 1700:251701:4.) Therefore, the Court adopts Endo’s definition:
A person of ordinary skill in the art of the King
Patents as of the June 26, 1991 priority date would be
of a compound of claim 1.” Claim 3 claims “The method according
to claim [2] wherein the condition is migraine.” Claim 6 claims
“A pharmaceutical composition comprising the compound according
to claim 1, or a physiologically acceptable salt thereof and a
physiologically acceptable carrier.” (PX-0001 col.20 ll.47-52,
57-59.)
27
a medicinal chemist with a Ph.D. or its equivalent and
2-5 years of experience in the pharmaceutical
industry, working in conjunction with both a
pharmacologist with a Ph.D. or its equivalent with
experience in the pharmaceutical industry and a
medical professional with experience in the treatment
of conditions for which a 5-HT1-like agonist is
indicated and/or drug development. (See Tr. 1608:1-9
(Rocco).)
Second, the Court notes that the parties have stipulated
that the priority date applicable to all claims at issue in this
case is June 26, 1991. (SF ¶ 34.)
A. Anticipation
Mylan argues that U.S. Patent No. 4,257,952 (“Mooradian
‘952”), entitled “3-Amino-Tetrahydrocarbazoles”, anticipates the
asserted claims in the ‘864 Patent. The Court disagrees.
“[T]he dispositive question regarding anticipation is
whether one skilled in the art would reasonably understand or
infer from a prior art reference that every claim element is
disclosed in that reference.” AstraZeneca v. Apotex, 633 F.3d
1042, 1055 (Fed. Cir. 2010) (quoting In re Baxter Travenol
Labs., 952 F.2d 388, 390 (Fed. Cir. 1991)) (internal quotations
and brackets omitted). In other words,
Claimed subject matter is “anticipated” when it is not
new; that is, when it was previously known.
Invalidation on this ground requires that every
element and limitation of the claim was previously
described in a single prior art reference, either
expressly or inherently, so as to place a [POSA] in
possession of the invention. See Schering Corp. v.
Geneva Pharms., Inc., 339 F.3d 1373, 1379 (Fed. Cir.
28
2003); Continental Can Co. USA v. Monsanto Co., 948
F.2d 1264, 1267-69 (Fed. Cir. 1991).
Sanofi–Synthelabo v. Apotex, Inc., 550 F.3d 1075, 1082 (Fed.
Cir. 2008), cert. den’d, 130 S. Ct. 493 (2009). Anticipation is
a question of fact, and the party invoking this defense must
establish it at trial by clear and convincing evidence.
AstraZeneca, 633 F.3d at 1055 (citing Sanofi–Synthelabo, 550
F.3d at 1082, and Purdue Pharma L.P. v. Boehringer Ingelheim
GmbH, 237 F.3d 1359, 1365 (Fed. Cir. 2001)).
Anticipation requires that “all limitations of the claimed
invention are described in a single reference, rather than a
single example in the reference.” Net MoneyIN, Inc. v. VeriSign,
Inc., 545 F.3d 1359, 1369 n.5 (Fed. Cir. 2008). The court must
look at the reference “as a whole” and determine whether it
discloses all elements of the claimed invention as arranged in
the claim. Id.; see also Cellectis S.A. v. Precision Bioscis.,
Inc., 937 F.Supp.2d 474, 487 (D. Del. 2013) (“As noted above, a
prior art reference must disclose all of the limitations of the
claim, ‘arranged or combined in the same way as in the claim,’
to anticipate a claim.” (quoting Net MoneyIN, Inc., 545 F.3d at
1370)).
Mooradian ‘952 is a prior art patent that was considered by
the PTO in the prosecution of the ‘864 Patent and is in fact
listed as a reference on the cover page of the ‘864 Patent. (PX-
29
0001, at [56]; accord DTX-1077 at 191.) It discloses a broad
class of compounds chemically designated as 3-(substitutedamino)-1,2,3,4-tetrahydracarbazoles with “analgetic and
psychotropic activities” as well as, in some cases,
antihistaminic activity. (DTX-1019, at [57].) The 1,2,3,4tetrahydracarbazole is characterized by a tricyclic ring core
structure as pictured below. (See, e.g., Johnson Tr. 760:13-14.)
(PX-0001, at [57].)
Claim 1 of Mooradian ‘952 claims a 3-(N==B)-9-R-1,2,3,4tetrahydracarbazole having the formula
where N==B is NHR’, NR’R” or NR’”-Y_NR’NR”, where R’ and R” are
lower-alkyl or AR-lower-alkyl, R’”is hydrogen and Y is loweralkylene; R is hydrogen, lower-alkyl, Ar-lower-alkyl or loweralkenyl, or R is Y-NR’R”, where Y, R’ and R” have the same
meaning given above. (DTX-1019 col.63 ll.4-22.) Claim 1 permits
Q1, Q2, Q3, and Q4 to be selected from a variety of substituents
listed in the claim. Thus, Mooradian ‘952 permits substitution
on the left-hand side of the tetrahydrocarbazole ring system at
30
the 5-, 6-, 7-, or 8-position. (Johnson Tr. 759:8-12.) A
carboxamido is one of the substituents. (DTX-1019 col.64 ll.16.)
It is undisputed that claim 1 of Mooradian '952
“encompasses frovatriptan” and “the elements of frovatriptan.”
(Rocco Tr. 1620:13-25, 1795:24-1796:1.) Specifically, Dr.
Johnson, Mylan's expert, testified that frovatriptan can be
envisaged where N==B is NHR’ and R’ is methyl; R is hydrogen; Q1
is CONR2R3 at the six position of the ring structure, and R2 and
R3 are hydrogen; and Q2, Q3, and Q4 are hydrogen at the five,
seven, and eight position. (Johnson Tr. 762:6-763:5.) However,
“[i]t is well established that the disclosure of a genus in the
prior art is not necessarily a disclosure of every species that
is a member of that genus.” Atofina v. Great Lakes Chem. Corp.,
441 F.3d 991, 999 (Fed. Cir. 2006). “If a prior art reference
merely discloses a genus and the claim at issue recites a
species of that genus, ‘the issue of anticipation turns on
whether the genus was of such a defined and limited class that
one of ordinary skill in the art could ‘at once envisage’ each
member of the genus.’” Cellectis, 937 F. Supp. 2d at 487
(quoting Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC, 683 F.3d
1356, 1361 (Fed. Cir. 2012)); see also Eli Lilly & Co. v. Zenith
Goldline Pharm., Inc., 471 F.3d 1369, 1376 (Fed. Cir. 2006)
(finding a POSA must be able to “at once envisage” each member
31
of a class of compounds); In re Gleave, 560 F.3d 1331, 1338
(Fed. Cir. 2009). The issue, then, is whether, the particular
genus disclosed in claim 1 of Mooradian ‘952 is so defined and
limited that a POSA can at once envisage each species.
Both experts agree that Mooradian ‘952 discloses a “broad
genus” of compounds with a variety of functional groups that can
be attached to the left ring, which ultimately embodies a very
“large number” of compounds. (Johnson Tr. 895:6-16; Rocco Tr.
1616:1-18, 1617:14-1618:14; see also Dr. Francis D. King
(“King”) Tr. 290:20-291:2 (“[G]enerically [Mooradian ‘952] does
disclose the Frovatriptan type compound, but it is only one of a
potential million plus compounds that that general structure
discloses.”). Endo’s expert, Dr. Rocco, testified that this
genus encompasses “millions, tens of millions” of compounds,
while Dr. Johnson, conceded that this “broad genus” of compounds
consisted of what “could be a large number” of individual
compounds. (Johnson Tr. 895:6-16.) Furthermore, it is undisputed
that frovatriptan is not among the approximately 297 compounds
disclosed in the Mooradian ‘952 specification (Johnson Tr.
895:22-25; Rocco Tr. 1620:3-10) or one of the eight compounds
specifically claimed. (Rocco Tr. 1619:21-1620:2; see also DTX1019 col.64.)
In looking at the patent as a whole, as this Court must,
see Net MoneyIN, Inc., 545 F.3d at 1369 n.5, the Court does not
32
find that claim 1 of the ‘864 Patent is anticipated by Mooradian
‘952. Dr. Rocco, whom this Court found persuasive, opined that,
although a POSA “could tease out the elements of frovatriptan”
from the broad disclosure in Mooradian ‘952, she would not
immediately envision the frovatriptan molecular structure.
(Rocco Tr. 1616:20-23, 1620:24-1621:3.) Dr. Rocco’s opinion is
supported by the patent’s list of four “preferred” groups of
compounds which provide limitations on the substituents in
certain positions on the compounds. See Brigham & Women’s Hosp.
Inc. v. Teva Pharms. USA, Inc., 761 F. Supp. 2d 210, 227-28 (D.
Del. 2011) (citing In re Petering, 301 F.2d 676, 681 (C.C.P.A.
1962)) (looking to preferred groups of compounds set forth in
prior art patent and determining that claims were not
anticipated); (DTX-1019 col.2 ll.19-41; Rocco Tr. 1616:141618:14). Although these preferred groups narrow the broader
genus of disclosed compounds in Mooradian ‘952, they still
encompass “hundreds or thousands of compounds.” (Rocco Tr.
1616:14-1617:14.) Even so, Drs. Rocco and Johnson agree that
none of these preferred groups include the frovatriptan
structure. (Rocco Tr. 1616:14-20, 1618:17-20; Johnson Tr. 896:125.) In fact, the “more preferred group” specifically excludes a
carboxamido group similar to the one that appears at the six
33
position of frovatriptan. (Rocco Tr. 1617:10-1618:15.) 20 Given
the compounds and preferred groups actually disclosed in
Mooradian ‘952, this patent does not provide any “motivation or
reason for anyone to pull [frovatriptan] out explicitly.” (See
Rocco Tr. 1625:13-21.)
Dr. Johnson testified, however, that Mooradian ‘952 teaches
a preference for each element of the frovatriptan compound - the
1,2,3,4-tetrahydrocarbazole core, the 3-methylamino, and the 6carboxamido – such that a POSA would “at once envisage”
frovatriptan. Claim 7 of Mooradian ‘952, which is the same
compound listed in Example 23, specifically claims a compound
containing a 3-methylamino. (Rocco Tr. 1796:7-1797:1; DTX-1019
col.64 l.29; id. col.29 ll.1-18.) However, the claim 7 compound
is the only claimed compound that contains a methylamino: five
of the seven claimed compounds contain a 3-dimethylamino, which
20
Dr. Rocco testified that:
There is no way that within this preferred group you
could even contemplate the carboxamide because
carboxamide isn’t lower alkyl, carboxamide is not
halo. Carboxamide is not an aromatic group bonded
through an oxygen, or is an aromatic group in and of
itself. So it seems to be excluding that type of
functionality group from this preferred group of
compounds . . . one of skill in the art looking at
this preferred group of compounds . . . could not
tease out from that group [carboxamido] because it's
not there . . .
(Rocco Tr. 1619:1-15.)
34
seems to suggest a preference for the dimethylamino substituent
over the methylamino. (See DTX-1019 col.64 ll.20-33.) At the
very least, the fact that only one of these compounds is a
methylamino undermines Dr. Johnson’s conclusion that Mooradian
‘952 teaches a 3-methylamino.
Admittedly, the only difference between the compound in
claim 7 and frovatriptan is the carboxamido group that appears
at the six position of frovatriptan. (Johnson Tr. 753:12-20.)
Dr. Johnson testified that Mooradian ‘952 indicates a “clear
preference” for placing a carboxamido group at either the six or
eight position (Tr. 764:10-765:17, 771:6-17), and a “clear
teaching” for the 6-carboxamido substituent (Tr. 777:8-12). In
support, he points to six examples reflecting a carboxamidoderivative substituent at the 6-position, 21 and seven examples at
the 8-position. 22 (Johnson Tr. 764:10-765:17, 771:6-17.) However,
as Dr. Rocco pointed out, most of these carboxamido-derivatives
are “very elaborate functional groups” that are “very different”
substitutions from the unsubstituted carboxamido that is in
frovatriptan. (Rocco Tr. 1628:4-1629:3.) Only the carboxamido
substituent in Example 250 is the same group as that in
21
The compounds that contain 6-carboxamido derivatives are
found in Examples 69, 71, 73, 74, 77, and 79 of DTX-1019.
22
The compounds that contain 8-carboxamido derivatives are
found in Examples 68, 70, 72, 75, 76, 78, and 250 of DTX-1019.
35
frovatriptan, and that group appears at the 8-position of the
disclosed compound. 23 (Johnson Tr. 765:20-766:6; Rocco Tr.
1799:2-19.) Thus, Mooradian ‘952 does not teach any preference
for an unsubstituted carboxamido at the 6-position. 24 (See Rocco
Tr. 1625:24-1627:1.)
The Court finds Dr. Rocco’s testimony to be credible and
persuasive. It is further influenced by the fact that Mooradian
‘952 was disclosed to the PTO during the prosecution of the ‘864
Patent and the PTO issued the ‘864 Patent notwithstanding this
reference. (PX-0001, at [56].) 25 See Minn. Mining & Mfg. Co., 976
23
Example 250 is 3-dimethylamino-8-aminocarbonyl-1,2,3,4tetrahydrocarbazole. (DTX-1019 col. 52 ll.8-24.) Mylan failed to
demonstrate why a POSA would be motivated to change the 3dimethylamino to a 3-methylamino, and also move the carboxamido
to the 6-position.
24
Dr. Johnson cites a statement contained within another
SKB patent as confirming his opinion that a POSA would at once
envisage the frovatriptan compound within Mooradian ‘952. That
patent states:
U.S. Pat. Nos. 4,257,952, 4,172,834, 4,062,864 and
3,959,309 describe a broad class of 3-amino and 3(substituted amino) tetrahydrocarbazoles having a
variety of substituents at the 5, 6, 7 and/or 8
positions, including inter alia the group -- CONR2R3
wherein R2 and R3 are hydrogen, lower alkyl or together
with the nitrogen atom form a heterocyclic ring.
(DTX-1395 col.1 ll.9-16; see also Johnson Tr. 767:15-769:22,
770:16-17.) However, this patent was filed December 16, 1993 and
claims priority to a foreign application dated December 21, 1992
(DTX-1395, at [22], [30])—both of which are after the priority
date applicable here.
25
Although Mylan makes much of the fact that Mooradian ‘952
was not “substantively discussed” during the prosecution of the
‘864 Patent, the file wrapper shows that the PTO examiner
36
F.2d at 1572 (“Where the PTO has considered a piece of prior
art, and issued a patent notwithstanding that prior art, a court
owes some deference to the PTO's decision.” (citations
omitted)). Cf. Sciele Pharma Inc., 684 F.3d at 1260.
