Acorda Therapeutics Inc. v. Actavis Laboratories FL Inc.
Filing
284
MEMORANDUM OPINION re bench trial decision. Signed by Judge Leonard P. Stark on 3/31/17. (ntl)
IN THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF DELAWARE
ACORDA THERAPEUTICS, INC., et al.
Plaintiffs,
Civil Action No. 14-882-LPS
(CONSOLIDATED)
V.
ROXANE LABO RA TORIES, INC., et al.
Defendants.
Jack B. Blumenfeld, Maryellen Noreika, MORRIS, NICHOLS, ARSHT & TUNNELL LLP,
Wilmington, DE
Aaron Stiefel, Daniel P. Di Napoli, Jeffrey Martin, David Harris, Philip Smithback, Stephanie M.
Piper, ARNOLD & PORTER KAYE SCHOLER LLP, New York, NY
Sylvia M. Becker, ARNOLD & PORTER KAYE SCHOLER LLP, Washington, DC
Soumitra Deka, ARNOLD & PORTER KAYE SCHOLER LLP, Palo Alto, CA
Jane Wasman, Anthony Michael, ACORDA THERAPEUTICS, INC., Ardsley, NY.
Attorneys for Plaintiffs.
John C. Phillips, Jr., Megan C. Haney, PHILLIPS, GOLDMAN, MCLAUGHLIN, & HALL,
P.A., Wilmington, DE
Charles B. Klein, WINSTON & STRAWN LLP, Washington, DC
George C. Lombardi, Samuel S. Park, Bryce A. Cooper, Reid Smith, WINSTON & STRAWN
LLP, Chicago, IL
Attorneys for Defendants Apotex Corp., Apotex, Inc., Teva Pharmaceuticals USA Inc.,
and Roxane Laboratories, Inc.
Richard K. Herrmann, Mary B. Matterer, MORRIS JAMES LLP, Wilmington, DE
Robert L. Florence, Karen L. Carroll, Michael L. Binns, PARKER POE ADAMS &
BERNSTEIN LLP, Atlanta, GA
Melanie Black Dubis, Catherine R.L. Lawson, Christopher M. Thomas, PARKER POE ADAMS
& BERNSTEIN LLP, Raleigh, NC
Attorneys for Defendant Mylan Pharmaceuticals Inc.
MEMORANDUM OPINION
March 31, 2017
Wilmington, Delaware
Acorda Therapeutics, Inc. and Alkermes Pharma Ireland Limited ("Plaintiffs") allege that
Apotex Corp., Apotex Inc., Mylan Pharmaceuticals Inc., Roxane Laboratories, Inc., and Teva
Pharmaceuticals, USA, Inc. ("Defendants") infringe several United States Patents. Patent No.
5,540,938 (the '"938 patent" or the "Elan Patent") relates to the use of a sustained-release
formulation of 4-AP, administered once or twice daily, to treat neurological diseases including
multiple sclerosis ("MS"). Patent Nos. 8,007,826 (the '"826 patent"), 8,663,685 (the '"685
patent"), 8,354,437 (the "'437 patent"), and 8,440,703 (the '"703 patent") (collectively, the
"Acorda Patents") relate to the use of 10 mg sustained-release formulations of 4-AP to treat
walking impairments in individuals with MS.
The Court adopted stipulated constructions for certain claim terms in the patents-in-suit.
(D.I. 187, 193) With respect to disputed claim terms, the Court held a claim construction hearing
on March 7, 2016 and issued an opinion and order on March 16, 2016. (D.I. 195, 196) In
September 2016, the Court held a four-day bench trial. (See D.I. 266-69) ("Tr.") The parties
have submitted a Statement of Uncontested Facts ("SUF'') (D.I. 252-1 Ex. 1) and their competing
versions of proposed findings of fact (D.I. 262, 263). They have also submitted extensive posttrial briefing, which concluded with supplemental letter briefs filed on March 6, 2017. (D.I. 265,
272, 273, 274, 278, 279) 1
Pursuant to Federal Rule of Civil Procedure 52(a), and after having considered the entire
1
The parties have also advised the Court of the recent conclusion of an inter partes review
("IPR"), in which the Patent Trial and Appeal Board ("PTAB") found that the Acorda Patents
had not been shown to be unpatentable. (See D.I. 280) As Defendants point out, two of the three
references the PTAB was considering are not part of the trial record here. (See D.I. 281)
1
record in this case and the applicable law, the Court concludes that: (1) Defendants have
stipulated that their proposed products infringe the asserted claims of the patents-in-suit;
(2) Defendants have failed to prove by clear and convincing evidence that the asserted claims of
the Elan Patent are invalid for obviousness; and (3) Defendants have proven by clear and
convincing evidence that the asserted claims of the Acorda Patents are invalid for obviousness.
The Court's findings of fact and conclusions oflaw are set forth in detail below.
FINDINGS OF FACT
This section contains the Court's findings of fact ("FF") on disputes raised by the parties
during trial, as well as facts to which the parties have stipulated. Certain findings of fact are also
provided in connection with the Court's conclusions of law.
A.
The Parties
i.
Plaintiffs
1.
Plaintiff Acorda Therapeutics, Inc. ("Acorda'') is a corporation organized and
existing under the laws of the State of Delaware, having a principal place of business at 420 Saw
Mill River Road, Ardsley, New York 10502. (SUF ii 1)
2.
Plaintiff Alkermes Pharma Ireland Limited ("Alkermes") is an Irish corporation
having a principal place of business at Connaught House, 1 Burlington Road, Dublin 4, Ireland.
(SUF if 2)
3.
Plaintiffs have standing with respect to each of Plaintiffs' claims asserted against
Defendants. (D.I. 254 ii 9)
ii.
Defendants
4.
Defendant Apotex Corp. (together with Apotex, Inc., "Apotex") is a corporation
2
organized and existing under the laws of the State of Delaware, having a principal place of
business at 2400 North Commerce Parkway, Suite 400, Weston, Florida 33326. (SUF ii 3)
5.
Defendant Apotex Inc. is a corporation organized and existing under the laws of
Canada, having its principal place of business at 150 Signet Drive, Toronto, Ontario M9L 1T9,
Canada. (SUF ii 4)2
6.
Defendant Mylan Pharmaceuticals Inc. ("Mylan") is a corporation organized and
existing under the laws of the State of West Virginia, having a principal place of business at 781
Chestnut Ridge Road, Morgantown, West Virginia 26505. (SUF ii 5)
7.
Defendant Roxane Laboratories, Inc. ("Roxane") is a corporation organized and
existing under the laws of the State of Nevada, having a principal place of business at 1809
·Wilson Road, Columbus, Ohio 43228. (SUF ii 6)
8.
Defendant Teva Pharmaceuticals USA, Inc. ("Teva") is a corporation organized
and existing under the laws of the State of Delaware, having a principal place of business at 1090
Horsham Road, North Wales, Pennsylvania 19454. (SUF ii 7)
B.
Multiple Sclerosis
9.
Multiple Sclerosis ("MS") is a chronic disease of the neuroimmunological system.
(Peroutka Tr. at 52-53 )3 MS causes a loss of myelin, the fatty material that insulates many of the
nerves in the central nervous system. (Peroutka Tr. at 53-54; see also Lublin Tr. at 392) This
2
0n March 28, 2017, the Court so ordered a stipulation of dismissal that was filed the day before
by Plaintiffs, Apotex Corp., and Apotex Inc. (See D.l. 283) As Apotex participated in the trial
and the post-trial briefing, the Court has included findings of fact that may be pertinent to the
now-resolved disputes between Plaintiffs and Apotex.
3
Citations to trial testimony are in the form: "([Witness name] Tr. at pp.-pp)".
3
loss of myelin is called demyelination. (Peroutka Tr. at 52-53; Lublin Tr. at 392)
10.
Demyelination slows or blocks the movement of nerve impulses along the nerve,
resulting in diminished coordination of nervous system signals. (Lublin Tr. at 392; Goodman Tr.
at 432-33) This disruption results in a wide variety of symptoms affecting a range of body parts
and systems. (Lublin Tr. at 392) The symptoms of MS may include walking impairment, visual
difficulty, fatigue, bladder dysfunction, tingling or pain, sexual dysfunctions, balance problems,
and cognitive changes. (Id.; Peroutka Tr. at 55; Goodman Tr. at 433)
11.
Weakness in the legs and/or alterations in walking are among the most common
symptoms of MS. (Peroutka Tr. at 55; Goodman Tr. at 432) Roughly 50-75% of MS patients
experience difficulty walking. (Peroutka Tr. at 55)
12.
MS may also cause brain scarring, which can lead to permanent symptoms and
make MS patients susceptible to seizures or convulsions. (Goodman Tr. at 430-31, 442)
13.
There is substantial variability in how MS manifests itself both among different
patients and within a single patient over time. (Goodman Tr. at 431-32, 434-36; Peroutka Tr. at
121) Any particular patient's symptoms may vary on a day-to-day, or even hour-to-hour, basis.
(Goodman Tr. at 435-36; Peroutka Tr. at 121-22)
C.
Treating MS
14.
There is presently no known cure for MS. (Peroutka Tr. at 53-54)
15.
Current treatments for MS fall into two categories: (1) the use of disease-
modifying agents, which alter the course of the disease and lessen the chance that a patient's
condition deteriorates; and (2) therapies that attempt to alleviate the individual symptoms of MS,
to improve a patient's quality of life. (Lublin Tr. at 393-94)
4
16.
Designing and interpreting the results of clinical trials for MS therapies is
complex because the wide variety of MS symptoms makes it difficult to select clinical endpoints
(i.e., measures of efficacy) and leads to mixed results. (Goodman Tr. at 436-37) In particular, it
can be difficult to determine whether changes in symptoms result from the treatment being
tested, from independent changes in the course of the disease, or from day-to-day variability in
symptoms. (Id. at 436-38)
17.
Placebo effect is also a problem in analyzing results of MS trials. (Lublin Tr. at
401-05) Placebo effect is an improvement in symptoms among test subjects who do not receive
a drug. (See id. at 412; Goodman Tr. at 468-69)
18.
There are a number of methods for assessing the disease state of a patient with
MS. Some measures consist of numerical scales designed to interpret patients' subjective ·
assessment of particular symptoms - such as fatigue or walking - or their condition in general.
(Goodman Tr. at 455, 481, 518-19) Other measures, such as timed walking tests, provide
objective, quantitative indications of results. (Lublin Tr. at 394)
19.
In addition to tests that measure clinically manifested symptoms, other tests
directly assess nerve impulse transmission. For example, researchers and clinicians can measure
subclinical visually evoked potentials ("VEP") to detect the speed of nerve impulse
transmissions. (JTX-0065; 4 Lublin Tr. at 394-96) Research established in the 1970s that VEP
could serve as a valuable test in the early diagnosis of MS. (JTX-0065; Lublin Tr. at 395-97) By
the 1980s and 1990s, VEP was also being used in conjunction with clinical metrics as a measure
4
Citations to exhibits admitted at trial are in the form: "([JTX or PTX or DTX]-####)," referring
to Joint Trial Exhibits, Plaintiffs' Trial Exhibits, or Defendants' Trial Exhibits, respectively.
5
of therapeutic efficacy in clinical trials. (JTX-0025) YEP is an especially useful tool because it
is not susceptible to placebo effect. (Lublin Tr. at 401-05)
D.
Ampyra®
20.
Acorda holds an FDA-approved New Drug Application ("NDA"), No. 022250,
for the use of 10 mg dalfampridine extended release tablets to improve walking in patients with
MS. (D.I. 1if30; SUF if 8) Acorda markets the approved drug product under the registered
name Ampyra®. (D.I. 1 if 30; SUF if 8)
21.
Dalfampridine, also known as fampridine, 4-Aminopyridine, or "4-AP," is the
active ingredient in Ampyra®. Ampyra® was the first FDA-approved use of 4-AP. (SUF if 9,
68)
22.
The FDA approved Ampyra® on January 22, 2010. (SUF if 67) Acorda has been
marketing and selling Ampyra® in the United States since March 2010. (Id. if 69)
i.
Active Ingredient (4-Aminopyridine)
23.
The 4-AP molecule improves nerve conduction by blocking potassium channels
and is sometimes referred to as a "potassium channel blocker." (Peroutka Tr. at 122)
24.
Adverse effects such as seizures have been related to 4-AP's potassium channel
blocking mechanism of action. (Goodman Tr. at 438-39, 482; Peroutka Tr. at 122) The concern
about seizures is heightened in MS patients because brain scarring associated with the disease
can increase seizure risk. (Goodman Tr. at 441-42)
ii.
Ampyra® Label
25.
The "INDICATIONS AND USAGE" portion of Ampyra®'s label states that
"AMPYRA (dalfampridine) is indicated as a treatment to improve walking in patients with
6
multiple sclerosis (MS). This was demonstrated by an increase in walking speed .... " (JTX0076 at AMPDELOl 70808; SUF ii 73) Improvement of walking in MS patients is Ampyra®'s
only approved use. (SUF ii 9)
26.
The "DOSAGE AND ADMINISTRATION" portion of Ampyra®'s label states:
The maximum recommended dose of AMPYRA is one 10 mg
tablet twice daily, taken with or without food, and should not be
exceeded. Doses should be taken 12 hours apart. Tablets should
only be taken whole; do not divide, crush, chew, or dissolve.
Patients should not take double or extra doses if a dose is
missed .... No additional benefit was demonstrated at doses
greater than 10 mg twice daily and adverse reactions and
discontinuations because of adverse reactions were more frequent
at higher doses.
(JTX-0076 at AMPDELOl 70808; SUF ii 74)
27.
The "DESCRIPTION" portion of Ampyra®'s label states that "AMPYRA
(dalfampridine) is a potassium channel blocker, available in a 10 mg tablet strength. Each tablet
contains 10 mg dalfampridine, formulated as an extended release tablet for twice-daily oral
administration." (JTX-0076 at AMPDELOl 70811; SUF ii 75)
E.
The Elan Patent
28.
The FDA's "Approved Drug Products with Therapeutic Equivalence Evaluations"
("Orange Book") lists the Elan Patent with respect to Ampyra®. (SUF ii 12)
i.
Development
29.
In the 1980s, Dusan Stefoski and Floyd A. Davis of the Rush Medical School
began to develop immediate release formulations of 4-AP to treat MS. (JTX-0112; JTX-0043)
30.
By 1990, Elan Corporation PLC ("Elan") entered into an agreement with Rush to
allow Elan to use Rush's research on 4-AP to develop pharmaceutical formulations of the drug.
7
(Fogarty Tr. at 158-59) At the time, Elan was at the forefront of the development of sustainedrelease formulations. (Id. at 159-60; Myers Tr. at 151; Fassihi Tr. at 325)
31.
Sustained-release formulations release a drug continuously over a long period of
time, such that, compared to an immediate release formulation, the body absorbs drug more
slowly, the drug's concentration in the body peaks later, and the drug dissipates from the body
more slowly. (Kibbe Tr. at 186) As a result, a sustained-release formulation of a drug is
effective for longer than an immediate release formulation of the same drug. (Id.)
32.
The inventors of the Elan Patent required about three or four weeks to design
three or four sustained-release 4-AP formulations "on paper," and about a day thereafter to
actually prepare a sustained-release formulation of 4-AP. (Myers Tr. at 154-55) In preparing
formulations, one of the inventors, Dr. Michael Myers, used sustained-release platforms with
which he already had experience, then substituted 4-AP for the active ingredients he had
previously used, and "adjusted the platforms with routine testing" until he obtained the desired
dissolution pattern. (Id. at 211)
ii.
Patent and Claims
33.
The United States Patent and Trademark Office ("USPTO") issued the Elan
Patent, entitled "Formulations and Their Use in the Treatment of Neurological Diseases," on July
30, 1996. (JTX-0001; SUF if 10) The inventors listed on the face of the Elan Patent are Joseph
G. Masterson and Michael Myers. (JTX-0001; SUF if 13)
34.
The Elan Patent is a divisional of U.S. Application No. 73,651 ("Application No.
73,651 "),filed June 7, 1993, which issued as U.S. Patent No. 5,370,879 on December 6, 1994.
(JTX-0001) Application No. 73,651 was a continuation of U.S. Application No. 786,400, filed
8
November 1, 1991, which was subsequently abandoned by the applicant. (Id.; SUP if 11 )5 The
Elan Patent also claims priority to an Irish patent application filed November 2, 1990. (SUP
if 11)
The Elan Patent expires on July 30, 2018. (Id.)
35.
Elan is named on the face of the Elan Patent as the assignee on the patent. (JTX-
0001) Acorda has an exclusive license to the Elan Patent. (SUP if 15) Alkermes, which
acquired Elan, is the successor-in-interest to the Elan Patent. (Goodman Tr. at 535)
36.
Plaintiffs assert that Defendants infringe claims 3 and 8 of the Elan Patent. (SUP
37.
Claims 3 and 8 both depend from claim 1. Claim 1 recites:
ir 16)
A method for the treatment of a neurological disease where the
disease is characterised by a slowing of nerve impulse
. transmission, which comprises administering to a patient in need
thereof a medicament containing a mono- or di-aminopyridine
active agent, said medicament being effective to permit sustained
release of said mono- or di-aminopyridine active agent at a rate
allowing controlled absorption thereof which achieves
therapeutically effective blood levels over a 12-24 hour period
when administered on a once- or twice-daily basis.
(JTX-0001 at 22:16-25)
38.
