BIAL - PORTELA & CA S.A. et al v. Alkem Laboratories Limited et al

Filing 271

OPINION Signed by Judge Colm F. Connolly on 9/15/2022. (nmf)

IN THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF DELAWARE
BIAL-PORTELA & CA. S.A.,
)
BIAL-HOLDING, S.A. and
)
SUNOVION PHARMACEUTICALS)
INC.,
)
Plaintiffs,
)
)
v.
)
)
ALKEM LABORATORIES
)
LIMITED,
)
)
Defendant.
)
BIAL-PORTELA & CA. S.A., )
BIAL-HOLDING, S.A. and
)
SUNOVION PHARMACEUTICALS)
INC.,
)
)
Plaintiffs,
)
)
v.
)
)
ALKEM LABORATORIES
)
LIMITED,
)
)
Defendant.
)

Civ. No. 18-304-CFC-CJB

Civ. No. 20-786-CFC-CJB

BIAL-PORTELA & CA. S.A., )
BIAL-HOLDING, S.A. and
)
SUNOVION PHARMACEUTICALS)
INC.,
)
)
Plaintiffs,
)
)
v.
)
)
)
ALKEM LABORATORIES
)
LIMITED,
)
Defendant.
)

Civ. No. 21-186-CFC

Steven J. Balick, Andrew C. Mayo, ASHBY & GEDDES, Wilmington, Delaware;
James B. Monroe, Jennifer H. Roscetti, Charles T. Collins-Chase, Lauren J.
Dowty, Meredith H. Boerschlein, Ryan V. McDonnell, FINNEGAN,
HENDERSON, FARABOW, GARRETT & DUNNER, LLP, Washington, District
of Columbia
Counsel for Plaintiffs Bial-Portela & CA. S.A.and Bial-Holding, S.A.
Jack B. Blumenfeld, Karen A. Jacobs, Jennifer Ying, MORRIS, NICHOLS,
ARSHT & TUNNELL LLP, Wilmington, Delaware
Counsel for Plaintiff Sunovion Pharmaceuticals Inc.

11

Benjamin J. Schladweiler, Samuel L. Moultrie, GREENBERG TRAURIG, LLP,
Wilmington, Delaware; Aaron F. Barkoff, Alejandro Menchaca, Rajendra A.
Chiplunkar, Ben J. Mahon, Ashley M. Ratycz, MCANDREWS, HELD &
MALLOY, LTD., Chicago, Illinois

Counsel for Defendant

OPINION

September 15, 2022
Wilmington, Delaware
111

COLMfONNOLLY
CHIEF JUDGE
This patent infringement case arises out of the submission by Defendant
Alkem Laboratories Limited (Alkem) of an Abbreviated New Drug Application
(ANDA) to the U.S. Food and Drug Administration (FDA) for approval to market
a generic version of APTIOM®, a pharmaceutical that is orally administered once
a day in tablet form to treat epileptic seizures called partial-onset seizures.
APTIOM® is marketed by Plaintiffs BIAL - PORTELA & CA S.A., BIAL HOLDING, S.A., and Sunovion Pharmaceuticals Inc. (collectively, Bial). The
active pharmaceutical ingredient (API) in APTIOM® is eslicarbazepine acetate.
Bial has asserted six claims across five patents. It alleges that Alkem's
submission of its ANDA to the FDA constitutes infringement under 35 U.S.C.

§ 271(e)(2)(A) of claim 3 of U.S . Patent No. 10,675,287 (the #287 patent), claim 5
of U.S. Patent No. 10,695 ,354 (the #354 patent), claims 7 and 8 of U.S. Patent No.
10,702,536 (the # 536 patent), claim 20 of U.S. Patent No. 9,763,954 (the #954
patent), and claim 17 of U.S. Patent No. 10,912,781 (the #781 patent). None of the
six asserted claims cover the compound eslicarbazepine acetate; rather, five of the
claims cover methods of administering eslicarbazepine acetate and one of the
claims is a formulation claim for a tablet with eslicarbazepine acetate as the APL
Alkem denies that it infringes claim 17 of the #781 patent and claim 20 of the #954

2

patent and further alleges that all six asserted claims are invalid. It has also filed
counterclaims seeking declaratory judgments of noninfringement and invalidity of
the asserted patents.
I held a three-day bench trial, and, as required by Federal Rule of Civil
Procedure 52(a)(l), I have set forth separately below my findings of fact and
conclusions of law. I write primarily for the parties.

I.

THE STATUTORY AND REGULATORY FRAMEWORK

The ANDA procedures out of which this case arise were established by FDA
regulations promulgated pursuant to the Federal Food, Drug, and Cosmetic Act
(FDCA), 21 U.S.C. § 301 et seq., and specifically by the so-called Hatch-Waxman
Amendments to the FDCA. Justice Kagan provided in Caraco Pharmaceutical

Laboratories, Ltd. v. Novo NordiskA/S, 566 U.S. 399 (2012), this helpful summary
of the provisions of the Amendments and the FDA regulations that bear on this
case:
The FDA regulates the manufacture, sale, and labeling of
prescription drugs under a complex statutory scheme. To
begin at the beginning: When a brand manufacturer wishes
to market a novel drug, it must submit a new drug
application (NDA) to the FDA for approval. The NDA
must include, among other things, a statement of the
drug's components, scientific data showing that the drug
is safe and effective, and proposed labeling describing the
uses for which the drug may be marketed. The FDA may
approve a brand-name drug for multiple methods of use-either to treat different conditions or to treat the same
condition in different ways.
3

Once the FDA has approved a brand manufacturer's drug,
another company may seek permission to market a generic
version pursuant to legislation known as the HatchWaxman Amendments. Those amendments allow a
generic competitor to file an abbreviated new drug
application (ANDA) piggy-backing on the brand's NDA.
Rather than providing independent evidence of safety and
efficacy, the typical ANDA shows that the generic drug
has the same active ingredients as, and is biologically
equivalent to, the brand-name drug. As we have
previously recognized, this process is designed to speed
the introduction of low-cost generic drugs to market.
Because the FDA cannot authorize a generic drug that
would infringe a patent, the timing of an ANDA's
approval depends on the scope and duration of the patents
covering the brand-name drug. Those patents come in
different varieties. One type protects the drug compound
itself. Another kind ... gives the brand manufacturer
exclusive rights over a particular method of using the drug.
In some circumstances, a brand manufacturer may hold
such a method-of-use patent even after its patent on the
drug compound has expired.
To facilitate the approval of generic drugs as soon as
patents allow, the Hatch-Waxman Amendments and FDA
regulations direct brand manufacturers to file information
about their patents. The statute mandates that a brand
submit in its NDA the patent number and the expiration
date of any patent which claims the drug for which the
brand submitted the NDA or which claims a method of
using such drug. And the regulations issued under that
statute require that, once an NDA is approved, the brand
provide a description of any method-of-use patent it
holds. That description is known as a use code, and the
brand submits it on FDA Form 3542. . . . [T]he FDA does
not attempt to verify the accuracy of the use codes that
brand manufacturers supply. It simply publishes the
codes, along with the corresponding patent numbers and
4

expiration dates, in a fat, brightly hued volume called the
Orange Book (less colorfully but more officially
denominated Approved Drug Products With Therapeutic
Equivalence Evaluations).
After consulting the Orange Book, a company filing an
ANDA must assure the FDA that its proposed generic drug
will not infringe the brand's patents. When no patents are
listed in the Orange Book or all listed patents have expired
(or will expire prior to the ANDA' s approval), the generic
manufacturer simply certifies to that effect. Otherwise,
the applicant has two possible ways to obtain approval.
****[One of those ways] is to file a so-called paragraph
IV certification, which states that a listed patent "is invalid
or will not be infringed by the manufacture, use, or sale of
the generic drug." 21 U.S.C. § 355G)(2)(A)(vii)(IV). A
generic manufacturer will typically take this path in either
of two situations: if it wants to market the drug for all uses,
rather than carving out those still allegedly under patent;
or if it discovers, as described above, that any carve-out
label it is willing to adopt cannot avoid the brand's use
code. Filing a paragraph IV certification means provoking
litigation. The patent statute treats such a filing as itself
an act of infringement, which gives the brand an
immediate right to sue [under 35 U.S.C. § 271(e)(2)(A)].
Assuming the brand does so, the FDA generally may not
approve the ANDA until 30 months pass or the court finds
the patent invalid or not infringed. Accordingly, the
paragraph IV process is likely to keep the generic drug off
the market for a lengthy period, but may eventually enable
the generic company to market its drug for all approved
uses.
566 U.S. at 404-08 (irrelevant citations and internal quotation marks omitted).

5

Il.

FINDINGS OF FACT

A.

Introduction

1)

BIAL - PORTELA & CA S.A., is a Portuguese corporation, No. 18-

3041, D.I. 235, Ex. 111, and the assignee of the asserted patents, D.I. 235, Ex. 1

1117, 26, 36, 47, 58.
2)

BIAL - HOLDING, S.A. is a Portuguese corporation having its

principal place of business in Portugal. D.I. 235, Ex. 112. Although BIAL HOLDING has been a named Plaintiff since the filing of the initial complaint, see
D.I. 1, no evidence about BIAL - HOLDING or its connection to this lawsuit was
adduced during trial. The only reference specific to BIAL - HOLDING in the
pretrial order simply identifies it as a Portuguese corporation having its principal
place of business in Portugal. D.I. 235, Ex. 1 ,r 2. Nonetheless, the pretrial order
defines "Plaintiffs" as BIAL - PORTELA, BIAL - HOLDING, and Sunovion and
also states that "no party contests Plaintiffs' standing for purposes of these actions,
and the parties agree that no proof of standing needs to be adduced at trial." D.I.
235

,r 26.

1 Although

the three cases have not been consolidated, they were tried together.
Because identical briefs were filed in all three cases, I cite only to one docket.
Thus, all D.I. citations refer to the No. 18-304 case docket.
6

3)

Sunovion, a Delaware corporation with its principal place of business

in Massachusetts, D.I. 235, Ex. 113, is the holder ofNDA No. 022416 for
APTIOM® (eslicarbazepine acetate) Tablets in 200, 400, 600, and 800 mg dosage
forms. The FDA approved this NDA for use as an adjunctive therapy for partialonset seizures in November 2013 and for use as a monotherapy for partial-onset
seizures and pediatric use in August 2015. D.I. 235, Ex. 11167-70.
4)

The Orange Book for APTIOM® lists the #954, #287, #354, #536,

and #781 patents. D.I. 235, Ex. 1171.
5)

Sunoyion is the exclusive licensee of the asserted patents in the

United States. D.I. 235, Ex. 1167.
6)

Alkem is an Indian corporation with its principal place of business in

India. D.I. 235, Ex. 114.
7)

Alkem has submitted ANDA No. 211199, seeking approval to engage

in the commercial manufacture, use, sale, and/or importation of eslicarbazepine
acetate tablets in 200, 400, 600, and 800 mg dosage forms. D.I. 235, Ex. 1 173.
Alkem's ANDA No. 211199 contains certifications pursuant to 21 U.S.C.

§ 355G)(2)(A)(vii)(IV) that the #954, #287, #354, #536, and #781 patents are
invalid, unenforceable, and/or would not be infringed. D.I. 235, Ex. 1174.

7

B.

Witnesses
1.

8)

Fact Witnesses

Mark Duffy is the director of strategy and business development for

Bial. Tr. at 50:20-23. Duffy testified about the licensing agreement for
APTIOM® that Bial has with Sunovion. See, e.g., Tr. at 50:24-51:4.
11)

Patricio Soares da Silva is a named inventor on the #954, #287, #354,

and #536 patents. JTX 6; JTX 7; JTX 8; JTX 9. Soares da Silva started working
for Bial in 1993. Tr. at 83 :2-6. While there, he helped develop the compound
eslicarbazepine acetate and APTIOM®. Tr. at 84:9-18.
12)

Ricardo Lima is a named inventor on the #781 patent. JTX 10. Lima

began working for Bial in 2000. Tr. at 172:14-16. While there, he helped develop
the compound eslicarbazepine acetate and APTIOM®. Tr. at 173:1-9.
13)

Jose Luis da Almeida was a practicing physician for a few years

before entering the pharmaceutical industry, where he worked with Soares da
Silva. Tr. at 391:3-14. He is a named author on the Almeida 2002 abstract. Tr. at
391:15-24.
14)

Ujwal Chhabra testified on Alkem' s behalf about Alkem' s ANDA

label and the use of microcrystalline cellulose. Tr. at 400:8-11. Alkem adduced
no evidence at trial about Chhabra' s qualifications, his employment, or ties to
Alkem, and thus I have no idea how he is connected to Alkem or this action. See

8

Tr. at 400:12-04:3; D.I. 235. I would have struck his testimony for lack of
foundation had Bial objected to it.
15)

Prashant Mandagade works with Alkem's laboratories in Mumbai.

Tr. at 404:9-10. Mandagade worked as the head of the formulation development
department and was involved in the formulation development for eslicarbazepine
acetate. Tr. at 406:4-9.
16)

Emily Bulat testified as Sunovion's 30(b)(6) witness on marketing

and sales. Tr. at 715:17-22. Prior to leaving Sunovion, Bulat was the Executive
Director of US neurology marketing. Tr. at 716:13-15.