The Court concludes that Defendants have not established by
clear and convincing evidence that Mooradian ‘952 anticipates
the compound claimed in claim 1 of the ‘864 Patent because
(i) Mooradian ‘952 discloses a “broad genus” that encompasses
millions of compounds, (ii) this broad genus is narrowed into
“preferred” groups of compounds that still include thousands of
compounds but do not include frovatriptan, and (iii) Mooradian
‘952 does not teach a preference for either the 3-methylamino or
an unsubstituted carboxamido group at the 6-position. See, e.g.,
Brigham & Women’s Hosp. Inc., 761 F. Supp. 2d at 227-28 (finding
that a POSA would not “at once envisage” the claimed compound
from a prior art patent that disclosed a broad genus of
compounds and a narrower list of preferred compounds that did
not include the challenged compound); Hoffmann-La Roche Inc. v.
initialed the reference sheet to indicate that this reference
was considered and the Court will not assume otherwise. (DTX1077 at 191.) Notably, the applicants specifically directed the
Examiner to Mooradian ‘952: “Applicants take this opportunity to
call to the Examiner’s attention U.S. Patent 4,257,952, issued
March 24, 1981 to Mooradian, which is believed to be of
particular relevance to the subject matter of this invention.”
(Id. at 118.) Yet, the Examiner permitted the claims. (Id. at
99-100.)
37
Cobalt Pharms. Inc., No. 07-4539, 2010 WL 4687839, at *5 (D.N.J.
Nov. 10, 2010) (“Cobalt has not persuaded this Court that, based
on the statements of preference, a skilled artisan could at once
envision the species that is ibandronic acid. On this record,
this Court cannot conclude that Cobalt is more likely than not
to be able to prove anticipation by the Van Duzee patent by
clear and convincing evidence.”).
Because claim 1 is not anticipated by Mooradian ‘952, as a
matter of law its dependent claims are not anticipated. Corning
Glass Works v. Sumitomo Elec. USA, Inc., 868 F.2d 1251, 1256 n.4
(Fed. Cir. 1989) (“Because we conclude that claim 1 is not
anticipated, claim 2, which is dependent on claim 1, need not be
separately discussed.”); RCA Corp. v. Applied Digital Data Sys.,
Inc., 730 F.2d 1440, 1446 (Fed. Cir. 1984) (same); see also
Carnegie Mellon Univ. v. Marvell Tech. Grp., Ltd., No. 09-290,
2011 WL 4527353, at *5 (W.D. Pa. Sept. 28, 2011) (same).
B. Obviousness
Mylan next contends that each asserted claim of the ‘864
Patent is invalid as obvious as of the priority date. A patent
is invalid as obvious if the differences between the claimed
invention and prior art are such that the invention as a whole
would have been obvious to a POSA at the time the invention was
made. Sciele Pharma Inc., 684 F.3d at 1259 (quoting 35 U.S.C. §
103(a)). Whether a patent claim is obvious is a question of law
38
based on four underlying facts:
1) the scope and content of the
prior art; (2) the level of ordinary skill in the pertinent art;
(3) the differences between the prior art and the claims at
issue; and (4) such secondary considerations as commercial
success, long felt but unsolved need, and the failure of others.
Id. (quoting Graham v. John Deere Co., 383 U.S. 1, 17-18
(1966)); see also KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398,
406 (2007). Generally, this inquiry considers whether a person
skilled in the art would have had (1) a reason to combine the
teachings of the prior art references to achieve the claimed
invention, and (2) a reasonable expectation of success in doing
so. 26 In re Cyclobenzaprine Hydrochloride Extended-Release
Capsule Patent Litig., 676 F.3d 1063, 1068-69 (Fed. Cir. 2012)
(internal citations omitted).
In KSR, the Supreme Court cautioned that this inquiry must
be “expansive and flexible” and must account for the fact that a
POSA is also “a person of ordinary creativity, not an
automaton.” Id. at 415, 421. There need not be “precise
26
The Court notes that “[o]bviousness does not require
absolute predictability of success. . . . For obviousness under
§ 103, all that is required is a reasonable expectation of
success.” In re O’Farrell, 853 F.2d 894, 903-04 (Fed. Cir.
1988); see also Bayer Schering Pharma AG v. Barr Labs., Inc.,
575 F.3d 1341, 1350 (Fed. Cir. 2009); Pfizer, Inc. v. Apotex,
Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007).
39
teachings directed to the specific subject matter of the
challenged claim, for a court can take account of the inferences
and creative steps that a [POSA] would employ.” Id. at 418.
Importantly, “if a technique has been used to improve one
device, and a [POSA] would recognize that it would improve
similar devices in the same way, using the technique is obvious
unless its actual application is beyond his or her skill.” Id.
at 417. Relevant to this analysis is whether there was a reason
or motivation to combine the known elements in the manner
claimed by the patent. Id. at 418. Indeed, “[o]ne of the ways in
which a patent’s subject matter can be proved obvious is by
noting that there existed at the time of invention a known
problem for which there was an obvious solution encompassed by
the patent’s claims.” Id. at 419-20. “[I]n many cases a person
of ordinary skill will be able to fit the teachings of multiple
patents together like pieces of a puzzle.” Id. at 420.
Finally, an invention is “obvious-to-try” and therefore
invalid under 35 U.S.C. § 103 if it results from a skilled
artisan merely pursuing “known options” from “a finite number of
identified, predictable solutions.” In re Cyclobenzaprine, 676
F.3d at 1070 (quoting KSR, 550 U.S. at 421) (internal quotations
omitted).
In conducting its analysis, the Court must be cognizant
that “[a]lmost any invention, no matter how nonobvious at the
40
time, will appear obvious when looking backward from the
solution. It is for that reason that ‘[c]are must be taken to
avoid hindsight reconstruction by using the patent in suit as a
guide through the maze of prior art references, combining the
right references in the right way so as to achieve the result of
the claims in suit’.” Janssen Pharmaceutica N.V. v. Mylan
Pharmas., Inc., 456 F. Supp. 2d 644, 662 (D.N.J. 2006) (citation
omitted and emphasis in original).
Mylan submits that the asserted claims of the ‘864 Patent
are (1) obvious in light of prior art references Mooradian ‘952
and/or Mooradian 1977, 27 when considered alone or in combination
with a POSA’s knowledge as of the priority date; (2) obvious in
light of 5-CT as the appropriate lead compound; and (3) obvious
in light of prior art which would motivate a POSA to modify 5-CT
to obtain frovatriptan with a reasonable expectation of success.
Subsumed within this last argument is the assumption that a POSA
would begin with 5-CT, which as set forth below, the Court
rejects.
1. Mooradian ‘952 and Mooradian 1977 Do Not Render the
Asserted Claims Obvious
Mylan asserts that Mooradian ‘952 and Mooradian 1977, alone
or in combination, render the claims obvious. The Court
27
Adam Mooradian et al., 3-Aminotetrahydrocarbazoles as a
New Series of Central Nervous System Agents, J. Med. Chem., Vol.
20, No. 4 (1977) (“Mooradian 1977”).
41
disagrees. Individually and separately, these references teach a
preference for a 3-dimethylamino substituent, which is not found
within frovatriptan, and do not suggest a preference for a 6carboxamido. They further do not suggest utility in treatment of
a condition wherein a 5-HT1-like agonist is indicated (claim 2)
or migraine (claim 3). And, of particular importance to the
Court, both Mooradian ‘952 and Mooradian 1977 were disclosed to
and considered by the PTO during prosecution of the ‘864 Patent,
and yet the PTO issued the ‘864 Patent notwithstanding these
prior art references. (PX-0001, at [56]; DTX-1077 at 191.) The
Court accords some deference to the PTO’s findings in this
regard. See Sciele Pharma Inc., 684 F.3d at 1260.
As explained in detail above, Mooradian ‘952 disclosed a
very broad genus of 3-(substituted-amino)-1,2,3,4tetrahydracarbazole compounds, and in some ways teaches away
from frovatriptan. For instance, the broad genus of compounds
disclosed by Mooradian ‘952 is narrowed into “preferred” groups
of compounds that still include thousands of compounds but do
not include frovatriptan. Indeed, as Dr. Rocco opined, as least
one of these “preferred” groups explicitly excludes and
therefore teaches away from inclusion of a carboxamido similar
to that of frovatriptan. (See Rocco Tr. 1618:10-14); Galderma
Labs., L.P. v. Tolmar, Inc., 737 F.3d 731, 738 (Fed. Cir. 2013)
(“A reference may be said to teach away when a person of
42
ordinary skill, upon reading the reference, would be discouraged
from following the path set out in the reference, or would be
led in a direction divergent from the path that was taken by the
applicant.” (citing DePuy Spine, Inc. v. Medtronic Sofamor
Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009))). In
addition, as set forth above, Mooradian ‘952 teaches a
preference for a 3-dimethylamino substituent, which would lead a
POSA away from frovatriptan. (See DTX-1019 col.64 ll.24-33.)
Five of the seven specifically-claimed compounds in Mooradian
‘952 include 3-dimethylamino while only one compound includes a
3-methylamino substituent. (DTX-1019 col.64 ll.20-33.) Thus,
Mylan has failed to demonstrate by clear and convincing evidence
that the 3-methylamino-6-carboxamido-1,2,3,4-tetrahydracarbazole
(claim 1) is obvious in light of Mooradian ‘952.
Likewise, nothing in Mooradian 1977 renders the
frovatriptan compound obvious to a POSA. The underlying premise
of Mooradian 1977 was that “3-aminocarbazoles might have central
nervous system activity paralleling the tryptamine types.” (DTX1082 at 487.) The authors prepared and studied a variety of 3substituted amino-1,2,3,4-tetrahydracarbazole compounds,
including compounds with 3-methylamino and 3-dimethylamino
substituents. (See DTX-1082 at 487-88.) Thus, as with Mooradian
‘952, Mooradian 1977 teaches a preference for a 3-dimethylamino
substituent. In testing ptosis prevention, Compound 3, a
43
dimethylamino, showed approximately three times the activity
level of Compound 2, a methylamino. (DTX-1082 at tbl. II; see
also Johnson Tr. 882:6-12.) Notably, as the authors explained,
“It became apparent that 3 (Table II) [the dimethylamino] was
the most interesting CNS compound in the series and this
compound was studied in great detail.” (DTX-1082 at 487; Johnson
Tr. 1138:19-1139:10.) 28 Dr. Johnson agreed that Mooradian was
“really highlighting compound three” in this paragraph. (Johnson
Tr. 1138:19-1139:10; see also Johnson Tr. 902:14-17 (activity
results in ptosis assay “showed a Mooradian preference for the
dimethylamino”).) Because the Mooradian references reflect a
clear preference for the dimethylamino substituent, it is
unclear why a POSA would be motivated to modify a 3-methylaminotetrahydrocarbazole.
Mooradian 1977 also does not teach or express any
preference for a 6-carboxamido substituent, which Dr. Johnson
concedes. (Johnson Tr. 753:15-20.) 29 Table III of Mooradian 1977
28
As discussed infra, Table III consists entirely of 3dimethylaminotetrahydrocarbazoles further reflecting Mooradian’s
focus on dimethylamino compounds. (See Rocco Tr. 1634:6-11 (“So
what Dr. Mooradian, being informed from his experiments from
table 2, has now fixed this to the dimethylamino since that
looked to be the compound that was particularly
active . . . .”).)
29
See also Johnson Tr. 754:5-14 (“A class of molecules that
were not in the 1977 paper were specifically carboxamido
group . . . .”).
44
is entirely devoted to substitutions at the 6- and 8- positions
of the 3-dimethylamino-tetrahydrocarbazole structure, but none
of these substitutions is a 6-carboxamido group. (See DTX-1082
tbl. III.) Furthermore, the authors concluded that with the
exception of two compounds containing substitutions at the 8position, none of the listed compounds were as potent as the
original unsubstituted 3-dimethylamino-tetrahydrocarbazole.
(DTX-1082 489-90 & tbl. III.) Mylan does not persuasively
explain how a POSA reviewing this reference would find it
obvious to modify the 3-aminotetrahydrocarbazole by adding a 6carboxamido group. 30 Mooradian ‘952 does not assist Mylan in this
regard because, as explained above, the Court rejects Mylan’s
contention that Mooradian ‘952 teaches a preference for the 6carboxamido group among the numerous permissible substituents
along the left side of the tetrahydrocarbazole ring system set
forth therein.
30
To the extent Mylan relies upon 5-CT as teaching the
addition of a 6-carboxamido group for improved selectivity, the
Court finds that any motivation to combine these elements is
undermined by the authors’ comments regarding the reduced
potency of such a substitution. Moreover, the testimony cited by
Mylan as validating the principle that a POSA would view the 6carboxamido group (which is ostensibly similar to the 5carboxamido group of 5-CT) as providing selectivity for the 5HT1-like receptors does not substantiate this view. Rather, Dr.
King was asked if 5-CT was preferred over 5-HT and not
specifically about the functions of a 6-carboxamido group. (See
King Tr. 283:3-284:14.) In any event, Mylan failed to
persuasively demonstrate that a carboxamido group on a different
core structure would exhibit identical properties.
45
In addition, the types of activities disclosed in Mooradian
‘952 and Mooradian 1977 would direct a POSA who was pursuing a
novel 5-HT1-like agonist away from utilizing the 3-aminotetrahydrocarbazole. (See Rocco Tr. 1635:12-23.) Neither
Mooradian reference explicitly discusses utility of the
compounds as 5-HT1-like agonists or in the treatment of
migraine. 31 (See, e.g., Johnson Tr. 897:3-5 (noting nothing in
Mooradian ‘952 is addressed to 5-HT1-like receptors).) Nor do the
Mooradian references mention serotonin. 32 (See Johnson Tr.
893:14-894:4, 894:19-895:5, 897:3-8.)
The Mooradian ‘952 compounds exhibited “analgetic and
psychotropic activities” as well as, in some cases,
31
See Rocco Tr. 1621:9-16 (“Q. Is there anything in the
Mooradian ‘952 patent that indicates any of these compounds
would have utility for migraine treatment? A. No, it does not.
Q. Is there anything in the Mooradian ‘952 patent that would
counsel somebody of skill in the art in 1991 to make a migraine
treatment? A. No.”); Rocco Tr. 1857:25-1858:2 (nothing in
Mooradian 1977 “teaches toward migraine, nothing teaches toward
serotonin, nothing teaches toward serotonin 1B, 1D or 1F or
anything”); Nelson Tr. 1271:5-7 (“I could find no evidence in
[Mooradian ‘952 or Mooradian 1977] that these
tetrahydrocarbazoles in fact interacted with serotonin systems
at all.”).
32
Nelson Tr. 1277:20-1278:8 (“Q. Doctor Nelson, on the
whole, what do these references teach regarding the activities
of 3-amino tetrahydrocarbazoles that were appreciated at the
time of the invention? A. Yeah, from my reading of this
literature, I don't see any evidence that would lead one to
suspect that these compounds had any activities on serotonincontaining systems in the body. . . . [B]ut we have no evidence
that suggests that they interact with serotonin systems from
these publications.”).