Claim 3 also depends from claim 2. Claim 2 recites: "[a] method according to
claim 1, wherein the neurological disease is characterised by demyelination of the central
nervous system." (JTX-0001 at 22:26-28) Claim 3 recites: "[a) method according to claim 1 or
2, wherein the neurological disease is multiple sclerosis." (Id. at 22:29-30)
39.
Claim 8 recites: "[a] method according to claim 1, wherein the active agent is 4-
5
lt is undisputed that the priority date for the Elan Patent is November 1, 1991. (See D.I. 272 at 2
n.4)
9
aminopyridine." (JTX-0001at22:50-51)
iii.
4-AP: Scope and Content of the Prior Art
40.
A German paper first identified 4-AP in 1902. (Peroutka Tr. at 73) The drug was
subsequently used as a bird toxin and as an agent to induce seizures in animals. (Fassihi Tr. at
361)
41.
4-AP was first used in humans in studies conducted in the 1970s, when a Swedish
group tested the drug in connection with neurological diseases that resulted in muscle weakness
associated with an impasse in nerve transmission. (Peroutka Tr. at 73)
42.
A 1980 British study examined the effect of 4-AP on rats with demyelinated
nerves and suggested that the drug could be used to improve their condition. (Peroutka Tr. at 7374)
43.
In 1981, Drs. Nicholas M.F. Murray and John Newsom-Davis disclosed the use of
4-AP in pharmaceutical preparations, to evaluate the safety and efficacy of the drug. (Peroutka
Tr. at 74; JTX-0089)
a.
44.
Stefoski
In 1987, Stefoski and Davis, researchers at Rush Medical School, conducted a
study and published a paper entitled "4-Aminopyridine Improves Clinical Signs in Multiple
Sclerosis," Annal. Neural., 21:71-77 (1987) ("Stefoski"). (JTX-0112) Stefoski is a printed
publication in the United States and available to persons of ordinary skill in the art in 1987.
(SUF iJ 62)
45.
Stefoski studied the effect of 4-AP on VEP, ocular motor function, and motor
function (defined by the researchers as power, coordination, and gait). (JTX-0112 at 71) The
10
researchers monitored 12 MS patients and five men without MS before, during, and after IV
injection of seven to 35 mg of 4-AP. (Id.) Stefoski found that ten of the 12 MS patients showed
mild to marked improvement, with vision improving in seven patients, ocular motor function
improving in five patients, and motor function improving in five patients. (Id.) Some of the
improvements developed within minutes and at doses as low as two mg. (Id.) Stefoski
concluded that 4-AP might be useful in treating MS patients, adding that studies were "currently
in progress to determine the clinical usefulness of 4-AP as a symptomatic treatment." (Id. at 75)
46.
A later article by Christopher T. Bever et al., "The Effects of 4-Aminopyridine in
Multiple Sclerosis Patients," Neurology, 44: 1054-59 (1994), stated that the conclusions to be
drawn from the results reported in Stefoski were "limited by questions about blinding, failure to
randomize treatment, and failure to either use prospectively-defined neurologic deficits or adjust
significance levels to compensate for multiple comparisons." (JTX-0028 at 1058) A later article
by Bever also noted several limitations with Stefoski, including that it was small in size, did not
use a randomized treatment design, was not double-blind, involved only short-term use of 4-AP,
and relied on outcome measures that were not widely accepted. (JTX-0027 at S 119)
b.
4 7.
Davis
In February 1990, Stefoski and Davis published a paper entitled "Orally
Administered 4-Aminopyridine Improves Clinical Signs in Multiple Sclerosis," Annal. Neural.,
27:186-92 (1990) ("Davis"). (JTX-0043) Davis is a printed publication published in the United
States and available to persons of ordinary skill in the art in 1990. (SUF iJ 47)
48.
Davis examined the effect of 4-AP at doses of 10-25 mg versus a placebo. (JTX-
0043 at 186) Fifteen patients received immediate-release capsules of 4-AP and five received
11
placebo. (Id.) Davis found that all patients experienced mild to marked improvements, with
motor function (defined by the researchers as power, coordination, and gait) improving in nine of
13 subjects. (Id.) Davis further found that improvements were observed with use of doses as
low as 10 mg. (Id.) No serious adverse events, such as seizures, occurred in patients taking 1025 mg doses of the drug. (Id. at 191) Although the study became unblinded, several patients
demonstrated reversible improvements in YEP that could not be explained by placebo effect.
(Id.) Davis concluded that orally-administered 4-AP produces clinically important improvements
in multiple chronic deficits resulting from MS. (Id.)
49.
A later article by Christopher T. Bever et al., "The Effects of 4-Aminopyridine in
Multiple Sclerosis Patients," Neurology, 44:1054-59 (1994), described the conclusions that could
be drawn from the results reported in Davis were "limited by questions about. blinding, failure to
randomize treatment, and failure to either use prospectively-defined neurologic deficits or adjust
significance levels to compensate for multiple comparisons." (JTX-0028 at 1059) A still later
article by Bever also noted that Davis had several limitations, including that it was small in size,
did not use a randomized treatment design, was not double-blind, involved only short-term use of
4-AP, and relied on outcome measures that were not widely accepted. (JTX-0027 at Sl 19)
c.
50.
Murray
In 1981, Nicholas M.F. Murray et al. published a paper entitled "Treatment with
Oral 4-Aminopyridine in Disorders of Neuromuscular Transmission," Neurology, 31:265-81
(1981) ("Murray"). Murray is a printed publication published in the United States and available
to persons of ordinary skill in the art in 1991. (JTX-0089)
51.
Murray reports on a study evaluating 4-AP as an immediate release oral
12
preparation in nine patients: four with Eaton-Lambert syndrome, four with congenital
myasthenia, and one with myasthenia gravis. 6 (JTX-0089 at 265) The patients in Murray
received a starting dose of 10 mg/twice daily, which was gradually increased, depending on
response, to up to 200 mg daily. (Id. at 266)
52.
Of the nine patients in the study, one had an "acute confusional episode" and
three others experienced seizures. (JTX-0089 at 270) Murray concluded that "[t]he central
effects of 4-AP, especially seizures, limit its use." (Id.)
iv.
Sustained-Release Technology: Scope and Content of the Prior Art
53.
Every active pharmaceutical ingre.dient (e.g., 4-AP) is unique, with its own
physical-chemical properties and pharmacokinetics. (See Fassihi Tr. at 340) There was (and is)
no sustained-release formulation that works for all drugs. (Id.)
54.
In 1990-91, the FDA had not developed guidelines to aid pharmaceutical
companies in developing sustained-release formulations. (JTX-0108)
55.
Once a product has been widely-consumed in immediate release form,
information about the safety, efficacy, and pharmacokinetics of the drug becomes available.
(Fassihi Tr. at 336-38) In 1990-91, all of the drugs that were commercially available in
sustained-release dosage forms had previously been approved by the FDA in immediate release
forms. (Id. at 335-36, 366)
6
Dr. Goodman testified that the diseases studied in Murray differ from MS because they are
diseases relating to different parts of the nervous system: whereas MS is a disease of the central
nervous system, the diseases studied in Murray are diseases of the peripheral nervous system and
neuromuscular junction. (Goodman Tr. at 440, 442-43)
13
a.
56.
Remington's (1985 and 1990)
"Sustained-Release Drug Delivery Systems," Remington's Pharmaceutical
Sciences, Alfonso R. Gennaro ed., 18th ed., pp. 1676-93 (1990) ("Remington's") is a printed
publication published in the United States and available to persons of ordinary skill in the art in
1990. (JTX-0081; SUF ~ 59) Remington's is an authoritative treatise on the subject of
pharmaceutical formulations. (See Peroutka Tr. at 81 (describing Remington's as "the Bible of
pharmaceuticals sciences"))
57.
The 1985 edition of Remington's highlights that, prior to 1990, there were
numerous sustained-release drugs on the market. (JTX-0082 at 1644) ("1985 Remington's")
The 1990 edition of Remington's lists five types of sustained-release formulation "platforms"
(e.g., encapsulated dissolution) and 39 FDA-approved, commercially-available sustained-release
products. (JTX-0081at1683-86) The 1990 edition ofRemington's also explains how to make a
sustained-release drug using each of the disclosed platforms, listing excipients appropriate for
each. (Id.)
58.
The 1985 edition of Remington's includes a table setting forth various known
advantages of sustained-release formulations. (JTX-0082 at 1646) One recognized advantage of
sustained release is improved patient compliance, as the less frequently a patient has to take a
dose the more likely a patient will be to take the required doses. (Id.)
59.
The 1985 edition of Remington's also lists several characteristics of a drug that
are compatible with a sustained-release formulation. First, a drug with a relatively short-half-life
is a good candidate for sustained release because sustained release eliminates the need for
14
frequent dosing. 7 (JTX-0082 at 1647-50) Second, a drug with efficient absorption is a good
candidate for sustained release. (Id.) Third, a drug requiring a relatively small dose is a good
candidate for sustained-release dosing because the resulting sustained-release product will not be
too large to swallow. (Id.) Finally, because sustained-release dosage forms are often used to
treat chronic conditions that require consistent concentration of drug in the blood stream for a
long period, drugs used to treat chronic conditions are good candidates for sustained-release
formulations. (Id.)
b.
60.
Robinson & Lee
Robinson & Lee, whose full title is Methods to Achieve Sustained Drug Delivery
and is authored by Joseph R. Robinson and Vincent Hon-Leung Lee, is a printed publication in
the United States and available to persons of ordinary skill in the art in 1978. (JTX-0079)
Robinson & Lee is an authoritative treatise on the subject of pharmaceutical formulations. (See
Kibbe Tr. at 236-37 (describing Robinson as "a real authority on sustained release"))
61.
The 1990 edition of the Robinson & Lee treatise stated that the design of a
sustained-release product was "normally a very difficult task." (PTX-0095 at 201) It further
explained that the "[ s]uccessful fabrication of sustained-release products ... involves
consideration of the physical-chemical properties of the drug, pharmacokinetic behavior of the
drug, route of administration, disease state to be treated and, most importantly, placement of the
drug in a dosage form that will provide the desired temporal and spatial delivery pattern for the
7
Dr. Peroutka testified that a person of ordinary skill in the art ("POSA") would understand that a
drug in an immediate release formulation must be administered approximately once every halflife in order to maintain a consistent level of drug in a patient's blood. Thus, if a drug has a halflife of 3-4 hours, a patient must take the drug once every 3-4 hours to maintain a consistent
concentration of it in the body. (Peroutka Tr. at 61)
15
drug." (Id. at 199; see also Fassihi Tr. at 326-27, 329-30)
c.
62.
Uges
In 1982, Donald R.A. Uges et. al. published a paper entitled "4-Aminopyridine
Kinetics," Clin. Pharmacol. Ther. 31(5):587-593 (1982) ("Uges"). Uges is a printed publication
published in the United States and available to persons of ordinary skill in the art in 1990. (JTX0137)
63.
Uges examined the pharmacokinetics of 4-AP in nine healthy subjects. (JTX-
0137) The subjects received three different administrations of 20 mg of 4-AP: intravenous
administration ("IV"), administration via an uncoated (immediate release) tablet, and
administration via an enteric (delayed release) dose. (Id.) Uges reported that the half-life of 4AP is about four hours. (Id.) Uges also reported that the bioavailability (percent absorption) of
enteric-coated tablets was 95% ± 29%, suggesting that the drug was highly bioavailable even
when release was delayed. (Id.) Finally, Uges taught that almost 100% of the drug was excreted
unchanged in the urine, regardless of how the drug was administered. (Id.)
F.
The Acorda Patents
i.
Development
64.
Dr. Ron Cohen founded Acorda in 1993. (Cohen Tr. at 277) Dr. Cohen learned
of 4-AP through Dr. Andrew Blight, one of Acorda's first employees, who had previously done
some exploratory work with 4-AP and spinal cord injury. (Id. at 278-79) Acorda initially
focused on developing immediate-release formulations of 4-AP. (Id. at 280)
65.
In 1997, Elan licensed the Elan Patent to Acorda, allowing Acorda to use Elan's
sustained-release 4-AP formulations for clinical trials in spinal cord injury patients. (Cohen Tr.
16
at 280-81; JTX-0020) In 1998, Elan and Acorda expanded the license to give Acorda exclusive
rights over the use of the 4-AP formulations, including for use in the treatment of MS. (Cohen
Tr. at 303-04; JTX-0021) Acorda did not do any independent development or formulation work
on any sustained-release formulation of 4-AP but, instead, used Elan's formulation in its trials.
(Cohen Tr. at 304; Blight Tr. at 163)
66.
Prior to licensing its sustained-release formulations to Acorda, Elan conducted a
double-blind, randomized, placebo-controlled, 161-patient study of the safety and efficacy of
twice-daily sustained-release formulations of 4-AP in MS patients. (PTX-0360) (the "Elan
Study") Patients in the 4-AP group initially received 12.5 mg doses/twice daily, a dose that was
increased by 5 mg every two weeks until the patients either experienced intolerable side effects
or reached the maximum dose of 22.5 mg/twice daily. (Id. at 8-9) The primary endpoint of the
study was the Expanded Disability Status Scale (EDSS), a composite measure of functioning that
was widely accepted in the MS community. (Id. at 1; JTX-0104 at 817; Goodman Tr. at 284,
467) The only outcome measure with a statistically significant difference compared to placebo
was the secondary outcome measure of lower extremity muscle strength; all other secondary
outcome measures, including ambulation, showed no statistically-significant difference from
placebo. (PTX-0360 at 101-02)
67.
In 2000 and 2001, Acorda conducted a 36-patient study on the use of sustained-
release formulations of 4-AP to treat MS (the "MS-F201 Study"). (See PTX-0466A; Cohen Tr.
at 287-88) The 25 patients in the 4-AP group received initial doses of 10 mg/twice daily for the
first week of the study, with dosages increasing by 5 mg per week to a maximum of 40 mg/twice
daily. (Cohen Tr. at 288) The outcome measures of the study included fatigue, a lower
17
extremity manual muscle test, the multiple sclerosis functional composite (including a timed 25foot walk), and subjective measures. (Id. at 289) The study failed as to all of the prospectivelydefined outcome measures other than the lower-extremity manual muscle test. (Id. at 289-90)
The results of the timed 25-foot walking test were not statistically significant, as members of the
placebo group showed greater improvement than the 4-AP group in multiple weeks. (PTX0466A; Cohen Tr. at 290-92) In three of the seven weeks, the placebo group demonstrated
greater improvement than the members of the 4-AP group had exhibited during the 10 mg/twicedaily week. (PTX-0466A at 63) However, a post-hoc analysis of the data analyzing walking
speed (rather than time) indicated a statistically-significant difference between the 4-AP and
placebo groups when the 4-AP results were aggregated across all of the various doses combined
together. (Cohen Tr. at 292; Goodman Tr. at 478-79) .
68.
In 2003, Acorda conducted a 206-patient, "Phase II" study regarding the use of
sustained-release 4-AP to improve walking speed in patients with MS. (PTX-0168A ("the MSF202 Study")) The study explored sustained-release doses of 10 mg, 15 mg, and 20 mg 4-AP
administered twice daily. (Cohen Tr. at 293) The study included a two-week up-titration period
to limit side effects, followed by a twelve-week period of stable dosing. (Id. at 295) None of the
4-AP groups demonstrated a statistically significant difference in walking speed compared to
placebo. (Id. at 296-98) However, a post-hoc, unblinded "responder" analysis indicated that the
responders were, overwhelmingly, members of the 4-AP group (p < 0.0001). (Id.) The
responder analysis also indicated that there was no meaningful difference in efficacy among the
10 mg, 15 mg, and 20 mg 4-AP groups. (Id. at 298-99)
69.
Following the Phase II study, Acorda conducted two Phase III studies of 4-AP,
18
using 10 mg/twice-daily dosing and the walking improvement responder analysis as a
prospectively-defined primary outcome measure. (Cohen Tr. at 299-300) Both studies were
successful (p <0.0001). (Id.)
ii.
Patents and Claims
70.
The inventors listed on the face of the Acorda Patents are Andrew R. Blight and
Ron Cohen. (See JTX-0002; JTX-0003; JTX-0004; JTX-0005; SUF i\i\ 21, 27, 33, 39)
71.
Acorda is listed as the assignee of each of the Acorda Patents. (See JTX-0002;
JTX-0003; JTX-0004; JTX-0005; SUF i\i\ 22, 28, 34, 40) 8
a.
72.
The '826 Patent
The USPTO issued the '826 patent, entitled "Sustained Release Aminopyridine
Composition," on August 30, 2011. (SUF if 18)
73.
The '826 patent issued from U.S. Patent Application No. 111010,828, which was
filed on December 13, 2004, and claims priority to U.S. Provisional Application No. 60/560,894,
filed on April 9, 2004. (See JTX-0002; SUF if 19) The patent expires on May 26, 2027. (SUF
ii 19)
74.
Plaintiffs assert that Defendants infringe claims 1, 7, 38, and 39. (SUF if 23)
75.
Claim 1 recites:
A method for maintaining a therapeutically effective concentration
of 4-aminopyridine in order to improve walking in a human with
multiple sclerosis in need thereof, said method comprising:
orally administering to the human a sustained release composition
of 10 milligrams of 4-aminopyridine twice daily for a day; and
8
lt is undisputed that the priority date for each of the Acorda Patents is April 9, 2004. (See D.I.