2.
17)

Dial's Expert Witnesses

John Koleng has a Ph.D. in pharmaceutical drug delivery. Tr. at

286:1-6; PTX 388. Koleng has worked in pharmaceutical development since
1996, working on drug product formulation, manufacturing, and testing dosage
forms. Tr. at 286:7-11; PTX 388. Koleng is an expert in the design, evaluation,
and formulation of drug products. Tr. at 289:19-24.
18)

James Wheless is a licensed physician who specializes in neurology

with a subspecialty of epilepsy. Tr. at 214:3-5; PTX 426. Wheless sees over 100
patients in his clinic a month, and almost all are epilepsy patients. Tr. at 216:1218. Wheless has been involved in clinical drug development for over 30 years and
has been involved in over 150 clinical trials-most of which were related to

9

partial-onset epilepsy and intractable epilepsy. Tr. at 216:22-17:7; PTX 426.
Wheless is an expert in clinical and research-based neurology, including the
treatment of patients suffering from epilepsy with partial-onset seizures and
patients with intractable epilepsy. Tr. at 218:16-21.
19)

John Jarosz is an economist with graduate degrees in law and

economics. Tr. at 361 :1-8; PTX 1161. Jarosz is an expert in the economics of
intellectual property protection and valuation. Tr. at 62:4-8.
20)

Robert Williams has a Ph.D. in pharmaceuticals, is a professor of

pharmaceutics, and serves as division head of molecular pharmaceutics and drug
delivery at the University of Texas at Austin. Tr. at 816:24-18:16; PTX 550.
Williams is an expert in the design, evaluation, and formulation of drug products.
Tr. at 818:25-19:5.
21)

Barry Gidal has a Doctor of Pharmacy degree and completed a post-

doctoral fellowship in clinical pharmacokinetics in epilepsy. Tr. at 806:16-07:6;
PTX 1160. Gidal is an expert in clinical phannacokinetics of anti-epileptic
medications. Tr. at 809:22-25.

3.
22)

Alkem's Expert Witnesses

Ivan Hofmann is an economist with a focus on pharmaceutical

economics and intellectual property economics. Tr. at 720: 11-22, 721 :5-8; DTX
240.

10

23)

Jason McConville has a Ph.D. in pharmaceutics that covers drug

delivery systems and aspects of pharmacokinetics. Tr. at 639:8-11; DTX 101.
McConville is a professor of pharmaceutics at the University of New Mexico and
has a research lab there in which he studies drug formulation and drug delivery.
Tr. at 639:22-25. McConville is an expert in pharmaceutical compositions and
methods of making them. Tr. at 642:24-43:4.
24)

Michael Rogawski has a Ph.D. in pharmacology and a medical degree

from Yale. Tr. at 559:8-11; DTX 2. Rogawski was previously employed as the
chief of epilepsy research at the National Institutes of Health and is currently a
professor in the UC Davis Department of Neurology. Tr. at 559:12-24. Rogawski
is an expert in neurology and pharmacology, specializing in anti-seizure
medications. Tr. at 570:12-16.
25)

Patrick Ronaldson has a Ph.D. in pharmaceutical sciences and is a

professor of pharmacology at the University of Arizona, teaching in the medical
school and pharmacology graduate program. Tr. at 409:1-9, 411:15-19; DTX
204A. Ronaldson has been a researcher in the field of neuropharmacology for 20
years. Tr. at 420:21-25. Over Bial's objection, Alkem offered Ronaldson as an
expert in the field of neuropharmacology, which includes the pharmacology of
anticonvulsive drugs. Tr. at 426:25-27:10.

11

C.

The Asserted Patents
1.

26)

The #287, #354, and #536 Patents (The Once-Daily Methods
of Dosing Patents)

The parties and witnesses refer to these three patents together as the

"once-daily patents."

27)

The once-daily patents are directed to administering eslicarbazepine

acetate once-daily to treat partial-onset seizures. JTX 7; JTX 8; JTX 9.
28)

Bial asserts infringement of claim 3 of the #287 patent. D.I. 235,

Ex. 1 ,r 30. Unasserted independent claim 1 of the #287 patent reads:
A method for treating a patient with partial-onset seizures
comprising administering once-daily about 1,200 mg of
eslicarbazepine acetate to the patient, wherein the patient
is a human.
D.I. 235, Ex. 1 131. Claim 3 depends from claim 1 and reads: "The method of
claim I, wherein the about 1,200 mg of eslicarbazepine acetate is administered
orally." D.I. 235, Ex. 1 ,r 32. Alkem does not contest infringement of this claim.
D.I. 235, Ex. 1,I133-34.
29)

Bial asserts infringement of claim 5 of the #354 patent. D.I. 235,

Ex. 1 ,r 41. Unasserted independent claim 1 of the #354 patent reads:
A method for treating a patient with partial-onset seizures,
comprising administering once-daily from about 800 mg
to about 1800 mg of eslicarbazepine acetate to the patient,
wherein the patient is a human.

12

D.I. 235, Ex. 1 ,r 42. Claim 5 depends from claim 1 and reads: "The method of
claim 1, comprising administering once-daily about 800 mg of eslicarbazepine
acetate to the patient." D.I. 235, Ex. 1 ,r 43. Alkem does not contest infringement
of this claim. D.I. 235, Ex. 1 ,r,r 44-45.
30)

Bial asserts infringement of claims 7 and 8 of the #536 patent. D.I.

235, Ex. 1 ,r 51. Unasserted independent claim 1 of the #536 patent reads:
A method for treating a patient with partial-onset seizures,
comprising: administering once-daily to a patient in need
thereof a pharmaceutical composition consisting
essentially of eslicarbazepine acetate, wherein the oncedaily administration is pharmacologically effective to treat
partial-onset seizures in the patient, and wherein the
patient is a human.
D.I. 235, Ex. 1 ,r 52. Claim 7 depends from claim 1 and reads: "The method of
claim 1, wherein the pharmaceutical composition is administered once-daily in an
amount consisting essentially of about 400 mg of eslicarbazepine acetate." D .I.
235, Ex. 1 ,r 53. Claim 8 depends from claim 1 and reads: "The method of claim 1,
wherein the pharmaceutical composition is administered once-daily in an amount
consisting essentially of about 600 mg of eslicarbazepine acetate." D.I. 235, Ex. 1

,r 54.

Alkem does not contest infringement of these claims. D.I. 239 ,r,r 5-6.
31)

The once-daily patents share the same written description. D .I. 23 5,

Ex. 1 ,r 29.

13

32)

The priority date of the once-daily patents is May 6, 2005. JTX 7;

JTX 8; JTX 9.
33)

The parties stipulated that if Alkem proves one claim of the once-

daily patents is invalid, all of the asserted claims of these patents are invalid. D.I.
241 at 3. Alkem selected claim 3 of the #287 patent as the representative claim.
Tr. at 461:2-5 (Ronaldson).

2.
34)

The #954 Patent (The Method of Treatment Patent)

The #954 patent is directed to using eslicarbazepine acetate to treat a

patient who has previously been treated with oxcarbazepine but has ongoing
seizures. Tr. at 234:3-6 (Wheless); JTX 6.
35)

Bial asserts infringement of claim 20 of the #954 patent. D.I. 235,

Ex. 1 ,r 63. That claim reads:
A method for treating an intractable epilepsy condition
comprising administering to a subject in need thereof a
therapeutically effective amount of eslicarbazepine or
eslicarbazepine acetate wherein the subject has previously
been treated with oxcarbazepine, and wherein the
eslicarbazepine or eslicarbazepine acetate is administered
as a monotherapy for treating said condition.
D.I. 235, Ex. 1164.
36)

The parties agree that: (1) the phrase "wherein the subject has

previously been treated with oxcarbazepine" means "wherein the subject is
intractable to oxcarbazepine," D.I. 239 ,r 9, (2) the term "intractable" means

14

"difficult-to-treat or treatment( drug)-resistant and thus encompasses both
pharmacoresistant and refractory conditions," D.I. 55 at 4, (3) the term
"pharmacoresistant" means "a condition where the patient is not responsive to
pharmaceutical treatment at all," D.I. 55 at 4, and (4) the term "refractory" means
"a condition where the patient becomes progressively less responsive to their
medication and, in the case of epilepsy, suffers from an increasing number of
seizures," D.I. 55 at 4.

3.
37)

The #781 Patent (The Formulation Patent)

Bial asserts infringement of claim 17 of the #781 patent. D.I. 235,

Ex. 1 ,r 20. Unasserted independent claim 1 of the #781 patent reads:
A pharmaceutical composition consisting essentially of
eslicarbazepine acetate in combination with a binder and a
disintegrant, wherein eslicarbazepine acetate is present in
an amount of from 80 to 90 wt%, the binder is present in
an amount of from 3 to 10 wt%, and the disintegrant is
present in an amount of from 3 to 10 wt%, and wherein the
pharmaceutical composition exhibits a dissolution of at
least about 60% at about 30 minutes at a temperature of
37±0.5° C and a pH of about 4.5 using a paddle apparatus
at a speed of about 100 rpm.
D.I. 235, Ex. 1 ,r 21. Claim 17 depends from claim 1 and reads: "The
pharmaceutical composition of claim 1, further comprising a lubricant, and/or
glidant." D.I. 235, Ex. 1 ,r 22.

15

D.

Artisans of Ordinary Skill2
1.

38)

The #287, #354, and #536 Patents (the Once-Daily Patents)

During trial, I made a factual finding that an artisan of ordinary skill

for these patents would have a medical degree in the field of neurology with at
least two years of experience treating patients with epilepsy and have a Ph.D. in
pharmaceutical sciences, chemistry, or a related field, with at least two years of
post-graduate laboratory/industrial experience. Tr. at 882: 17-21.

39)

I confirm my finding that the artisan of ordinary skill would have a

medical degree. First, both inventors had medical degrees. Tr. at 874:2-4.
Second, the shared written description of the three patents discusses clinical
- studies, JTX 9 at 2:29-37, 7:37-10:4, and a medical doctor would be needed to
"engage in clinical studies," Tr. at 872:8-14; see also Tr. at 872:21-73:23
(Alkem's counsel agreeing that a medical doctor would be needed to "participate
in the clinical trial[,]" that "Ronaldson cannot, himself, supervise a Phase I
study[,]" and that "legally supervis[ing] a Phase I study" is different than
"review[ing] Phase I study results and interpret[ing] them[.]"). Third, the written
description teaches that the compound will be administered by "any route known
to those skilled in the art." JTX 9 at 6:40-45; see also Tr. at 880:7-9 ("There's

2 Determination

of the level of ordinary skill in the pertinent art is. a factual inquiry.
Daiichi Sankyo Co. v. Matrix Lab ys, Ltd., 619 F.3d 1346, 1352 (Fed. Cir. 2010).

16

also clinical discussions that would say we need a doctor administering the
compound by methods known to an artisan of ordinary skill[.]"). Fourth, the
written description refers to "a pharmacologically effective amount" and teaches
that the amount "will vary according to various well-known and understood
factors, such as, for example, the condition being treated and the physiological
characteristics of the patient" but that the amount "will be well within the ability of
one skilled in the art to determine." JTX 9 at 7:3-12; see also Tr. at 880:10-13
("The determination of the effective amount based on physiological characteristics
of the patient being treated ... would say you need a doctor.").

40)

I also confirm my finding at trial that the artisan of ordinary skill

would have a Ph.D. in a pharmaceutical science or related field. One inventor had
a Ph.D., and there is extensive pharmacological discussion throughout the patents'
shared written description. See JTX 9 at 3:1-5 (discussion of half-lives); 3:40-45
(discussion of the rate of exposure, the Cmax, the extent of exposure, and the area
under the curve (AUC)), 5:30-6:30 (same); 4:37-5:4 (discussion of formulation of
pharmaceutical compositions); 11: 10-15: 19 (derivation of pharmacokinetic
parameters); 1:23-27 (discussion of metabolite toxicity and drug potency); 2:5362 (discussion of sustained relief delivery systems of predecessor drugs).

41)

Alkem' s expert, Ronaldson, has a Ph.D. in pharmaceutical sciences.

Tr. at 411: 15-19 (Ronaldson). But Ronaldson does not have a medical degree, is

17

not a practicing physician, and has never treated a patient with epilepsy or
prescribed an antiepileptic drug to a patient. Tr. at 536:8-18 (Ronaldson).
Ronaldson did not rely on any other expert, including any medical doctor or
Alkem' s expert Rogawski, in developing his opinions, and he limited his opinions
"to the pharmacology of eslicarbazepine acetate and to the knowledge, experience,
and skills of a person of ordinary skill in the art with a Ph.D. in pharmacology."
538:11-18 (Ronaldson). Accordingly, Ronaldson does not meet the definition of
an artisan of ordinary skill.
42)

Bial's expert, Wheless, is a licensed physician who specializes in

neurology with a subspecialty in epilepsy. Tr. at 214:3-5. Wheless does not have
a Ph.D. in pharmaceutical sciences or a related field. See PTX 426. Lacking this
qualification, Wheless, alone, does not meet the definition of an artisan of ordinary
skill. Wheless' s testimony that he considered and agreed with the opinions of
Gidal does not save him because that testimony was cursory and conclusory. See
Tr. at 776:19-77:2 (Wheless). Moreover, Wheless explicitly stated that he was
giving his opinion from the perspective of a medical doctor in the field of

18

neurology with at least two years of experience treating patients with epilepsy. Tr.
at 805:8-19. 3
43)

"To offer expert testimony from the perspective of a skilled artisan in

a patent case-like for claim construction, validity, or infringement-a witness
must at least have ordinary skill in the art." Kyocera Senco Indus. Tools Inc. v.

lnt'l Trade Comm 'n, 22 F.4th 1369, 1376-77 (Fed. Cir. 2022). Accordingly, I will
exclude Wheless's and Ronaldson's testimony on both ultimate conclusions of
validity of the once-daily dosing patents and "underlying technical questions"
"such as the nature of the claimed invention, the scope and content of the prior art,
the differences between the claimed invention and the prior art, or the motivation
of one of ordinary skill in the art to combine ... references to achieve the claimed
invention." HVLP02, LLC v. Oxygen Frog, LLC, 949 F.3d 685, 689 (Fed. Cir.
2020) (internal quotation marks and citation omitted). As a practical matter, this
evidentiary ruling did not affect the ultimate disposition of Alkem' s invalidity
claims, and for completeness I make certain findings of fact below based on
Wheless' s and Ronaldson' s testimony.