46
antihistaminic activity. (DTX-1019, at [57].) Mylan contends
that because ‘952 mentions analgetic activities and the
disclosed compounds are structurally similar to 5-HT, a POSA
would have deemed these compounds to be suitable as antimigraine agents.
However, a reference to analgetic properties
refers to ameliorating pain “[i]n a very broad non-specific,
non-mechanistic way” and thus would not be interpreted as
teaching to migraine or serotonergic activity. (Rocco Tr.
1801:25-1802:9.) Mylan did not seriously dispute that although
analgesics may be used in connection with migraine treatment,
analgetic compounds are not a specific migraine treatment that
targets the mechanics or causes of migraine. Therefore, a POSA
would be unlikely to view such non-specific analgetic activity
as a motivation to modify a 3-amino-tetrahydrocarbazole and
create a migraine or 5-HT1-like agonist compound.
Moreover, Mooradian ‘952 measured analgetic activity using
a “crude screening tool” known as a phenylquinone-induced
writhing assay, which involved injecting phenylquinone into the
abdominal cavity of rodents. (DTX-1019 col.17 ll.15-35; Nelson
Tr. 1274:19-21.) However, as Dr. Nelson testified certain
deficiencies in this test, such as false positives, had long
been recognized in the art. (Nelson Tr. 1274:9-25; see also PX-
47
0130 33 at 240.) One type of compound that results in a false
positive are antihistamines, which are not deemed analgesics.
(See Nelson Tr. 1276:3-8 (citing PX-0130 at 240).) Thus, Dr.
Nelson concluded that “it might not be unexpected if
antihistamines are positive in this writhing test that the
carbazoles [in the Mooradian references] would also be positive
in this writhing test” in light of Mooradian’s recognition that
some of the compounds exhibited antihistaminic activity. As a
POSA would be aware that antihistamines provide a false positive
in a writhing assay, it is not clear that a POSA would even
attribute much weight to these results in terms of any purported
analgetic properties of the disclosed 3-aminotetrahydrocarbazoles. (See Nelson Tr. 1276:16-25.)
Mooradian ‘952 also tested compounds for psychotropic
activity using an assay that evaluated whether a compound
inhibited or reversed reserpine-induced ptosis. 34 (DTX-1019
col.17 ll.19-35.) Dr. Johnson testified that since the 1960s it
was known that reserpine could trigger migraine, and therefore
the ptosis assay would suggest to a POSA some utility in using
33
L.C. Hendershot & Janet Forsaith, Antagonism of the
Frequency of Phenylquinone-induced Writhing in the Mouse by Weak
Analgesics and Nonanalgesics (Sept. 19, 1958).
34
Ptosis referred to drooping of the eyelids, which was
effected through the administration of reserpine. (See, e.g.,
Johnson Tr. 680:4-9.)
48
tetrahydrocarbazoles in treating migraine. (Johnson Tr. 680:1417 (discussing PX-0394 35 at 149).) However, in that same
publication, the authors noted that “reserpine-induced headache
is qualitatively different to [sic] a migraine attack.” (PX-0394
at 149.) Moreover, by 1991, it had been determined that “there
was no involvement of serotonin depletion caused by reserpine in
this phenomenon of ptosis.” (Nelson Tr. 1271:21-1274:4 (citing
PX-0188 at 514).) This would suggest that the reserpine assay
would not be relied upon by a POSA as an indication of antimigraine activity. In fact, Dr. Nelson testified that he was
unaware of anyone using reserpine-induced ptosis to evaluate
compounds for migraine efficacy. (Nelson Tr. 1274:5-7.) Dr.
Johnson, who himself has never used this assay to test compounds
for potential use in migraine, also acknowledged that this assay
has never been identified as having a specific relationship to
migraine. (Johnson Tr. 892:7-14.) 36
Regardless, that the Mooradian ‘952 compounds exhibited
antihistaminic activity would discourage a POSA, and therefore
teach away, from the use of the 3-amino-tetrahydrocarbazoles in
35
PX-0394 (Merton Sandler & Geralyn M. Collins, Migraine: A
Spectrum of Ideas (1990)).
3636
Admittedly, there are no whole animal behavioral models
to test for migraine. Rather, many mechanistic tests have been
relied upon as substitutes. (See, e.g., Johnson Tr. 892:23893:3.)
49
the treatment of migraine due to the sedative effect of
antihistamines. (Rocco 1804:19-1805:3 (“In fact, a lot of drug
discovery effort goes into preventing compounds with
antihistaminic activity from getting into the brain.”); Nelson
Tr. 1278:9-17 (“I think what one would have known about
tetrahydrocarbazoles would have made one reluctant to go in that
direction because you wouldn’t want an anti-migraine drug that
had the side effects of an antihistamine or of a D-2 receptor
antagonist. So I think it actually teaches away from using the
carbazoles.”).) See Tec Air, Inc. v. Denso Mfg. Mich., Inc., 192
F.3d 1353, 1360 (Fed. Cir. 1999) (noting a reference “teaches
away” when a POSA would be discouraged from following the path
of the reference or would be led in a different direction).
For similar reasons the reported activities of the
Mooradian 1977 compounds, which were tested for their
antidepressant and antipsychotic activity, would not suggest the
use of 3-amino-tetrahydrocarbazoles for treatment of a condition
wherein a 5-HT1-like agonist is indicated or migraine.
Specifically, the Mooradian 1977 compounds were evaluated in
terms of their “chlorpromazine-like” and “imipramine-like
activity,” and the authors concluded that “some of the compounds
appear to exhibit both chlorpromazine-like and imipramine-like
activity, others only chlorpromazine-like, and others only
imipramine-like activity.” (DTX-1082 at 489.) Chlorpromazine was
50
developed to treat schizophrenia, while imipramine was a
depression and anxiety drug. (Johnson Tr. 877:3-21.) Neither of
these drugs were used to treat migraine. (Id.) In evaluating
chlorpromazine-like activity, the authors tested “prevention of
reserpine-induced ptosis in mice” as an “index of antidepressant
activity.” (DTX-1082 at 489, 491; see also Johnson Tr. 890:1315.) And in evaluating imipramine-like activity, the authors
tested the compounds for “[p]revention of d-amphetamine-induced
stereotypes behavior in rats” as an “index of antipsychotic
activity.” (DTX-1082 at 489; see also Johnson Tr. 890:18-891:2.)
In terms of the ptosis assay, the authors reported that many of
the listed compounds were inactive, meaning they did not prevent
ptosis. (DTX-1082.) Mylan’s experts failed to convincingly
demonstrate why a POSA would have been motivated to explore
these compounds as 5-HT1-like agonists on the basis of these
activities. Rather, Mylan once again relies upon the results of
the reserpine-induced ptosis assay as indicative of antimigraine activity. However, as discussed above, any connection
between reserpine and serotonin, which had become the focus of
migraine treatment as of the priority date, had been soundly
discredited.
Mylan also attempts to rely on the fact that the Mooradian
1977 compounds were posited as having “central nervous system
activity paralleling the tryptamine types.” However, the Court
51
is persuaded by Endo’s argument that this general statement
alone would not indicate utility in a migraine treatment or
indicate activity at the relevant serotonin receptors. This is
because serotonin is just one “typtamine-type” molecule, and
“tryptamine-type” activity can include activity at any serotonin
receptor, which may encompass a broad range of biological
activities. (See Johnson Tr. 889:8-15.) Moreover, not all
“tryptamine analogs” will be 5-HT1-like agonists. (See, e.g.,
Peroutka Tr. 624:24-625:18.)
In sum, the Court finds the testimony of Drs. Rocco and
Nelson to be credible and persuasive, and determines that as of
the priority date, a POSA would not have been motivated to make
and modify or create a tetrahydrocarbazole compound for migraine
treatment. (See Rocco Tr. 1692:9-12.) Even when the Mooradian
references are considered in combination with the knowledge of a
POSA, Mylan has failed to produce clear and convincing evidence
that a POSA would have reason to ignore the clear preference for
a dimethylamino substituent, and then add a 6-carboxamido
substituent when Mooradian 1977 suggests that 6-position
substituents decreased potency. (See Rocco Tr. 1636:2-6); see
also Arkie Lures, Inc. v. Gene Larew Tackle, Inc., 119 F.3d 953,
957 (Fed. Cir. 1997) (“It is insufficient to establish
obviousness that the separate elements of the invention existed
in the prior art, absent some teaching or suggestion, in the
52
prior art, to combine the elements.”). Even assuming that a POSA
would have reason to combine the elements to create
frovatriptan, Mylan has failed to convincingly demonstrate why a
POSA would have utilized any such compound in the treatment of a
condition wherein 5-HT1-like agonist is indicated or migraine in
light of the biological activity data provided in the Mooradian
references. See Sandt Tech., Ltd. v. Resco Metal & Plastics
Corp., 264 F.3d 1344, 1356 (Fed. Cir. 2001); 35 U.S.C.A.
§ 282(a) (West 2012) (“[D]ependent claims shall be presumed
valid even though dependent upon an invalid claim.”).
2. A POSA Would Not Have Used 5-CT as a Lead Compound
as of the Priority Date
Mylan also argues that the claims are obvious pursuant to a
structural obviousness analysis wherein a POSA would have
selected 5-CT as the lead compound. “Proof of obviousness based
on structural similarity requires clear and convincing evidence
that a medicinal chemist of 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.” Daiichi Sankyo
Co., Ltd. v. Matrix Labs., Ltd., 619 F.3d 1346, 1352 (Fed. Cir.
2010) (affirming district court’s finding that asserted claims
were not obvious under structural obviousness analysis because
53
defendant failed to demonstrate POSA would have chosen compounds
as lead compounds), cert. den’d, 131 S. Ct. 1678 (2011). This
two-part analysis looks, first, to whether a POSA would have
selected the asserted prior art compound as a lead and, second,
whether the prior art provided a POSA with a reason or
motivation to modify the lead compound to create the claimed
compound with a reasonable expectation of success. See Otsuka
Pharm. Co., Ltd. v. Sandoz, Inc., 678 F.3d 1280, 1291-92 (Fed.
Cir. 2012), cert. den’d, 133 S. Ct. 940 (2013). The choice of
lead compound is based upon evidence of the relevant chemical
properties, including any “positive attributes such as activity
and potency” as well as any negative properties or adverse side
effects. See id. (citations omitted); Takeda Chem. Indus., Ltd.
v. Alphapharm Pty., Ltd., 492 F.3d 1350, 1359 (Fed. Cir. 2007)
(“Significantly, the closest prior art compound (compound b, the
6–methyl) exhibited negative properties that would have directed
one of ordinary skill in the art away from that compound. . . .
The evidence showed that it was not obvious to try.”). Mylan
bears the burden of proof, and cannot meet its burden merely by
pointing to structural similarities between the claimed compound
and the potential lead compound. Daiichi Sankyo Co.., 619 F.3d
at 1354 (“[P]roving a reason to select a compound as a lead
compound depends on more than just structural similarity, but
also knowledge in the art of the functional properties and
54
limitations of the prior art compounds.” See [Eli Lilly & Co. v.
Zenith Goldline Pharms., Inc., 471 F.3d 1369, 1377–79 (Fed. Cir.
2006)]. Potent and promising activity in the prior art trumps
mere structural relationships.”).
Mylan contends that several prior art publications teach
the choice of 5-CT as the lead compound and that a POSA starting
with 5-CT would have found it obvious to conformationally
constrain 5-CT to form the tetrahydrocarbazole in a single step,
followed by routine methylation to obtain frovatriptan. However,
the Court finds that while the discovery of 5-CT may have
initially represented an advance in the field of migraine, the
subsequent development of sumatriptan reflected a significant
shift in the field such that a POSA desiring to create a 5-HT1like agonist or anti-migraine compound would have chosen
sumatriptan as the lead compound.
A lead compound is considered the starting point for
further development of a pharmaceutical compound, and is chosen
based upon an evaluation of certain characteristics including
“indications of potency and efficacy and selectivity and, of
course, chemical modifiability” as well as the compound’s safety
profile. (Johnson Tr. 794:5-12, 787:8-24; accord Johnson Direct
Slide 49; Rocco Tr. 1640:20-1641:3, 1644:6-1646:19); see also
Otsuka, 678 F.3d at 1291. A drug’s potency refers to the amount
of the compound required to effect a biological response when
55
the compound interacts with a particular receptor. (See Rocco
Tr. 1644:14-20.) Efficacy indicates whether the compound
alleviates a condition or otherwise causes the desired
functional activity. (See Rocco Tr. 1644:23-1645:5; Johnson Tr.
787:14-16.) Selectivity refers to the extent a molecule prefers
one targeted receptor to the exclusion of another. (See Rocco
Tr. 1645:7-10.) And, modifiability refers to whether a chemist
can easily vary chemical segments so as to improve any
shortcomings. (Rocco Tr. 1646:7-16; accord Johnson Tr. 787:1924.) In lead compound selection, none of these factors are
considered in isolation. (See Rocco Tr. 1643:22-1644:5; Johnson
Tr. 794:5-12; Johnson Direct Slide 49.)
Mylan’s argument that 5-CT would be chosen as the lead
compound prioritizes potency to the exclusion of any other
desired characteristics and fails to account for any unwanted
side effects. For example, Mylan relies upon Connor 1989 as
support for its conclusion that a POSA would choose 5-CT as a
lead compound. (See DTX-1216 37 at 379.) In that article, the
authors determined that 5-CT was the most potent agonist for
contracting canine and primate basilar arteries. (Id.) However,
the article also stated that 5-CT’s “contractile effect” in the
37
H.E. Connor et al., Characterization of 5-HT receptors
mediating contraction of canine and primate basilar artery by
use of GR43175, a selective 5-HT1-like receptor agonist, 96 Br.
J. Pharmacol. 379 (1989) (“Connor 1989”).
56
canine basilar artery was “small” compared to sumatriptan but
that both agonists produced a similar maximum response in the
primate basilar artery. (Id. at 384.) Mylan ignores these
qualitative findings, focusing instead on quantitative potency
data, thus undermining its argument.
Of even greater significance, however, Mylan’s lead
compound arguments contravene the evidence submitted at trial,
which shows the shifting tides in the fields of 5-HT1-like
agonists and migraine treatment. A review of Glaxo’s work on
classification of 5-HT receptors was published in 1990 by
Humphrey et al. (PX-0394 38.) It described that, by the early
1980s, Glaxo’s attempt to identify 5-HT receptor subtypes led to
the identification of 5-CT, “which appeared to be a very potent
and selective agonist for the receptor in the dog saphenous
vein.” (See PX-0394 at 152 (citation omitted).) As Dr. Nelson
explained, Glaxo’s work on 5-CT “opened up a way to study a
particular family of serotonin receptors, the 5-HT1 family of
receptors.” (Nelson Tr. 1193:4-13.) However, Humphrey 1990
reported that Glaxo had begun to move away from 5-CT because it
was discovered that 5-CT exhibited “marked hypotensive
properties in vivo owing to an even more potent activation of a
38
P.P.A. Humphrey et al., 5-HT in migraine: evidence from
5-HT1-like receptor agonists for a vascular aetiology, in
MIGRAINE: A SPECTRUM OF IDEAS 147 (1990) (“Humphrey 1990”).