272 at 2 n.4)
19
thereafter, maintaining administration of 4-aminopyridine by orally
administering to said human a sustained release composition of 10
milligrams of 4-aminopyridine twice daily for a time period of at
least two weeks, whereby an in vivo 4-aminopyridine CmaxSS:CminSS
of 1.0 to 3.5 and a CavSS of 15 ng/ml to 35 ng/ml are obtained in the
human.
(JTX-0002 at 27:17-30)
76.
Claim 7 depends from claim 6. Claim 6 recites:
A dosing regimen method for providing a 4-aminopyridine at a
therapeutically effective concentration in order to improve walking
in a human with multiple sclerosis in need thereof, said method
compnsmg:
initiating administration of 4-aminopyridine by orally
administering to said human a sustained release composition of 10
milligrams of 4-aminopyridine twice daily for a day without a prior
period of 4-aminopyridine titration, and then, maintaining
administration of 4-aminopyridine by orally administering to said
human a sustained release composition of 10 milligrams of 4aminopyridine twice daily;
without a subsequent period of 4-aminopyridine titration, whereby
an in vivo 4-aminopyridine CmaxSS:CminSS of 1.0 to 3.5 and a CavSS
of 15 ng/ml to 35 ng/ml are maintained in the human.
(JTX-0002 at 27:41-57) Claim 7 recites: "[t]he method of claim 6, whereby an increase in
walking speed is obtained in said human." (Id. at 27:58-59)
77.
Claims 38 and 39 depend from claim 37. Claim 37 recites:
A method of increasing walking speed in a human multiple
sclerosis patient in need thereof comprising orally administering to
said patient a sustained release composition of 10 milligrams of 4aminopyridine twice daily for a time period of greater than two
weeks, wherein said sustained release composition provides a
mean T max in a range of about 2 to about 5 .2 hours after
administration of the sustained release composition to the patient.
(JTX-0002 at 30:14-21)
20
78.
Claim 38 recites: "[t]he method of claim 37 wherein the sustained release
composition elicits a Cmaxss:CminSS ratio of 1.0 to 3.5 when administered b.i.d. [i.e., twice daily] or
administered at 12-hour intervals to a human." (JTX-0002 at 30:22-25)
79.
Claim 39 recites: "[t]he method of claim 37 wherein said time period is twelve
weeks." (JTX-0002 at 30:26-27)
80.
The parties have stipulated that if the two-week limitations (of, for example, claim
37) is obvious, then the 12-week limitations (of, for example, claim 39) are also obvious. (D.I.
254 if 5) This stipulation applies to all of the Acorda Patents. (Id.
b.
81.
iii! 6-8)
The '685 Patent
The US PTO issued the '685 patent, entitled "Sustained Release Aminopyridine
Composition," on March 4, 2014. (SUF if 36)
82.
The '685 patent issued from U.S. Patent Application No. 13/187,158. (See JTX-
0005; SUF if 37) The application was a continuation of U.S. Patent Application No. 11/010,828,
which was filed on December 13, 2004, and claims priority to U.S. provisional application No.
60/560,894, filed on April 9, 2004. (SUF if 37) The patent expires on January 18, 2025. (Id.)
83.
Plaintiffs assert that Defendants infringe claims 3 and 5 of the '685 patent. (SUF
84.
Claim 3 depends from claim 2, which depends from claim 1. Claim 1 recites:
ir 41)
A method of improving walking in a human multiple sclerosis
patient in need thereof comprising orally administering to said
patient a sustained release composition of 10 milligrams of 4aminopyridine twice daily for a time period of at least two weeks,
wherein the sustained release composition further comprises one or
more pharmaceutically-acceptable excipients.
(JTX-0005 at 27:22-28) Claim 2 recites: "[t]he method of claim 1 wherein said sustained release
21
composition provides a mean Tmax in a range of about 2 to about 6 hours after administration of
the sustained release composition to the patient." (Id. at 28:1-4) Claim 3 recites: "[t]he method
of claim 2 wherein the sustained release composition is capable of providing, upon
administration to the patient, a release profile of 4-aminopyridine extending over at least 6
hours." (Id. at 28:5-8)
85.
Claim 5 depends from claim 1 and recites: "[t]he method of claim 1 wherein the
sustained release composition provides an average plasma concentration at steady state in
humans in the range of about 15 ng/ml to about 35 ng/ml." (JTX-0005 at 28:14-17)
c.
86.
The '437 Patent
The USPTO issued the '437 patent, entitled "Method of Using Sustained
Release Aminopyridine Compositions," on January 15, 2013. (SUF if 24)
87.
The '437 patent issued from U.S. Patent Application No. 11/102,559, which was
filed on April 8, 2005, and claims priority to U.S. Provisional Application No. 60/560,894, filed
on April 9, 2004. (See JTX-0003; SUF if 25) The patent expires on December 22, 2016. (SUF
88.
Plaintiffs assert that Defendants infringe claims 1, 2, 5, 22, 32, 36, and 37 of the
'43 7 patent. (SUF if 29)
89.
Claim 1 recites:
A method of increasing walking speed in a human multiple
sclerosis patient in need thereof comprising orally administering to
said patient a sustained release composition of 10 milligrams of 4aminopyridine twice daily for a time period of at least two weeks,
wherein said 10 milligrams of 4-aminopyridine twice daily are the
only doses of 4-aminopyridine administered to said patient during
said time period.
22
(JTX-0003 at 27:55-61)
90.
Claim 2 recites:
A method of improving walking in a human multiple sclerosis
patient in need thereof comprising orally administering to said
patient a sustained release composition of 10 milligrams of 4aminopyridine twice daily for a time period of at least two weeks,
wherein said 10 milligrams of 4-aminopyridine twice daily are the
only doses of 4-aminopyridine administered to said patient during
said time period.
(JTX-0003 at 27:62-67)
91.
Claim 5 depends from claim 1 and recites: "[t]he method of claim 1 wherein said
time period comprises twelve weeks." (JTX-0003 at 28:16-17)
92.
Claim 22 depends from claim 18, which depends from claim 1. Claim 18 recites:
"[t]he method of claim 1 wherein said sustained release composition is a tablet." (JTX-0003 at
28:48-49) Claim 22 recites: "[t]he method of claim 18 wherein said tablet exhibits a release
profile to obtain a Cavss of about 15 ng/ml to about 35 ng/ml." (Jd. at 28:55-57)
93.
Claim 32 recites:
A method of increasing walking speed in a human multiple
sclerosis patient in need thereof comprising orally administering to
said patient a sustained release tablet of 10 milligrams of 4aminopyridine at about every 12 hours for a time period of at least
two weeks, wherein said 10 milligrams of 4-aminopyridine at
about every 12 hours are the only doses of 4-aminopyridine
administered to said patient during said time period.
(JTX-0003 at 29:10-17)
94.
Claim 36 depends from claim 32 and recites: "[t]he method of claim 32 wherein
said time period comprises twelve weeks." (JTX-0003 at 30:11-12)
95.
Claim 37 depends from claim 33. Claim 33 recites:
23
A method of improving walking in a human multiple sclerosis
patient in need thereof comprising orally administering to said
patient a sustained release tablet of 10 milligrams of 4aminopyridine at about every 12 hours for a time period of at least
two weeks, wherein said 10 milligrams of 4-aminopyridine at
about every 12 hours are the only doses of 4-aminopyridine
administered to said patient during said time period.
(JTX-0003 at 29: 17-24) Claim 37 recites: "[t]he method of claim 33 wherein said time period
comprises twelve weeks." (Id. at 30:13-14)
d.
96.
The '703 Patent
The USPTO issued the '703 patent, entitled "Method of Using Sustained
Release Aminopyridine Compositions," on May 14, 2013. (SUF if 30)
97.
The '703 patent issued from U.S. Patent Application No. 13/299,969. (See JTX-
0004; SUF if 31) The application was a continuation of U.S. Patent Application No.11/102,559,
which was filed on April 8, 2005, and claims priority to U.S. Provisional Application No.
60/560,894, filed on April 9, 2004. (SUF if 31) The patent expires on April 8, 2025. (Id.)
98.
Plaintiffs assert that Defendants infringe claims 36, 38, and 45 of the '703 patent.
(SUF if 35)
99.
All of the asserted claims depend from claim 2. Claim 2 recites:
A method of improving lower extremity function in a human
multiple sclerosis patient in need thereof comprising orally
administering to said patient a sustained release composition of 10
milligrams of 4-aminopyridine twice daily for a time period of at
least two weeks.
(JTX-0004 at 29:63-67)
100.
Claim 36 recites: "[t]he method of claim 2, wherein the lower extremity function
is walking, and wherein said sustained release composition provides a release profile to obtain a
24
Cavss of about 15 ng/ml to about 35 ng/ml." (JTX-0004 at 31:28-31)
101.
Claim 38 recites: "[t]he method of claim 2, wherein the lower extremity function
is walking, and wherein said sustained release composition provides a mean Tmax in a range of
about 2 to about 6 hours after administration of the sustained release composition to the patient."
(JTX-0004 at 31 :36-40)
102.
Claim 45 recites: "[t]he method of claim 2, wherein the lower extremity function
is walking, and wherein said time period is more than two weeks." (JTX-0004 at 32:20-22)
iii.
Scope and Teachings of the Prior Art9
103.
It was well-known and accepted prior to the priority dates of the patents-in-suit
that impaired walking is a common symptom of MS. (Peroutka Tr. at 56)
. 104.
It was known and accepted prior to the priority dates of the patents-in-suit that MS
is a chronic disease that requires ongoing treatment. (Peroutka Tr. at 52)
a.
105.
Van Diemen
Harriet A.M. Van Diemen et al., "4-Aminopyridine in Patients with Multiple
Sclerosis: Dosage and Serum Level Related to Efficacy and Safety," Clin. Neuropharmacol.,
16(3): 195-204 (1993) ("Van Diemen"), is a printed publication published in the United States
and available to persons of ordinary skill in the art in 1993. (PTX-0330)
106.
Van Diemen evaluated the "relationship between dosage, serum level, efficacy,
and safety" of 4-AP in 70 patients with MS. (PTX-0330 at 196) The study examined both
intravenous and oral administration of 4-AP for up to 12 weeks. (Id.) For oral doses, the
9
All references that constitute prior art to the Elan Patent are also prior art to the Acorda Patents.
The Elan Patent itself, which was published in 1996, is also prior art to the Acorda Patents. (See
JTX-0001)
25
researchers used an individualized titration scheme based on tolerability up to a maximum
amount calculated based on patient weight. (Id. at 196-97) The study assessed efficacy by
"registering horizontal smooth pursuit eye movements." (Id. at 197) Van Diemen concluded
that "higher dosages and serum levels are likely to produce greater improvement in those MS
patients who are capable of favorably responding to 4-AP." (Id. at 203)
b.
107.
Polman
Chris H. Polman et al., "4-Aminopyridine in the Treatment of Patients with
Multiple Sclerosis," Arch. Neural., 51 :292-296 (March 1994) ("Polman"), is a printed
publication published in the United States and available to persons of ordinary skill in the art in
2003. (JTX-0095)
108.
Polman disclosed an open-label, unblinded study of the treatment of 23 MS
patients with 4-AP and placebo. (JTX-0095 at 295) The study employed an upward titration
dosing scheme based on tolerability up to a maximum (determined based on weight) over the
course of four to eight weeks. (Id. at 293) Polman measured efficacy based on subjective
information collected from patients during clinic visits. (Id.)
109.
Polman reported that "[i]mprovements in fatigue and ambulation were mentioned
quite often by the patients as being responsible" for positive effects. (JTX-0095 at 295) Two
patients in the Polman study had to discontinue their use of 4-AP due to seizures. (Id. at 292)
c.
110.
Schwid
Steven R. Schwid et al., "Quantitative Assessment of Sustained Release 4-
Aminopyridine for Symptomatic Treatment of Multiple Sclerosis," Neurology, 48:817-21 (April
1997) ("Schwid"), is a printed publication published in the United States and available to persons
26
of ordinary skill in the art in 1997. (JTX-0104)
111.
Schwid summarizes the Elan Study. (See supra if 66) Schwid reports that the
Elan Study consisted of administering a sustained-release formulation of 4-AP to 161 MS
patients for six weeks. (JTX-0104 at 817) Schwid further explains that the Elan study used a
sustained-release formulation of 4-AP because high serum concentrations of 4-AP were
associated with seizures and toxicity. (Id.) Schwid also states that the Elan Study did not
"establish clinical efficacy" because there was no improvement in EDSS relative to placebo 22% of patients in both groups showed improvement. (Id.)
112.
Schwid also reports the results of an original study involving the use of sustained-
release 4-AP in MS patients. (JTX-0104 at 817) The Schwid study was a randomized, placebocontrolled, crossover design in ten MS patients. (Id. at 817-18) All ten patients were randomly
assigned to receive either a placebo or 17 .5 mg sustained-release 4-AP twice daily for seven
days. (Id.) After an intervening washout period of seven days, the patients that had received
placebo treatment were given 4-AP, and vice versa, for an additional seven days. (Id.)
113.
The Schwid study did not disclose any prospectively-defined efficacy outcome
measure. (JTX-0104 at 817) Instead, the Schwid study was designed to assess a variety of
quantitative measurements, including maximum voluntary isometric contraction, manual muscle
testing, grip strength, time to ambulate eight meters, time to climb four stairs, EDSS score, and
global impression score. (Id.)
114.
Schwid reported that nine out often MS patients experienced improvements in
timed gait relative to the placebo group. (JTX-0104 at 820) This was the only outcome measure
for which the Schwid study demonstrated a statistically significant improvement relative to
27
placebo (p = 0.02). (Id.) However, the statistically significant result was not adjusted for the fact
that multiple outcome measures were included in the study. 10 (See id.)
115.
Schwid reported that the mean serum level of 4-AP during treatment was "65±25
ng/ml (range, 34-99)" and that the treatment "appeared particularly efficacious in subjects who
achieved serum 4AP levels above 60 ng/ml." (JTX-0104 at 819-20) Schwid also stated that
"[n]one of the patients with a serum level less than 60 ng/ml felt better (according to their global
impressions) on 4AP SR than placebo." (Id. at 819) Conversely, all patients with serum levels
above 60 ng/ml demonstrated improvement in timed gait, grip strength, and subjective
impression. (Id. at 820)
116.
The Schwid authors (among them, Dr. Andrew Goodman, Plaintiffs' expert
witness at trial) suggested further studies of 4-AP, stating, "[i]n addition to establishing efficacy
in larger trials, future studies of 4AP SR will need to examine long-term efficacy and tolerability
as well as further refine dosing regimens to optimize delivery despite a relatively narrow
therapeutic window." (JTX-0104 at 820)
d.
117.
Goodman I
Dr. Andrew Goodman et al., "Placebo-Controlled Double-Blinded Dose Ranging
Study ofFampridine-SR in Multiple Sclerosis," Multiple Sclerosis, 8:Sl 16-Sl 17 (P308) (July
2002) ("Goodman I"), is a printed publication (abstract) published in the United States and
available to persons of ordinary skill in the art in 2002. (See JTX-0062) The lead author of
10
Dr. Goodman testified that studies that evaluate multiple efficacy endpoints can result in falsepositive findings. (See Goodman Tr. at 471-72, 562-64; see also PTX-0416 at 5 (Solari)) Dr.
Goodman opined that, adjusted for the number of measures assessed in Schwid, the timed gait pvalue would be 0.14, indicating a 14% likelihood that the measured result was due to chance.
(Goodman Tr. at 562-63)
28
Goodman I, Dr. Andrew Goodman, appeared at trial as one of Plaintiffs' expert witnesses.
(Goodman Tr. at 474)
118.
Goodman I disclosed the results of Acorda's MS-F201 study- a randomized-
double-blind, placebo-controlled, dose-ranging study of 4-AP in MS patients. (JTX-0062 at
Sl 16) Goodman I explained that the MS-F201 study's "primary aim" was to "determine the
safety and tolerability of escalating doses of a sustained-release ('SR') formulation given orally
to patients with MS." (Id.) Goodman I also stated that the MS-F201 study aimed "to explore
efficacy over a broad dose range using measures of fatigue and motor function." (Id.)
119.
Goodman I reported that the MS-F201 study involved 36 patients who were
randomized to treatment (25 patients) and placebo ( 11 patients) groups. (JTX-0062 at S 116-17)
The treatment group received placebo for the first week, 20 mg of 4-AP per day during the
second week, and then an additional 10 mg per day each subsequent week to a maximum of 80
mg/day during the eighth week of the study. (Id. at S 117) Five subjects withdrew due to adverse
side effects: two due to seizures, one due to tremors, one due to dizziness and nausea, and one
due to leg pain. (Id.)
120.
Goodman I stated that analysis of the MS-F201 study data "showed statistically
significant improvement from baseline compared to placebo in functional measures of mobility
(timed 25 walking speed; p=0.04) and lower extremity strength (manual muscle testing;
p=0.01). 11 (JTX-0062 at Sl 17) None of the other measures showed "significant treatment
effects." (Id.)
11
Dr. Goodman testified that the p-values reported in Goodman I reflected the aggregated value
for the treatment group as a whole, including all dosages, and did not reflect the results
associated with any single dosage. (Goodman Tr. at 482-84)
29
121.
Goodman I also observed that "[ d]ose response curves showed increasing benefit
in both measures in the 20 to 50 mg/day range." (JTX-0062 at Sl 17)
e.
122.
Goodman Poster
The Goodman Poster is a poster presented at the September 2002 annual meeting
of the America's Committee for Treatment and Research in Multiple Sclerosis, held in
Baltimore, Maryland. (See JTX-0080; JTX-0080A) The Goodman Poster was a public
presentation in the United States and available to a person of ordinary skill in the art in
September 2002. (See Goodman Tr. at 523-24)
123.