3

I also note that Gidal testified that he did not do any analysis on what level of
skill an ordinary artisan would have had and that he instead "applied" "Wheless' s
offered level of skill" in forming his opinions. Tr. 815 :5-12.
19

2.
44)

The #954 Patent (the Method of Treatment Patent)

Wheless defined the artisan of ordinary skill for this patent as "a

clinician that was prescribing medication ... with a neurology background [and] at
least a couple of years' experience in treating epilepsy, typically a physician" or "a
medical doctor in the field of neurology with at least two years of experience
treating patients with epilepsy." Tr. at 781:18-23, 805:8-15.
45)

Alkem offers a definition for the artisan of ordinary skill for this

patent in its proposed findings of fact without a record citation. See D.I. 264 ,r 124.
Accordingly, I will adopt Bial' s definition.
46)

Alkem' s expert, Rogawski, is a medical doctor with a Ph.D. in

pharmacology and experience in treating patients with epilepsy. Tr. at 559:8-11,
559:12-24.
47)

Bial' s expert, Wheless, is a medical doctor who treats epilepsy

patients and is also a professor of pediatric neurology at the University of
Tennessee. Tr. at 214:3-16:18.
48)

Both experts qualify as artisans of ordinary skill under Bial's

definition above.

3.
49)

The #781 Patent (The Formulation Patent)

The parties offered at trial similar definitions of the artisan of ordinary

skill for this patent. Bial's expert testified that his opinion would not change ifl

20

were to adopt Alkem's definition of a skilled artisan. See Tr. at 820:25-21:7
(Williams). Accordingly, I will adopt Alkem' s definition of an artisan of ordinary
skill as someone with a Ph.D. in pharmaceutical sciences or a closely related field
and experience in research related to pharmaceutical dosage forms or someone
with at least a Bachelor's or Master's degree in pharmaceutical sciences and three
to five years of practical experience in formulating drugs. Tr. at 641 :20-42:6
(McConville).
50)

Bial's expert, Koleng, has a Ph.D. in pharmaceutical drug delivery

and has worked in pharmaceutical development since 1996. Tr. at 286:1-11.
Koleng qualifies as an artisan of ordinary skill for this patent.
51)

Alkem' s expert, McConville, has a Ph.D. in pharmaceutics and has a

research lab in which he studies drug formulation and drug delivery. Tr. at 639:825. McConville qualifies as an artisan of ordinary skill for this patent.

E.

Facts Relevant to Infringement
1.

52)

The #954 Patent (Method of Treatment)

Alkem's proposed label is copied from the APTIOM® label and does

not contain any carve-outs for patients who are intractable to oxcarbazepine-i.e.,
the patient population covered by claim 20 of the #954 patent.

21

53)

Physicians and healthcare providers will prescribe, and patients will

use, Alkem's product per the FDA-approved labeling. Tr. at 401:22-25, 403:1215 (Chhabra).
54)

Bial' s expert, Wheless, testified, and Alkem does not dispute, that

doctors prescribe Aptiom® to patients who are intractable to oxcarbazepine-i.e.,
the patient population covered by claim 20 of the #954 patent. I find therefore that
it is more likely than not that doctors would prescribe Alkem's generic product to
patients who are intractable to oxcarbazepine.
55)

Alkem's package insert has instructions regarding dosage strengths

and dosing regimen to treat partial-onset seizures. PTX 173; Tr. at 403:8-11
(Chhabra).
56)

Bial's expert, Wheless, testified that "there are several areas in

[Alkem's] label" that "encourage" doctors to use Alkem's generic product to treat
patients who are intractable to oxcarbazepine. I did not, however, find his
testimony credible on this point.
57)

Wheless testified specifically that Section 1 of Alkem' s label would

encourage the treatment of this patient population. That section is titled
"Indications and Usage" and it states that "[s]slicarbazepine acetate tablets are
indicated for the treatment of partial-onset seizures in patients 4 years of age and
older." PTX 173 at 3. Section 1 does not provide any instructions or

22

recommendations for prescribing the product to patients that have previously been
treated with oxcarbazepine. And, indeed, Wheless testified that "there's nothing
there that would say I could not use it in folks that were previously on
oxcarbazepine, or even currently on, and convert them to this product. So that
would encourage me that that's something I could do." CITE (emphasis added). I
do not find it credible to testify under oath that the absence of an instruction not to
prescribe a medication to a particular patient group constitutes an instruction or
encouragement to prescribe the medication to that group.
58)

Wheless next cited Section 4 of the label as an "area" that "would

encourage" doctors to prescribe Alkem generic product to patients who are
intractable to oxcarbazepine. That section includes a contraindication that
instructs healthcare providers not to administer Alkem' s generic product to a
patient who has a hypersensitivity to oxcarbazepine or eslicarbazepine acetate.
PTX 173 at 5. But that contraindication does not provide any instructions or
recommendations for prescribing the product for the patient population at issue in
the #954 patent. See Tr. at 602:13-17 (Rogawski testifying that a
"contraindication in a group that is hypersensitive" to oxcarbazepine does not
"recommend to a POSA, or a healthcare practitioner, [that] the product ought to be
used in a population of patients who are intractable to oxcarbazepine").

23

59)

Finally, Wheless testified, and Bial argues that the results of a study

discussed in Section 14.1 of Alkem's label "will instruct healthcare providers to
administer Alkem's generic APTIOM® product to th[e] population of patients"
that is "intractable to oxcarbazeprine because "6.6% of patients in the Section 14.1
study were ... intractable to oxcarbazeprine." D.I. 261

,r,r 144, 145.

But it cannot

be inferred from Section 14.1 that 6.6% of the patients in the study discussed in
that section were intractable to oscarbazeprine, and thus Section 14.1 does not
"instruct" healthcare providers to administer Alkem' s generic product to that
population of patients. As Alkem' s expert, Rowgowski, credibly testified:
[S]ome of the patients [in the Section 14.1 study] were
actually limited in terms of the dose that they were allowed
on in the baseline period. And so some of these patients
in the baseline period might have had a subtherapeutic
dose of oxcarbazepine. So really, you can't use this study
as a way of determining whether a patient who 1s
refractory to oxcarbazepine would respond to
eslicarbazepine [acetate] and have a better result.
Tr. at 604:19-05:1; see also PTX 173 at 26 (stating that patients in Section 14.1
study "experienced at least 4 seizures during the baseline period ... while
receiving 1 or 2 AEDs (both could not be sodium-channel blocking drugs, and at
least one AED was limited to 2/3 of a typical dose).").
60)

In sum, nothing in Alkem' s label teaches, recommends, or -encourages

using its generic product in patients who are intractable to oxcarbazepine, and
nothing in the label suggests that using the product in that patient population
24

specifically would be a "medically desirable activity." See Tr. at 605:24-06:5
(Rogawski). Accordingly, Alkem' s label does not establish that Alkem intends for
its product to be used in this patient population.
61)

Bial adduced no other evidence at trial probative of whether Alkem

intends for its product to be prescribed to the specific patient population claimed in
claim 20 of the #954 patent. Thus, Bial did not established by a preponderance of
the evidence that Alkem intends to induce doctors to prescribe its generic product
specifically to patients who are intractable to oxcarbazepine.

2.
62)

The #781 Patent (Formulation)

Alkem's proposed label states:

Table 2.3.P.l•l: Uait Composidoa olEsJicarba~iae Acetate Tablets 200 mg. 400 mg. 600 mg & 800 mg.

~&M1h!ff:~~;;~:~~~~~.;;i~~~r;~~;~~1~1~l~J:

-~~;~;:~.:~~~~-~~. =~~ ... _~;~~;f£1~~i~~~t;;;;g~~~j_J~~;~~t~~~~-2~~~it~~;_:J}£i:ipJ1)t{;t~t~t~~~J.!.:~~~~-(~~#~~~t:J~~kil~·.;J[![11:~~IfJ1ti
1

Eslicarbazq,ine Acetat1!•

1H

200.00

83.33 %

400.00

83.33 %

600.00

8.J.33 %

83.ll %

800.00

Mtive
PbanrulccutiQI

Iff81'0dicnt
Croscmmdlose Sodium

Copwidonc
( Plasdune S630)

Copovidone
tPludono S6JO)

Purified Water#

USP.NF

JS.00

6.25 %

30.00

6.25 %

4S.OO

6.2.S %

60.00

6.25 %

Disimegrant

USP/NF

7.50

l.12 %

15.00

3 12%

22.S0

3.12 %

30.00

3 12 %

Binder

llSPlNF

8.75

IUO

J.o4!"tl

26.23

J Jb4%

Jsoo

I 3.64% I

Binder

USP

q.s

qs

q.s

qs

qi

q,s

Solvent

q.s

q.s

I

I

~·~~-- ··::_~~~~:·:_~~;~,~~~~1~4{~}1~}~t{~~1,i~~l~TI~~~,~:it~i~f.t:.fjt~~lt~~!I¾Gt§}1¥f~!i[~2~;ffit.i,iif}i~~~~ju:~jJ~nir1~:nt\
Mic~~~J:~ose••

USP/NF

S.2S

218%

to.so

2.18%

1S.75

2.18%

2LOO

218%

I

Diluent

Colloidd Silicon Dioxide

USP/NF

1.10

0.45%

2.22

US%

3.30

0.4S%

4.40

0.45 % :

Olidant

Sodium $1e4ryl fumaratc:

USP/NF

2..40

100%

•UO

100%

120

100%

9.60

l 00 %

PTX 118 at 6.

25

i

1

!

Lubricant

63)

As seen in the label, Alkem's generic tablets contain 2.18 wt%

microcrystalline cellulose, which the label identifies as a diluent (i.e., a diluting
agent). PTX 118 at 6.
64)

It is undisputed that microcrystalline cellulose can act as both a

diluent and a disintegrant. D.I. 265 at 19. The parties dispute, however, whether
Bial proved at trial that microcrystalline cellulose acts a disintegrant in Alkem' s
ANDA product. Based on Koleng' s testimony, I find that Bial established by a
preponderance of the evidence that microcrystalline cellulose acts a disintegrant in
Alkem's ANDA product.
65)

Koleng credibly testified that pharmaceutical formulators use

microcrystalline cellulose as a disintegrant because of its "good wicking properties
and hydrogen bonds between adjacent matchstick-like bundles that break when
exposed to water." PTX 896 at 2; see also PTX 1214 at 101, 175; Tr. at 331:9-15
(Koleng). He also credibly testified that microcrystalline cellulose's disintegrant
properties are inherent and that therefore microcrystalline cellulose will "exhibit its
wicking properties" and act as a disintegrant in a compound regardless of the
amount of the microcrystalline cellulose in the compound. See Tr. at 331:9-15.
As Koleng noted, even if the amount of microcrystalline cellulose is relatively
small in a compound, its disintegrant functionality "remains." Tr. at 340:8-12.

26

66)

Alkem did not offer at trial any testimony to rebut Koleng's testimony

about microcrystalline cellulose's disintegrant properties, and thus no witness
testified that microcrystalline cellulose would not or could not function as a
disintegrant in Alkem's ANDA product.
67)

Consistent with Koleng's testimony, the #781 patent's written

description identifies microcrystalline cellulose as a "suitable disintegrant." JTX
10 at 6:9-41.
68)

Multiple references identify microcrystalline cellulose as a

disintegrant and support Koleng' s testimony that microcrystalline cellulose's
disintegrant functionality is an inherent property. See PTX 896 at 2 (research
article titled "Functionality of Disintegrants and Their Mixtures in Enabling Fast
Disintegration of Tablets by a Quality by Design Approach" teaching that
"[m]icrocrystalline cellulose, commonly used as a filler in tablet formulations, is
not considered to be a superdisintegrant but reported to possess good wicking
properties and hydrogen bonds between adjacent matchstick-like bundles that
break when exposed to water''); PTX 899 at 21 (book titled "Modern
Pharmaceutics" teaching that "[s]ome forms of [microcrystalline cellulose] have
been shown to be highly porous, with strong 'wicking' tendencies, thereby making
them good disintegrants"); PTX 406 at 3 (book titled "Handbook of
Pharmaceutical Excipients" teaching that, [i]n addition to its use as a

27

binder/diluent, microcrystalline cellulose also has some . . . disintegrant properties
that make it useful in tableting"); see also Tr. at 330:5-19 (K.oleng identifying the
references).
69)

Different publications recommend various concentration ranges for

microcrystalline cellulose when it is used as a disintegrant. See PTX 898 at 13 (up
to 10%); PTX 1214 at 115 (reporting "very good disintegrant properties" at
concentrations "as low as 10%"); PTX 406 at 3 ( 5 to 15%). But Alkem did not
identify any publication that stated or suggested that microcrystalline cellulose
would not or could not function as a disintegrant if its concentration range were
below the ranges identified in the publications.