57
5-HT receptor type which mediated vasodilation.” (PX-0394 at 152
(citation omitted); see id. at 157.) Glaxo therefore “continued
to make tryptamine analogues in the belief that [it] might
identify a tryptamine agonist which stimulated only one of these
5-HT1-like receptors–the one which mediates the vasoconstrictor
action of 5-HT in the dog saphenous vein.” (PX-0394 at 152.)
This research led to the development of AH25086 and sumatriptan,
identified in some literature as GR43175, 39 which displayed a
preferred selectivity profile. (See id. at 152-153; Nelson Tr.
1198:23-1199:10; see generally Nelson Tr. 1193:14-1197:4; see
also Johnson Tr. 915:20-22 (“Glaxo rejected 5-CT as the compound
for development and instead moved forward with two other
compounds, correct? A. It appears so.”).)
Dr. Rocco persuasively testified that, as of the priority
date, a POSA would not have chosen 5-CT as the lead compound in
light of the discovery of sumatriptan. 40 (See Rocco Tr. 1641:2125, 1643:22-1644:5.) Sumatriptan was considered by the art to be
a pivotal discovery in the field of migraine. (See, e.g., DTX-
39
Rocco Tr. 1663:6-7.
40
Mylan challenges Dr. Rocco’s opinions as improperly based
upon consideration of triptans that were marketed after the
priority date. (See Rocco Tr. 1841:19-22.) However, Dr. Rocco
explained that these post-priority date references were “meant
to highlight and show the trajectory, the evolution of the
field” and did not affect his opinion as to what a POSA would
understand as of the priority date. (Rocco Tr. 1937:14-1938:1.)
The Court finds this testimony credible.
58
1380 41 at S10 (“The development of sumatriptan revolutionized the
acute treatment of migraine and led to the availability of a
number of other triptans.”).) For example, in 1988, Doenicke et
al. reported the results of human clinical studies on
sumatriptan and concluded that the novel compound “may represent
an important advance in the treatment of acute migraine.” (DTX1382 42 at 1309.) Dr. Johnson agreed with this assessment (Johnson
Tr. 915:5-12), and acknowledged that Doenicke 1988 created a
“buzz” in the field about sumatriptan (Johnson Tr. 911:21-22).
(See also PX-0394 at 160 (“Excitingly, the more detailed
clinical evaluation of GR43175 has shown it to be very effective
in aborting an acute migraine attack also when administered
subcutaneously and orally . . . .” (citations omitted)); id. at
163 (sumatriptan “promises to provide a major breakthrough in
the migraine therapy”) (citations omitted).) Thus, “by the time
of the priority date [] 5-CT was passé as . . . a lead []
41
Patrick P.A. Humphrey, The Discovery of a New Drug Class
for the Acute Treatment of Migraine, 47 Headache S10 (April
2007) (“Humphrey 2007”). Although this publication was printed
long after the priority date, the Court may properly rely upon
this article as describing the state of the art as of the
priority date. Plant Genetic Sys., N.V. v. DeKalb Genetics
Corp., 315 F.3d 1335, 1344 (Fed. Cir. 2003) (“‘This court has
approved use of later publications as evidence of the state of
art existing on the filing date of an application.’” (citations
omitted)).
42
Alfred Doenicke et al., Possible Benefit of GR43175, a
Novel 5-HT1-like Receptor Agonist, for the Acute Treatment of
Severe Migraine, Lancet 1309 (June 11, 1988) (“Doenicke 1988”).
59
molecule for development of a new [] migraine entity.” (See
Nelson Tr. 1191:25-1192:3.)
The Court finds the testimony of Endo’s experts to be
persuasive and supported by the evidence, which demonstrates
that as of the priority date the field of migraine had undergone
a sea change through the discovery and testing of sumatriptan.
Dr. Rocco opined that a medicinal chemist “would start with
sumatriptan because sumatriptan embodies the knowledge that got
you from 5-CT to that selective potent agent that had efficacy
in the clinic [i.e., sumatriptan].” (Rocco Tr. 1651:15-20.) Dr.
Nelson further testified that a POSA looking to create a
migraine treatment was “starting out after we were all aware of
Sumatriptan’s desirable properties and going back to 5CT would
be like trying to sort of reinvent the wheel. You want to start
with your wheel that you had and make it better.” (Nelson Tr.
1197:5-9.) As of the priority date, sumatriptan had become the
“gold standard molecule” and, accordingly, the choice of a lead
compound in any further migraine development. (See Nelson Tr.
1191:4-10 (“Well, I think it’s pretty clear at the time of the
priority date that sumatriptan was that gold standard molecule.
And if we wanted to be successful in the migraine market
bringing a new drug, that we were going to have [to] produce a
molecule that was as good, minimally as good as sumatriptan but
hopefully better than sumatriptan in some way in its therapeutic
60
effects.”).) 43 Mylan has failed to demonstrate why a POSA would
have been motivated to ignore this significant breakthrough in
favor of reverting back to 5-CT as a starting point for further
development.
This is especially true in light of the availability of
human clinical data for sumatriptan, which would be of
particular significance to a POSA evaluating potential lead
compounds. (See Rocco Tr. 1649:18-1650:2); Janssen Pharmaceutica
N.V. v. Mylan Pharms., Inc., 456 F. Supp. 2d 644, 664 (D.N.J.
2006) (“The second problem with Defendants’ approach is that it
looks at the rat data to the exclusion of any other references,
such as the extremely relevant and important human test data.”).
While human clinical studies were never conducted on 5-CT and it
was never utilized as a migraine treatment (Peroutka Tr. 620:1216), 44 publications reported the results of such studies on
43
Mylan’s citation to U.S. Patent No. 4,252,803 (filed Oct.
10, 1979), which covers 5-CT and related compounds, is
unavailing. (DTX-1386, at [57]; Johnson Tr. 805:16-807:10.) This
patent was issued in 1981, years prior to the discovery of
sumatriptan with its greater selectivity properties that
counseled away from 5-CT as a lead compound.
44
Mylan places great weight on a study reflecting that 5-CT
was 20 times more potent in contracting the human basilar artery
tissue than sumatriptan. (See Johnson Tr. 804:17-805:3; DTX-1217
(Andrew A. Parsons et al., 5-HT1-like receptors mediate 5hydroxytryptamine-induced contraction of human isolated basilar
artery, 96 Br. J. Pharmacol. 434-449 (1989) (“Parsons 1989”)),
at 436, tbl. 1.) But that article also suggests that those
results for 5-CT were not “reproducible”, which in turn
undermines the reliability of such data. (DTX-1217 at 434;
accord Rocco Tr. 1664:6-12 (noting reproducibility of results
61
sumatriptan as early as 1988. 45 (See Nelson Tr. 1193:14-1197:4;
DTX-1382 at 1309.) Doenicke et al. reported that intravenous
infusion of GR43175 (i.e., sumatriptan), a 5-HT1-like agonist,
“resulted in rapid and complete relief of symptoms” in 71% of
migraine attacks and “improvement to a non-migrainous residual
headache” in approximately 15% of the remaining attacks. (See
DTX-1382 at 1309; see also Peroutka Tr. 550:9-25 (acknowledging
“the bottom line was [sumatriptan] worked”).) 46 The article
further notes that treatment with sumatriptan was “well
tolerated” and patients experienced minimal adverse side
effects. (DTX-1382 at 1309.) Hence, as of the priority date
sumatriptan had demonstrated qualities a POSA would look for in
a potential migraine candidate—efficacy, tolerability, and
minimal side effects in humans. 47 (Cf. Rocco Tr. 1643:22-1644:5.)
would be important to a POSA, who would view this as assurance
that the results are reliable and could be replicated in any
further experimentation).)
45
Sumatriptan was launched in 1993 in the United States
under the brand name “Imitrex.” (SF ¶ 22.)
46
See also Johnson Tr. 911:23-912:9 (acknowledging other
studies published in 1991 showed the efficacy of sumatriptan and
noting in 1991 sumatriptan went on the market in one European
country); Peroutka Tr. 620:3-9 (“Q. And as of 1991 it had been
reported to be [an] extremely effective acute treatment of
migraine and to cause minimal side effects, correct? A. Correct.
Q. And as of 1991 it was in Phase 3 clinical trials in the U.S.
with promising results, correct? A. Correct.”).
47
Mylan also cites evidence concerning sumatriptan’s low
oral bioavailability and relatively short duration of action as
further evidence why 5-CT would be the chosen lead compound. Dr.
Johnson testified, however, that “5-CT is a fairly polar
62
In addition, several of the prior art publications on which
Mylan relies underscore the negative vasodilation effects of 5CT, which would counsel a POSA away from its selection as a lead
compound. See Alphapharm Pty., Ltd., 492 F.3d at 1357-60
(finding compound was not lead where prior art taught negative
side effects). Under the vascular hypothesis of migraine, it was
believed that “dilated cranial blood vessels gave rise to
migraine” and that by constricting those blood vessels through
activation of certain receptors, one could alleviate migraine.
(See Rocco Tr. 1641:10-18.) For instance, Connor 1989 showed 5CT to be a “potent agonist at the 5-HT1-like receptor mediating
relaxation in cat saphenous vein and porcine vena cava, through
a direct effect on the vascular smooth muscle,” contrary to
sumatriptan. (DTX-1216 at 384-85 (emphasis added and internal
citations omitted).) 48 As Dr. Rocco opined, a POSA selecting a
potential lead compound would “want to avoid the [compound]
molecule so it isn’t going to pass membranes terribly well,”
which “from the point of view of developing a drug, [is] a
serious drawback.” (Johnson 789:7-15.) It also has low
lipophilicity and reduced oral bioavailability, which would also
be considered negative attributes in a potential drug. (See
Johnson 790:-17.)
48
See also PX-0394 (noting 5-CT “had marked hypotensive
properties in vivo owing to an even more potent activation of a
5-HT receptor type which mediated vasodilation”); PX-0198 at
201, tbl.1 (noting 5-CT, unlike sumatriptan, caused “vascular
smooth muscle relaxation, hypotension, [and] tachycardia in the
cat”).
63
that’s mediating the thing that you’re trying to avoid in the
first place or trying to mitigate [vasodilation or
vasorelaxation].” (Rocco Tr. 1662:6-18; see also id. 1669:19-25
(explaining “vascular smooth muscle relaxation” means “dilation
of a blood vessel” which would be inconsistent with a migraine
treatment).) Similarly, Saxena 1985 demonstrated certain
vasodilation effects of 5-CT. (DTX-1080 49 at 533.) Dr. Saxena
hypothesized that the arteriovenous anastomoses is dilated too
much in migraine and that constricting the anastomoses could
have an anti-migraine effect. (See Johnson 796:12-800:11.) He
concluded that 5-CT constricted arteriovenous anastomoses but
dilated arterioles. (DTX-1080 at 533.) However, the authors also
acknowledged “[v]asodilation was observed in several tissues”
for 5-CT, and that 5-CT caused an increase in conductance which
can be indicative of increase in blood flow in the cerebral
hemisphere. (DTX-1080 at 533, 540; see Rocco Tr. 1684:71685:25.) When starting with the hypothesis that migraine is
caused by too much cerebral blood flow, and data suggests that
5-CT may increase cerebral blood flow, it is hard to see why a
POSA would choose this compound as a lead compound after
49
Pramod R. Saxena & Pieter D. Verdouw, 5-Carboxamide
tryptamine, a compound with high affinity for 5hydroxytryptamine1 binding sites, dilates arterioles and
constricts arteriovenous anastomoses, 84 Br. J. Pharmac. 533
(1985) (“Saxena 1985”).
64
sumatriptan was discovered. (See also DTX-1469 50 at tbl. 1
(noting “smooth muscle relaxation” effect of 5-CT).)
Although Dr. Johnson testified that some dilation or
vascular smooth muscle relaxation would not necessarily deter a
POSA from selecting 5-CT as the lead compound, available data
suggested that blood flow in the cerebral hemisphere remained
relatively flat with 5-CT treatment. (Johnson Tr. 935:12-23,
936:23-937:3; DTX-1080 at 537; see also Rocco Tr. 1684:13-24
(noting cerebral blood flow remained flat).) Dr. Johnson did not
adequately explain why a POSA interested in affecting blood flow
issues in the brain would choose 5-CT in the face of this data
when vasodilation of other areas had been observed.
In addition, sumatriptan demonstrated greater selectivity
among the 5-HT1-like receptors than 5-CT. Both parties agree that
5-CT is a non-selective agonist of the entire 5-HT1 family of
receptors, meaning that it binds to all 5-HT1 receptors. (See,
e.g., PX-0198 51 at 201, tbl. 1; see also Johnson Tr. 1120:23-24
(noting 5-CT “works at all 5-HT1-like subtypes”).) In fact, 5-CT
was used to define the 5-HT1 receptor family: the 5-HT receptors
50
P.B. Bradley et al., Commentary: Proposals for the
Classification and Nomenclature of Functional Receptors for 5Hydroxytryptamine, Neuropharm., Vol. 25, No. 6, 563 (1986)
(“Bradley 1986”).
51
Pramod R. Saxena and Michel D. Ferrari, 5-HT1-like
receptor agonists and the pathophysiology of migraine, 10 TiPS
200 (May 1989) (“Saxena & Ferrari 1989”).
65
that demonstrated greater sensitivity to 5-CT than to 5-HT were
referred to as 5-HT1-like receptors. (PX-0394 at 152 (citing DTX1469); Rocco Tr. 1650:8-12.) 5-CT’s lack of differentiation
among the 5-HT1-like receptors in part prompted Glaxo to continue
making tryptamine analogs in the hope of identifying an agonist
that targeted the 5-HT1-like receptor responsible for mediating
vasoconstriction. (PX-0394 at 152-53.) As noted, this work led
to the development of sumatriptan, which became the new “gold
standard molecule.” Saxena & Ferrari 1989 demonstrated that 5-CT
was an agonist for nearly all of the 5-HT1-like receptors, while
sumatriptan showed selectivity for what the authors identified
as the 5-HT1x receptor subtype. 52 (PX-0198 at 201, tbl. 1.) It is
undisputed that as of the priority date a POSA would understand
the 5-HT-1B and 5-HT-1D receptors to be of interest in the
treatment of migraine, but there is also some evidence that the
5-HT-1A could not be definitively ruled out as relevant. (See,
e.g., Peroutka Tr. 546:19-547:19; Rocco 114:16-21, 144:20145:7.)