Like Goodman I, the Goodman Poster reports results from the MS-F201 study.
(Goodman Tr. at 479-80)
124.-
The Goodman Poster reports that the MS-F201 study was designed to
"[ d]etermine [the] safety of multiple doses of [sustained-release 4-AP] (one week each of 20
mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day and 80 mg/day)" and to
"[ o]btain evidence of efficacy and dose-response using several outcome measures." (JTX0080A) The poster identifies multiple efficacy endpoints, including the timed 25-foot walk,
manual muscle testing, and patient self-reports using subjective fatigue scales. (Id.)
125.
The Goodman Poster disclosed that the MS-F201 study data reflected statistically
significant improvements in the timed 25-foot walk and manual muscle test relative to placebo.
(JTX-0080A (stating that MS-F201 study showed "[s]ignificant benefit on timed walking")) The
poster also reported a greater improvement in fatigue in the placebo-treated group as compared to
the 4-AP treated group. (Id.)
126.
The Goodman Poster includes a graph (reproduced below) entitled "Dose
30
Response 25 Ft. Walk" which shows the measured improvement in walking among members of
the treatment group at each dose. (JTX-0080A) The graph does not include data for the placebo
group. (Id.)
Dose Response 25 ft.. Walk
...
·-
--- ~
~
!'":L-:;::;;
..,,C<.}t~I~~
. i
127.
The Goodman Poster disclosed adverse events in the treatment group "consistent
with the findings of previous studies." (JTX-0080A) It also noted that further study was
required to determine whether there was a seizure risk in the disclosed dose range. (Id.)
f.
128.
Goodman II
Dr. Andrew Goodman et al., "Placebo-Controlled Double-Blinded Dose Ranging
Study ofFampridine-SR in Multiple Sclerosis," Neurology, vol. 60 (Supp. l):A167 (March
2003) ("Goodman II"), is a printed publication published in the United States and available to
persons of ordinary skill in the art in March 2003. (See JTX-0061) The lead author is again Dr.
Andrew Goodman. (Goodman Tr. at 479)
129.
Goodman II disclosed the results of the MS-F201 study. (Goodman Tr. at 479)
31
g.
130.
Hayes
Keith C. Hayes et al., "Pharmacokinetic Studies of Single and Multiple Oral
Doses ofFampridine-SR (Sustained-Release 4-Aminopyridine) in Patients with Chronic Spinal
Cord Injury," Clin. Neuropharmacol., 26(4):185-92 (2003) ("Hayes III"), is a printed publication
published in the United States and available to persons of ordinary skill in the art in 2003. (JTX0069)
131.
Hayes reported the pharmacokinetic ("PK") data from early Acorda clinical trials
using 4-AP with patients having spinal cord injuries. (Peroutka Tr. at 87-88; JTX-0069 at 191;
JTX-0002 at 25:1-28) The first study evaluated single doses of sustained-release 4-AP (10 mg,
15 mg, 20 mg, and 25 mg) administered once a week for 4 weeks in 14 patients with spinal cord
injuries. (JTX-0069 at 186) The second study examined the effect of multiple oral doses of
sustained-release 4-AP (10 mg, 15 mg, 20 mg, and 25 mg, each given twice daily for six days
and once on the seventh day) in six patients with spinal cord injury. (Id.)
132.
Hayes reported that the plasma half-life of 4-AP was 5.6 to 7.6 hours; that the
peak plasma concentration of 4-AP shortly after doses was 2.6 to 3.7 hours; and that 4-AP
concentrations reached steady state after four days of twice-daily administration. (JTX-0069 at
185) 12
h.
133.
Solari
Alessandra Solari et al., "Aminopyridines for Symptomatic Treatment in Multiple
12
The Tmax' Cavg at steady state, and ratio of Cmax to Cmin at steady state are all within the claimed
pharmacokinetic ranges of the Acorda Patents. (Compare JTX-0069 with JTX-0002) The '826
patent refers to the data in Hayes, and one of this patent's tables is identical to a table disclosed
in Hayes. (Kibbe Tr. 223:25-224:15)
32
Sclerosis," Cochrane Review, The Cochrane Library, Issue 2 (2003) ("Solari"), is a printed
publication published in the United States and available to persons of ordinary skill in the art in
2003. (See PTX-0416)
134.
Solari is a systematic review of the literature related to 4-AP, including a meta-
analysis of the few randomized clinical trials of 4-AP that had been conducted in MS patients.
(PTX-0416 at 1) Solari excluded from its analysis several prior art studies, including Hayes and
the MS-F201 study disclosed in the Goodman references. (Id.)
135.
Among the studies considered, Solari found that 54% of patients taking 4-AP
experienced improved motor functions, compared with only 7% of patients taking placebo.
(PTX-0416 at 1) However, Solari noted that "publication bias remain[ed] a pervasive problem,"
as well as the "distinct possibility of false positive findings" in trials where" the primary
endpoint was not specified." (Id. at 1, 5) Solari concluded that, while "[p]otassium blocking
drugs [including 4-AP] may be able to improve nerve function in nerves without enough
myelin," there was at that time "not enough evidence about the safety of these drugs or whether
[symptomatic] benefits are certain." (Id. at 15)
G.
Secondary Considerations
i.
Commercial Success
136.
Annual net sales of Ampyra® in the United States were $133.1 million in 2010,
the year of its launch, and increased to $436.9 million in 2015. (PTX-0795 at 1) Total sales
were $1.7 billion by the end of 2015. (See id.) Net income from those sales was $998.7 million.
(See id.)
13 7.
The volume of Ampyra® tablets sold increased from 8 million in 2010 to
33
16.6 million in 2015, despite an increase in price per tablet from $17 to $26. (Bell Tr. at 578,
592) From 2011 (the first full year of sales) through 2015, domestic unit sales (tablets) of
Ampyra® grew at an average rate of 8% per year, and net sales (dollars) increased at an average
rate of 20% per year. (PTX-0794; PTX-0795; PTX-0796) Over this same period, Acorda's
annual marketing expenditures decreased. (Bell Tr. at 590)
138.
Acorda receives additional revenue from milestone and royalty payments
associated with licenses it granted to Biogen to sell dalfampridine outside the U.S. (PTX-0733 at
25-27) Payments from Biogen have totaled approximately $135 million to date. (Id.)
139.
Surveys have found that 87% of Ampyra® prescribers and 83-87% of Ampyra®
patients were moderately to highly satisfied with the drug. (PTX-0556 at 7; PTX-0547 at 4;
PTX-0549 at 4) Sales to patients continuing with Ampyra® therapy accounted for 76-78% of
Ampyra®'s revenue in 2012-13. (PTX-0579 at 2; PTX-0604 at 3) Patients' ability to renew
prescriptions was in some cases contingent upon whether the patients could demonstrate to their
insurance companies that they had experienced improvements in walking. (PTX-0543 at 2;
PTX-0603 at l; PTX-0664 at 5)
140.
Ampyra® is promoted to physicians and patients only as a treatment to improve
walking in patients with MS. (PTX-0111at20; PTX-0115; PTX-0116; PTX-0119; PTX-0121;
PTX-0556 at 8, 10; PTX-0586 at 25) Acorda's key Ampyra® messages to physicians and
patients are based on clinically meaningful improvement in walking speed. (Id.)
141.
The commercial opportunity for Ampyra® is constrained by its limited indication
(improving walking in patients with MS) and the relatively small proportion of MS patients (2530%) who are eligible to take the drug. (McDuff Tr. at 630; JTX-0076; DTX-0419; DTX-0057)
34
Ampyra® sales revenue is equal to approximately 2-3% of the total sales of the top ten MS
drugs. (McDuff Tr. at 633-34)
142.
Plaintiffs' expert, Dr. Bell, opined that the preclinical costs associated with
developing Ampyra® were lower than for the typical drug, because 4-AP was a pre-existing
drug. (Bell Tr. at 595-96)
143.
The expected success rate for Ampyra® was higher than average, for reasons
including that it is an orphan drug. (Bell Tr. at 596)
ii.
Long-Felt Need
144.
Difficulty walking is one of the most common difficulties faced by MS patients.
(Goodman Tr. at 432, 511) The symptoms of MS that affect mobility have a significant impact
on independence, quality oflife, safety, and financial and emotional health. (Id. at 432, 512) MS
patients often cite walking impairments as among the most devastating symptoms of their
disease. (Id. at 432)
145.
The FDA granted priority review to Acorda's Ampyra® New Drug Application.
(Cohen Tr. at 300) The FDA's decision to grant priority review indicated that the FDA
considered Ampyra® a potentially important therapy for an important condition. (Goodman Tr.
at 512)
146.
Ampyra® is the first and only FDA-approved drug indicated for improving
walking in patients with MS. (Goodman Tr. at 512-13) However, only 15-20% of the patients
who suffer from walking difficulties are prescribed Ampyra®. (Id. at 539-40)
iii.
Failure of Others
147.
Elan attempted to demonstrate the effectiveness of 4-AP in treating MS but failed
35
to show therapeutic efficacy (using the EDSS test). (Goodman Tr. at 513)
148.
Sanofi-Aventis attempted to create a therapy, Nerispirdine, to improve walking in
MS patients. (See PTX-0569 (Nerispirdine Report); Lublin Tr. at 411-12) The active ingredient
in Nerispirdine was (like 4-AP) a potassium channel blocker. (Lublin Tr. at 412) Like Acorda's
Ampyra® trial, the Sanofi-Aventis Nerispirdine trial used a timed 25-foot walk as a measure of
efficacy and used a responder analysis to analyze whether the data reflected efficacy. (PTX0569; Lublin Tr. at 412) Sanofi-Aventis found "no evidence" of efficacy. (Lublin Tr. at 412)
H.
Defendants' ANDAs
149.
Each Defendant filed an ANDA, pursuant to the Food, Drug, and Cosmetic Act,
21 U.S.C. § 301 et. seq. ("FDCA"), seeking approval to engage in the commercial manufacture,
sale, or use of dalfampridine (10 mg) oral extended release tablets before the patents-in-suit
expire. (SUF iii! 78, 98, 111, 131)
150.
In connection with the filing of its respective ANDA, each Defendant submitted a
Paragraph IV certification under 21 U.S.C. § 355U)(2)(A)(vii)(IV), alleging that each of the
patents-in-suit is invalid, unenforceable, or will not be infringed by the commercial manufacture,
use, or sale of that defendant's generic dalfampridine tablet. (SUF at iii! 79, 99, 112, 132)
I.
Infringement
151.
Each Defendant has stipulated that the filing of its ANDA with the FDA, seeking
approval to market its generic dalfampridine tablets prior to the expiration of the patents-in-suit,
infringed the asserted claims of the patents-in-suit under 35 U.S.C. § 271(e)(2)(A), to the extent
those claims are found to be valid and enforceable. (D.I. 254 if 1)
152.
Each Defendant has stipulated that the asserted claims of the patents-in-suit would
36
be infringed by use of the proposed generic products that are the subject of its ANDA, to the
extent those claims are valid and enforceable. (D.1. 254 ,-r 2)
J.
Fact Witnesses
153.
Dr. Ron Cohen was called by Plaintiffs to testify live at trial as a fact witness. Dr.
Cohen is a medical doctor and a named inventor on the Acorda Patents. (Cohen Tr. at 274) He
is the President and CEO of Acorda, which he founded in 1993. (Id. at 274, 277)
154.
Michael Myers testified by deposition. Mr. Myers is a named inventor of the Elan
Patent and was designated as Alkermes' Rule 30(b)(6) witness on numerous topics. (Tr. at 148)
155.
Mairead Fogarty testified by deposition. Ms. Fogarty was designated as
Alkermes' Rule 30(b)(6) witness on numerous topics. (Tr. at 158)
156.
Andrew Blight testified by deposition. Mr. Blight is a named inventor of the
Acorda Patents and was designated as Acorda's Rule 30(b)(6) witness on numerous topics. (Tr.
at 161)
157.
K.
The Court found all of the fact witnesses who testified to be credible.
Expert Witnesses
i.
Plaintiffs' Experts
158.
Dr. Reza Fassihi testified on behalf of Plaintiffs as an expert witness in
pharmaceutics and, in particular, sustained-release formulations. (Fassihi Tr. at 320-21) Dr.
Fassihi is a professor of pharmacy at Temple University School of Pharmacy. (Id. at 315) He
holds a Ph.D. in pharmaceutics from Brighton University (U.K.). (Id. at 316; JTX-0040 at 3) A
majority of Dr. Fassihi's publications relate to the development of sustained-release
pharmaceutical formulations. (Fassihi Tr. at 320; see also JTX-0040 at 6-22)
37
159.
Dr. Andrew Goodman testified on behalf of Plaintiffs as an expert in neurology
and, in particular, MS, the treatment of MS, and clinical trials in MS. (Goodman Tr. at 428) Dr.
Goodman is a Professor of Neurology at the University of Rochester, where he directs the
Immunology and Multiple Sclerosis Division within the Department of Immunology. (Id. at 424)
He has for decades specialized in treating MS patients and conducting MS clinical trials, treating
thousands of MS patients, publishing widely regarding MS, and training other doctors regarding
the care of MS patients. (Id. at 423-27) Dr. Goodman has also advised and consulted with Elan
for many years, beginning in 1994. (Id. at 536) He has served as a paid consultant for Acorda
since the late 1990s, and in the course of his consulting relationship he worked with the inventors
of the Acorda Patents on the development of Ampyra®. (Id.) He continues to receive
compensation from Acorda when he attends meetings of its MS advisory committee. (Id. at 53 7)
160.
Dr. Fred Lublin testified on behalf of Plaintiffs as an expert in neurology, with
specific expertise in research on MS and care of patients with MS. (Lublin Tr. at 392) Dr.
Lublin is a board-certified neurologist and Professor of Neurology at the Icahn School of
Medicine at Mount Sinai in New York. (Id. at 386) He has for decades specialized in treating
MS patients and conducting MS clinical trials, treating thousands of MS patients, publishing
widely regarding MS, and training other doctors regarding the care of MS patients. (Id. at 38890)
161.
Dr. Gregory Bell testified on behalf of Plaintiffs as an expert in the economics of
the pharmaceutical industry. (Bell Tr. at 576) Dr. Bell is a Group Vice President at Charles
River Associates, a global economics and management consulting firm, where he is the global
head of the life sciences practice and works on, among other things, new drug strategy, product
38
launches, pricing, and market strategy. (Id. at 573-74) He earned a Ph.D. in business economics
and an M.B.A. (Id. at 573)
ii.
Defendants' Experts
162.
Dr. Stephen Peroutka testified on behalf of Defendants as an expert in neurology,
pharmacology, and drug development. (Peroutka Tr. at 49) Dr. Peroutka is currently Vice
President of Neuroscience and Global Therapeutic Head of inVentiv Health, a company that
focuses on neurosciences. (Id. at 4 7) Previously, Dr. Peroutka worked as an Assistant Professor
of Neurology at Stanford University and in the neuroscience sector of the pharmaceutical
industry. (Id. at 45-4 7) He also treated roughly 100 MS patients during the 1980s. (Id. at 45)
Dr. Peroutka holds an M.D. and a Ph.D. in pharmacology and experimental therapeutics. (Id.)
163.
Dr. Arthur Kibbe testified on behalf of Defendants as an expert in
pharmacokinetics and the development and evaluation of pharmaceutical dosage form
formulations, including immediate and sustained-release formulations. (Kibbe Tr. at 179-80)
Dr. Kibbe is an Emeritus Professor of Pharmacy at Wilkes University. (Id. at 177) Since 1989,
Dr. Kibbe has also served on the Steering Committee, as Editor-in-Chief, and as an author of 2025 monographs included in the Handbook of Pharmaceutical Excipients, an intemationallyrecognized reference text disclosing information on excipients, including those used to achieve
sustained release. (Id. at 176-78) He has almost 50 years of experience in the development and
formulation of pharmaceutical dosage forms, including the development of dosage forms to be
used for the first time in patients, as well as the development and review of pharmacokinetic
studies (although he has not researched or published on sustained-release pharmaceutical
39
formulations). (Id. at 175, 229-31) Among his other degrees, Dr. Kibbe holds a Master's Degree
in pharmaceutics, focusing on formulation development and pharmacokinetics. (Id. at 174)
164.
Dr. DeForest McDuff testified on behalf of Defendants as an expert on economics
and commercial success as it relates to patentability. (McDuff Tr. at 627) Dr. McDuff is a Vice
President at Intensity Corporation, a consulting firm with expertise in economics, finance, law,
computer sciences, and data science. (Id. at 626) He has substantial experience in the
pharmaceutical industry, including working on approximately 20 cases considering commercial
success. (Id. at 627) He holds a Ph.D. in economics. (Id. at 626)
165.
The Court found each of the expert witnesses who testified for each side to be
credible.
L.
Person Having Ordinary Skill in the Art
166.
The parties have offered different definitions of a person of ordinary skill in the
art ("POSA"). Plaintiffs define POSA as having "the knowledge of someone with an M.D. with
experience treating MS patients and a Ph.D. in pharmaceutics, or pharmacology, and at least five
years of experience in clinical research and drug development, including researching, designing,
and testing drug formulations, particularly for the treatment of multiple sclerosis." (D.I. 262 ~
68) Defendants' definition differs from Plaintiffs' only in that Defendants do not believe that a
POSA must have experience treating MS patients. (See D.I. 252-1 Ex. 3 ~~ 22-24) All of the
testifying experts agreed, however, that their opinions regarding obviousness would be the same
regardless of which definition the Court adopts. (Peroutka Tr. at 72; Kibbe Tr. at 184; Fassihi
40
Tr. at 323; Lublin Tr. at 406; Goodman Tr. at 430) Therefore, the Court need not make an
express finding as to which party's definition of a POSA it will use. 13
167.