F.

Facts Relevant to Invalidity
1.

The #287, #354, and #536 Patents (the Once-Daily Patents)
a.

Prior Art
1)

70)

The #646 Patent

U.S. Patent No. 5,753,646 (the #646 patent) is prior art to the onc.e-

daily patents. DTX 427. The #646 patent described and claimed the active
pharmaceutical ingredient eslicarbazepine acetate. DTX 427 at 1:35-64 (claiming
"10-acetoxyl 0, 11-dihydro-5H-dibenz/b,f/azepine-5--carboximide"); Tr. at
91:23-92:3 (Soares de Silva explaining that "10-acetoxyl0,11-dihydro-5Hdibenz/b,f/azepine-5--carboximide" is eslicarbazepine acetate). The #646 patent

28

discloses that eslicarbazepine acetate has "valuable pharmaceutical properties" for
the treatment of epilepsy. DTX 427 at 3:52-56.
71)

The #646 patent discloses a method of treating a patient with epilepsy

by administering a composition containing eslicarbazepine acetate. DTX 427 at
claims 5 and 7. The #646 patent does not disclose once-daily dosing or a dosage
amount. See generally DTX 427.

2)
72)

Almeida 2002

Almeida 2002, an abstract of a paper titled "P460 Pharmacokinetic

profile of BIA 2-093, a putative new antiepileptic drug, after single and multiple
administration in human healthy volunteers," is prior art to the once-daily patents.
PTX 329; Tr. at 391:15-92:10 (presentation date).
73)

Alkem contends that Almeida 2002 "expressly stated the reasonable

expectation of success" for dosing eslicarbazepine acetate once-daily and that "[a]ll
that remained [after Almeida 2002] was to confirm the efficacy of eslicarbazepine
acetate through clinical trials." D.I. 263 at 13. See also D.I. 263 at 15 ("[T]he
conclusion in Almeida 2002 that eslicarbazepine acetate was 'expected to be
compatible with a once a day administration' confirms that a POSA would have
had a reasonable expectation of success in dosing eslicarbazepine acetate oncedaily. ").

29

74)

Almeida 2002 was presented at the Fifth European Congress on

Epileptology in Spain in 2002 and is not a complete recitation of, but contains data
from, two studies. Tr. at 391:15-92:76 (Almeida); Tr. at 110:10-13 (Soares da
Silva); PTX 329. Those studies were intended to test the tolerability, safety, and
pharmacokinetic properties of BIA 2-093 in healthy subjects. Tr. at 392:21-93:1
(Almeida); see also PTX 329 at 4 (study conducted in healthy volunteers). BIA 2093 is eslicarbazepine acetate. Tr. at 170:3-8 (Soares da Silva).
7 5)

Almeida 2002 teaches the oral administration of BIA 2-093

(eslicarbazepine acetate) up to 1,200 mg in human subjects. See PTX 329 at 4
(groups of eight healthy male subjects received single oral doses ofup to 1,200 mg
of BIA 2-093).
76)

Almeida 2002 states that "[t]he pharmacokinetic profile described

here for BIA 2-093 is expected to be compatible with once a day administration."
PTX 329 at 5. The authors of Almeida 2002 testified that they expected that oncedaily administration could be used safely, Tr. at 398:19-24 (Almeida), but that the
data from Almeida 2002 was not "enough to show that you could treat partial-onset
seizure patients once-daily" because the study had been conducted with healthy
subjects. Tr. at 111 :5-9 (Soares da Silva); Tr. at 398:2-18 (Almeida testifying
"the results in healthy subjects cannot be extrapolated to patients" with epilepsy). I
found the authors to be credible when testifying about this point and find that

30

Almeida 2002 discloses only that once-daily dosing is safe and tolerable, not that
once-daily dosing is also efficacious to treat partial-onset seizures.
77)

Alkem' s expert, Ronaldson, admitted during his testimony that

Almeida 2002 was a Phase I study conducted in healthy subjects to "look at safety
and tolerability," "determine what dose range is going to be tolerable," and "get
some additional pharmacokinetic information that you can use to guide further
clinical trials on that drug." Tr. at 492:18-25.
78)

Almeida 2002 does not disclose an expectation that once-daily

administration of eslicarbazepine acetate would or could treat partial-onset
seizures. See Tr. at 493:1-8 (Ronaldson testifying with regards to Almeida 2002:
"[A] Phase I trial is essentially a gate.... [When] you are able to demonstrate that
the drug doesn't cause any serious adverse events in healthy human subjects, and
when you can establish a range of doses that's tolerated in those human subjects,
that gives you the capability of being able to move forward with pertinent
information in humans that would allow you to proceed to testing in a Phase II
trial.")

3)
79)

Almeida 2003

Almeida 2003, titled "Safety, Tolerability and Pharmacokinetic

Profile of BIA 2-093, a Novel Putative Antiepileptic Agent, during First

31

Administration to Humans," discloses a Phase I, single dose study in healthy
volunteers, PTX 330, and is prior art to the once-daily patents. PTX 330.
80)

Alkem contends that Almeida 2003 "provided additional

phannacokinetic data from the Phase I clinical studies, confirming that
eslicarbazepine acetate was expected to be compatible with once-daily dosing."
D.I. 263 at 22. See also D.I. 263 at 23 ("Ronaldson explained through an example
that, based on the phannacokinetic data presented in Almeida 2003, a once-daily
dose of 1200 mg of eslicarbazepine acetate would have been preferred over a
twice-daily dose of 600 mg of eslicarbazepine acetate . . . . [And] Almeida 2003
concluded that there were no adverse events within the tested dosage range of 201200 mg. For these reasons, Almeida 2003 is additional evidence of a motivation
to dose eslicarbazepine acetate once-daily and a reasonable expectation of
success.").
81)

The Phase I study disclosed in Almeida 2003 examined the safety,

tolerability, pharmacokinetics, and pharmacodynamics of treating healthy human
volunteers with single doses of BIA 2-093. PTX 330 at 2; Tr. at 84:24-85:1
(definition of BIA 2-093 ). Almeida 2003 reported that "oral administration of BIA
2-093 at doses up to 1,200 mg appeared to be safe and was well tolerated by the
subjects in this study." PTX 330 at 14. Almeida 2003 also presented data about
the pharmacokinetics and the phannacodynamics of eslicarbazepine acetate's

32

primary active metabolite, BIA 2-005, and minor metabolite, oxcarbazepine. PTX
330 at 7-12.
82)

The field of the invention-pharmaceuticals used to treat epilepsy-is

complex and requires a high skill level. See Tr. at 875:23-76:1 (Alkem counsel
acknowledging that "pharmaceutical R&D is very arduous and takes a long time"),
876:5-16 (Bial counsel arguing that "the level of skill [for development of drugs]
is high"), 881 :3-9 (Bial counsel characterizing epilepsy as a "very complex
disorder"). And, as noted above, an artisan of ordinary skill in the field would
have both a medical degree and a Ph.D. in a pharmaceutical science. Lacking both
of these qualifications, I am unable without expert testimony to determine with an
abiding conviction that it is highly probable that Almeida 2003 discloses oncedaily dosing to treat partial-onset seizures based on the reported pharmacological
data. See Perfect Web Techs., Inc. v. Info USA, Inc., 587 F.3d 1324, 1330 (Fed. Cir.
2009) ("If the relevant technology were complex, the court might require expert
opinions."); cf Tr. at 825:13-15 (Williams declining to offer testimony about
pharmacokinetics because, despite having a Ph.D. in pharmaceuticals generally, he
is not a "pharmacokineticist").
83)

I also find that even if I had not excluded Ronaldson' s testimony, that

testimony did not establish clearly and convincingly that Almeida 2003 discloses
once-daily dosing to treat partial-onset seizures based on the reported

33

pharmacological data. Ronaldson affirmed without objection on direct
examination in response to a blatantly leading question that "Almeida 2002
provided us this conclusion that eslicarbazepine acetate was expected to be
compatible with once-daily dosing." Tr. 503:4-7. And he testified on direct
examination that Almeida 2003 disclosed that the Cma,/ of a dose of 600 mg of
eslicarbazepine acetate was lower than the Cmax of a dose of 1,200 mg and that,
even if two doses of 600 mg were administered twelve hours apart, the Cmax of the
two doses would be lower than the Cmax of a single dose of 1,200 mg. Tr. at
504:1-05:11. But on cross-examination, Ronaldson conceded that he had not

offered an opinion that "the concentrations that were detected in the Phase I trial
[disclosed in Almeida 2003] would truly be efficacious." Tr. at 549:21-25.

4)
84)

Trileptal® Label

It is undisputed that the Trileptal® label is prior art to the once-daily

patents. See generally D.I. 262. The active ingredient of Trileptal® is
oxcarbazepine. DTX 438. Oxcarbazepine was known to be an effective treatment
for partial-onset seizures. DTX 438 at 4. The Trileptal® label taught
administering oxcarbazepine at least twice-daily. Tr. at 758:11-12 (Wheless); Tr.
at 542:16-43:12 (Ronaldson); DTX 438 at 21.

4

Cmax is the maximum plasma concentration that is achieved after a dose. Tr. at
502:14-17 (Ronaldson).
34

85)

Alkem contends that the Trileptal® label "is further evidence that

eslicarbazepine acetate would have been expected to be effective for the treatment
of partial-onset seizures" because eslicarbazepine acetate and oxcarbazepine
metabolize into the same "primary active metabolite responsible for the
antiepileptic activity[.]" D.I. 263 at 23. See also D.I. 263 at 24-25 ("[T]he halflife of [the active metabolite] was known to be longer when it was formed from
eslicarbazepine acetate, and thus it would have been expected that eslicarbazepine
acetate should be dosed differently than oxcarbazepine[,]" so "there would have
been a motivation at least to confirm that once-daily dosing of eslicarbazepine
acetate would be effective, based on the express disclosures in the prior art.").
86)

But the Trileptal® label does not (1) reference eslicarbazepine acetate,

(2) make any comparison between oxcarbazepine and eslicarbazepine acetate, or
(3) suggest that eslicarbazepine acetate should be dosed differently than
oxcarbazepine. See DTX 438. Accordingly, the Trileptal® label does not teach
administering eslicarbazepine acetate once-daily. See Tr. at 549:4-8 (Ronaldson
testifying: "I have not estimated any efficacy of eslicarbazepine acetate. All I
stated is that because the two compounds [eslicarbazepine acetate and
oxcarbazepine] produce the same active metabolite, there is a reasonable
expectation of success that you would get efficacy from eslicarbazepine acetate.").

35

b.
87)

Obviousness of Asserted Claims

For the reasons stated in paragraphs 70 to 86, the #646 patent,

Almeida 2002, Almeida 2003, and Trileptal®, considered individually or
collectively, do not disclose that once-daily dosing of eslicarbazepine acetate is
efficacious to treat partial-onset seizures. Alkem therefore did not show by clear
and convincing evidence that an artisan of ordinary skill would have had a
reasonable expectation of success in using once-daily dosing of eslicarbazepine
acetate to treat partial-onset seizures.
88)

The benefits of once-daily dosing generally include patient

convenience and improved patient adherence to the medication regimen. Tr. at
224:1-5, 229:2-9 (Wheless). But Ronaldson admitted on cross-examination that

fluctuations in blood plasma concentration of a compound where the concentration
falls below the therapeutic range for the compound should be avoided when
administering anti-epileptic drugs because a concentration below the therapeutic
range would not be expected to be efficacious and would increase the risk of the
patient experiencing breakthrough seizures. Tr. at 540: 19-41 :2, 545 :3-10. He
also admitted that "a greater fluctuation in blood plasma levels would occur with a
higher Cmax and lower Cmin," Tr. at 541 :3-8, and that "[a]s of the priority date of
the once-daily patents ... you would expect to see a greater fluctuation in blood
levels with a once-daily dosing regimen as compared to a twice-daily dosing

36

regimen." Tr. at 541 :3-22. Based on this testimony, I find that dosing once-daily
has a higher risk of the blood plasma concentration of the active compound falling
below the therapeutic level than dosing twice-daily has, and accordingly, I find
that, even if an artisan of ordinary skill generally preferred to dose once-daily, the
artisan would not have been motivated to dose an anti-epileptic drug (including
eslicarbazepine acetate) once-daily.
89)

On cross-examination, Ronaldson admitted, "In my testimony today, I

didn't state anything regarding the fact that the concentrations that were detected in
the Phase I trial would truly be efficacious. It's just that there's a reasonable
expectation of success moving forward into a Phase II trial." Tr. at 549: 17-25; see

also Tr. at 513 :3-9 (Ronaldson testifying "a person of ordinary skill in the art
would have had a reasonable expectation of success of moving this drug forward
towards ... Phase II clinical trials"). I find that his testimony suggests only that an
artisan of ordinary skill would have a reasonable expectation of success for moving

towards a Phase II trial but not necessarily for treating partial-onset seizures.
Further, an artisan of ordinary skill would be concerned about the risks associated
with a blood plasma concentration falling below the therapeutic range. See Tr. at
540: 19-41 :2, 545 :3-10, 541 :3-8, 541 :3-22 (Ronaldson).
90)

I have no record evidence identifying a therapeutic range for

eslicarbazepine acetate, so I cannot conclude that the pharmacokinetic information

37

· reported in Almeida 2003 would inform an artisan of ordinary skill that
administering 1,200 mg eslicarbazepine acetate once-daily would keep the blood
concentration within the therapeutic range. Thus, there is no evidence that an
artisan of ordinary skill would have a reasonable expectation of success of treating
epilepsy with once-daily dosing of eslicarbazepine acetate as claimed in the
patents. If anything, the record evidence suggests that an artisan of ordinary skill
would doubt that dosing once-daily would be successful.
91)

Thus, I find that Alkem did not show by clear and convincing

evidence that an artisan of ordinary skill would have had the motivation to dose
eslicarbazepine acetate once-daily with a reasonable expectation of success for
treating partial-onset seizures.

c.