Mylan’s focus on the claim language in the ‘864 Patent
referring to 5-HT1-like agonists, without differentiation among
any subtypes, is misplaced. The evidence overwhelmingly
52
At that time, the 5-HT1 receptor subtypes had not been
fully identified; hence the authors referred to the two as-yetunnamed 5-HT1-like receptor subtypes as 5-HT1x and 5-HT1y. (Rocco
Tr. 1666:8-1667:6.)
66
demonstrated that the state of the art as of the priority date
had already moved away from 5-CT in particular, and toward
sumatriptan, a compound that had been proven in clinical trials
to be safe and effective without the unwanted side effects of 5CT.
Although Mylan correctly notes that the prior art may
suggest multiple compounds as lead compounds, that does not
change Mylan’s burden to demonstrate by clear and convincing
evidence that a POSA would have chosen 5-CT after sumatriptan.
See Daiichi Sankyo Co., 619 F.3d at 1354 (“While the lead
compound analysis must, in keeping with KSR, not rigidly focus
on the selection of a single, best lead compound, see [Altana
Pharma AG v. Teva Pharms. USA, Inc., 566 F.3d 999, 1008 (Fed.
Cir. 2009)], the analysis still requires the challenger to
demonstrate by clear and convincing evidence 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. Here, the district court did not commit error, let
alone clear error, in finding that Mylan failed to meet that
burden.”). Here, Mylan has failed to persuasively demonstrate
that a POSA would choose 5-CT over a successor compound with
greater selectivity and proven efficacy in human clinical
trials. See Arkie Lures, 119 F.3d at 957-58 (“The question
67
is . . . whether it was obvious to do so in light of all the
relevant factors.”). 53
3. Secondary Considerations
The final Graham factor addresses secondary considerations,
which may be used to rebut a prima facie showing of obviousness.
Ormco Corp. v. Align Tech., Inc., 463 F.3d 1299, 1311 (Fed. Cir.
2006) (citing WMS Gaming, Inc. v. Int’l Game Tech., 184 F.3d
1339, 1359 (Fed. Cir. 1999); In re Kahn, 441 F.3d 977, 985-86
(Fed. Cir. 2006)). These considerations include
“commercial
success, long felt but unsolved needs, failure of others, etc.,
[which] might be utilized to give light to the circumstances
surrounding the origin of the subject matter sought to be
patented” and “may have relevancy” as indicia of obviousness or
nonobviousness.
Graham v. John Deere Co., 383 U.S. 1, 17-18
(1966). In light of the Court’s determination that Mylan has
failed to meet its burden of demonstrating prima facie
obviousness, the Court need not consider these indicia of
nonobviousness. See Takeda Chem. Indus., Ltd. v. Alphapharm
53
Mylan’s alleged “real world evidence” that 5-CT was in
fact the chosen lead compound for development of sumatriptan and
frovatriptan does not alter this Court’s analysis. See Daiichi
Sankyo Co., 619 F.3d at 1354 (“[T]he attribution of a compound
as a lead compound after the fact must avoid hindsight bias; it
must look at the state of the art at the time the invention was
made to find a motivation to select and then modify a lead
compound to arrive at the claimed invention.” (original
emphasis)).
68
Pty., Ltd., 492 F.3d 1350, 1363 (Fed. Cir. 2007) (“In light of
our conclusion that Alphapharm failed to prove that the claimed
compounds would have been prima facie obvious, we need not
consider any objective indicia of nonobviousness.”); Otsuka
Pharm. Co., Ltd. v. Sandoz, Inc., 678 F.3d 1280, 1296 (Fed. Cir.
2012) (“Because we agree with the district court that the
Defendants failed to prove that claim 12 of the ‘528 patent
would have been prima facie obvious over the asserted prior art
compounds, we need not address the court’s findings regarding
objective evidence of nonobviousness.”).
Accordingly, the Court finds that Mylan has failed to meet
its burden of demonstrating by clear and convincing evidence
that the claims of the ‘864 Patent are invalid as obvious. Cf.
AstraZeneca LP v. Breath Ltd., No. 08-1512, 2013 WL 1385224, at
*10-*26 (D.N.J. Apr. 03, 2013) (finding claims invalid as
obvious), overruled on other grounds No. 2013-1312, 2013 WL
5813759 (Fed. Cir. Oct. 30, 2013).
C. Written Description and Enablement
Mylan also argues that the asserted claims of the ‘864
Patent are invalid under 35 U.S.C. § 112 for failure to provide
an adequate written description and lack of enablement of the
full scope of the claims. In particular, Mylan maintains that
the U.K. application and the ‘864 Patent fail to describe and
enable (1) the separation of the enantiomers of frovatriptan;
69
(2) the salt-hydrate of frovatriptan; or (3) the treatment of
migraine that is expected to present. Citing to certain
statements SKB made to the PTO during prosecution of the Borrett
Patents, Mylan argues that Endo should be judicially estopped
from asserting that the U.K. application and the ‘864 Patent
disclose and enable “the specific R(+)-enantiomer of
frovatriptan, or its particular salt-hydrate form.” (Mylan’s Br.
Regarding Endo’s Inconsistent Positions (“Defs.’ J.E. Br.”),
Dkt. Ent. 192 at 1.) The Court first addresses Mylan’s judicial
estoppel argument.
1. Endo Will Not Be Judicially Estopped Based Upon
Statements SKB Made to the PTO in Connection With
the Borrett Patents
During prosecution of the ‘501 Patent, 54 which contained
claims directed to the R(+)-frovatriptan monosuccinate
monohydrate compound, the PTO rejected certain claims “as
constituting attempted non-statutory double patenting (obvious)”
over claims of the ‘864 Patent that cover “the enantiomers of
the 3-methylamino compounds”. (DTX-1427 at MYL-FRO 0047551
(citing PX-0001 col.2 ll.36-38).) In response, SKB told the PTO
that “None of the enantiomer, the particular salt form, or the
54
Rodney C. Young is a named inventor on both the ‘864
Patent and the Borrett Patents. (DTX-1078, at [75]; DTX-1399, at
[75]; PX-0001, at [75].) However, the Borrett Patents were filed
after Dr. Young left SKB. (Dr. Rodney Young (“Young”) Tr. 378:516.)
70
hydrate [of (+)-6-carboxamido-3-N-methylamino-1,2,3,4tetrahydrocarbazole succinate monohydrate] were specifically
disclosed in WO 93/00086.” 55 (DTX-1427 at MYL-FRO 0047556.) SKB
also submitted the declaration of Andrew Parsons, a senior
biologist involved with the frovatriptan research team. (Id. at
MYL-FRO 0047559-64.) Parsons declared that “WO 93/00086 . . .
discloses the racemic mixture (Cmpd. 2 herein), 3-methylamino-6carboxamido-1,2,3,4-tetrahydrocarbazole hydrochloride salt.
Neither WO 93/00086, nor the ‘864 patent specifically teach the
enantiomeric form of Cmpd. 2, or the specific salt form or the
hydrate which is Cmpd. 1, claimed in this application.” (Id. at
MYL-FRO 0047563.) 56 Based upon SKB’s representation, the PTO
ultimately allowed the claims to proceed. (Id. at MYL-FRO
0047565-66.)
As discussed above, judicial estoppel is properly employed
where (1) a party asserts irreconcilably inconsistent positions;
(2) in bad faith; and (3) “judicial estoppel is tailored to
address the affront to the court’s authority or integrity.” Dam
55
International application publication no. WO93/00086, is
the application that issued as the ‘864 Patent. (PX-0001, at
[87].)
56
Likewise, the ‘603 Patent characterizes WO93/00086 as
describing the “3-N-methylamino-6-carboxamido-1,2,3,4tetrahydrocarbazole (as the hydrochloride salt),” which was
“obtained only as mixtures of enantiomers,” and explains that
the inventors “have now isolated the individual isomers.” (DTX1399 col.1 ll.40-50.)
71
Things from Denmark, a/k/a Troll Company ApS, v. Russ Berrie &
Co., Inc., 290 F.3d 548, 559-60 (3d Cir. 2002) (internal
quotations and citations omitted). For purposes of this
analysis, the Court assumes that the position that SKB took
before the PTO is inconsistent with the position that Endo now
urges this Court to adopt. 57 The question then becomes whether
this Court may judicially estop Endo from arguing that the ‘864
Patent describes and enables the frovatriptan enantiomers and
salt-hydrate on the basis of SKB’s prior statements to the PTO.
The Court finds that it should not.
Mylan has submitted no evidence demonstrating that Endo
expressly or impliedly adopted the statements made in connection
with the Borrett Patents or has otherwise pursued the
57
The Court is not persuaded that the two statements are
inconsistent in all respects. First, it is true that the ‘864
Patent does not specifically teach the (R)-(+) frovatriptan in
the particular salt-hydrate form in the detail set forth in the
Borrett Patents. But that does not necessarily mean that a POSA
would understand the inventor to not have possession of the
subject matter. Nor does it mean that a POSA could not make and
use the invention, including the (R)-(+) frovatriptan enantiomer
in its salt-hydrate form, without undue experimentation based
upon the patent specification. Second, Dr. Rocco noted that, in
the pharmaceutical industry, process chemists will frequently
file patents “on the perfected commercial ways” of creating a
compound, which could explain why the later, more
particularized, Borrett Patents were sought. (Rocco Tr. 1747:214.) Such an interpretation is borne out by many of the related
GSK documents. (See, e.g., DTX-1398 ¶ 3 (Record of Invention)
(“The resolution process has enabled the use of a short, 3-stage
route to [frovatriptan]. Previously, this compound could only be
prepared by N-methylation of SB-205555, a low yielding 8-stage
process.”).)
72
interpretation of the ‘864 Patent that is set forth therein. In
fact, the evidence demonstrates just the opposite: Endo did not
initially pursue an infringement action with respect to the
Borrett Patents. Rather, it was Mylan that first raised the
Borrett Patents as part of a counterclaim seeking a declaration
of non-infringement and invalidity. (See Answer ¶¶ 19-28.) Endo
then granted Mylan a covenant-not-to-sue on the Borrett Patents
and, consequently, Mylan’s counterclaim was dismissed. 58 (See
Order of Dismissal, Dkt. Ent. 19.) Notably, Mylan has presented
no evidence that Endo has ever pursued an action for
infringement of the Borrett Patents against Mylan or any other
party. The record thus suggests that Endo simply disagrees with
SKB’s later interpretation as to the teachings of the ‘864
Patent and has chosen to abandon that interpretation.
For similar reasons, the Court is not persuaded that the
record reflects any evidence of bad faith on Endo’s part in
pursuing its current position. Mylan contends that bad faith can
be inferred from the fact that inconsistent positions were
taken. However, as discussed, Endo has never expressed agreement
with that position and, absent such evidence, the Court does not
58
Notably, the record does not demonstrate that this
covenant-not-to-sue was entered into in bad faith. Rather, it
seems to this Court that Endo made a deliberate choice to
litigate the purportedly broader claims presented in the ‘864
Patent instead of pursuing the more limited claims set forth in
the Borrett Patents.
73
infer bad faith. See Price v. Del. Dep’t of Corr., 40 F. Supp.
2d 544, 556 (D. Del. 1999) (declining to apply judicial estoppel
where no evidence of party’s bad faith). Judicial estoppel is an
equitable doctrine invoked at the court’s discretion to protect
the integrity of the courts and the judicial process. Montrose
Med. Group Participating Sav. Plan v. Bulger, 243 F.3d 773, 77980 (3d Cir. 2001).
The Court is also guided in part by Federal Circuit case
law, which makes clear that statements made during the
prosecution of a later, unrelated patent—such as the Borrett
Patents—cannot be used to interpret claims of an earlier patent.
See Pfizer, Inc. v. Ranbaxy Labs. Ltd., 457 F.3d 1284, 1290
(Fed. Cir. 2006); cf. Goldenberg v. Cytogen, Inc., 373 F.3d
1158, 1167-68 (Fed. Cir. 2004) (contents of another patent may
not be used to construe claims of patent at issue absent a
formal relationship or incorporation by reference of the other
patent’s terms); Abbot Labs. V. Dey, L.P., 287 F.3d 1097, 110306 (Fed. Cir. 2002) (statements made during prosecution of an
earlier-filed patent do not create estoppel as to scope of
claims of later-filed patent). The Court sees no reason this
principle should not apply outside the context of claim
construction.
Furthermore, the cases on which Mylan primarily relies do
not support its position. In Alcohol Monitoring Systems, Inc. v.
74
ActSoft, Inc., No. 07-02261, 2011 WL 5075619 (D. Colo. Oct. 25,
2011), the earlier patent was assigned to one of the named
inventors, Jeffrey Hawthorne, who was also a co-founder and
Chief Technology Officer for plaintiff. Id. at *1. Hawthorne
subsequently obtained an unrelated patent on a similar subject
by making statements to the PTO that distinguished the claims of
the later patent from those of the earlier patent. Id. at *1-2.
In applying judicial estoppel, the court specifically noted the
nexus between the parties asserting the allegedly inconsistent
positions. Id. at *5 n.2 (“Plaintiff does not argue a lack of
identity between the positions Hawthorne took in regard to the
‘940 application and positions plaintiff may now take in regard
to Claim 14(e). . . . Moreover, given Mr. Hawthorne’s position
at plaintiff, there is no inequity in finding such identity.”).
No such identity of parties exists here.
MobileMedia Ideas, LLC v. Apple Inc., 907 F. Supp. 2d 570
(D. Del. 2012), is similarly inapposite. There the plaintiff
claimed an earlier priority date for the patent at issue based
upon an application for the ‘979 patent. Id. at 621. The court
held that the plaintiff was judicially estopped from asserting a
position on the scope of the ‘979 patent that was inconsistent
with the position it took during prosecution of that same
patent. Id. at 623. That is not the situation here.
75
For these reasons, the Court will not judicially estop Endo
from asserting that the ‘864 Patent teaches the frovatriptan
enantiomers and salt-hydrates. 59 The Court hastens to note,
however, based on Endo’s decision to pursue the ‘864 Patent in
this litigation, Endo certainly would be estopped from pursuing
either an inconsistent position on the teachings of the ‘864
Patent or the Borrett Patents in future litigation.
2. Legal Standards
Mylan also contends that the ‘864 Patent fails for lack of
written description and enablement. In order to be valid, a
patent must contain a written description of the invention that
59
Endo also argues in its post-trial brief, consistent with
the objections it set forth in the Pretrial Order, that the
Borrett Patents and the Parsons Declaration are inadmissible
hearsay. (See Ex. G, Dkt. Ent. 172.) Endo, however, failed to
assert a timely objection when these documents were first
admitted into evidence and has therefore waived any such
objection. (See Tr. 307:8-308:2 (DTX-1078); Tr. 821:2-9 (DTX1399, DTX-1078); Tr. 850:22-855:8 (DTX-1427); cf. Tr. 1743-61.)