A POSA at the priority date would have understood that all scientific studies are
subject to limitations, including investigator bias, number of subjects, and limitations on the
inferences that may be drawn from various statistical analyses. (Peroutka Tr. at 143) It is
common for authors of journal articles to comment on limitations of studies reviewed in their
papers. (Id.) Persons of ordinary skill in the art consider these limitations in the context of the
reported study results and the teachings of the prior art. (Id.)
168.
A POSA at the priority date of the Acorda Patents would have understood that
MS studies are particularly unpredictable in view of the great variability in MS patients'
responses to treatment and the high risk of placebo effect. (See Lublin Tr. at 401-04; Goodman
Tr. at 436-38)
LEGAL STANDARDS
I.
Presumption of Validity
An issued patent is presumed to be valid. See 35 U.S.C. § 282. Therefore, to invalidate a
patent, a party must carry its burden of proof by "clear and convincing evidence." See Procter &
Gamble Co. v. Teva Pharm. USA, Inc., 566 F.3d 989, 994 (Fed. Cir. 2009). Clear and
convincing evidence is evidence that "proves in the mind of the trier of fact an abiding
conviction that the truth of [the] factual contentions [is] highly probable." Intel Corp. v. ITC,
946 F .2d 821, 830 (Fed. Cir. 1991) (internal quotation marks omitted; first alteration in original).
13
See generally Supernus Pharms. Inc. v. Actavis Inc., 2016 WL 527838, at *5 (D.N.J. Feb. 5,
2016) (making no express finding of POSA when there was no material difference between
plaintiffs and defendant's definitions and court's analysis was same under either definition).
41
A defendant's burden to prove obviousness is "especially difficult when the prior art [on which
the party relies] was before the PTO examiner during prosecution of the application." HewlettPackard Co. v. Bausch & Lamb Inc., 909 F.2d 1464, 1467 (Fed. Cir. 1990).
II.
Obviousness
A patent may not issue "if the differences between the claimed invention and the prior art
are such that the claimed invention as a whole would have been obvious before the effective
filing date of the claimed invention to a person having ordinary skill in the art to which the
claimed invention pertains." 35 U.S.C. § 103(a). Obviousness is a question oflaw based on
underlying factual findings concerning: (1) the scope and content of the prior art; (2) the
differences between the claims and the prior art; (3) the level of ordinary skill in the art; and
(4) objective considerations of nonobviousness. See Graham v. John Deere Co:, 383 U.S. 1,
17-18 (1966).
To prove that a patent is obvious, a party must demonstrate "that a skilled artisan would
have had reason to combine the teaching of the prior art references to achieve the claimed
invention, and that the skilled artisan would have had a reasonable expectation of success from
doing so." In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676
F.3d 1063, 1069 (Fed. Cir. 2012) (internal quotation marks and citation omitted); see also
Amgen, Inc. v. F. Hoffman-La Roche Ltd., 580 F.3d 1340, 1362 (Fed. Cir. 2009) ("An
obviousness determination requires that a skilled artisan would have perceived a reasonable
expectation of success in making the invention in light of the prior art."). While an analysis of
any teaching, suggestion, or motivation to combine known elements is useful to an obviousness
42
analysis, the overall obviousness inquiry must be expansive and flexible. See KSR Int 'l Co. v.
Teleflex, Inc., 550 U.S. 398, 415, 419 (2007).
The use of hindsight is not permitted when determining whether a claim would have been
obvious to one having ordinary skill in the art. See id. at 421 (cautioning against "distortion
caused by hindsight bias" and obviousness "arguments reliant upon ex post reasoning"). To
protect against the improper use of hindsight when assessing obviousness, the Court is required
to consider objective (or "secondary") considerations of non-obviousness, such as commercial
success, failure of others, unexpected results, and long-felt but unmet need. See, e.g., Leo
Pharm. Prods., Ltd. v. Rea, 726 F.3d 1346, 1358 (Fed. Cir. 2013). Secondary considerations
"may often be the most probative and cogent evidence in the record" relating to obviousness.
Strata.flex, Inc. v. Aeroquip Corp., 713 F.2d 1530, 1538 (Fed. Cir. 1983).
DISCUSSION
I.
The Elan Patent
The asserted claims of the Elan Patent - claims 3 and 8 - require that the claimed
sustained-release formulation of 4-AP is directed to a "method of treatment of a neurological
disease" by administering a sustained-release mono- or di-aminopyridine "which achieves
therapeutically effective blood levels over a 12-24 hour period when administered on a once- or
twice-daily basis." 14 (JTX-0001 at 22: 16-25) The Court previously construed the term
"therapeutically effective blood levels" as meaning "blood levels sufficient to produce a
therapeutic effect." (D.l. 195 at 6)
14
Claim 3 specifies that the neurological disease is MS. (JTX-0001 at 22:29-30) Claim 8
specifies that the aminopyridine is 4-AP. (Id. at 22:50-51)
43
Defendants argue that claims 3 and 8 of the Elan Patent are obvious because the prior art
taught the use of sustained-release drug formulations as well as the use of 4-AP to treat MS, and
a POSA would have been motivated to combine these prior art teachings and to have a
reasonable expectation of success in doing so. (See D.I. 265 at 17) Plaintiffs do not dispute that,
as of the priority date of the Elan Patent, 15 4-AP was a known drug (see D.I. 272 at 14) and
sustained release was a known formulation type (see id. at 20). Plaintiffs do dispute, however,
whether a POSA would have had a reasonable expectation of success in developing a sustainedrelease formulation of 4-AP . 16 In particular, Plaintiffs contend that a POSA would not have had
a reasonable expectation of success in using any 4-AP formulation to treat MS - and emphasize
that such a person would not have reasonably expected success with a sustained-release
formulation. (See id. at 25)
Defendants have the burden to prove invalidity by clear and convincing evidence. See
Otsuka, 678 F.3d at 1289-90; Procter & Gamble Co., 566 F.3d at 994. As explained below, the
Court concludes that Defendants have failed to meet their burden to establish that the Elan Patent
is invalid for obviousness. Although Defendants have shown that a POSA would have had a
15
Plaintiffs "rely[]" on a November 1991 priority date. (D.I. 265 at 11 n.1) "Defendants'
arguments do not tum on whether the date for determining prior art is November 1990 or
November 1991." (Id.)
16
Plaintiffs frame their discussion regarding the teachings of the prior art as posing a question of
whether a POSA would have been "motivated to develop" a sustained-release formulation of 4AP, given how little was known about the drug's safety and efficacy. (D.I. 272 at 14-20)
(internal punctuation omitted) In substance, however, Plaintiffs' arguments relate more so to
whether the prior art would have given a POSA a reasonable expectation of success in
developing any formulation of 4-AP to treat MS. (See id. at 25) Specifically, Plaintiffs argue
that "proof of safety and efficacy beyond what could be gleaned from [the prior art] would be
needed to motivate a POSA to undertake the development of a sustained-release formulation of
4-AP." (Id. at 19)
44
reasonable expectation of success in using 4-AP to treat MS, Defendants have not shown that a
POSA would have had a reasonable expectation of success in developing an effective sustainedrelease formulation of the drug.
A.
Use of 4-AP to Treat MS
The parties dispute whether a POSA would have had a reasonable expectation of success
in using any formulation of 4-AP to treat MS. Defendants argue that the prior art establishes that
4-AP could be used to treat MS. In support of their contention, Defendants cite principally to
two categories of prior art: (1) Stefoski and Davis (collectively, the "Rush Studies"), which
describe the use of 4-AP to improve symptoms in MS patients, and (2) early human studies and
animal models that explore 4-AP's safety and benefits in improving neurotransmission. (See D.I.
265 at 12-15) Plaintiffs contend that this prior art amounts to "at best, fragmentary hints" that 4AP could be a clinically useful treatment for MS - particularly given the questions about the
safetyof4-AP. (D.I. 272at16)
The Court is persuaded that the Rush Studies establish that a POSA would have had a
reasonable expectation of success of administering 4-AP to achieve a therapeutic effect in MS
patients. In the first study, reported in Stefoski, 12 patients with MS and five men without MS
received intravenous doses of between seven and 35 mg of 4-AP. (Findings of Fact ("FF") ,-i 45)
As Plaintiffs acknowledge, most of the MS patients demonstrated some improvement in
symptoms, including vision, ocular motor function, and motor function (defined as power,
coordination, and gait). (Id.) Stefoski concluded that "4-AP lessens multiple neurological
deficits in multiple sclerosis" and "suggests a clinical usefulness for [4-AP]." (JTX-0112 at 71,
76) Similarly, the second study, reported in Davis, found that orally administered 4-AP produces
45
clinically important improvements in multiple, chronic deficits resulting from MS. (JTX-0043 at
186) Davis was a placebo-controlled study of the effect of 10-25 mg immediate-release doses of
4-AP in 20 MS patients (15 patients received 4-AP and five patients received placebo). (FF
if 48) Davis reported mild to marked improvement in all patients, including improvements in
motor coordination in nine out of 13 subjects tested. (Id.)
In addition to suggesting that 4-AP could improve symptoms of MS, the Rush Studies'
findings about 4-AP's safety suggested that there would be a viable therapeutic window for the
drug (i.e., a range of doses at which the drug was both non-toxic and had therapeutic effects).
Davis, for example, reported no serious adverse events in patients taking 10-25 mg oral doses.
Davis concluded that, even in light of prior research indicating that 4-AP could cause seizures,
the results of the reported study suggested that 10-25 mg per day could be a "safe and effective
therapeutic window for orally administered 4-AP for visual and motor deficits in ... MS
patients." 17 (JTX-0043 at 191)
Plaintiffs argue that the Rush Studies provide a limited basis for drawing conclusions
about the possible therapeutic effects of 4-AP. As the 1994 Bever article points out, and as Dr.
Fassihi testified at trial, the Rush Studies were conducted in small numbers of patients, "did not
use randomized treatment design, were not double-blinded, and relied on outcome measures that
17
Defendants argue that Murray, along with two studies conducted in the 1970s, also established
the safety oflong-term use of 4-AP in humans. (See D.I. 265 at 12-13) Although these studies
tend to suggest that 4-AP is not toxic in all patients, a POSA would have found the data in these
studies to have limited probative value in assessing the safety of 4-AP in MS patients,
particularly concerning the seizure risk associated with the use of 4-AP in MS patients. This is
because each of the three earlier studies were conducted in patients who suffered from medical
conditions that, unlike MS, do not affect the central nervous system. (See D.I. 272 at 14) Dr.
Goodman testified that a POSA would have understood that MS patients had a greater risk of
suffering seizures than did the patients in the Murray study. (See Goodman Tr. at 441-42)
46
were not widely accepted." (Fassihi Tr. at 355) Indeed, Stefoski and Davis themselves draw
qualified conclusions from the Rush Studies. 18 Stefoski describes the need to conduct further
studies to assess the "possibility" that 4-AP would have "clinical usefulness." (JTX-0112 at 76)
Similarly, Davis notes that the "possible use of oral 4-AP as a clinical treatment in MS requires
further study to assess long-term efficacy, safety, and patient selection criteria." (JTX-0043 at
190)
The Court agrees with Plaintiffs that a POSA would have found in the results of the Rush
Studies only limited information regarding the safety and efficacy of 4-AP for treating MS. A
POSA would have understood that additional clinical research would be needed to establish,
among other things, 4-AP's therapeutic effects and the dosages necessary to achieve them. (See
JTX-0043 at 190) Further, a POSA would have understood that additional testing would be
required to establish that the drug could meet the FDA's standards of safety and efficacy. (See
id.)
Still, as even Plaintiffs acknowledge, the prior art need not contain "[ c]onclusive proof of
efficacy" in order to support a finding that a POSA would have been motivated to develop, and
would have had a reasonable expectation of success in developing, a medical treatment. See
Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014). Rather, a POSA
need only have a "reasonable expectation of success in developing [the claimed invention]."
Allergan, Inc. v. Sandoz, Inc., 726 F.3d 1286, 1292 (Fed. Cir. 2013).
18
As Defendants note, however, the studies' titles both state that 4-AP "improves clinical signs in
multiple sclerosis." (See D.I. 273 at 7) (internal quotation marks omitted)
47
Here, the patentee broadly claimed the use of 4-AP to achieve blood levels having any
"therapeutic effect." (D.I. 195 at 6) The prior art would have given a POSA a reasonable
expectation of success in using 4-AP to achieve a therapeutic effect in MS patients. Although
the Rush Studies each involved a limited number of patients and did not include statistical
analysis (see D.I. 272 at 15), a vast majority of patients involved in these studies reported some
improvement in symptoms. Further, the trials reported that many patients experienced
improvements in VEP, a test that is indisputably immune to placebo effect. (See D.I. 265 at 15;
D.I. 272 at 17; JTX-0043 at 190; FF~ 48) This result would have allayed a POSA's concerns
that the Rush Studies' results were attributable to the placebo effects often observed in MS trials.
(See D.I. 265 at 15) Similarly, the results were consistent with a small animal study that showed
that 4-AP could "reverse and improve" the disruption in nerve flow caused by demyelination. ·
(D.I. 263
~
55) Consistent with these results, the authors of the Rush Studies concluded that 4-
AP produced improvements in the condition of MS patients (despite noting that the studies did
not conclusively establish 4-AP's "clinical" usefulness). Similarly, Stefoski concluded that "the
magnitude of the improvements ... observed without serious side effects suggests a clinical
usefulness for [4-AP], administered orally in selected patients" (JTX-0112 at 76), and Davis
concluded that "orally administered 4-AP produces clinically important improvements in
multiple, chronic deficits in MS" (JTX-0043 at 186).
48
Taken as a whole, 19 the evidence would have strongly suggested to a POSA at the
pertinent time that 4-AP could be used to improve symptoms of MS. Thus, the Court concludes
that a POSA would have had a reasonable expectation that 4-AP would be "therapeutically
effective" in treating MS. 20 (JTX-0001 at 22:23)
B.
Developing a Sustained-Release Dosage Form
Having found that a POSA would have had a reasonable expectation of success in using
4-AP to treat MS, the Court must next determine whether a POSA would also have had a
reasonable expectation of success in developing a sustained-release formulation of 4-AP to treat
MS. It is undisputed that the asserted claims of the Elan Patent are directed to sustained-release
formulations of 4-AP. (Kibbe Tr. at 219; Fassihi Tr. at 374) Thus, the parties' dispute centers
19
The parties' post-trial briefs addressed two other sources of evidence regarding whether the
prior art taught the use of 4-AP to treat MS. Defendants argue that the Elan Patent itself
characterizes the prior art as establishing that 4-AP could be used to treat MS patients. (See D.I.
265 at 15) Citing a Davis and Stefoski study, the Elan Patent explains that 4-AP had previously
been found to "alleviat[e] symptoms in MS patients." (JTX-0001 at 1:53-54) Plaintiffs contend
that these statements do not refer to the published prior art discussed above, pointing out that the
conditions of the study described are inconsistent with those outlined by the Rush Studies. (See
D.I. 272 at 17-18) In Plaintiffs' view, the cited statements reflect only "the inventors' personal
knowledge about the continuing work by Davis and Stefoski" and cannot support a finding as to
a POSA's expectations based on publicly-available prior art. (Id.) The parties also dispute
whether a later published study- Stefoski and Davis, "4-Aminopyridine In Multiple Sclerosis:
Prolonged Administration," Neurology, 41: 1344-48 (Sept. 1991) ("Stefoski II") - should be
treated as prior art. Defendants contend that this study precedes the priority date of the Elan
Patent (see D.I. 265 at 16 n.2); Plaintiffs counter that Defendants waived any right to discuss the
study because they identified the paper as prior art only with respect to the Acorda Patents. (See
D.I. 272 at 18-19) Because the Court has found that the Rush Studies, even by themselves,
establish that a POSA would have had a reasonable expectation of success in using 4-AP to treat
MS, the Court does not need to make any findings as to the disputes described in this footnote.
Resolution of these disputes would not alter the Court's pertinent conclusions.
20
As the Court noted in its claim construction opinion, decreasing or preventing symptoms is one
type of therapeutic effectiveness. (See D.I. 195 at 6-7)
49
on whether development of a sustained-release dosage form would have been obvious to a
POSA.
Defendants argue that a POSA would have had a reasonable expectation of success in
developing such a formulation because a POSA would have recognized the advantages of such a
dosage form for 4-AP and would have found the development process to be routine. (See D.I.
265 at 30-31) Plaintiffs respond that there was insufficient information in the prior art to provide
a POSA with a reasonable expectation of success in developing such a formulation. (See D.I.