Objective lndicia of Nonobviousness
1)

92)

Unexpected Results

One study cited in the once-daily patents was a Phase II study

conducted by Soares da Silva. See Tr. at 113:4-15:8 (Soares da Silva). The study
investigated the efficacy of dosing eslicarbazepine once-daily. PTX 489; Tr. at
113:15-25 (Soares da Silva). Soares da Silva testified that he was surprised to find
that dosing once-daily had better results than dosing twice-daily for reducing
seizures. Tr. at 114:22-15:2. Because Almeida 2002's conclusion does not

38

establish an expectation of efficacy from once-daily dosing, I will credit Soares da
Silva's testimony that he was surprised by the Phase II results.

2)
93)

Industry Skepticism

Alkem does not dispute that APTIOM®'s recommended once-daily

administration, as described in the product label, is covered by the asserted claims
of the once-daily patents. See generally D.l. 264; see also Tr. at 234:19-22
(Wheless); PTX 453 at 7-8.
94)

Wheless testified that physicians were skeptical of dosing APTIOM®

once-daily. Tr. at 226:20-27:4. And Ronaldson testified that ''[a]s of the priority
date of the once-daily patents ... you would expect to see a greater fluctuation in
blood levels with a once daily dosing regimen as compared to a twice daily dosing
regimen." Tr. at 541 :3-22. Given the consistency of the experts' testimony, I will
credit Wheless' s testimony that physicians were skeptical of once-daily dosing.

3)
95)

Commercial Success

The record contains much testimony about the commercial success of

APTIOM®. See, e.g., PTX 1176 (showing that APTIOM® has one of the highest
market shares of branded antiepileptic drugs); Tr. at 368:2-7 (Jarosz comparing
APTIOM®'s success to its competitor's). Bial does not dispute that the #646
patent was a blocking patent, but Bial adduced record evidence suggesting that the
once-daily dosing was a driver of the commercial success of APTIOM®. See Tr.

39

at 369:22-70: 12 (Jarosz); PTX 594 at 33, 46, 59 (physicians identifying convenient
dosing as a key reason they chose APTIOM® over other options). Thus, even if
the #646 patent covers the compound, I find that the once-daily dosing method
contributed to APTIOM®'s success.
96)

APTIOM®'s revenue and profits rose over the past three years despite

a drop in marketing spend. Tr. at 733:10-14 (Hofmann admitting that marketing
spend has dropped); PTX 307 at 5-7. Thus, I conclude that, even if marketing
spend played a role in APTIOM®'s commercial success, it is not solely
responsible for APTIOM®'s success.
97)

Becaus~ Bial has demonstrated that dosing eslicarbazepine acetate

once-daily had surprising results, was received by skepticism, and contributed to
APTIOM®'s commercial success, I find that the secondary considerations of
nonobviousness suggest that an artisan of ordinary skill would not view the oncedaily patents as obvious.

2.
98)

The #954 Patent (Method of Treatment)

The #954 patent reports that both oxcarbazepine and eslicarbazepine

acetate are converted by metabolism to eslicarbazepine (i.e., S-licarbazepine).
JTX 6 at 3:45-55, 1:45-47. Eslicarbazepine acetate is converted to Slicarbazepine and R-licarbazepine in a 19-to-1 ratio, and oxcarbazepine is
converted to the same metabolites in a 4-to-1 ratio respectively. Tr. at 577:2-15

40

(Rogawski). S-licarbazepine and R-licarbazepine are enantiomers of one another
(i.e., their structures are mirror images). Tr. at 588:9-89:6 (Rogawski).
99)

The #954 patent implies that eslicarbazepine acetate will have

improved effects over oxcarbazepine because, although both drugs metabolize into
the same metabolites, eslicarbazepine acetate more favorably metabolizes into Slicarbazepine than oxcarbazepine does. JTX 6 at 4:8-37; Tr. at 88:16-89:2 (Soares
da Silva). The #954 patent describes four examples that purport to demonstrate
enhanced brain penetration or other enhanced effects for S-licarbazepine as
compared to R-licarbazepine. The first example involved administering Slicarbazepine or R-licarbazepine to mice and measuring the blood/plasma ratio of
these drugs over time. JTX 6 at 9:35-10:14. The second example involved
administering to the mice P-glycoprotein and multidrug resistance protein
inhibitors to determine whether such inhibitors affect the uptake of S-licarbazepine
or R-licarbazepine into the brain. 5 JTX 6 at 9:47-63. The third example involved
kindling studies in mice to which S-licarbazepine or R-licarbazepine had been
administered. JTX 6 at 10:15-30. The fourth example involved injecting formalin
into the paws of mice to induce paw licking. JTX 6 at 10:31-44.

5

P-glycoprotein and multidrug resistance protein are drug transporters present in
the brain, and the inhibitors competitively block the transport of other substrates by
the transporters. JTX 6 at 2:5-7, 3:30-33.
41

100) The earliest priority date listed on the #954 patent is January 15, 2007.
JTX6.

a.

Written Description

101) On cross-examination Soares da Silva acknowledged that "there [is]
no study in humans described anywhere in the #954 patent where the human
patient or subject of the study was intractable to oxcarbazepine and shown to
respond to eslicarbazepine acetate[.]" Tr. at 153:16-21.
102) With regards to the experiments discussed in the patent, Soares da
Silva testified that the only data in the #954 patent relevant to an intractable
epilepsy condition are shown in Figures 4 and 5. Tr. at 145:4-16. The data shown
in Figures 4 and 5 were obtained from a kindling mouse experiment modeling
epileptogenesis. 6 Tr. at 146:10-13 (Soares da Silva). When asked, "[the kindling
mouse model is] not actually a model of intractable epilepsy, is it?", Soares da
Silva explained that, "[i]f the animal becomes resistant to the efficacy of the drug,
then we can assume that the condition is intractable to that particular ... drug,"
and he agreed that the kindling mouse model "is a model of intractable epilepsy if

6

A kindling model involves "impulsing an electrical stimulus, either by an
electrode implanted in the brain ... or by applying a stimulus to the corneas of the
eyes" repeatedly until the animal becomes epileptic. Tr. at 526:7-13 (Rogawski).
Epileptogenesis is the process by which seizures become progressively more
severe and eventually resistant to antiepileptic therapy. Tr. at 146:14-21 (Soares
da Silva).
42

and when the animal becomes resistant to the drug[.]" Tr. at 147:1-18. When
shown Figures 4 and 5, Soares da Silva identified day six as the day on which the
mice became resistant to the drug. Tr. at 147:19-48:8. But Soares da Silva
acknowledged that the data gathered after day six shows no difference in efficacy
between S-licarbazepine and R-licarbazepine. Tr. at 149:6-18. Consistent with
that admission, Rogawski explained that, based on Figures 4 and 5, once the mice
are "fully kindled, they're now in a refractory state, and neither S-licarbazepine or
R-licarbazepine, even at these very high doses, ... [are showing] any activity ...
[so] the model is inconclusive." Tr. at 593:21-94:6. Accordingly, I find that the
data after day six are not suggestive that S-licarbazepine treats intractable epilepsy
better than R-licarbazepine treats it.
103) Further, although Soares da Silva explained that "S-licarbazepine
treat[ment] ... protect[ed against] the development of seizure severity in this
model of intractability," Tr. at 140:24-41:5, Claim 20 does not teach prevention of

development of intractable epilepsy but rather treatment of intractable epilepsy in
patients not responsive to oxcarbazepine. Similarly, although Soares da Silva
testified that the days before day six are "relevant because the patient has become
intractable to some drugs," Tr. at 151:9-19, nothing in the patent suggests that,
during those days, the mice were intractable to oxcarbazepine specifically. And
any conclusion that could be drawn about mice could not be extended to humans.

43

See Tr. at 791 :5-8 (Wheless) ("[I]f all we had was a kindling experiment, looking
in a mouse model with kindling and giving the drug for a couple of weeks, I would
say yes, that would not tell me how I leap from there to its use in humans."). Thus,
even if I were to credit Soares da Silva's conclusion about the relative efficacy of
S-licarbazepine and R-licarbazepine for the prevention ofdevelopment of
intractable epilepsy, Bial has not shown that such a conclusion is probative of
relative efficacy of the metabolites for treatment of intractable epilepsy.
Accordingly, I find that Figures 4 and 5 do not establish that eslicarbazepine
acetate would treat patients intractable to oxcarbazepine.
104) Regarding the remaining studies described in the patent, even if
Wheless were correct that those studies demonstrate a difference in brain
penetration between S-licarbazepine and R-licarbazepine generally, see Tr. at
785:17-87:25, Soares da Silva admitted that the data that relates S-licarbazepine
and R-licarbazepine to intractable epilepsy are represented only in Figures 4 and 5,
see Tr. at 145:4-16. Thus, I conclude that the other studies are not probative of
whether eslicarbazepine acetate treats patients intractable to oxcarbazepine.
105) Soares da Silva also offered testimony regarding a "P-gp hypothesis,"
explaining that "S-licarbazepine is not a substrate for P-gp" and so "patients with
intractable epilepsy over expressing P-gp and treated with oxcarbazepine would

44

have less amount of the R-licarbazepine entity in their brains because of the over
expression of P-gp." Tr. at 131 :22-32:7. But the patent acknowledges that,
[a]lthough the multidrug transporter [P-gp] hypothesis of
intractable epilepsy is biologically plausible, it has not
been proven. Despite the fact that high P-gp expression
has been shown in epileptogenic brain tissue from patients
with intractable epilepsy, adequate controls are lacking, as
it is impossible to compare this tissue directly with tissue
from patients who respond well to AED treatment
(because these patients do not need to undergo surgical
resection of epileptogenic foci). Consequently, it is not
clear whether the increased P-gp expression in patients
with drug-resistant epilepsy is a cause of
pharmacoresistance or just a result of uncontrolled
seizures--or an epiphenomenon that occurs in epileptic
brain tissue irrespective of drug response.
JTX 6 at 3:11-24 (citation omitted; emphasis added); see also 2:42-46 ("Because
multidrug transporters such as P-gp ... accept a wide range of drugs as substrates,
overexpression of such efflux transporters in the [blood brain barrier] would be one

likely explanation for resistance to various AEDs in a patient with intractable
epilepsy." (citation omitted; emphasis added)); 3:61-62 ("P-gp may play a role in
the resistance to oxcarbazepine[. ]" (emphasis added)). I find that this discussion in
the patent is simply a research hypothesis. See Tr. at 578:14-59:1 (Rogawski)
("[The P-gp theory is] an interesting hypothesis, but as time has gone on, we've
downgraded it in terms of its potential truth, because it hasn't really helped us with
the understanding the issue of pharmaco-resistance. ").

45

106) Thus, I find that Alkem has established by clear and convincing
evidence that the data presented in the patent does not show that eslicarbazepine
acetate could be used to effectively treat a patient intractable to oxcarbazepine and
that the theories of why eslicarbazepine acetate might be effective in these patients
are simply research hypotheses. See Tr. at 572:11-17 (Rogawski testifying,
"[T]here [isn't] any information in the patent relevant to an intractable epilepsy
condition in a patient who had been previously ... treated with oxcarbazepine. In
fact, oxcarbazepine wasn't really studied in the examples that were provided in the
patent.").

b.

Enablement

107) Although the written description teaches administering
eslicarbazepine acetate once-daily and formulating "in any suitable manner, such
as an oral dosage form, such as a tablet or capsule," JTX 6 at 12:66-13:4, 8:7-9,
and, at the time of the invention, a Phase II study instructing how to dose this
medication in epileptic patients existed, Tr. at 792:9-14 (Wheless), "the claim of
the patent doesn't really explain how to practice the invention, [i.e.] how to treat a
patient with an intractable epilepsy condition with [eslicarbazepine acetate] in a
situation where they have failed to respond to oxcarbazepine," Tr. at 597:23-98:21
(Rogawski), and the patent lacks working examples, Tr. at 598 :23-25 (Rogawski).
Thus, I find that an artisan of ordinary skill's ability to dose eslicarbazepine acetate

46

for patients with epilepsy generally is not probative of an ability to dose for
patients intractable to oxcarbazepine in the absence of any data suggesting that
eslicarbazepine acetate would have any efficacy in this patient population. Cf Tr.
at 800:22-25 (Wheless admitting that the patent "does not describe any testing of
eslicarbazepine acetate in human patients who were intractable to the
oxcarbazepine").
108) Accordingly, for the same reasons discussed above regarding the
patent's written description, I find that Alkem has shown by clear and convincing
evidence that the patent does not teach an artisan of ordinary skill to use
eslicarbazepine acetate to treat patients intractable to oxcarbazepine without undue
experimentation.