See Gov’t of V.I. v. Archibald, 987 F.2d 180, 184 (3d Cir. 1993)
(“If a party fails to object in a timely fashion, the objection
is waived . . . .”). Further, to the extent Endo asserts that
its objections to these documents fall within its ongoing
objection to the “internal GSK and Vernalis documents,” such
argument is not supported by the record. First, the Borrett
Patents and the Parsons Declaration were not listed among those
internal GSK documents to which Endo objected, and they do not
bear a GSK bates-stamp. Second, the Court instructed Endo of the
importance of identifying the objected-to testimony so that the
Court could identify it and Endo did not do so with respect to
these particular documents until they were used with Dr. Rocco.
(See Tr. 743:21-22 (“When those areas that you have an objection
to are elicited, it would be important to lodge that
objection.”).)
76
“reasonably conveys to those skilled in the art that the
inventor had possession of the claimed subject matter as of the
filing date.” Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d
1336, 1351 (Fed. Cir. 2010) (en banc). This determination is a
question of fact that requires an “objective inquiry into the
four corners of the specification from the perspective of a
[POSA].” Id.; see also GlaxoSmithKline LLC v. Banner Pharmacaps,
Inc., No. 11-046, 2013 U.S. Dist. LEXIS 112440, at *10 (D. Del.
Aug. 9, 2013). Factors to consider include “‘the existing
knowledge in the particular field, the extent and content of the
prior art, the maturity of the science or technology, [and] the
predictability of the aspect at issue.’” Banner Pharmacaps,
Inc., 2013 U.S. Dist. LEXIS 112440, at *11 (quoting Ariad
Pharms., Inc., 598 F.3dat 1351).
Notably, the requisite level of detail “varies depending on
the nature and scope of the claims and on the complexity and
predictability of the relevant technology.” Banner Pharmacaps,
Inc., 2013 U.S. Dist. LEXIS 112440, at *10. The specification
need not include “every conceivable and possible future
embodiment of his invention.” Takeda Pharm. Co. v. TWiPharms.,
No. C-11-01609, 2013 U.S. Dist. LEXIS 72958, at *67 (N.D. Cal.
Apr. 8, 2013) (quoting Cordis Corp. v. Medtronic AVE, Inc., 339
F.3d 1352, 1365 (Fed. Cir. 2003)). Nor must it include
information that is well known in the art. Id. (quoting Epistar
77
Corp. v. Int’l Trade Comm’n, 566 F.3d 1321, 1336 (Fed. Cir.
2009)).
In addition, 35 U.S.C. § 112 requires that a patent
specification describe “the manner and process of making and
using [the invention], in such full, clear, concise, and exact
terms as to enable any person skilled in the art to which it
pertains, or with which it is most nearly connected, to make and
use [the invention], and shall set forth the best mode
contemplated by the inventor or joint inventor of carrying out
the invention.” 35 U.S.C. § 112(a). In other words, the
specification must “enable a [POSA] to make and use the
invention.” Banner Pharmacaps, Inc., 2013 U.S. Dist. LEXIS
112440, at *33. This requirement is met when, at the time of
filing the application, a POSA, having read the specification,
could practice the invention without “undue experimentation.”
Cephalon, Inc. v. Watson Pharms., Inc., 707 F.3d 1330, 1336
(Fed. Cir. 2013). To determine whether undue experimentation is
required the court must weigh many factual considerations,
including:
(1) the quantity of experimentation necessary, (2) the
amount of direction or guidance presented, (3) the
presence or absence of working examples, (4) the
nature of the invention, (5) the state of the prior
art, (6) the relative skill of those in the art,
(7) the predictability or unpredictability of the art,
and (8) the breadth of the claims.
78
Id. (citing In re Jack R. Wands, 858 F.2d 731, 737 (Fed. Cir.
1988)). Importantly, “‘[i]t is unnecessary to spell out every
detail of the invention in the specification’ . . . and the
patent application does not need to disclose specific examples
corresponding to every claimed embodiment.” Pfizer, Inc. v. Teva
Pharmaceuticals U.S.A. Inc., 882 F. Supp. 2d 643, 682 (D. Del.
2012) (quoting Falko—Gunter Falkner v. Inglis, 448 F.3d 1357,
1366 (Fed. Cir. 2006)). Rather, there need only be a
“‘reasonable correlation’ between the disclosure and the
claims.” Id. at 682-83 (quoting Invitrogen Corp. v. Clontech
Labs., Inc., 429 F.3d 1052, 1071 (Fed. Cir. 2005)).
While written description and enablement are separate
considerations, they “often rise and fall together.” Ariad
Pharms., Inc., 598 F.3d at1352. Mylan’s written description and
enablement arguments are based on its assertions that the U.K.
application and the ‘864 Patent fail to describe and enable (1)
the separation of the enantiomers of frovatriptan; (2) the salthydrate of frovatriptan; or (3) the treatment of migraine that
is expected to present.
Before turning to the merits of these arguments, the Court
must address Mylan’s contention that the determination regarding
written description and enablement must be made based upon the
U.K. application alone because the ‘864 Patent claims priority
to the filing date of the U.K. application. In response, Endo
79
essentially argues that Mylan waived its ability to contest
whether the U.K. application describes and enables the full
scope of the claims because the parties stipulated to a priority
date of June 26, 1991. (See SF ¶ 34.) The Court does not agree
with Endo’s position.
First, although Mylan stipulated to a priority date of June
26, 1991, it seems to this Court that Mylan intended only to
acknowledge the foreign application priority date listed on the
front of the ‘864 Patent. (See PX-0001, at [30].) Indeed,
Mylan’s contested facts in the Pretrial Order foreshadow its
written description and enablement arguments, including Mylan’s
position that the determination should be based on the U.K.
application. (See Tab C of the Pretrial Order ¶¶ 295-98.) 60
Therefore, contrary to Endo’s suggestion, Mylan is not now
attempting “to walk-back this agreement.” (Pl.’s Reply PostTrial Br. (“Pl.’s Reply Br.”) 15.) Second, a patent’s “priority
date” is a legal conclusion based upon questions of law, which
in turn are based upon factual determinations. See Chiron Corp.
v. Genentech, Inc., 363 F.3d 1247, 1253-54 (Fed. Cir. 2004). The
Court will not find that Mylan stipulated to any underlying
facts.
60
See id. ¶ 298 (“Moreover, even if post-priority date
portions of the specifications of the Patents-in-Suit that are
not contained in the UK application are considered, the post
priority added matter still does not enable a POSA . . . .”).
80
In any event, the Court finds that Mylan has failed to
demonstrate, by clear and convincing evidence, that either the
U.K. application on its own or the ‘864 Patent fail to
sufficiently describe or enable the asserted claims.
3. Compound of (general) formula (I)
During the claim construction phrase, Endo argued that
“compound of (general) formula (I)” should be construed to mean
any compound of formula (I) regardless of stereochemistry
whereas Mylan sought a construction that included the compound’s
stereochemistry. (Claim Constr. Op. 8-9.) Although the parties
agreed that “compound” includes “all R [enantiomers] and no S to
all S and no R, and every ratio in between,” Endo argued that
Mylan’s construction necessarily would impose limitations that
were not intended by the applicants. (Id. at 9 (citations and
quotations omitted).) Judge Irenas agreed with Endo and
construed “compound of (general) formula (I)” in claim 1 of the
‘864 Patent to refer to the formula “without regard to
stereochemistry.” (Claim Constr. Op. 10.) Mylan now contends
that because the claims were broadly construed, the U.K.
application and the ‘864 Patent must specifically describe and
enable the separation of the enantiomers of 3-methylamino-6carboxamido-1,2,3,4-tetrahydrocarbazole.
Endo maintains, however, that Mylan’s validity arguments
misconstrue Judge Irenas’ claim construction and therefore seek
81
to impose a heightened written description and enablement
requirement. Endo cites to Pfizer, Inc. v. Teva Pharmaceuticals
U.S.A. Inc., where the court similarly construed a claim to a
chemical compound to mean the compound without reference to its
stereochemistry. 882 F. Supp. 2d at 688. Defendant made the same
arguments Mylan asserts here: the patent failed to satisfy the
written description and enablement requirements because it did
not describe how to obtain the enantiomers, reflect evidence of
resolution or provide any characterizing data of the individual
enantiomers, and the compound had been obtained only as a
racemic mixture. Id. at 683-85, 700-01. The court rejected
defendant’s arguments.
In addressing enablement, the Pfizer court determined that
the
construction does not require the ‘692 application to
enable each conceivable mixture of 3-isobutylGABA’s
enantiomers-including ‘single optical isomer forms’ or
any other composition of that compound-in order to
satisfy the requirements of § 112. [] Contrary to the
defendants’ assertions, where a court, as it has here,
construes a claim to cover a chemical compound, the
specification is not deficient merely because it does
not disclose how to prepare a particular form of that
compound.
Id. at 688 (citing In re Hogan, 559 F.2d 595, 606 (C.C.P.A.
1977) (internal citation omitted)). The court then determined
that the relevant claim was enabled as the inventors
indisputably invented the compound, the specification taught the
82
preparation of a racemic mixture of the compound, and the
inventors had prepared the racemic compound. Id. at 689. It
further found the written description “more than sufficient to
convey to those of skill in the art the subject matter of the
claimed invention and that the inventors were in ‘possession of
it.’” Id. at 702.
The same outcome is dictated here. Judge Irenas’
construction did not include any stereochemical limitations and,
therefore, the disclosure is not insufficient due to failure to
describe how to obtain the particular (R)-(+) frovatriptan form
of the compound.
It is not seriously disputed that frovatriptan is included
among the compounds of formula (I) described in the U.K.
application. (See DTX-1077 at 230.) The application explains
that “a particularly preferred compound” is 3-amino-1,2,3,4tetrahydrocarbazole-6-carboxamide, and then sets forth a process
for the preparation of other novel compounds of formula (I).
(DTX-1077 at 231; see also Rocco Tr. 1704:11-17.) The synthesis
of this preferred compound is set forth in Example 2 of the
application (and the ‘864 Patent). (DTX-1077 at 240-41; PX-0001
9:48-10:18.) Even Dr. Johnson agreed this compound could be
converted to frovatriptan via a “routine,” “very simple”
methylation process, which is a “straightforward transformation
in chemistry.” (Johnson Tr. 812:25-813:21; Rocco Tr. 1742:7-17
83
(“I think when reading the specification of ‘864 [a POSA] would
realize in one step, you can convert an advanced intermediate
into R frovatriptan.”).) In addition, the U.K. application (and
the ‘864 Patent specification) state, “It will be appreciated
that compounds of formula (I) may contain one or more assymetric
centres, and such compounds will exist as optical isomers
(enantiomers). The invention thus includes all such enantiomers
and mixtures, including racemic mixtures, thereof.” (DTX-1077 at
230; PX-0001 col.2 ll.35-39.)
The ‘864 Patent specification provides additional details.
Dr. Rocco testified that a POSA would understand “3-methylamino6-carboxamido-1,2,3,4-tetrahydrocarbazole” in claim 1 of the
‘864 Patent to describe a racemic mixture as well as the
separated enantiomers. (Rocco Tr. 1728:17-1729:5.) The
intermediate compound disclosed in Example 2, 3-amino-6carboxamido-1,2,3,4-tetrahydrocarbazole (DTX-1077 at 240-41; PX0001 9:48-10:18), is then resolved into the individual
enantiomers via two methods (i.e., chiral chromatography and
fractional crystallization with a chiral salt) described in
Example 6 of the ‘864 Patent. (Rocco Tr. 1704:15-17.) Dr. Rocco
testified that these techniques for separating enantiomers were
well-known to a POSA as of the priority date, and that other
separation technologies were also known in the art. (Rocco Tr.
84
1702:20-1703:7, 1705:22-1706:3.) 61 Even Dr. Johnson agreed that a
POSA would “know the general techniques as to how to do it”
(Johnson Tr. 830:10-14.) 62 See also Pfizer Inc., 882 F. Supp. 2d
at 694 (finding that even in the absence of working examples, or
a description of starting materials and reactions conditions, a
POSA “could resolve the enantiomers based on the prior art
available detailing classical resolution and chemoenzymatic
synthesis without undue experimentation”).
The Court finds Dr. Rocco’s testimony credible. A POSA
would understand the chemical compound to describe the compound
as a racemic mixture or as each enantiomer. That in combination
with the resolution techniques well-known to a POSA renders the
61
See also Young Tr. 377:1-18 (explaining chiral
chromatography is “the sort of technique which is available to
chemists and anybody skilled in the art could perform that” as
of the priority date).
62
Although Dr. Johnson testified that resolution of the
enantiomers of frovatriptan would have been “highly
unpredictable” as of the priority date (Johnson Tr. 814:8-11),
this conclusory statement is contradicted by other evidence in
the record including his own testimony demonstrating that
resolution techniques were well-known to a POSA. Dr. Johnson
also acknowledged that optical rotation is a technique that
permits measurement of polarized light reflected by a molecule
and is a means of measuring whether you have an enantiomer.
(Johnson Tr. 833:5-20.) Thus, a POSA would know “how to do it”
and could determine “what they’ll look like” using these wellknown techniques. (See Johnson Tr. 830:18-25.) Furthermore, that
the techniques and methods are known in the art favors an
enablement finding even if the results of any resolution
processes may have been unpredictable. See Banner Pharmacaps,
Inc., 2013 U.S. Dist. LEXIS 112440, at *46.
85
disclosures in the U.K. application sufficient to reasonably
convey to those of skill in the art the subject matter of the
claimed invention and that the inventors were in “possession of
it.” See Pfizer Inc., 882 F. Supp. 2d at 702 (finding adequate
written description where application claimed inter alia racemic
and non-racemic mixtures of compound, and expert testified
chemists would understand disclosure to encompass all forms);
see also Takeda Pharm. Co., 2013 U.S. Dist. LEXIS 72958, at *67
(specification need not include “every conceivable and possible
future embodiment of his invention”) (quoting Cordis Corp., 339
F.3d at 1365). Certainly the processes set forth in Example 6 of
the ‘864 Patent, describing the resolution of the enantiomers of
an intermediate compound which could then be converted into
frovatriptan by a routine methylation satisfies the written
description requirement.
For similar reasons, the Court finds that claim 1 of the
‘864 Patent is enabled by both the U.K. application and the ‘864
Patent. Claim 1 encompasses the chemical compound without
reference to its stereochemistry. The U.K. application claims
both racemic mixtures and enantiomers of the claimed compounds,
and specifically claims an intermediate compound that could be
converted to frovatriptan via routine process. The disclosures
further explain various processes by which to obtain other novel
compounds of formula (I). Thus, because a POSA having read the
86
disclosures in either the U.K. application or the ‘864 Patent
could have prepared frovatriptan without undue experimentation,
the Court finds that the claim is enabled.