272 at 20-25)
The parties do not genuinely dispute that a POSA would have understood the
hypothetical advantages of a sustained-release formulation of 4-AP as compared to an immediate
release formulation. (See Fassihi Tr. at 325; Kibbe Tr. at 207-08) Dr. Peroutka testified that a
POSA would have concluded that 4-AP's short half-life (reported in Stefoski and Uges) and
narrow therapeutic window (reported in Davis) would make a sustained-release formulation of
the drug particularly advantageous, because a sustained-release formulation could overcome the
need for dosing at inconvenient three- or four-hour intervals. (Peroutka Tr. at 77-78, 81) Indeed,
Dr. Blight, one of the two named inventors on the Acorda Patents, testified that it was "not
unusual" or "particularly mysterious" to pursue development of a sustained-release formulation
for a drug with a short half-life. (Blight Tr. at 164)
Based on this testimony, it is evident that the prior art would have provided a clear
motivation for a POSA to prepare a sustained-release formulation of 4-AP. The Elan Patent
itself, in discussing the prior art, expressly states that "it can be appreciated ... that there is a
need for an improved dosage form" of 4-AP, as a POSA would have known based on the prior
50
art that "it is desirable that the drug be formulated so that it is suitable for once- or twice-daily
administration to aid patient compliance." (JTX-0001 at 2:8-12) Thus, the key factual dispute
for the Court to resolve is whether a POSA would have had a "reasonable expectation of
success" in developing a sustained-release formulation that could realize those hypothetical and
strongly-desired, benefits.
Defendants argue that the prior art supports such a finding. (See D.I. 265 at 30-33)
Defendants' expert, Dr. Kibbe, testified that development of a sustained-release formulation
would have been "straightforward" for a POSA in light of the information included in
Remington's, an indisputably authoritative treatise on pharmaceutical formulations. (Kibbe Tr.
at 208-11) Remington's discloses five sustained-release platforms, explains how to prepare
them, and lists appropriate excipients for each. (See id. at 208-09) Dr. Kibbe testified that a
POSA would have known how to choose a platform from among those listed; from there, could
perform compatibility tests to identify, within approximately four months, appropriate excipients;
could then make several prototypes over the course of a day or two; and thereafter could perform
dissolution testing to confirm that, when administered, the drug would have the desired release
profile. (See id. at 210-11)
Plaintiffs argue that Remington's demonstrates only that certain platforms had been used
to produce sustained-release formulations of other drugs but would not have provided a POSA
with sufficient information as to whether it was possible to develop a sustained-release
formulation of 4-AP that could achieve therapeutic blood levels. (See Fassihi Tr. at 328-29, 34345, 348-52) Plaintiffs' expert, Dr. Fassihi, highlighted several attributes of 4-AP that would have
made the development of a sustained-release formulation of it particularly challenging. He
51
explained that a POSA would have understood, based on the incidence of seizures in past trials
of immediate-release 4-AP, that there was only a limited range of concentrations over which 4AP was both effective and non-toxic. (See id. at 328, 350) This combination of potency and
potential toxicity would have complicated the design of a sustained-release formulation because
of concerns related to dose-dumping and the need to achieve a uniform distribution of 4-AP
throughout the formulation. (See id. at 325-26, 328, 341-43) Further, 4-AP is highly soluble,
making it difficult to slow its release. (See id. at 342-43; see also Myers Tr. at 153-54; JTX0081 at 1679)
In addition to the uncertainty regarding whether it would be possible to overcome the
challenges posed by 4-AP's high solubility and narrow therapeutic window, Dr. Fassihi testified
that a POSA would have had insufficient information about 4-AP's pharmacokinetics. Unlike all
other sustained-release drugs that were on the market at the pertinent time, 4-AP had never been
approved by the FDA in an immediate-release form. (See Fassihi Tr. at 335-36, 366)
Consequently, there was a dearth of information about 4-AP's pharmacokinetics relative to what
would normally have been available to a POSA attempting to develop a sustained-release
formulation. (See id. at 336-38) In particular, a POSA would have known little about how 4-AP
is distributed, metabolized, and eliminated by the body when released at various points
throughout the gastrointestinal tract. (See id. at 337-38; see also id. at 326-27 (explaining that
sustained-release formulations differ from immediate release formulations because they travel
through gastrointestinal tract, which subjects sustained-release formulations to wider varieties of
environments)) The data presented in Uges, the only prior art publication containing any
52
pharmacokinetic information regarding 4-AP, reflected the results of only a small number of
patients and demonstrated a high degree of variability. (See id. at 348-52)
In Defendants' view, a POSA could have overcome the challenges Dr. Fassihi
highlighted by engaging in "routine experimentation[]." (D .I. 2 73 at 18) Dr. Kibbe testified that
resolving concerns unique to sustained-release formulations, such as avoiding "dose dumping,"
was a common consideration for formulators and part of the routine optimization process to
formulate a sustained-release drug. (Kibbe Tr. at 194-98) Similarly, Dr. Kibbe pointed out that
at least one polymer suitable for developing sustained-release formulations of soluble products
already existed in the prior art. (See id. at 209-10) Additionally, Dr. Kibbe disagreed with Dr.
Fassihi' s views about the impact of a lack of pharmacokinetic information, noting that all of the
available information about 4-AP's pharmacokinetics tended to suggest that the drug would be a
good candidate for sustained release. Dr. Kibbe noted that Uges reported that 4-AP had a short
(four-hour) half-life, high bioavailability, low risk ofbiotransformation, and a low risk of first
pass effect - all characteristics that made 4-AP a favorable candidate for the development of a
sustained-release formulation. (See id. at 201-02) 21 In Dr. Kibbe' s view, this information would
have given a POSA a reasonable expectation of success in developing a sustained-release 4-AP
formulation to treat MS. Based on this testimony, Defendants argue that, despite some
uncertainty about exactly which formulations would work, a POSA would have had a reasonable
expectation of success in developing a sustained-release formulation of 4-AP.
21
Dr. Peroutka further noted that, although the Uges study size was small, a POSA would be
encouraged by the consistency between the reported half-life and bioavailability data and
between the consistency of the half-life reported in Uges and the half-life reported in Stefoski.
(See Peroutka Tr. at 77-78)
53
The need to engage in routine testing or optimization efforts - even if expensive and
technically challenging - does not render an invention non-obvious, if a POSA would reasonably
expect the testing or optimization efforts to succeed. See Pfizer, Inc. v. Apotex, Inc., 480 F.3d
1348, 1367-68 (Fed. Cir. 2007). Thus, a POSA may have a reasonable expectation of success
despite "a showing of some degree of unpredictability in the art." Id. at 1364; see also Allergan,
726 F.3d at 1292.
The Federal Circuit's decision in Cyclobenzaprine is instructive. There, the Federal
Circuit considered a claim directed to a "method of relieving muscle spasms" which "provides
[a] therapeutically effective plasma concentration over a period of 24 hours .... " 22 676 F.3d at
1066 (brackets in original). Similar to here, the term "therapeutically effective plasma
concentration" was construed to mean "the amount of a drug required to ·produce the therapeutic
result." Id. at 1067 (internal quotation marks omitted). The Federal Circuit held that a POSA
would not have had a reasonable expectation of successfully developing a formulation to satisfy
the "therapeutically effective" limitation unless a POSA would have both (i) known what blood
levels would produce a therapeutic result and (ii) would have had a reasonable expectation of
success in developing a sustained-release formulation that could achieve those blood levels. See
id. at 1070 ("Because ... skilled artisans did not know the [relationship between the
pharmacokinetics and therapeutic effect] ... for the immediate-release formulation, there was no
way to match the dosage for the extended-release formulation to achieve a known therapeutic
effect.") (emphasis omitted) Absent specific knowledge of the relationship between the
22
Additional asserted claims specified particular pharmacokinetic values, including the
concentration of drug. See Cyclobenzaprine, 676 F.3d at 1066.
54
pharmacokinetics and therapeutic effectiveness, the Federal Circuit noted, the claims could not
be obvious without a "finding that the prior art would have taught or suggested a [specific]
therapeutically effective formulation to one of ordinary skill in the art." Id.
Ofrelevance to this case, the Federal Circuit's analysis in Cyclobenzaprine illustrates that
knowledge of a correlation between a particular set of pharmacokinetic values and the
therapeutic effectiveness of an immediate release formulation is not necessarily sufficient to
raise a reasonable expectation that a sustained-release formulation achieving the same
pharmacokinetic values would be therapeutically effective. See id. at 1071. The drug at issue in
Cyclobenzaprine had already been released in an immediate-release form, and its
pharmacokinetic parameters were available in the prior art. See id. Nevertheless, the Federal
Circuit rejected the argument that a POSA would have considered it obvious to "target extendedrelease [pharmacokinetic] values 'mirroring' - in other words, bioequivalent to - those of the
immediate release ... formulation." Id. at 1069. The Federal Circuit explained that, without a
known relationship between pharmacokinetics and effectiveness, "immediate-release
[pharmacokinetic] values are oflittle use in calculating extended-release values, [absent] proof
that a skilled artisan would expect the extended-release values to produce a therapeutic effect
solely because they are drawn from immediate-release values." Id. at 1071. Rather, a POSA
would need evidence that "in the specific context" of the drug at issue, a skilled artisan would
expect the particular "[pharmacokinetic] values drawn from the prior art to yield a therapeutically
effective formulation." Id. at 1072. Thus, without information about which particular
parameters (i.e. Tmax' Cmax' etc.) were crucial to therapeutic effectiveness, "[t]he fact that a skilled
artisan could have predicted [that a sustained-release formulation could achieve] a particular
55
blood plasma concentration ... does not mean that such knowledge would have provided a
skilled artisan a reasonable expectation of success." Id. at 1071.
As with the active ingredient at issue in Cyclobenzaprine, there was no well-characterized
relationship between 4-AP's pharmacokinetics and its therapeutic effects at the time of the
priority date of the El an Patent. (See Kibbe Tr. at 241) U ges, the only pharmacokinetic study of
4-AP available at that date, did not link pharmacokinetic data to therapeutic effects. The record
does not support a finding that U ges, combined with other prior art references, would have
allowed a POSA to infer the relationship between the pharmacokinetics and therapeutic effects.
As a result, a POSA would not have known what in vitro dissolution profile a sustained-release
formulation would have needed to achieve in order to maintain safe and effective therapeutic
blood levels of 4-AP over time. Thus, a POSA would not have had the information necessary to
assess whether a sustained-release formulation could be developed to achieve those blood levels.
See Cyclobenzaprine, 676 F.3d at 1071.
Absent prior art showing the 4-AP blood levels that would be therapeutically effective, a
POSA might nevertheless have formed a reasonable expectation of success in developing a
sustained-release formulation had the prior art "taught or suggested" that a particular formulation
could be effective. Id. at 1070. Here, however, the record lacks such evidence as well.
Although Dr. Kibbe testified that a POSA would be able to identify prior art sustained-release
platforms and excipients that would be particularly likely to complement 4-AP, given the drug's
characteristics (see, e.g., Kibbe Tr. at 208-10) (explaining that POSA would understand that
encapsulated dissolution, and particular known polymers, would be appropriate for 4-AP), he did
not testify as to why a "skilled artisan would have had a reasonable expectation [that these
56
platforms and excipients] would succeed in being therapeutically effective." Cyclobenzaprine,
676 F.3d at 1070 (emphasis added). Thus, while the record indicates that it may have been
obvious to experiment with certain approaches to developing a sustained-release formulation,
nothing in the record demonstrates that a POSA would have had a "reasonable expectation" that
at least one of those approaches would have resulted in a therapeutically effective sustainedrelease formulation of 4-AP. Id.
Defendants urge the Court overlook these evidentiary shortcomings, arguing that there is
no "credible evidence" to support a finding that a POSA would not have had "a reasonable
expectation of successfully formulating 4-AP into any of multiple available sustained-release
dosage forms." (D.I. 273 at 18) (emphasis in original) But the burden in this case does not
reside with Plaintiffs. Rather, it is Defendants' burden to present clear and convincing evidence
that a POSA would have had a reasonable expectation that one of the multiple available
sustained-release dosage forms could be combined with 4-AP to create a therapeutically effective
formulation when administered as claimed. Defendants have shown that the prior art included
many sustained-release platforms, that many drugs had been formulated using these sustainedrelease platforms, and that no affirmative evidence existed that would have dissuaded a POSA
from pursuing a sustained-release dosage form of 4-AP. Defendants have not shown, however,
that a POSA would have inferred from this evidence that success would reasonably be expected
from an attempt to develop a therapeutically-effective, sustained-release formulation for any
drug, and most particularly for 4-AP.
The Court is mindful that the evidence regarding the inventors' actual experience in
developing the invention of the Elan Patent is not inconsistent with Dr. Kibbe's testimony. Dr.
57
Myers, one of the inventors, stated that it took him only three or four weeks to put three or four
formulations of 4-AP on paper and then about a day actually to prepare a sustained-release
formulation of 4-AP. (See Myers Tr. at 154-55) Dr. Myers further explained that this process
essentially involved substituting 4-AP for the active ingredients he had previously used in
sustained-release platforms, and "adjust[ing] the platform[ s] with routine testing" until he
obtained the desired dissolution pattern. (Kibbe Tr. at 211) Among the disclosed sustainedrelease formulations in the Elan Patent is one platform that had been disclosed in the 1990
edition of Remington's. (See JTX-0001 at 4:41-46; Kibbe Tr. at 219-20)
While this evidence does nothing to discredit Dr. Kibbe' s testimony that developing a
sustained-release formulation of 4-AP was straightforward, it also does not help Defendants to
meet their burden of showing that a POSA would reasonably have expected it to be so. "[I]n
addressing the question of obviousness a judge must not pick and choose isolated elements from
the prior art and combine them so as to yield the invention in question if such a combination
would not have been obvious at the time of the invention." Abbott Labs. v. Sandoz, 544 F.3d
1341, 1348 (Fed Cir. 2008) (internal quotation marks omitted). Without the benefit of hindsight,
the record here does not support a finding that the approach taken by the Elan Patent represented
an "identified, predictable solution[]" that produced an "anticipated success." KSR, 550 U.S. at
421. As such, the Court finds that Defendants have not met their burden to establish, by clear
and convincing evidence, that the Elan Patent is invalid as obvious.
C.
Secondary lndicia of Non-Obviousness
As detailed below in the discussion of the Acorda Patents, the Court finds that Ampyra®
is a commercially successful product. This success has a nexus with the Elan Patent because, as
58
is undisputed, Ampyra®'s sustained-release formulation allowed for infrequent dosing that
improves patient compliance. (JTX-0001 at 2:22-32) As such, Court finds that the invention of
the Elan Patent likely contributes to this commercial success. This finding is further evidence
supporting the Court's conclusion that Defendants have failed to prove that the invention of the
Elan Patent is non-obvious.
D.
Section 112 Defenses
Defendants contend in the alternative that, if the Elan Patent is not found to be obvious,
then it should be found to be invalid for lack of adequate written description and/or lack of
enablement. See 35 U.S.C. § 112.23 Defendants' Section 112 defenses could likely be found to
have been waived, given the lack of evidence presented at trial. (See D.I. 272 at 57 n.38
(Plaintiffs arguing for waiver); D.I. 274 at 1 n.l (same); but see D.I. 273 at 22 ri.3 (Defendants
responding that they noted defenses in pretrial order, as well as in opening statement and closing
arguments at trial)) Indeed, these defenses barely even got mention at trial. 24 Notably, none of
the experts testified at trial about the Section 112 defenses and, accordingly, none opined that the
Elan Patent is invalid due to lack of enablement or written description. (See Tr. at 272)
23
See Teva Pharms. USA, Inc. v. Sandoz, Inc., 723 F.3d 1363, 1370 (Fed. Cir. 2013) (explaining
that test for enablement requires specification to teach one of skill in art "how to make and use
the full scope of the claimed invention without undue experimentation") (internal quotation
marks omitted); Regents of the Univ. of Cal. v. Eli Lilly & Co., 119 F.3d 1559, 1566 (Fed. Cir.
1997) (explaining that test for written description requires specification to describe invention in
sufficient detail that one of skill in art can conclude "the inventor invented the claimed
invention") (internal quotation marks omitted).
24
According to the index to the trial transcript, the terms "written description," "enablement," and
"112" were mentioned only five times over the four days of trial. (See Tr. at 800)
59
Even assuming these defenses were not waived, they are unavailing on the merits. To the
extent Defendants have articulated their Section 112 invalidity theory, it is a theory based on
contingencies which, given the Court's findings, have not been satisfied.
In the less than two pages (out of 66) Defendants devote in their opening brief to these
defenses, they explain that the defenses are predicated on the Court accepting certain arguments
or evidence relied on by Plaintiffs. (See D.I. 265 at 65-66; see also D.I. 273 at 2, 19-22)
Defendants argue: "In rebutting Defendants' evidence of obviousness for the Elan [P]atent,
Plaintiffs have repeatedly made arguments, or elicited testimony, that -
if accepted by the Court
- would render the Elan [P]atent invalid for lacking enablement or written description." (D.I.
265 at 65) (emphasis added) But (as best as the Court can tell) the Court has not "accepted"
these arguments or evidence relied on by Plaintiffs. Contrary to Plaintiffs' position, the Court
has found that a POSA would have been, at the priority date, motivated to use 4-AP to improve
walking in MS patients, and would have had a reasonable expectation of success in doing so, for
all the reasons Defendants contend.
So, for example, Defendants argue that "either Davis and Stefoski teach using 4-AP to
treat clinical symptoms of MS (including gait) or the Elan [P]atent is invalid for lacking
enablement and written description." (Id. at 66) The Court has found that Davis and Stefoski do
teach using 4-AP to treat clinical symptoms of MS (including gait). Hence, on Defendants' own
reasoning, it follows that the Elan Patent does not lack enablement or written description.