3.

The #781 Patent (Formulation)
a.

Prior Art

109) The #781 patent claims priority to Provisional Application No.
60/982,790 filed on October 26, 2007. 7 JTX 10.

1)

The #646 Patent

110) The #646 patent qualifies as prior art to the #781 patent. DTX 427.
The #646 patent discloses the compound eslicarbazepine acetate and teaches that it

7

Although these is some dispute over the priority date, Bial represents that the
difference in the priority dates does not matter for the asserted references. D.I. 262
,r 192. Thus, I will use October 26, 2007 for the priority date.
47

can be used to treat epilepsy. DTX 427 3:52-56, 1:11-16. The #646 patent also
discloses the use of excipients to make a pharmaceutical composition of
eslicarbazepine acetate. DTX 427 5:63-6:5; Tr. at 658:9-13 (McConville).

2)

Almeida 2002

111) Almeida 2002 was published in 2002 and qualifies as prior art to tp.e
#781 patent. PTX 329. The Patent Office was not made aware of Almeida 2002
during the prosecution of the #781 patent. Tr. at 838:22-39:4 (Williams).
Almeida 2002 discusses the results of a safety study of eslicarbazepine acetate.
PTX 329 at 5; Tr. at 170:3-8 (Soares da Silva). Almeida 2002 reports a Tmax8 for
the formulation between .75 and 4 hours. PTX 329 at 5. Approximately a .75 hour
Tmax is consistent with an immediate release profile. Tr. at 672:18-24
(McConville); Tr. at 825:10-12 (Williams). No expert provided an opinion about
the dissolution profile of a drug with a Tmax of four hours. See Tr. at 825:131-5
(Williams declining to testify about whether a T max of four hours is consistent with
immediate release). Thus, I find that an artisan of ordinary skill reading Almeida
2002 would conclude that the formulation of the compound in the study is
consistent with an immediate release formulation.

8

Tmax is the time at which Cmax is achieved. Tr. at 672:17-18 (McConville).
48

112) Almeida 2002 teaches that administering 1,200 mg of eslicarbazepine
acetate, and 1,200 mg is a high drug load. See Tr. at 660: 14-17 (McConville); see

also Tr. at 668:25-69:2 (Bial's counsel). Neither party has established whether the
study in Almeida 2002 discloses administering 1,200 mg in a single tablet or in
multiple tablets. See Tr. at 711 :9-12:7 (McConville). Thus, Almeida 2002 does
not explicitly disclose a high drug load formulation containing eslicarbazepine
acetate in a single tablet.

3)

Almeida 2003

113) Almeida 2003 was published in 2003 and qualifies as prior art to the
#781 patent. PTX 330. The Patent Office was not made aware of Almeida 2003
during the prosecution of the #781 patent. Tr. at 838:22-39:4 (Williams).
Almeida 2003 discloses the results of a Phase 1 "single-dose study" where healthy
volunteers were administered a "single dose" of eslicarbazepine acetate. Tr. at
7 61 :21-62: 1 (Wheless). Almeida 2003 discusses the use of tablets with lower
doses and presumedly multiple tablets were administered at once to achieve the
required dose. See PTX 330 at 3; Tr. at 830:7-15 (Williams). Thus, Almeida 2003
does not disclose a high drug load formulation containing eslicarbazepine acetate
in a single tablet.

49

4)

W0#294

114) WO 2005/092294 (WO #294) is titled "Oral Matrix Formulations
Comprising Licarbazepine" and qualifies as prior art to the #781 patent. DTX 117.
WO #294 discloses a tablet formulation of licarbazepine that is a mixture
containing the s-enantiomer of eslicarbazepine. DTX 117 at 2. WO #294
discloses the use of "binders, glidants, and disintegrants" in the tablets of
licarbazepine. Tr. at 677:7-14 (McConville); DTX 117 at 10. The tablet disclosed
in WO #294 is a bilayer tablet where one of the independent layers is "immediate
release." Tr. at 676:14-18 (McConville). WO #294 explains that at least 90% of
the drug in the immediate release layer is provided within half an hour, consistent
with the standard definition of an immediate-release dosage form. Tr. at 676:9-13
(McConville). Although McConville testified that the overall tablets of WO #294
had "55 to 80 precent" drug load, he did not testify that the immediate-release
portion on its own contained any particular drug load. See Tr. at 675:25-76:4.

5)

Franke

115) Franke et al US 2004/0185095 (Franke) was published on September
23, 2004 and qualifies as prior art to the #781 patent. DTX 122. Franke discloses
pharmaceutical compositions with 60 to 95 wt% of oxcarbazepine and 0.05 to 4 wt
% of disintegrant. DTX 122 at 1133-37. Figure 3 of Franke discloses immediate
release formulations where 90% of the drug is released in 15 minutes. Tr. at

50

682:5-10 (McConville explaining the dissolution profile is consistent with an
immediate release formulation); DTX 122 at Fig. 3. Franke also explains that
Franke's composition releases 85 to 95% of the active compound within 30
minutes. DTX 122 ,r,r 21-26. This release profile is consistent with the FDA's
definition of immediate release. See Tr. at 648 :9-17 (McConville). Franke further
discloses that the release profile of the composition is "only slightly below that of
tablets commonly marketed" and actually disparages "typical sustained release
formulations" as "ineffective." DTX 122 ,r 20. Thus, Franke discloses an
immediate release formulation. The dissolution conditions in Franke are different
from the dissolution conditions for the #781 patent, but the conditions in Franke
are standard test parameters for oxcarbazepine. Tr. at 683: 13-21 (McConville).
116) Although Franke does not disclose a formulation containing
eslicarbazepine acetate, it discloses a formulation with oxcarbazepine, which is a
compound with a solubility similar to the solubility of eslicarbazepine acetate. See
682:1-4 (McConville explaining that oxcarbazepine is classified as a poorly
soluble drug of the same class as eslicarbazepine acetate). Thus, Franke discloses
a formulation with a high load of a low solubility drug with an immediate release
dissolution profile. See Tr. at 695 :20-23 (McConville).

51

6)

Dudhara

117) Dudhara et al US 2003/0175353 (Dudhara) was published on
September 18, 2003 and qualifies as prior art to the #781 patent. DTX 123.
Dudhara discloses compositions, i.e., tablets, of carbamazepine with 60-85 wt %
of carbamazepine and 0.5-5 wt% croscarmellose sodium. DTX 123 at ,r 26. And
Dudhara teaches a controlled release formulation. See DTX 123 ,r,r 9-13. Dudhara
explains that its drug delivery system avoids the disadvantages associated with fast
drug absorption time and high peak plasma levels. DTX 123

,r 3.

Thus, Dudhara

does not teach immediate release. See Tr. at 834:2-14 (Williams).

7)

HPE

118) The Handbook of Pharmaceutical Excipients (HPE) was published in
2000 and qualifies as prior art to the #781 patent. DTX 107. HPE is a "go-to"
reference for pharmaceutical formulation scientists that describes the excipients
that one would need to make any type of dosage form, i.e., immediate or sustained
release. Tr. at 677:15-23 (McConville). It also offers weight percentage
recommendations for excipients. Tr. at 689:15-24 (McConville). Although no
reference discloses the exact amounts of the remaining excipients, an artisan of
ordinary skill could use the HPE to pick the amounts of excipients to use. See Tr.
at 689:15-24, 694:1-5 (McConville).

b.

Obviousness

119) Asserted claim 17 read in conjunction with independent claim 1 reads:
52

A pharmaceutical composition consisting essentially of
eslicarbazepine acetate in combination with a binder and a
disintegrant, wherein eslicarbazepine acetate is present in
an amount of from 80 to 90 wt%, the binder is present in
an amount of from 3 to 10 wt%, and the disintegrant is
present in an amount of from 3 to 10 wt%, and wherein the
pharmaceutical composition exhibits a dissolution of at
least about 60% at about 30 minutes at a temperature of
37±0.5° C. and a pH of about 4.5 using a paddle apparatus
at a speed of about 100 rpm, further comprising a
lubricant, and/or glidant.
120) The #781 patent is directed to "high drug loaded pharmaceutical
compositions containing the active drug substance eslicarbazepine acetate,
exhibiting an immediate-release dissolution profile with certain excipients and
excipient ranges." Tr. at 290:20-23 (Koleng). "High drug load" refers to the
requirement that 80 to 90 wt % of the pharmaceutical composition is
eslicarbazepine acetate. Tr. at 290:24-91:3 (Koleng); see also Tr. at 652:12-13
(McConville). "Immediate release" 9 refers to "the requirement that the dissolution
of the pharmaceutical composition is at least 60 percent at about 30 minutes under
the test conditions listed in the claim." Tr. at 291 :4-9 (K.oleng); see also Tr. at
652:15-24 (McConville).

9

The FDA defines immediate release as 85% of the drug dissolving in 30 minutes.
Tr. at 648:9-17 (McConville). McConville clarified that the dissolution profile in
the claim is a bit slower than the FDA's definition but is still consistent with an
immediate release. Tr. at 652:17-20.
53

121) Excipients are the "nondrug substance" of a pharmaceutical
composition and are usually "inactive or inert." Tr. at 293:18-20 (Koleng).
122) A diluent is an excipient added to a pharmaceutical formulation to
"bulk it up." Tr. at 295:1-2 (Koleng); PTX 1214 at 100; JTX 10 at 8:43-45. A
binder is a material added to a pharmaceutical formulation to add cohesiveness to
hold the components of the composition together. Tr. at 295: 19-22 (Koleng); PTX
1214 at 111; JTX 10 at 6:53-54. A lubricant is a material added to a
pharmaceutical formulation to reduce friction within a formulation. Tr. at 295 :2596:2 (Koleng); PTX 1214 at 116; JTX 10 at 7:48-53. A glidant is a material added
to a pharmaceutical formulation to improve powder flow. Tr. at 296:8-9 (Koleng);
PTX 1214 at 121; JTX 10 at 8:21-23. A disintegrant is a material added to a
pharmaceutical formulation to help it break up after administration once it hits an
aqueous environment (e.g., the liquid in the stomach after the tablet is swallowed).
Tr. at 296:13-17 (Koleng); PTX 1214 at 114; JTX 10 at 5:54-55.
123) I construed "a pharmaceutical composition consisting essentially of'
as "a pharmaceutical composition that consists at the very least of eslicarbazepine
acetate and can consist of other ingredients but only if those other ingredients do
not materially affect the basic and novel properties of the claimed composition."
D.I. 193.

54

124) I find that Alkem has shown by clear and convincing evidence that ( 1)
Almeida 2002 disclosed an immediate release formulation with eslicarbazepine
acetate as the active ingredient and administering a high drug load even if not all
contained in one tablet, see Tr. at 672:18-24 (McConville); Tr. at 825:10-12
(Williams), (2) Franke disclosed an immediate release formulation with a high
drug load of a compound that has comparable solubility to eslicarbazepine acetate,
see Tr. at 682:5-10, 695:20-23 (McConville), and (3) the HPE discloses
information regarding the remaining excipient amounts, see Tr. at 689: 15-24,
694:1-5 (McConville).
125) A formulation scientist would consider patient compliance and
convenience when formulating a pharmaceutical composition. Tr. at 694: 16-95: 1
(McConville); Tr. at 842:20-23 (Williams). Administering the required drug load
in a single tablet is the "gold standard," Tr. at 694: 19-23 (McConville), or
"optimum," Tr. at 843:3-6 (Williams). Thus, I conclude that a formulator would
have been motivated to make a single tablet containing 1,200 mg of
eslicarbazepine acetate after reading Almeida 2002. See Tr. at 712:1-7
(McConville testifying that "I do know that the [Almeida 2002] results point to a
single oral dose of a particular amount of drug. That would motivate me to make a
single tablet containing that amount of drug"). Because the parties agree that 1,200
mg is a high drug load, I find that Alkem has shown by clear and convincing

55

evidence that an artisan of ordinary skill would have been motivated by Almeida
2002 to create an immediate release formulation with a high drug load of
eslicarbazepine acetate in a single tablet. Further, an artisan of ordinary skill
would have been motivated to formulate this composition with eslicarbazepine
acetate accounting for 90 wt % because, if excipients accounted for more than 10

wt%, the tablet would be too big to swallow. Tr. at 709:11-13 (McConville).
126) Franke discloses pharmaceutical compositions of oxcarbazepine.
DTX 122. Oxcarbazepine is used to treat epilepsy and is structurally similar to
eslicarbazepine acetate. Tr. at 695 :20-23 (McConville). Eslicarbazepine acetate
and oxcarbazepine both exhibit low solubility. See Tr. at 682:1-4 (McConville). I
find that an artisan of ordinary skill would have had a reasonable expectation of
success in achieving the claimed invention because oxcarbazepine (Franke
reference) was successfully formulated with a comparable drug load and excipients
in the claimed ranges to be immediate release. See 679:13-80:7 (McConville
discussing the Franke reference); Tr. at 694:1-5 (McConville discussing what was
known in the art about excipients).
127) Further, in view of the ranges disclosed in the HPE, an artisan of
ordinary skill would be able to "select the right excipients to arrive at that profile
with that high drug load in a single tablet[.]" Tr. at 654:5-14 (McConville). Even
if some experimentation would be required, see Tr. at 823:5-10 (Williams), the

56

required experimentation would not be undue, see Tr. at 689:15-90:22
(McConville explaining how an artisan of ordinary skill would adjust the amounts
based on the HPE without need undue experimentation); see also DTX 122 ,r 20
(Franke reference disclosing that immediate release oxcarbazepine formulations
are common). Accordingly, I find that Alkem has shown by clear and convincing
evidence that an artisan of ordinary skill would have had a reasonable expectation
I

of success for creating the formulation described in claim 17 of the #781 patent.

c.