However, to the extent that the application would be
required to independently enable resolution of the enantiomers
of the chemical compound, but see Pfizer Inc., 882 F. Supp. 2d
at 688, such resolution is also enabled. This is because a POSA
having read the specification could have engaged in routine
experimentation using well-known resolution techniques to obtain
(R)-(+) frovatriptan. The ‘864 Patent explains this in even
greater detail as it exemplifies those methods for resolving the
intermediate compound. Moreover, Dr. Johnson testified that
optical rotation is a technique that permits measurement of
polarized light reflected by a molecule and is a means of
“measuring whether you [] have an enantiomer.” (Johnson Tr.
833:5-20.) Thus, a POSA could utilize well-known resolution
techniques to separate the enantiomers and would know such
separation was achieved based upon well-known techniques for
measuring such separation. 63 See Cephalon, Inc., 707 F.3d at
1338-39 (“[E]xtensive experimentation does not necessarily
63
The ‘864 Patent provides optical rotation data for the
intermediate compound. (Rocco Tr. 1705:19-21; PX-0001 col.11
ll.32-67.)
87
render the experiments unduly extensive where the experiments
involve repetition of known or commonly used techniques.”).
Mylan’s expert, Dr. Johnson, opined that neither the U.K.
application nor the ‘864 Patent describe or enable the
separation of the enantiomers. (Johnson Tr. 813:22-814:11,
832:16-834:10.) In rendering his opinion, Dr. Johnson placed too
much reliance on the absence of working examples describing the
synthesis of frovatriptan specifically or resolution of its
enantiomers and thus the Court discounts his testimony. (See
Johnson Tr. 825:7-826:2); see In re Borkowski, 422 F.2d 904, 908
(C.C.P.A. 1970) (“a specification need not contain a working
example if the invention is otherwise disclosed in such a manner
that one skilled in the art will be able to practice it without
an undue amount of experimentation”). Moreover, Dr. Johnson’s
written description opinion is based upon an incorrect
interpretation of the law requiring the inventors to have actual
physical possession of every embodiment of the claimed compound
as of the priority date. (Johnson Tr. 832:16-20 (“I think she’s
asking me did the inventors provide evidence that they actually
had in their possession the compound, the enantiomer as claimed.
. . . I don’t believe they did.”); id. at 833:1-3 (noting
absence of data demonstrating inventors “actually had [the
enantiomers] in their hand and had made measurements”).)
However, “because written description does not require reduction
88
to practice, the inventors did not have to physically possess
the invention or report such test results in the application.”
Pfizer Inc., 882 F. Supp. 2d at 704 (quoting Pfizer, Inc. v.
Ranbaxy Labs., Ltd., 405 F. Supp. 2d 495, 505 (D. Del. 2005),
rev'd in pan on other grounds, 457 F.3d 1284 (Fed. Cir. 2006)).
In an effort to demonstrate that enantiomeric resolution
required undue experimentation, Mylan relies on internal
documents produced by third-parties GlaxoSmithKline (“GSK”) and
Vernalis detailing Dr. Borrett’s post-priority date experiments
to resolve the enantiomers of frovatriptan. 64 These documents
consist of lab notebooks and progress reports, as well as a
Record of Invention, dating from November 1992 through September
1993. (See, e.g., DTX-1417 at GSK-FROVA00003316; DTX-1398.) Dr.
Borrett screened several chiral acids, but these acids resulted
in an enantiomeric excess below 10%. 65 (DTX-1418 at GSKFROVA00015491-92.) The reports determined that the frovatriptan
64
Endo challenged the admissibility of these documents on
several grounds including authenticity and hearsay. In addition,
Endo objected under Federal Rule of Evidence 703 to those
portions of Dr. Johnson’s opinion that rely or opine upon these
materials. Because the Court finds that these documents and Dr.
Johnson’s corresponding testimony do not materially alter its
opinion concerning enablement and written description, it
assumes, without deciding, their admissibility.
65
Enantiomeric excess, or e.e., reflects the amount of
desired enantiomer over the undesired enantiomer. (See Rocco Tr.
1732:13-1733:11; Johnson Tr. 841:10-21.) An e.e. less than 10%
would be deemed a poor resolution. (See Rocco Tr. 1732:131733:11.)
89
racemate could be resolved using D-pyroglutamic acid (DTX-1419
at GSK-FROVA00006793), 66 but that the purity of the acid was
deemed “critical to the success of the resolution”(DTX-1421 at
GSK-FROVA00006658). On September 3, 1993, Dr. Borrett completed
a Record of Invention describing a resolution procedure for the
frovatriptan racemate, internally designated as SB-205184, using
D-pyroglutamic acid. (Johnson Tr. 837:20-838:2.) Mylan argues
that the length of time it took Dr. Borrett to perfect this
technique, the fact that he did not do so until years after the
priority date, and the fact that some typical chiral acids did
not achieve the desired separation indicate that undue
experimentation was required. The Court disagrees.
These documents reflect SKB’s attempts to create a more
efficient and refined process for enantiomeric separation that
might be suitable for commercial development of the frovatriptan
product. Dr. Borrett’s laboratory notebooks reflect that, prior
to conducting his experiments, he received a sample of the R
enantiomer of frovatriptan, internally designated as SB 209509,
which purported to have an e.e.>99%. 67 (See Johnson Tr. 1032:3-9;
DTX-1417 at GSK-FROVA00003330; see also id. at GSK-FROVA00003332
66
D-pyroglutamic acid was a well-known optically-active
acid that was routinely available for use in fractional
crystallization. (Rocco Tr. 1733:12-1734:12.)
67
That Dr. Borrett determined the actual e.e. to be
approximately 86% is of no moment.
90
(received second sample).) Thus, by November 24, 1992, someone
had already successfully separated the R enantiomer of
frovatriptan. In describing the nature of his own invention, Dr.
Borrett confirms not only that separation of enantiomers was
possible prior to his experiments but also that his invention
was designed to enable commercialization of frovatriptan:
The resolution process has enabled the use of a short,
3-stage route to SB-209509. Previously, this compound
could only be prepared by N-methylation of SB-205555
[the intermediate compound or precursor to
frovatriptan], a low-yielding 8-stage process. The
process is amenable to scale up, and will enable
production of SB-209509 for foreseeable supply
requests. It may also be the method of choice for the
manufacturing route.
(DTX-1398 at GSK-FROVA00015607 (emphasis added).) Mylan failed
to convincingly demonstrate that an 8-stage process as compared
to a 3-stage process constitutes undue experimentation.
For similar reasons, SKB’s representations to the PTO in
conjunction with the Borrett Patents do not demonstrate that
separation of the enantiomers required undue experimentation.
Rather, those statements convey only that the enantiomer is not
“specifically disclosed.” Notably, when confronted with the
purportedly inconsistent statements made in the Borrett Patents
and related documents, Dr. Rocco’s opinion that the ‘864 Patent
discloses and enables the separation of the enantiomers did not
change. He remarked, in the pharmaceutical industry, the
discovery lab that invents a compound does not focus on
91
perfecting commercialization techniques for that compound.
(Rocco Tr. 1746:2-1747:14.) Rather, the compound is frequently
passed off to the process chemists who later file patents “on
the perfected commercial ways” of creating a compound, which
could explain why the later, more particularized, Borrett
Patents were sought. (Rocco Tr. 1747:2-14; see also DTX-1398);
see Banner Pharmacaps, Inc., 2013 U.S. Dist. LEXIS 112440, at
*43
(“The evidence shows that GSK’s difficulties with the
hydrated solvate of dutasteride pertained to its attempt to
shepherd the form into the development stage.”). 68
Accordingly, the Court finds that Mylan has failed to
demonstrate, by clear and convincing evidence, that the Patent
is invalid for failure to describe or enable separation of the
frovatriptan enantiomers.
4. Salt-hydrates
Mylan next contends that the claims are invalid because the
U.K. application and the ‘864 Patent fail to describe and enable
the creation of salt-hydrates. The Court disagrees.
68
Mylan also points to evidence that Dr. Young, a named
inventor on the ‘864 Patent, testified that he was not
successful in separating the enantiomers of the 3-amino-6carboxamido-1,2,3,4-tetrahydrocarbazole. (Young Tr. 381:17382:17.) However, he also stated that he had used only one
approach “which is available to chemists to resolve a compound,”
but it was not successful. (Id.) This testimony does not suggest
significant, let alone, undue experimentation.
92
Judge Irenas construed “salt, solvate or hydrate thereof”
in claim 1 as “one or more of a salt, hydrate, or solvate
thereof” as he saw “no basis for finding that ‘salt’ does not
also include a salt that is also a hydrate or also a [solvate].”
(Claim Constr. Op. 12, 14.) The parties agreed that salt should
be similarly construed in claim 6, which refers to “a
physiologically acceptable salt thereof.” (Id. at 11.)
Endo argues that the Court’s claim construction did not
encompass a discrete salt-hydrate combination and therefore the
U.K. application and the ‘864 Patent need not explicitly
describe or enable such a combination. In support, Endo relies
primarily on GlaxoSmithKline LLC v. Banner Pharmacaps, Inc. 2013
U.S. Dist. LEXIS 112440, at *16. There, the court construed the
term “solvate” as “a complex formed by dutasteride with a
solvent in which dutasteride is reacted or from which it is
precipitated or crystallized.” Id. at *5. In determining that
the specification need not “independently describe crystalline,
precipitated, and reacted solvates as subgroups of the genus of
pharmaceutically acceptable solvates,” the court noted that “the
drug compound is the key structural feature of the solvate.” Id.
at *16. Likewise, the drug compound here is the key feature and,
as discussed above, frovatriptan is adequately disclosed and
enabled. Furthermore, Endo is correct that “to meet the written
description requirement, ‘[a]n applicant is not required to
93
describe in the specification every conceivable and possible
future embodiment of his invention.’” Takeda Pharm. Co., 2013
U.S. Dist. LEXIS 72958, at *67 (quoting Cordis Corp., 339 F.3d
at 1365). The salt-hydrate is merely a different form of the
claimed compound. See Banner Pharmacaps, Inc., 2013 U.S. Dist.
LEXIS 112440, at *36. As such, the patent need not independently
describe or enable a discrete salt-hydrate combination.
Dr. Rocco, whom this Court found credible, opined that the
‘864 Patent discloses and teaches a POSA “to make salts and salt
hydrates, or any combination of both.” (See Rocco Tr. 1741:1320, 1742:19-1743:3.) Dr. Rocco testified that a salt could be
hydrous or anhydrous, and a person would not know if it was one
or the other unless it was specified. (Rocco Tr. 101:8-12; see
also King Tr. 190:8-23 (stating that it cannot be determined
from the information provided in Example 24 whether it contains
water); Young Tr. 381:3-5 (noting Example 24 does not identify
if it is a salt hydrate).) The ‘864 Patent discloses that
“solvates and hydrates of compounds of formula (I)” are also
included within the scope of the invention. (PX-0001 col.3 ll.68.) 69 Moreover, Example 5 of the ‘864 Patent discloses the
69
See also DTX-1077 at 236 (“The present invention
therefore provides in a further aspect pharmaceutical
compositions comprising a compound of formula (I) or a
physiologically acceptable salt or solvate thereof and a
physiologically acceptable carrier.”).
94
preparation of a monohydrate form of 3-amino-6-carboxamido1,2,3,4-tetrahydrocarbazole. (PX-0001 col.11 ll.4-28; see also
Johnson Tr. 852:12-15.)
The U.K. application and the ‘864 Patent also indicate that
the disclosed compounds may include physiologically acceptable
salts, and specifies that those salts may be formed with
succinic acid:
Suitable physiologically acceptable salts will be
apparent to those skilled in the art and include for
example acid addition salts such as those formed with
inorganic acids e.g. hydrochloric, sulphuric or
phosphoric acids and organic acids e.g. oxalic,
succinic, maleic, acetic or fumaric acid.
(DTX-1077 at 231; see also PX-0001 2:66-3:3; Rocco Tr. 1707:231708:18.) Both provide numerous examples of salts formed using
some of these listed acids. (See, e.g., PX-0001 at Exs. 1
(hydrochloride salt), 7 (oxalate salt), 9 (hemioxalate salt);
DTX-1077 at 239-40.) Indeed, Example 24 of the ‘864 Patent
details the synthesis of the frovatriptan compound as the
hydrochloric salt, though the specification does not identify
whether it yields a salt-hydrate form. (See King Tr. 190:8-23;
Young Tr. 374:7-8, 381:3-8.)
Because a salt may be either hydrous or anhydrous and
absent certain identifying information a POSA cannot
definitively rule out the presence of water in a salt, it is
difficult for this Court to understand why a POSA would not
95
believe that the inventors were in possession of a salt-hydrate
based upon the disclosures contained in either the U.K.
application or the ‘864 Patent. This is especially true with
respect to the ‘864 Patent specification, which exemplifies the
creation of both a salt and a hydrate form of the covered
compounds. See Banner Pharmacaps, Inc., 2013 U.S. Dist. LEXIS
112440, at *16 (“There is no reason why a person skilled in the
art would not credit a patentee with possession of a solvate
merely because the patentee did not disclose solvates formed by
each solvation process.”).
As Mylan’s expert, Dr. Lee, acknowledged, the methods of
salt creation were known to a POSA as of the priority date. If a
scientist wanted to make a salt, she would first dissolve the
free base in a solvent and then add an acid. (Lee Tr. 493:612.) 70 Example 24 details the synthesis of frovatriptan as the
hydrochloride salt, which Dr. Lee agreed hypothetically could be
converted into the frovatriptan free base and reacted with a
different acid to form a different salt. (Lee Tr. 492:8-493:4.)
He further testified that following this process using succinic
70
Dr. Johnson and Dr. Lee conclusorily asserted that salt
and salt-hydrate formation as of the priority date were
unpredictable, but the Court does not credit this testimony in
light of the other contradictory evidence. Even if the
characteristics of the resultant salt were unknown, the
testimony makes clear that the process of obtaining a salt was
routine and well-known to a POSA. See Banner Pharmacaps, Inc.,
2013 U.S. Dist. LEXIS 112440, at *46.
96
acid, which is listed in the patent specification and U.K.
application among the acids that could be used, could produce a
succinic salt. (Lee Tr. 492:8-493:4.) 71 Moreover, Mylan’s own
documents demonstrate that the frovatriptan free base combined
with succinic acid in a solvent forms frovatriptan succinate
monohydrate, a salt-hydrate. (Lee Tr. 496:18-22; PX-0059 at MYLFRO0045949.) 72
Mylan attempts to rebut this evidence through the testimony
of Dr. Lee, whose colleague, Dr. Michael Rodgers, attempted to
replicate a fraction of the experiment set forth in Example 24.