Defendants expand their arguments in their reply brief, stating:
[Plaintiffs] further refer to the prior art as providing "meager data"
with only "fragmentary hints" that 4-AP might have some clinical
usefulness in MS patients. If true, these are significant admissions
60
under 35 U.S.C. § 112, given that the Elan [P]atent claims methods
of "treatment" for MS, and the patent disclosure does not identify
any 4-AP testing conducted independently by the inventors.
(D.I. 273 at 19) (emphasis added; internal citation omitted) But, again, the Court has not been
persuaded that the statements Defendants here call out are "true." The Court has found for
Plaintiffs on the parties' dispute as to the invalidity of the Elan Patent based on other grounds. It
follows, again, that Defendants have failed to prove their Section 112 defenses.
In sum, assuming the defenses have not been waived, Defendants have failed to meet
their burden to prove, by clear and convincing evidence, that the Elan Patent is invalid due to
lack of enablement or written description.
II.
The Acorda Patents
The asserted claims of the Acorda Patents are directed to a method of improving walking
in a human with multiple sclerosis by administering a 10 milligram dose of 4-AP twice per day,
for either two weeks or twelve weeks. 25 Certain claims also require that this dosage regimen
produce particular pharmacokinetic results. 26 (See, e.g., JTX-0002 at 27:55-57; JTX-0003 at
28:55-57; JTX-0004 at 31 :28-31) Certain claims further mandate that there be no titration before
or after administration of the 10 mg/twice-daily dose. (JTX-0002 at 27:48-49) Defendants argue
that all of these claims are obvious because the prior art would have given a POSA a reasonable
expectation of success in combining these limitations. (See D.I. 265 at 38-43) Plaintiffs disagree
25
As noted earlier, the parties have stipulated that if the claims requiring stable dosing for two
weeks are obvious, then the twelve-week limitations are obvious as well. (D.I. 254 iii! 5-8)
26
The claims including pharmacokinetic or release profile limitations are: claims 1, 7, 38, and 39
of the '826 patent; claims 3 and 5 of the '685 patent; claim 22 of the '437 patent; and claims 36
and 38 of the '703 patent.
61
and further argue that secondary indicia of non-obviousness preclude a finding that the invention
of the Acorda Patents was obvious. (See D.I. 272 at 31)
As explained below, the Court concludes that Defendants have shown that the prior art
taught the four disputed limitations: the use of 4-AP to improve walking; the use of a 10
mg/twice-daily dosage; the use of stable dosing; and the inherent pharmacokinetic limitations.
The Court finds that a POSA would have been motivated to combine these limitations with a
reasonable expectation of success. The Court also agrees with Defendants that the secondary
indicia do not support a finding of non-obviousness with respect to any claim. As such, the
asserted claims of the Acorda Patents are invalid. 27
A.
Use of 4-AP to Improve Walking
All of the asserted claims of the Acorda Patents are directed to methods of administering
sustained-release 4-AP to "improving walking." (JTX-0003 at 27:62-67) It is undisputed that
the claims do not require that the patents be effective to treat MS in all patients. (See D.I. 265 at
50; D.I. 272 at 38) Thus, the parties' dispute with respect to this limitation centers on whether
the claimed studies would provide a POSA with a reasonable expectation that 4-AP could be
27
Defendants contend that the Acorda Patents "are presumed obvious as a matter oflaw, because
they simply claim an optimized dose selected from a discrete, narrow range of doses disclosed in
the prior art," including the Elan Patent. (D.I. 265 at 5) (emphasis in original) (citing Tyco
Healthcare Grp., LP v. Mut. Pharm. Co., 642 F.3d 1370, 1372-73 (Fed. Cir. 2011); Galderma
Labs., L.P. v. Tolmar, 737 F.3d 731, 738 (Fed. Cir. 2013)) Plaintiffs disagree, arguing that
"unlike in Galderma and Tyco, there was no prior art teaching that any dose of 4-AP - any single
dose or any range of doses - was safe and effective to improve walking or increase walking
speed in MS patients. The Acorda inventors were not seeking to improve upon what was already
a known process, and their invention was not the mere optimization of a known dose range."
(D.I. 272 at 54) (emphasis in original) Given the Court's conclusion that Defendants have
proven, by clear and convincing evidence, that the asserted claims of the Acorda Patents are
obvious, it is unnecessary for the Court to also determine whether these claims should be
presumed obvious.
62
successfully used as claimed to treat (i.e., achieve therapeutically-effective blood levels in) even
a single patient. (See D.I. 272 at 38)
Defendants argue that the prior art made it obvious to a POSA that 4-AP could be used to
treat impaired walking in some MS patients. For this contention, Defendants rely on three prior
art references: Schwid, Goodman I, and the Goodman Poster. (See D.I. 265 at 38-41)
Schwid begins by disclosing the failure of the Elan Study, a rigorous clinical trial into the
effect of sustained-release 4-AP on EDSS in MS patients. 28 (See JTX-0104 at 817) Schwid
theorized that EDSS - which is a composite of several measures of effectiveness, including
improvements in walking - "may have been an inadequate outcome variable" for measuring the
effectiveness of 4-AP. (Id.) Schwid thus tested seven outcome measures that the authors
thought might be "more sensitive." (Id.) Doing so, Schwid found a statistically significant
improvement in only one measure: timed gait, which was found to be improved in nine out of 10
patients, in comparison to the placebo group. (See id.)
The Goodman references disclose the results of the MS-F201 study, which, like the
Schwid study, examined multiple outcome measures. The Goodman references disclose that the
MS-F201 study was randomized, double-blinded, and placebo-controlled. Goodman I explains
that one of the goals of the MS-F201 study was "to explore efficacy over a broad dose range
using measures of fatigue and motor function," and it concludes that the study data "showed
statistically significant improvement from baseline compared to placebo in functional measures
28
The trial was multi-center, double-blind, and placebo-controlled, and it used parallel-groups
involving 161 patients who took 4-AP for six weeks. (See JTX-0104 at 817) Plaintiffs' expert,
Dr. Goodman, testified that Schwid disclosed "all of the key characteristics one looks for" to
obtain "a rigorous assessment of efficacy." (Goodman Tr. at 468)
63
of mobility (timed 25 walking speed; p=0.04) and lower extremity strength (manual muscle
testing; p=0.01)." (JTX-0062 at S116-l 7) Likewise, the Goodman poster reports a "[s]ignificant
benefit on timed walking" and a "[s]ignificant benefit on lower extremity strength." (JTX0080A)
Defendants argue that these prior art references - viewed in light of earlier studies, such
as Stefoski (which showed that 4-AP improved MS symptoms), Davis (which showed that 4-AP
improved motor function), and Polman (which showed that 4-AP could improve ambulation)represent the culmination of a "consistent march by those skilled in the art towards using 4-AP to
improve walking in MS patients." (D.I. 273 at 31)
Defendants' characterization of the prior art is not entirely persuasive. It understates the
complexity and uncertainty of the prior art, given what a POSA would know about both the
broader content of the prior art related to 4-AP and the challenges of interpreting MS studies
more generally. In particular, Defendants ignore the fact that the Schwid and MS-F201 studies
arose in the midst of significant uncertainty in the field of 4-AP research. Each study came in the
wake of the larger and more "rigorously designed" Elan study, which failed to show that 4-AP
had an effect on EDSS (which includes a walking component). (Goodman Tr. at 469) Although
researchers believed that alternative outcome variables could be more appropriate, it was not yet
clear that any variable would meet the requirements for clinical approval. The 2003 Solari
review, which analyzed the results of the Schwid and Van Diemen studies, concluded that the
information then available allowed "no unbiased statement about safety or efficacy of
aminopyridines for treating MS symptoms." (PTX-0416 at 1)
64
As Plaintiffs point out, both the Schwid and MS-F201 studies were exploratory studies,
designed to identify possible alternatives to EDSS as measures of efficacy, rather than studies
aimed at establishing effectiveness of the tested drug. Neither study includes a single, predefined measure of efficacy; instead, each consider multiple possible measures. (See D.I. 272 at
33) A POSA would understand that the risk of a false positive result is higher for such studies
than it is for studies with a single, pre-defined endpoint. (See Goodman Tr. at 472; PTX-0416 at
5 (recognizing "[a] distinct possibility of false positive findings" in studies involving multiple
measures of effectiveness)) 29 As Plaintiffs' expert Dr. Goodman explained, a POSA would have
recognized that the statistical significance of the Schwid and MS-F201 results did not account for
the increased probability of obtaining a false positive in the study as a whole. 30 (Goodman Tr. at
472)
Further, a POSA at the pertinent date would have known that "complexity, variability,
and [the] high placebo effect that characterize MS ... complicate the design and interpretation of
MS trials." (D.I. 272 at 38) Also, as Solari noted, "publication bias remain[ed] a pervasive
problem" in MS studies, meaning a POSA would have been concerned that the prior art may
have misleadingly excluded studies showing no effect. 31 (PTX-0416 at 1)
29
As evidence of this concept, Plaintiffs point out that "leads that had appeared promising on the
basis of [earlier] reports of small, multiple-endpoint studies were not" reproduced in later studies.
(D.I. 272 at 35) (comparing Polman's report of improvement in fatigue with Goodman's finding
of no such improvement)
30
Plaintiffs argue that, were a POSA to adjust the results of the Schwid and MS-F201 studies, the
study results would not be statistically significant. (See D.I. 272 at 61 (arguing that adjusted pvalue for Schwid would be 0.14); id. at 66 (arguing that adjusted p-value for MS-F201 would be
0.16))
31
Plaintiffs note that Acorda itself opted in some cases not to publish data related to failed trials.
(See D.I. 272 at 50-51)
65
Taking all of this into account, the Court concludes that a POSA would have examined
and interpreted the prior art holistically and cautiously. Despite all of Plaintiffs' valid concerns,
the Court finds that Defendants have proven, by clear and convincing evidence, that a POSA
would have formed a reasonable expectation of success based on Schwid and Goodman, in light
of the totality of the prior art. That neither Schwid nor the Goodman references report on the
results of a randomized, placebo-controlled study that was "properly designed to assess efficacy"
would be taken into account by a POSA, but would not have led a POSA to conclude that there
was not a reasonable expectation of success in using 4-AP to improve walking speed. (D.I. 272
at 38)
Several aspects of the record support the Court's conclusion on this issue. First, both the
Schwid and MS-F201 studies have two of the three characteristics Plaintiffs deem essential to a
persuasive efficacy study: each is randomized and placebo-controlled. (See id.) The studies' key
shortcomings are their relatively small size and multi-endpoint, exploratory design. (See id.)
While these features increase the probability of obtaining a false positive result (see Goodman
Tr. at 472; PTX-0416 at 5), the combined message a POSA would have discerned from Schwid
together with the Goodman references was a reasonable expectation of success in treating
walking with 4-AP. Just as conducting a study with multiple endpoints increases the overall
likelihood of uncovering at least one false-positive, obtaining the same result in a second study
decreases the likelihood that the first result was a fluke. (See D.I. 273 at 31-33)
Considering the prior art as a whole would not have tempered a POSA's expectations.
The results Schwid and Goodman present are consistent with the results of earlier studies such as
Polman, in which patients subjectively reported improvements in ambulation (see JTX-0095 at
66
295), and Davis, in which patients demonstrated improvements in motor function (see JTX-0043
at 186). These results are also consistent with Solari, which reported that a meta-analysis of past
studies of aminopyridines (including 4-AP) suggested that such drugs improved ambulation in
MS patients (p < 0.001). (See PTX-0416 at 1) Considering these results in light of the VEP
results reported in the Rush Studies, which demonstrated that 4-AP had real physiological effects
in MS patients at doses falling within a viable therapeutic window, 32 the prior art would not have
undermined the conclusion that a POSA would have drawn from the combination of Stefoski and
Goodman: that 4-AP could reasonably be expected to be successful in improving walking in
patients with multiple sclerosis. 33
Plaintiffs argue that this view of the prior art fails to take account of contemporaneous
uncertainty about the usefulness of 4-AP that only Acorda's later studies have made it possible to
disregard. (See D.I. 272 at 52) (arguing that Defendants' view of prior art "us[ es] the path
actually followed by the inventors as a map" to "argue that it would have been obvious to follow
32
As discussed above with respect to the Elan Patent, the pre-Elan Patent prior art would have
given a POSA a reasonable expectation of success in finding a viable therapeutic window for 4AP, despite incidents of seizures and other side effects in some patients. None of the subsequent
studies presents results that would have negated this conclusion. Indeed, Goodman stated that 4AP' s safety profile was "consistent with previous experience." (JTX-0080A)
33
Plaintiffs suggest that a POSA would consider the results of the Schwid and MS-F201 studies
to be inconsistent with the results of the Elan Study, as reported in Schwid. (See D.l. 272 at 4647) The Court disagrees. The Elan Study failed to show a statistically significant improvement
in MS symptoms as measured by EDSS, a composite measure of functioning. (See id. at 37)
Walking is just one component of the EDSS scale. Thus, a finding of no statistically significant
improvement in EDSS as a whole is not inconsistent with improvements in walking. In fact, the
Schwid study showed a statistically significant improvement in walking, but not in EDSS. (See
JTX-0104 at 817, 820) Therefore, the Court finds that a POSA would not assign great weight to
the results of the Elan Study in assessing whether it was reasonable to expect that 4-AP could be
used to treat walking, specifically.
67
that path with a reasonable expectation of success") In the Court's view, Plaintiffs' position
unreasonably suggests that proof of obviousness in this case must include at least one prior art
study demonstrating, to a statistically significant certainty, that the use of 4-AP is effective to
treat walking in MS patients. The law does not set the bar that high. In the context of
obviousness, an "expectation of success need only be reasonable, not absolute." Pfizer, 480 F.3d
at 1364 (stating patentee cannot avoid finding of obviousness "simply by a showing of some
degree of unpredictability in the art so long as there was a reasonable probability of success");
Hoffmann-LaRoche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014) ("Conclusive proof
of efficacy is not necessary to show obviousness."); In re Merck & Co., 800 F .2d 1091, 1097
(Fed. Cir. 1986) ("Obviousness does not require absolute predictability.").
For these reasons, Defendants have shown by clear and convincing evidence that a POSA
would reasonably expect that 4-AP could be used to improve walking in at least some MS
patients. Given this evidence, the Court finds that the use of 4-AP to treat walking in MS
patients would have been obvious to a POSA.
B.
Use of 10-mg, Twice-Daily Dosing
The asserted claims of the Acorda Patents are directed to the use of 10 mg, twice-daily
doses of sustained-release 4-AP to improve walking in a patient with MS. The parties dispute
whether the claims' 10 mg/twice-daily dosing pattern would have been obvious to a POSA.
Defendants argue that the claimed dosing pattern is unpatentably obvious under an
"obvious-to-try" standard. An invention may be obvious to try "[w]hen there is a design need or
market pressure to solve a problem" and the invention is one of "a finite number of identified,
predictable solutions" to that problem. KSR, 550 U.S. at 421. In Defendants' view, the 10
68
mg/twice-daily dose of the claims was one of a finite number of doses that a POSA would have
reasonably expected to be effective based on the prior art. Defendants point out that both Schwid
and Goodman disclosed studies that showed statistically significant benefits in walking among
MS patients who took 10-20 mg of 4-AP in sustained-release form twice daily. (See JTX-0104
at 817) The Goodman Poster, which described the MS-F201 study as being designed to
"[d]etermine [the] safety of' sustained release, concluded that the study showed "[e]vidence of
dose-response in [the] 20-40 mg/day range" and "[l]ittle added benefit, and increased [adverse
events] at doses above 50 mg/day." (JTX-0080A) In Defendants' view, a POSA who had
reviewed these references would have reasonably expected that the 10-20 mg/twice-daily dosages
of 4-AP disclosed in the prior art would be effective to treat walking in patients with MS. (See
D.I. 265 at 44)
Plaintiffs' response includes the observation that some of the prior art suggested that 4AP was more effective in higher doses - including doses higher than 20 mg, twice per day. Van
Diemen, a prior art study designed to assess the relationship among dosage, serum level, safety,
and efficacy, concluded that "higher doses and serum levels are likely to produce greater
improvement in those MS patients who are capable of favorably responding to 4-AP." (PTX0330 at 203) Likewise, Schwid concluded that "[t]reatment appeared particularly efficacious in
subjects who achieved serum ... levels above 60 ng/ml." (JTX-0104 at 820) Lastly, as
Defendants' expert Dr. Peroutka admits, the pharmacokinetic information available to a POSA
indicated that a dose higher than 25 mg/twice daily would be required to sustain that serum level.
(See Peroutka Tr. at 130-31; see also Goodman Tr. at 508)
69
Although the prior art might have given a POSA reasons to consider a broader range of
doses than 10-20 mg/twice daily, the prior art as a whole nevertheless suggests a "finite" set of
plausible solutions. A set of solutions is "finite" within the meaning of KSR when the prior art
provides direction about "which parameters were critical" or "which of many possible choices is
likely to be successful," and thereby reduces the options to a set that is "small and easily
traversed." Bayer Schering Pharma AG v. Barr Labs., Inc., 575 F.3d 1341, 1347 (Fed. Cir.
2009) (internal quotation marks omitted). While the prior art may have generally suggested that
4-AP would be more effective in higher doses, the art also reduced the set of plausible doses
because it suggested that higher doses of 4-AP were more likely to cause adverse events. The
Goodman Poster, for example, explains that, "consistent with prior experience," adverse events
were more likely at doses beyond 25 mg/twice daily. (JTX-Q080A) Thus, while it is unclear
what the highest dosage is that a POSA would have reasonably explored based on the prior art,
the prior art reduced the range of doses falling within 4-AP's perceived therapeutic window to a
fairly narrow band. (See Peroutka Tr. 104) (explaining that POSA would be motivated to find
lowest effective dose of 4-AP based on prior art showing that serious adverse events are more
likely to occur at higher dosages) As such, the prior art showed that the "field of endeavor" was
limited to a "finite" number of solutions. KSR, 550 U.S. at 420.