Objective lndicia of Nonobviousness

128) Bial points to two objective indicia of nonobviousness: unexpected
results and copying.
129)

With respect to unexpected results, Lima, a named inventor on the

#781 patent, testified that he was surprised when his team finally manufactured the
composition because they experienced "significant challenges" related to "the
characteristics" of eslicarbazepine acetate, including poor bulk density, poor
flowability, and poor water solubility. Tr. 174:17-75:20; see also Tr. at 182:2-13
(Lima testifying, "We used multiple formulations, multiple approaches, ...
performed several experiments, ... used different strategies, and sometimes a
combination of the strategies[.]"). But I find that this testimony is not clearly at
odds with McConville's testimony. McConville explained that a formulator would
start with excipients in the range recommended by the HPE and then adjust the

57

amounts or switch to a different excipient as necessary. Tr. at 690:10-22. He also
testified that high drug loads of several compounds that "fall into the bio
classification system ... that have low solubility" are used for the treatment of
epilepsy, so an artisan of ordinary skill would know that use of a disintegrant is
necessary. Tr. at 694:6-11. And this testimony is corroborated by Franke. See
DTX 122. Thus, I do not find Lima's cursory comment about his surprise to be
probative of nonobviousness. See Millennium Pharms., Inc. v. Sandoz Inc., 862
F.3d 1356, 1368 (Fed. Cir. 2017) ("Unexpected results are shown in comparison to
what was known[.]").
13 0) With respect to copying, it is undisputed that Alkem designed its
formulation to be similar to APTIOM®. Tr. at 400: 17-01 :3 (Chhabra). But I do
not find that fact to be probative of nonobviousness since "a showing of
bioequivalence is required for FDA approval" of Alkem's tablet formulation.
Bayer Healthcare Pharms., Inc. v. Watson Pharms., Inc., 713 F.3d 1369, 1377

(Fed. Cir. 2013).

Ill.

LEGALSTANDARDS
A.

Infringement
1.

Direct Infringement

Analyzing infringement involves two steps. The first step is to construe
disputed patent terms consistently with how they would be understood by an

58

artisan of ordinary skill. Phillips v. AWH Corp., 415 F.3d 1303, 1313 (Fed. Cir.
2005) (en bane). The second step is to determine whether the accused products or
methods infringe the patent by comparing those products or methods to the
construed claims. Markman v. Westview Instruments, Inc., 52 F.3d 967, 976 (Fed.
Cir. 1995) (en bane), aff'd, 517 U.S. 370 (1996). The first step in the infringement
analysis is a question of law; the second is a question of fact. Glaxo, Inc. v.

Novopharm, Ltd., 110 F.3d 1562, 1565 (Fed. Cir. 1997). A patentee bears the
burden of proving infringement by a preponderance of the evidence. Envirotech

Corp. v. Al George, Inc., 730 F.2d 753, 758 (Fed. Cir. 1984). Direct infringement
requires that "every limitation set forth in a claim ... be found in an accused
product, exactly." Southwall Techs., Inc. v. Cardinal JG Co., 54 F.3d 1570, 1575
(Fed. Cir. 1995) (citation omitted).
When the ANDA specification does not answer the question of
infringement, " [t]he relevant inquiry is whether the patentee has proven by a
preponderance of the evidence that the alleged infringer will likely market an
infringing product." Glaxo, 110 F.3d at 1570. In such cases, "[w]hat is likely to
be sold, or, preferably, what will be sold, will ultimately determine whether
infringement exists." Id.

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2.

Induced Infringement

"Whoever actively induces infringement of a patent shall be liable as an
infringer." 35 U.S.C. § 271(b ). A finding of inducement requires establishing an
underlying act of direct infringement, that the defendant had knowledge of or was
willful blind to the direct infringement, and that the defendant's specific intent was
to encourage the acts that constituted direct infringement. See DSU Med. Corp. v.

JMS Co., 471 F.3d 1293, 1303, 1306 (Fed. Cir. 2006) (en bane in relevant part).
"Where the proposed label instructs users to perform the patented method[,] the
proposed label may provide evidence of the ANDA applicant's affirmative intent
to induce infringement. When proof of specific intent depends on the label
accompanying the marketing of a drug inducing infringement by physicians, the
label must encourage, recommend, or promote infringement. The contents of the
label itself may permit the inference of specific intent to encourage, recommend, or
promote infringement." Vanda Pharms. Inc. v. W.-Ward Pharms. Int'/ Ltd., 887
F.3d 1117, 1129 (Fed. Cir. 2018) (internal quotation marks, citations, and original
alterations omitted).

B.

Inalidity
1.

Obviousness

Under § 103 of the Patent Act, a patent "may not be obtained ... if the
differences between the subject matter sought to be patented and the prior art are
such that the subject matter as a whole would have been obvious at the time the
60

invention was made to a person having ordinary skill in the art to which said
subject matter pertains." 35 U.S.C. § 103. As the Supreme Court explained in the
seminal case Graham v. John Deere Co., 383 U.S. 1 (1966), under§ 103, "[a]n
invention which has been made, and which is new in the sense that the same thing
has not been made before, may still not be patentable if the difference between the
new thing and what was known before is not considered sufficiently great to
warrant a patent." Id. at 14. Section 103 ensures that "the results of ordinary
innovation are not the subject of exclusive rights under the patent laws." KSR Int'/

Co. v. Teleflex Inc., 550 U.S. 398, 427 (2007). "Were it otherwise patents might
stifle, rather than promote, the progress of useful arts." Id. (citing U.S. Const. art.
I, § 8, cl. 8).
The Court reaffirmed in KSR that the "framework" set out in the following
paragraph from Graham governs the application of§ 103, id. at 406:
While the ultimate question of patent validity is one of
law, the[§] 103 condition [of patentability] ... lends itself
to several basic factual inquiries. Under[§] 103, the scope
and content of the prior art are to be determined;
differences between the prior art and the claims at issue
are to be ascertained; and the level of ordinary skill in the
pertinent art resolved. Against this background, the
obviousness or nonobviousness of the subject matter is
determined.
Such secondary considerations as
commercial success, long felt but unsolved needs, failure
of others, etc., might be utilized to give light to the
circumstances surrounding the origin of the subject matter
sought to be patented. As indicia of obviousness or
nonobviousness, these inquiries may have relevancy.
61

Graham, 383 U.S. at 17-18 (citations omitted).
It is clear that under this framework, a district court must consider in an
obviousness inquiry the three primary factors identified by the Court in Graham:

(1) the scope and content of the prior art, (2) the differences between the prior art
and the claims at issue, and (3) the level of ordinary skill in the pertinent art.
Obviousness is assessed based on the perspective of an artisan of ordinary
skill at the time of the invention. Unigene Labs., Inc. v. Apotex, Inc., 655 F.3d
1352, 1360 (Fed. Cir. 2011). The court therefore needs to guard against "hindsight
bias" that infers from the inventor's success in making the patented invention that
the invention was obvious. In re Cyclobenzaprine Hydrochloride Extended-

Release Capsule Patent Litig., 676 F.3d 1063, 1079 (Fed. Cir. 2012). The ultimate
question in the obviousness analysis is "whether there was an apparent reason [for
an artisan of ordinary skill] to combine [at the time of the invention] the known
elements in the fashion claimed by the patent at issue." KSR, 550 U.S. at 418.
"The analysis is objective." Id. at 406. Thus, a court must determine whether an
artisan of ordinary skill "would have had reason to combine the teaching of the
prior art references to achieve the claimed invention, and ... would have had a
reasonable expectation of success [in] doing so." In re Cyclobenzaprine, 676 F.3d
at 1069.

62

The party challenging the patent's validity bears the burden of proving
obviousness by clear and convincing evidence. Id. at 1068-69. In weighing the

Graham factors to decide whether the party has met that burden, the district court
must be guided by common sense. Wyers v. Master Lock Co., 616 F.3d 1231,
1238 (Fed. Cir. 2010). Indeed, "the legal determination of obviousness may
include recourse to logic, judgment, and common sense, in lieu of expert
testimony." Id. at 1239. In KSR, the Supreme Court warned lower courts to avoid
"[r]igid preventative rules that deny factfinders recourse to common sense" and to
employ instead "an expansive and flexible approach" under the Graham
framework. KSR, 550 U.S. at 415,421. Thus, the district court may "reorder[] in
any particular case" the "sequence" in which it considers the Graham factors. Id.
at 407. And although a court should consider carefully the published prior art,
"[t]he obviousness analysis cannot be confined by ... overemphasis on the
importance of published articles and the explicit content of issued patents." Id. at
419.
"[A]ny need or problem known in the field of endeavor at the time of
invention and addressed by the patent can provide a reason for combining the
elements in the manner claimed." Id. at 420. And "[t]he combination of familiar
elements according to known methods is likely to be obvious when it does no more
than yield predictable results." Id. at 416. "[T]he fact that a combination was

63

obvious to try might show that it was obvious under§ 103." Id. at 421. But a
combination is obvious to try only "[w]hen there is a design need or market
pressure to solve a problem and there are a finite number of identified, predictable
solutions" in the prior art at the time of the invention. Id. And the court must also
be mindful that "when the prior art teaches away from combining certain known
elements, discovery of a successful means of combining them is more likely to be
nonobvious." Id. at 416.
"While the ultimate determination of obviousness under § 103 is a question
of law, it is based on several underlying factual findings, including (1) the scope
and content of the prior art; (2) the level of ordinary skill in the pertinent art; (3)
the differences between the claimed invention and the prior art; and (4) evidence of
secondary factors, such as commercial success, long-felt need, and the failure of
others." Daiichi, 619 F.3d at 1352.

2.

Written Description

Section 112 of the Patent Act requires that the specification of a patent
"contain a written description of [(1 )] the invention, and of [(2)] the manner and
process of making and using it, in such full, clear, concise, and exact terms as to
enable any person skilled in the art to which it pertains ... to make and use the
same." 35 U.S.C. § 112 (2006). Courts refer to these two requirements
respectively as adequate written description and enablement.

64

The "hallmark" of an adequate written description is "disclosure." Ariad
Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en bane).

A patent must "reasonably convey[] to those skilled in the art that the inventor had
possession of the claimed subject matter as of the filing date" to satisfy the written
description requirement. Id. An applicant establishes it was in possession of the

•

invention "by describing the invention with all its claimed limitations."
Lockwood v. Am. Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997) (emphasis

omitted). This description can be made using "words, structures, figures,
diagrams, formulas, etc." Id. A patentee can also "rely on information that is
'well-known in the art' to satisfy written description." Streck, Inc. v. Rsch. &
Diagrzostic Sys., Inc., 665 F.3d 1269, 1285 (Fed. Cir. 2012) (citation omitted). A

challenger to the patent must prove invalidity based on inadequate written
description by clear and convincing evidence. lnvitrogen Corp. v. Clontech
Lab ys, Inc., 429 F .3d 1052, 1072 (Fed. Cir. 2005). Whether the written

description requirement has been met is a question of fact. Id.

3.

Enablement

To satisfy§ 112's enablement requirement, the written description must
provide a description that enables an artisan of ordinary skill to practice the full
scope of the claimed invention without undue experimentation. Wyeth & Cordis
Corp. v. Abbott Lab ys, 720 F.3d 1380, 1384 (Fed. Cir. 2013). "That some

65

experimentation is necessary does not preclude enablement; the amount of
experimentation, however, must not be unduly extensive." Atlas Powder Co. v.

E.I. du Pont De Nemours & Co., 750 F.2d 1569, 1576 (Fed. Cir. 1984). "Whether
undue experimentation is needed is not a single, simple factual determination, but
rather is a conclusion reached by weighing many factual considerations[,]"
including "(l) 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." In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988).
"Tossing out the mere germ of an idea does not constitute enabling
disclosure[;]" instead "reasonable detail must be provided in order to enable
members of the public to understand and carry out the invention." Genentech, Inc.

v. Novo Nordisk AIS, 108 F.3d 1361, 1366 (Fed. Cir. 1997). "[T]hat a specification
need not disclose what is well known in the art ... is merely a rule of
supplementation, not a substitute for a basic enabling disclosure." Id. "[W]hen
there is no disclosure ... of any of the conditions under which a process can be
carried out, undue experimentation is required; there is a failure to meet the
enablement requirement that cannot be rectified by asserting that all the disclosure
related to the process is within the skill of the art." Id. A "specification [that]

66

provides only a starting point, a direction for further research" is not enabled. See
id.
A challenger must prove invalidity based on non-enablement by clear and
convincing evidence. MagSil Corp. v. Hitachi Glob. Storage Techs., Inc., 687 F.3d
1377, 1380 (Fed. Cir. 2012). "Enablement is a question of law based on
underlying facts." Wyeth & Cordis, 720 F.3d at 1384.
IV.