(See Lee Tr. 428:3, 428:8-17, 400:5-13.) The experiment yielded
a salt but not a salt-hydrate, which Mylan contends demonstrates
that the patent fails to enable creation of a salt-hydrate.
However, cross-examination of Dr. Lee raised several
71
Mylan cites Dr. Lee’s testimony that a POSA replacing
hydrochloric acid in Example 24 with succinic acid would have no
expectation of successfully obtaining a succinic salt because of
a BOC protecting group that prevents a substituent from reacting
with other chemicals. (Lee Tr. 415:20-419:18.) However, Dr. Lee
later testified that absent this BOC group, succinic acid could
be reacted with the free base to form a succinic salt. (Lee Tr.
492:4-14.)
72
The Court recognizes that PX-0059 is a post-priority date
document that is irrelevant to the state of the art as of the
priority date and the Court does not rely upon it for that
purpose. However, this document does not contradict either Dr.
Rocco’s testimony regarding a POSA’s understanding of the ‘864
Patent or Dr. Lee’s testimony that such a process could form a
succinic salt. Cf. Plant Genetic Sys., N.V. v. DeKalb Genetics
Corp., 315 F.3d 1335, 1344 (Fed. Cir. 2003).
97
deficiencies in the experimental process, including the use of
certain intermediate compounds that may not have exhibited the
same purity level or other identifying characteristics as the
original compounds created in Example 24. (Lee Tr. 428:8-17,
429:12-22.) In addition, Mr. Rodgers completed two runs and each
time he obtained a different quantity of the compound, which
each had a different melting point. Significantly, neither of
these iterations resulted in a compound with a quantity or
melting point identical to that set forth in the patent. 73 As
Endo notes, Dr. Lee did not provide a satisfactory explanation
as to these experimental differences but explained some of them
could be the result of “simple experimental error.” (Lee Tr.
482:16-18.) These and other inconsistencies called into question
the accuracy of Mr. Rodgers’ results, as well as the validity of
the conclusions drawn therefrom. (See, e.g., Lee Tr. 468:13-15;
compare DTX-1202 with PX-0001 col.16 ll.42-67; Rocco Tr.
1713:15-17 (“same compounds of the same purity should have the
same melting point”).)
In any event, whether Example 24 yields only a salt does
not undermine Dr. Rocco’s testimony that the patent enables a
73
Example 24 yielded 80 mg of the compound with a melting
point of 327-328°. The first run of Mr. Rodgers’ experiment
yielded 64.5 mg with a melting point of 296-297°, while the
second run yielded 45.9 mg with a melting point of 291-293°.
(PX-0001 col.16 ll.60-63; DTX-1202 at 3, 4-6; Lee Tr. 482:2-13,
489:19-25, 491:14-23.)
98
POSA to create salts, salt-hydrates, or any combination thereof.
Mylan’s entire argument regarding the lack of disclosure and
enablement of a salt-hydrate boils down to the fact that neither
the U.K. application nor the ‘864 Patent specification contain
an example explicitly identifying the formation of a salthydrate of frovatriptan. (Cf. Johnson Tr. 851:24-853:2
(explaining basis of his opinion is that none of the examples
reflect a salt-hydrate).) However, it is well-established that
neither the written description nor enablement requirement
mandates inclusion of examples or an actual reduction to
practice. See In re Borkowski, 422 F.2d 904, 908 (C.C.P.A. 1970)
(“a specification need not contain a working example if the
invention is otherwise disclosed in such a manner that one
skilled in the art will be able to practice it without an undue
amount of experimentation”); Takeda Pharm. Co., Ltd. V. TWi
Pharms., Inc., 2013 U.S. Dist. LEXIS 72958, at *66-67 (citing
Falko—Gunter Falkner, 448 F.3d at 1366-67). Thus, while the
Court may look to any examples in the specification, see Boston
Sci. Corp. v. Johnson & Johnson, 647 F.3d 1353, 1364 (Fed. Cir.
2011), the absence of such examples alone does not necessitate a
finding that the patent is invalid due to an insufficient
written description or lack of enablement.
To the extent Mylan relies upon the statements made during
the prosecution of the Borrett Patents, these documents are of
99
limited relevance as they acknowledge only that the ‘864 Patent
does not specifically teach the particular (R)-(+) frovatriptan
enantiomer salt-hydrate. (See DTX-1427 at MYL-FRO0047563.) But
that opinion—offered by an individual whose credibility the
Court did not have an opportunity to consider—does not address
whether practicing the invention of the ‘864 Patent would
require undue experimentation, which is the standard applicable
here.
The cases on which Mylan relies are unavailing, as the
courts there found the asserted claims were not enabled based on
the underdeveloped state of the art at the time. See, e.g.,
Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 1361-62
(Fed. Cir. 2007) (claims invalid for failure to enable
transformation of monocot cells, which was not possible under
the state of the art as of the filing date); Alza Corp. v. Andrx
Pharms., 603 F.3d 935, 941 (Fed. Cir. 2010) (finding claims were
not enabled because relevant field “was not mature” and the
claimed dosage was considered a “‘breakaway’ from the prior
art”). On the contrary, here, there is evidence that salt
formation methods were known to a POSA and Mylan did not
persuade the Court that the creation of a salt-hydrate, as
opposed to the anhydrous salt, would require undue
experimentation as of the priority date.
100
The Court thus concludes that Mylan has failed to meet its
burden of demonstrating a lack of sufficient written description
or enablement of a salt-hydrate.
5. Treatment
Mylan also argues that claims 2 and 3 of the ‘864 Patent
are not sufficiently described or enabled because the U.K.
application and the ‘864 Patent are silent as to the treatment
of migraine that is “expected to present.” Mylan relies
exclusively on the testimony of Dr. Peroutka, who provided
opinions on these issues only “to the extent the court
construes” the asserted claims “to encompass the prophylactic
treatment of migraine.” (See Tr. 578:8-16 (quoting DTX-1219
¶¶ 13-14 (Expert Report of Dr. Peroutka)).) Because Judge Irenas
subsequently construed “treatment” as “treatment without
prophylaxis” (Claim Constr. Op. 20), Endo argues that Dr.
Peroutka has not provided a relevant opinion under the current
claim construction.
In response, Mylan contends that by interpreting
“treatment” to include relief from a condition that is “expected
to present,” the Court carved out a portion of what is medically
considered to be, in essence, prophylactic treatment and
attributed it to “treatment”. (See Tr. 581:1-10; Peroutka Tr.
101
591:9-592:16.) 74 Critical to Mylan’s argument is its view that
“expected to present” encompasses the anticipation of migraine
in the absence of either symptoms or headache pain. (Peroutka
Tr. 592:12-14 (“So this construction would clearly cover, I mean
it says it right there, taking it this [sic] in anticipation,
meaning when there is [sic] no symptoms.”).) But this view
ignores the context in which Judge Irenas referred to migraine
that is “expected to present” and therefore completely distorts
the Court’s claim construction.
Mylan initially sought a construction of “treatment” that
included prophylactic treatment, which Dr. Peroutka defined as
“‘routinely administering the claimed compounds regardless of
the presence of headache pain.’” (Claim Constr. Op. 15, 17
(quoting Peroutka Report ¶ 36).) The Court rejected this
construction, noting that a POSA would understand prophylaxis to
be distinct from treatment. (Id.) In explaining this
determination, the Court cited Dr. Rocco who defined treatment
as the “administration of a compound for the purpose of
providing relief from a condition at the time at which that
condition has presented or is expected to present.” (Id. (citing
Rocco Report ¶¶ 69-70) (emphasis added).) Judge Irenas disagreed
74
Dr. Peroutka explained that “the way the judge split it
up, he kind of took what I would call as a physician prophylaxis
and he put it into the, quote, treatment group, not really
separating acute from prophylaxis.” (Tr. 592:9-14.)
102
with Mylan’s assertion that this language referred to
prophylaxis. (Id.)
Significantly, the Court went on to say that
[f]or example, as both parties have noted, migraines
are often preceded by any number of symptoms, such as
an aura or nausea. Thus, when a migraine sufferer
experiences such a symptom, she can expect that a
migraine will occur and thus take medication to treat
the oncoming migraine. Or in the case of menstrual
migraines, the patient could take the medication
around the time each month that she would expect the
migraines to present.
(Id. (emphasis added).) When read in the context of this
discussion, which Mylan sidesteps, a migraine is “expected to
present” when a migraine sufferer experiences any symptoms that
are understood to typically accompany migraine. The same
analysis applies to menstrual migraines, but the symptoms
experienced coincide with the time of a woman’s menses.
Regardless of the type of migraine (menstrual migraine or
classic migraine), a migraine sufferer knows that a migraine is
imminent at the point when her symptoms first appear, and she
may treat it through administration of a drug. In other words,
the Court drew the line separating “treatment” and “prophylaxis”
at the point when migraine symptoms begin to manifest.
As the Court implied, it would be irrational to construe
providing relief in the face of symptoms (but prior to actual
headache pain) as “prophylaxis” rather than as “treatment”.
According to Dr. Peroutka, migraine is a syndrome and proceeds
103
in stages: “a migraine is not just that middle section of
headache, it’s the 12 hours leading up and a post phase of about
23.” (Peroutka Tr. 535:7-536:1.) The period of time preceding
the headache phase is referred to as the “prodromal phase,”
which may last up to twelve hours. (Peroutka Tr. 535:7-536:1.)
During this phase people may experience a variety of symptoms
such as fatigue, mood changes, and aura. (Id.; see also Johnson
Tr. 659:7-660:2 (explaining that “classic migraine” sufferers
experience aura, scintillating scotoma or jagged flashing
lights, as well as autonomic disturbances such as nausea).) The
prodromal phase is succeeded by the headache phase characterized
by severe head pain, and then a recovery phase. A migraine
sufferer experiencing light sensitivity or an aura would not
wait to treat the oncoming headache until she was in the midst
of the headache phase and already suffering severe pain. Hence,
the Court’s construction of treatment as including treatment of
a migraine that is expected to present, i.e. where a migraine
sufferer is experiencing migraine symptoms but may not be
suffering head pain, recognizes the existence of this prodromal
phase of a migraine.
Because Mylan’s argument is founded upon a faulty and
interpretation of the Court’s claim construction, Mylan has
failed to present clear and convincing evidence that claims 2
and 3 lack a sufficient written description and are not enabled.
104
Dr. Peroutka testified that there are certain “very well-known
triggers” that may induce a migraine in a particular individual.
(Peroutka Tr. 595:6-597:15.) 75 Stress, diet, wine consumption,
altitude or weather changes, and lack of sleep are among these
triggers. (Id.) Once an individual has identified her particular
trigger, she may be able to anticipate when she will suffer a
migraine. (Peroutka Tr. 597:4-6; Grosberg Tr. 1375:1-7.)
However, the ‘864 Patent contains no information regarding these
triggers or when, how much, how often, and how to administer the
compound for the “anticipatory” treatment of migraines.
(Peroutka Tr. 597:12-22; see also Peroutka Tr. 610:23-611:9
(patent does not contain dosing information or frequency of
dosing).) As Mylan explains, “For example, if a patient gets
migraine regularly when the weather changes, and the weatherman
predicts a 70% chance of rain, does that mean that the
migraineur expects a migraine to present? And if so, when and in
what amounts of drug should the migraineur take?” (Mylan’s Resp.
to Endo’s Opening Post-Trial Br., Dkt. Ent. 207, at 18.)
However, this exemplifies the fundamental problem with Mylan’s
argument—Dr. Peroutka’s testimony improperly injects a truly
75
Dr. Grosberg, Endo’s expert, similarly testified that “a
number of patients will notice that their migraine attacks can
be particularly triggered by identifiable exposures, whether
it’s stress, certain types of food, the changes in weather” and
consequently their attacks may be “predictably triggered.”
(Grosberg Tr. 1375:1-7.)
105
prophylactic element into “treatment,” contrary to the Court’s
claim construction, and then uses that definition as the
foundation for his flawed opinion. The definition of treatment
relied upon is thus outside the scope of this Court’s claim
construction and cannot serve as the basis for declaring the
patent invalid.
Contrary to Mylan’s argument, both the ‘864 Patent and the
U.K. application describe a week-long treatment regimen that
includes dosing information. In particular, the ‘864 Patent
provides:
The physiologically acceptable compounds of the
invention will normally be administered in a daily
dosage regimen (for an adult patient) of, for example,
an oral dose of between 1 mg and 500 mg, preferably
between 10 mg and 400 mg, e.g. between 10 and 250 mg
or an intravenous, subcutaneous, or intramuscular dose
of between 0.1 mg and 100 mg, preferably between 0.1
mg and 50 mg, e.g. between 1 and 25 mg of the compound
of the formula (I) or a physiologically acceptable
salt thereof calculated as the free base, the compound
being administered 1 to 4 times per day. Suitably the
compounds will be administered for a period of
continuous therapy, for example for a week or more.
(PX-001 col.7 ll.56-67; see also DTX-1077 at 237.) This
disclosure clearly identifies a dosage amount, how many times a
day to administer that dosage amount, and for how long the
treatment may be continued. It thus provides a sufficient
written description. Moreover, Mylan did not submit evidence to
suggest that the disclosed treatment regimen fails to enable the
effective treatment of migraine, as this Court has construed it.
106
Indeed, Dr. Peroutka testified that “taking any triptan,
including frovatriptan, regularly during a period of days when a
migraine attack is likely . . . one would expect that [] a
reduction in overall moderate and severe headaches might occur
over a period of several days.” (Peroutka Tr. 626:4-628:10.) As
such, Mylan has failed to overcome the presumption of validity.
See Sciele Pharma Inc., 684 F.3d at 1260.
III.
Exceptional Case Under 35 U.S.C. § 285
Endo seeks costs and attorneys’ fees under 35 U.S.C. § 285
“on the basis of Mylan’s litigation misconduct and
unprofessional behavior.” (Pl.’s Br. at 35.) This request is
denied. The Court sees no basis whatsoever for holding that
Mylan engaged in misconduct warranting an exceptional case
finding under § 285. Quite the contrary. Indeed, both parties
litigated this case vigorously, effectively, and in good faith.
The Court commends counsel.
107
CONCLUSION
For the foregoing reasons, the Court finds that Mylan has
failed to demonstrate by clear and convincing evidence that the
‘864 Patent is invalid as anticipated, obvious, or due to an
insufficient written description or lack of enablement.
Accordingly, the Court enters judgment in favor of Endo and
against Mylan. An appropriate Order will issue herewith.
Date: January 28, 2014
s/Renée Marie Bumb
RENÉE MARIE BUMB
UNITED STATES DISTRICT JUDGE
108
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