CONCLUSIONS OF LAW
A.

Infringement
1.

The #954 Patent (Method of Treatment)

Bial contends that Alkem will induce infringement of claim 20 of the #954
patent with its ANDA. Alkem disputes only that it infringes claim 20' s limitation
"wherein the subject has previously been treated with oxcarbazepine." D.I.2931
8. Alkem argues, and I have already found as a factual matter, that Bial failed to
establish by a preponderance of the evidence that Alkem specifically intends to
encourage healthcare providers to prescribe its generic product to treat patients
who are intractable to oxcarbazeprine. Accordingly, Bial has failed to establish
infringement of claim 20. See Warner-Lambert Co. v. Apotex Corp., 316 F.3d
1348, 1364 (Fed. Cir. 2003) (The "mere knowledge of possible infringement by
others does not amount to inducement; specific intent and action to induce
infringement must be proven."); Vanda, 887 F.3d at 1129 ("It also must be
established that the defendant possessed specific intent to encourage another's
67

infringement and not merely that the defendant had knowledge of the acts alleged
to constitute inducement." (internal quotation marks and citation omitted)).

2.

The #781 Patent (Formulation)

Bial contends that Alkem's ANDA will infringe claim 17 of the #781 patent.
Alkem contests infringement of claim 17 only with respect to the limitation:
"consisting essentially of eslicarbazepine acetate in combination with a binder and
a disintegrant." D.I. 239 ,r 10. Alkem frames its argument in these words:
Alkem does not dispute that all of the claimed ingredients
are present in its ANDA product. But Plaintiffs must also
show that there are no unclaimed ingredients or, if there
are, that any such unclaimed ingredient does not materially
affect the basic and novel properties of the claimed
composition. They did meet that burden.
First, Plaintiffs failed to show the absence of unclaimed
ingredients. While Plaintiffs' expert labeled the 2.18 wt
% microcrystalline cellulose ("MCC") in Alkem' s ANDA
product a "disintegrant," the record shows that MCC does
not act as a disintegrant at such a low amount, and that it
instead serves as a diluent in Alkem' s product, consistent
with its identification in Alkem's ANDA.
D.I. 265 at 17-18 (citation omitted).
This argument fails because I found as a factual matter that that Bial
established by a preponderance of the evidence that microcrystalline cellulose acts
a disintegrant in Alkem's ANDA product.

68

B.

Validity
1.

The #287, #354, and #536 Patents (Methods of Dosing)

Alkem contends that the claims in the once-daily patents are invalid as
obvious in light of four prior art references: the #646 patent, Almeida 2002,
Almeida 2003, and the Trileptal® label. 10 But I have found as a factual matter that
these references, considered individually or collectively, do not disclose that oncedaily dosing of eslicarbazepine acetate is efficacious to treat partial-onset seizures,
and that Alkem therefore did not show by clear and convincing evidence that an
artisan of ordinary skill would have had a reasonable expectation of success in
using once-daily dosing of eslicarbazepine acetate to treat partial-onset seizures.
And I also found that the so-called secondary considerations of unexpected results,
industry skepticism, and commercial success support the conclusion that an artisan
of ordinary skill would not have viewed the methods of dosing patents as obvious.
For these reasons, I conclude as a matter of law that Alkem failed to establish that
representative claim 3 of the #287 patent and thus the other asserted claims from
the once-daily patents are invalid as obvious under § 103.

10

In a footnote, Alkem suggests that these claims are not patent eligible. D.I. 263
at 7 n.2. I decline to entertain this cursory argument made in passing. See John
Wyeth & Bro. Ltd. v. CIGNA Int'l Corp., 119 F.3d 1070, 1076 n.6 (3d Cir. 1997)
(" [A ]rguments raised in passing ( such as, in a footnote), but not squarely argued,
are considered waived."); SmithKline Beecham Corp. v. Apotex Corp., 439 F.3d
1312, 1320 (Fed. Cir. 2006) ("[A]rguments raised in footnotes are not preserved.").
69

2.

The #954 Patent (Method of Treatment)
a.

Written Description

Alkem contends that claim 20 of the #954 patent is invalid because it has
inadequate written description. Specifically, it argues that the patent's
specification
does not provide any example relevant to treating an
intractable epilepsy condition, and most notably does not
provide any example in which a patient (or animal model)
intractable
to
oxcarbazepine
is treated with
eslicarbazepine acetate. Further, because oxcarbazepine
and eslicarbazepine acetate metabolize into the same
active metabolite, l\.1HD, a POSA would not expect
eslicarbazepine acetate to be effective in a patient who is
intractable to oxcarbazepine.
D.I. 263 at 26-27 (citation omitted).
Bial counters that
The [#]954 patent's example reporting the brain access of
eslicarbazepine and R-licarbazepine further informs a
skilled artisan that oxcarbazepine and eslicarbazepine
acetate would not yield the same treatment results because
eslicarbazepine is not a substrate for P-gp, while Rlicarbazepine and oxcarbazepine are. This disclosure
would have led a skilled artisan to conclude that
eslicarbazepine acetate could effectively treat an
intractable epilepsy condition (consistent with Phase II
clinical study data demonstrating efficacy in intractable
epilepsy patients) even where oxcarbazepine did not.
D.I. 256 at 32 (citation omitted).

70

"An inventor need not prove that a claimed pharmaceutical compound
actually achieves a certain result. But when the inventor expressly claims that
result, [Federal Circuit] case law provides that such result must be supported by
adequate disclosure in the specification." Biogen Int 'l G]y[J3H v. Mylan Pharms.

Inc., 18 F.4th 1333, 1343 (Fed. Cir. 2021) (internal quotation marks, citation, and
alteration omitted). Since Bial claims treatment of partial-onset seizures with
eslicarbazepine acetate in patients intractable to oxcarbazepine, "[w ]hat matters for
purposes of the [written description] inquiry in this case is whether, at the time of
filing the disclosure ... a skilled artisan could deduce simply from reading the
specification that [eslicarbazepine acetate] would be a therapeutically effective
treatment for [partial-onset seizures in patients intractable to oxcarbazepine]." Id.
at 1343-44.
I have found as a factual matter that Alkem has established by clear and
convincing evidence that no data in the patent suggests that eslicarbazepine acetate
could be used to effectively treat a patient intractable to oxcarbazepine. Instead,
the patent offers at most a research hypothesis. Thus, "[r]egardless of whether
[Bial] had in fact hypothesized or even conceived of the idea of treating [partialonset seizures in patient intractable to oxcarbazepine] with [eslicarbazepine
acetate] ... the law is clear that a patent cannot be awarded for mere theoretical
research without more[.]" Id. at 1344.

71

Accordingly, I find that Alkem has established by clear and convincing
evidence that an artisan of ordinary skill would not conclude that the inventor was
in possession of the invention, and thus, claim 20 of the #954 patent is invalid for
lack of adequate written description under§ 112. See Ariad, 598 F.3d at ("Patents
are not awarded for academic theories ... [and] research hypotheses do not qualify
for patent protection[.]").

b.

Enablement

Alkem also contends that the #954 patent is "invalid for lack of
enablement." D.I. 263 at 32. Specifically, it contends that the patent does not
explain how to treat a patient with eslicarbazepine acetate who is intractable to
oxcarbazepine and that therefore an artisan of ordinary skill could not practice the
method of claim 20 without undue experimentation. D.I. 263 at 32. Bial argues in
response that an artisan of ordinary skill would have known how to treat patients
using eslicarbazepine acetate generally and that the steps for treating a patient
intractable to oxcarbazepine are the same as the steps for treating other patients, so
an artisan could have treated patients intractable to oxcarbazepine without undue
experimentation. D.I. 256 at 31.
Alkem' s enablement argument is based on the same theory as its written
description argument: the patent does not teach how to treat a patient who is
intractable to oxcarbazepine and is "at best" a "hypothesis for further

72

investigation." D.I. 263 at 32-33. "[W]here there is no indication that one skilled
in the art would accept without question statements as to the effects of the claimed
drug products and no evidence has been presented to demonstrate that the claimed
products do have those effects, an applicant has failed to demonstrate sufficient
utility and therefore cannot establish enablement." Rasmusson v. SmithKline
Beecham Corp., 413 F.3d 1318, 1323 (Fed. Cir. 2005) (internal quotation marks,

citation, and alterations omitted). I have found as a factual matter that Alkem has
shown by clear and convincing evidence that the patent does not present evidence
to demonstrate that eslicarbazepine acetate would have the claimed effect of
treating partial-onset seizures in patients intractable to oxcarbazepine and is solely
a research hypothesis.
Bial argues that, because an artisan of ordinary skill would understand how
to dose eslicarbazepine acetate for intractable patients, undue experimentation
would not be required to practice the claim. D.I. 256 at 31. Although a "patent
does not need to guarantee that the invention works for a claim to be enabled,"
Alcon Rsch. Ltd. v. Barr Lab ys, Inc., 745 F.3d 1180, 1189 (Fed. Cir. 2014), a

patent must have sufficient disclosures such that a "skilled artisan would not have
questioned the utility of the claimed formulation and would be able to make and
use the claimed invention without undue experimentation," see Allergan, Inc. v.
Sandoz Inc., 796 F.3d 1293, 1310 (Fed. Cir. 2015) (finding the patent enabled

73

when it disclosed "actual in vitro and in vivo data, showing that increasing the
amount of BAK unexpectedly increased the permeability ofbimatoprost across
ocular membranes"). Here, because I have found as a factual matter that the data
disclosed in the written description fails to convey that eslicarbazepine acetate
would treat patients intractable to oxcarbazepine, I conclude that an artisan of
ordinary skill would require undue experimentation to practice the claim.
I find that Alkem has shown by clear and convincing evidence that the
method claimed by #954 patent is at best plausible, thus failing to satisfy the
enablement requirement under§ 112. See Rasmusson, 413 F.3d at 1325 ("If mere
plausibility were the test for enablement under section 112, applicants could obtain
patent rights to 'inventions' consisting of little more than respectable guesses as to
the likelihood of their success. . . . That scenario is not consistent with the
statutory requirement that the inventor enable an invention rather than merely
proposing an unproved hypothesis."). Accordingly, I conclude as a matter of law
that Alkem has established by clear and convincing evidence that claim 20 of the
#954 patent is invalid under § 112 for lack of enablement.

3.

The #781 Patent (Formulation)

Alkem contends that the #781 patent is invalid in light of seven prior art
references: the #646 patent, Almeida 2002, Almeida 2003, WO #294, Franke,
Dud.hara, and HPE.

74

Bial argues that the references do not disclose a high drug load formulation
of eslicarbazepine acetate with an immediate-release dissolution profile. D.I. 256
at 35. I found as a factual matter, however, that Alkem established by clear and
convincing evidence that Almeida 2002 disclosed administering a large dose of
eslicarbazepine acetate with an immediate-release dissolution profile.
Bial further argues that Alkem failed to establish that a skilled artisan would
have been motivated to combine the prior-art disclosures with a reasonable
expectation of success. D.I. 256 at 35. But I found as a factual matter that Alkem
established by clear and convincing evidence that an artisan of ordinary skill would
have been motivated to combine the teachings of the prior art after reading
Almeida 2002, would have had a reasonable expectation of success of achieving
the claimed composition given the Franke reference, and could have achieved the
claimed formation without undue experimentation given HPE. I note also that
Almeida 2002 was not considered by the patent examiner during prosecution. See

Microsoft Corp. v.141 Ltd. P'ship, 564 U.S. 91, 111 (2011) (explaining that
"invalidity defense by clear and convincing evidence may be easier to sustain"
when the "PTO did not have all material facts before it" during prosecution).
Bial argues that the secondary considerations of unexpected results and
copying counsel against a finding of obviousness. D.I. 256 at 51-52. But I have
found as a factual matter that neither consideration is probative of nonobviousness.

75

In short, I have found as a factual matter that Alkem established by clear and
convincing evidence that a formulator would have been motivated to make a single
tablet containing 1,200 mg of eslicarbazepine acetate after reading Almeida 2002
and that based on the disclosures in Franke and HPE an artisan of ordinary skill
would have had a reasonable expectation of success for creating the formulation
described in claim 17 of the #781 patent. Accordingly, Alkem established by clear
and convincing evidence that claim 17 of the #781 patent is invalid as obvious
under§ 103.

V.

CONCLUSION
For the reasons discussed above, I find that Bial has established that

Alkem's ANDA will infringe claim 17 of the #781 patent, but it has not established
that Alkem will induce infringement of claim 20 of the #954 patent. I also find
Alkem has established that claim 20 of the #954 patent is invalid under§ 112 and
that claim 17 of the #781 patent is invalid under§ 103. But I find that Alkem has
not established that claim 3 of the #287 patent, claim 5 of the #354 patent, or
claims 7 and 8 of the #536 patent are invalid under§ 103.
The Court will issue an Order directing the parties to submit a proposed
order by which the Court may enter final judgments consistent with this Opinion.

76