Plaintiffs further argue that, even if the prior art suggested a "finite" set of doses, the
claimed dosing scheme would not have been among them. They note that the Goodman
references, which disclose the only study that specifically explored dosages as low as 10
mg/twice daily, supply no dosage-specific information regarding the performance of 4-AP versus
placebo. Instead, the references report that the MS-F201 study demonstrated statistically-
70
significant improvements in the timed walk and manual muscle test for the treatment group as a
whole (i.e., based on combining the data for each patient at each dosage level). (Goodman Tr. at
482-84; Peroutka Tr. at 137-38) Thus, the study did not disclose a statistically-significant
treatment effect at a dose of 10 mg/twice daily, or at any other single, specific dose. (Peroutka
Tr. at 137-38) In Plaintiffs' view, the limited information regarding this dose would preclude a
POSA from having a reasonable expectation that the dose would be successful. (See D.I. 272 at
66-70)
Plaintiffs' contention, however, proves too much. On their reasoning, a POSA could not
have had a reasonable expectation of success in treating walking with any of the 4-AP doses
disclosed in the Goodman references - despite the fact that the results of treatment with those
dosages, taken as a whole, show.ed a statistically-significant effect on walking in MS patients simply because the significance of each individual result was unknown. This reasoning is
unpersuasive. Furthermore, the Goodman references are not silent as to the results of individual
doses. Instead, Goodman states that the results showed "evidence of a dose response in the 20 to
40 milligram per day range," indicating that patients taking these dosages of 4-AP demonstrated
a greater response to treatment than did patients receiving placebo. (Tr. at 801; see also
Goodman Tr. at 4 77-78 ("[A] dose response curve is looking at a series of increasing or
decreasing doses, and assessing the effects seen at the different dose levels ... to see whether or
not there is a pattern of correlation between ... increasing a dose and increasing a response."))
A POSA would have inferred from this finding that patients' walking responded to 4-AP dosed
71
at a 10 mg level. 34 Consequently, a POSA would consider 10 mg/twice daily to be among the
finite group of doses of sustained-release 4-AP that could reasonably be expected to improve
walking in MS patients. 35 As the lowest of the range of encouraging doses, 1Omg/twice daily
would have been an attractive starting point for a POSA.
Given this evidence, the Court finds that the use of a 10 mg sustained-release dose of 4AP twice per day to treat walking in MS patients would have been obvious to a POSA at the
priority date of the Acorda Patents.
C.
Use of Stable Dosing/No Titration
Each of the asserted claims of the Acorda Patents is directed to administration of a
"stable" dosing regimen of 10 mg sustained-release 4-AP. 36
34
Plaintiffs argue that a POSA would not draw this inference because the Goodman references do
not state that the dose response was statistically significant or highlight how the doses in this
range compared to placebo. (See D.I. 272 at 66-71) While the Court agrees with Plaintiffs that a
POSA would not infer anything about the statistical significance of any individual dose based on
the Goodman references' claims about a dose response, the Court also finds that a POSA would
have understood the Goodman authors to have considered the results of the placebo group before
representing that there was "evidence of a dose response" in the listed range. (Tr. at 733) Put
differently, a POSA would assume that a printed publication presented at an academic conference
did not omit context that a POSA would have found material to interpreting the study results.
(See generally Goodman Tr. at 525)
35
Dr. Goodman indicated at trial that this is the message that the Goodman Poster was intended to
convey. (See Goodman Tr. at 529-30) Dr. Goodman also conceded that a POSA would have
been motivated based on the results of the MS-F201 study to design a study "along the lines of
what became the [subsequent Acorda MS-F]202 study," which explored sustained-release doses
of 10 mg, 15 mg, and 20 mg/twice daily to treat walking in patients with MS. (Id. at 559; see
also PTX-0168A)
36
Some of the claims require that the claimed 10 mg/twice-daily dose be administered for a
specified period (i.e., two weeks or twelve weeks) and that the claimed dose be the only dose of
4-AP administered during that period. Other asserted claims specify that there be no titration
before or after administration of the 10 mg/twice-daily dose - precluding any adjustment of the
dosage at any time. These differences are not material to the Court's analysis. Nor do the parties
argue that they are. (See generally D.I. 272 at 30)
72
The parties disagree about whether a POSA would have had a reasonable expectation of
success in improving walking in a patient with MS by administering a stable dose of 10
mg/twice-daily 4-AP over several weeks. Defendants argue that a POSA would have expected
success with stable dosing because the prior art suggests that it can be safe and effective.
References including Van Diemen and Polman included reports of safe and effective long-term
use of stable dosing of immediate-release 4-AP. (See PTX-0330 at 196; JTX-0095 at 294)
Further, the MS-F201 study reported in Goodman indicates that 4-AP can be used safely over the
long-term; although participants received escalating rather than stable doses, the study did not
report unexpected adverse effects with use over several weeks. (See JTX-0080A) (stating that
observed safety profile was "consistent with the findings of previous studies") Dr. Peroutka
testified that a POSA would have had a reasonable expectation of success with stable dosing
because nothing in the prior art suggested that 4-AP could not be used chronically. (See Peroutka
Tr. at 104)
Plaintiffs argue that a POSA would not have had a reasonable expectation that stable
dosing would be safe and effective because "[n]o prior art reference cited by [D]efendants shows
the administration of any stable dose of 4-AP ... for more than a single week." (D.I. 272 at 78)
Plaintiffs add that prior art studies, including Murray and Polman, demonstrated that 4-AP could
cause adverse effects, including seizures. (See id. at 79)
As discussed above, however, any concerns a POSA would have had in light of these
studies would not have been sufficient to preclude a reasonable expectation that 4-AP could be
used to treat MS. Plaintiffs offer no evidence indicating why stable, long-term dosing would
change or magnify these concerns. Thus, the Court is not persuaded that safety concerns would
73
have undermined a POSA's otherwise reasonable expectation of success in implementing stable
dosing of 10 mg of sustained-release 4-AP twice daily. See generally Allergan, 726 F.3d at 1293
(stating that finding of nonobviousness cannot be predicated solely on "no reasonable
expectation of success in view of the general unpredictability of the formulation arts").
Plaintiffs also argue that stable dosing without titration would not have been obvious to a
POSA because the prior art taught that titration or dose escalation could be used to "gain
maximum efficacy while seeking to avoid adverse events." (D.I. 272 at 82) Plaintiffs argue that
this art would "not have provided a POSA with a reasonable expectation of success" in any
dosing regimen other than titration. (Id. at 42) But while it may be true that the prior art's
consistent use of titration did not specifically support stable dosing, it also did not undermine the
other evidence in the prior art that supports a finding that a.POSA would have had a reasonable.
expectation of success with stable dosing.
Plaintiffs' post-trial brief suggests that their argument regarding the titration schemes of
the prior art may be better understood in connection with the "motivation to combine" prong of
the obviousness inquiry. (See, e.g., id. at 40) ("The prior art taught upward titration as a means
of addressing 4-AP's narrow therapeutic index.") Plaintiffs point to Dr. Goodman's testimony
that there were "all kinds of' alternative dosing schemes that might be attractive to a POSA.
(Goodman Tr. at 551-52) They further argue that titration could be preferable to stable dosing,
as it could allow a POSA to optimize the dosage on a patient-by-patient basis. (See D.I. 272 at
82)
Even crediting these arguments, however, the Court finds that a POSA would have been
motivated to seek a stable dose of 4-AP. Dr. Peroutka stated this very opinion, explaining that
74
stable dosing was particularly desirable for treating MS, a chronic disease requiring long-term
treatment. (See Peroutka Tr. at 99) Similarly, Dr. Goodman conceded that, in at least some
circumstances, "it would be desirable that one would have some ... dose that ... the patient
would be prescribed to take on a regular basis."37 (Goodman Tr. at 553)
Because the evidence in the record reflects that a POSA would have been motivated to
pursue stable dosing and would have had a reasonable expectation of success in doing so, the
Court finds that stable dosing of a 10 mg sustained-release dose of 4-AP twice per day to treat
walking in MS patients would have been obvious to a POSA.
D.
Pharmacokinetic Limitations
Several of the asserted claims of the Acorda Patents specify particular pharmacokinetic
parameters or a particular release profile to be achieved by administering the specified dosing
regimen to improve walking or increase walking speed.
The pharmacokinetic ranges listed in the asserted claims of the Acorda Patents fall within
the ranges previously disclosed in Hayes. (See Peroutka Tr. at 96-97; JTX-0069 at 185-86)
Hayes is a prior art study that disclosed the pharmacokinetics of a 10 mg sustained-release
formulation when administered twice a day for six consecutive days, and once daily on the
seventh day. (See JTX-0069 at 186) It is undisputed that the Hayes researchers used the
Ampyra® formulation in their study. (See D.I. 272 at 71) There is also no disagreement that the
37
Dr. Goodman also testified that a POSA "could look at the entirety of the art and still believe
that there was a desire to increase, escalate, titrate doses towards higher levels." (Goodman Tr. at
552) Even accepting this opinion as true, however, does not overcome the Court's finding that
there was a motivation to identify a stable dose as well. The goal of a stable dose (for at least
some MS patients) and the goal of a dose that could be titrated upwards (perhaps for other
patients) are not incompatible.
75
pharmacokinetic parameters reported in Hayes are inherent properties of that formulation. (See
D.I. 265 at 42-43)
To Defendants, it follows that inclusion of the pharmacokinetic parameters in the claims
cannot render the claims non-obvious. (See id. at 48) This position assumes that a POSA would
have been aware that a sustained-release dosage form achieving the pharmacokinetic parameters
disclosed in Hayes would have resulted in an improvement in walking, as required by the
asserted claims. (See D.I. 279 at 4; Cyclobenzaprine, 676 F.3d at 1071) While the record on this
issue is not as clear as the Court would have hoped, the Court ultimately finds that Defendants
have met their burden of proof with respect to the PK limitations of the Acorda Patents.
Plaintiffs insist that Defendants failed to prove that the PK parameters of the asserted
claims of the Acorda Patents "are inherent properties of the administration of every sustainedrelease formulation of 4-AP administered at 10 mg BID." 38 (D.I. 272 at 83; see also id. at 84
(arguing that "most significantly" "there is nothing in the prior art identifying the
pharmacokinetic values recited in the claims as being effective to improve walking or increase
38
In their supplemental letter brief, Plaintiffs argue that the Court previously "reject[ ed] an
argument that 'conflate[d] the difference between PK data and dose-efficacy results'" inAvanir
Pharmaceuticals, Inc. v. Actavis South Atlantic LLC, 36 F. Supp. 3d 475 (D. Del. 2014). (D.I.
279 at 4) (quoting Avanir, 36 F. Supp. 3d at 501) In Plaintiffs' view, Avanir supports Plaintiffs'
contention that it was not obvious that the PK values disclosed in Hayes would lead to improved
walking in patients with MS. (See id.) The Court disagrees. The instant case is distinguishable
from Avanir because, here, several experts testified as to the relationship between the PK values
disclosed in the prior art and improved walking in patients with MS. (See, e.g., Goodman Tr. at
510 (stating that PK profiles reported in Hayes "may certainly show the pharmacokinetic profile
that[] [is] analogous to what would be found in MS patients"); Kibbe Tr. at 224 (stating that
POSA would expect no difference in PK results from dosing patients with MS or patients with
spinal cord injuries)) By contrast, in Avanir, "[b]oth sides' experts agreed [that] the disclosed ...
dose ranges ... in the [prior art] were not directed to the treatment of PBA." Avanir, 36 F. Supp.
3d at 501.
76
walking speed in MS patients")) The Court disagrees. Instead, the Court agrees with Defendants
that the pharmacokinetic responses that are incorporated as limitations into certain asserted
claims of the Acorda Patents are "inherent in the claimed dosing and [are] taken directly from the
prior art." (D.I. 265 at 5 (citing JTX-0002 at 23:1-23; JTX-0069 at AMP-DEF-000498, Table
2) 39 ; see also Goodman Tr. at 510 (stating that PK profiles reported in Hayes "may certainly
show the pharmacokinetic profile that[] [is] analogous to what would be found in MS patients");
Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012) ("[A]n obvious
formulation cannot become nonobvious simply by administering it to a patient and claiming the
resulting serum concentrations."))
Further, the parties recently submitted supplemental letter briefs to respond to questions
from the Court. (See D.I. 278, 279) Having considered the letter briefs, and having considered
the evidence of record, the Court agrees with Defendants that they have proven that, at the
priority date of the Acorda Patents, a POSA would have been aware that a sustained-release
dosage form achieving the pharmacokinetic parameters disclosed in Hayes III would have been
associated with an improvement in walking in MS patients. (See D.I. 278 at 4) (citing evidence)
E.
Secondary lndicia of Non-Obviousness
Plaintiffs argue that four secondary considerations support the non-obviousness of the
Acorda Patents: commercial success, unexpected results, failure of others, and long-felt but
unmet need. Defendants respond that none of these factors is probative of non-obviousness. As
39
At trial, in response to the Court's questioning, Plaintiffs' counsel conceded that the claimed
PK data were obvious. (See Tr. at 793-94) ("It was known in the art that a sustained-release
formulation of 10 megs BID could achieve that PK, [but] not that that PK would yield any
efficacy for walking.")
77
discussed below, the Court finds that secondary considerations do not support a finding of nonobviousness in this case.
1.
Commercial Success
Commercial success can be an indication of nonobviousness "because the law presumes
an idea would successfully have been brought to market sooner, in response to market forces, had
the idea been obvious to persons skilled in the art." Merck & Co. v. Teva Pharm. USA, Inc., 395
F.3d 1364, 1376 (Fed. Cir. 2005). Evidence of commercial success is only relevant, however,
when it "results from the claimed combination of elements that constitutes the invention," rather
than being attributable to what was "already known in the prior art" or to the benefits of
"unclaimed features." ArcelorMittal France v. AK Steel Corp., 700 F.3d 1314, 1326 (Fed. Cir.
2012). Thus, a party proffering evidence of commercial success must demonstrate that there is a
"causal relation or 'nexus' between an invention and commercial success of a product
embodying that invention." Merck, 395 F.3d at 1376.
The parties here dispute both whether Ampyra® is a commercial success and whether any
commercial success it has achieved has a nexus with the invention claimed in the Acorda
Patents. For the reasons discussed below, the Court finds that Ampyra® is a commercial success
and that there is a nexus between that success and the features claimed in the Acorda Patents.
However, the Court also finds that this success does not support a finding that the Acorda Patents
are non-obvious because the existence of a "blocking" patent provides an independent,
alternative reason why a POSA would not have attempted to develop the invention claimed in the
Acorda Patents.
78
a.
Ampyra® is a commercial success
Ampyra® has demonstrated considerable success. Between its launch in 2010 and the
end of 2015, domestic sales of Ampyra® reached $1. 7 billion and profits reached nearly $1
billion. (D.I. 262 if 157) Over that time-frame, sales of Ampyra® tablets more than doubled,
even as the price per tablet increased from $17 to $26. (Id.) Acorda was also able to license
Ampyra® to another drug company, Biogen, to sell the drug outside the United States - a
partnership that has led to an additional $13 5 million in royalties to date. (Id.)
Defendants argue that these sales data do not support a finding of commercial success
because the projected sales of Ampyra® are insufficient to cover the costs of its development.
Defendants' expert, Dr. McDuff, made several estimates of the cost of developing Ampyra®,
accounting for factors such as (1) direct expenditures on research and development;
(2) success rates; (3) development time; and (4) costs of capital. (See D.I. 265 at 63) After
tailoring his estimates to reflect several factors specific to Ampyra®, he found that the present
value of Ampyra®'s profits, even projected until the Acorda Patents' 2027 expiration date, does
not exceed the estimated costs of Ampyra®'s development. (See id.)
In Defendants' view, the entire cost of developing Ampyra® is relevant to the analysis
because no "rational decision[]maker" would proceed to develop a drug unless he or she
expected its eventual revenues to cover its development costs. (Id.) Thus, the decision to
proceed with incurring the costs of development gives some indication as to what, at a minimum,
a rational decisionmaker expected the commercial opportunity for the drug to be. (McDuff Tr. at
629) If a drug does not realize at least that commercial opportunity, Defendants argue, then the
drug is commercially unsuccessful from the perspective of one who has invested in the process
79
of bringing it to market. (See id.) In Defendants' view, if a drug is unsuccessful according to
this analysis, then it is unclear whether the invention had not been previously brought to market
because (i) it was non-obvious or, instead, because (ii) it was obvious but a rational
decisionmaker would have known that its commercial potential was too limited to justify the
costs of its development.
Examination of Ampyra®'s development history demonstrates that a comparison of
actual sales to total development costs constitutes an inappropriate portrayal of how a rational
decisionmaker would have analyzed Ampyra®'s commercial potential. As Defendants
themselves note, the Acorda inventors licensed the Elan Patent in 1997, with the intention of
developing a drug for treatment of spinal cord injuries and MS. (See D.I. 265 at 61-62) It was
only after expending considerable time and money on licensing a formulation and conducting
clinical trials that the Acorda patentees recognized the likelihood that the drug would be suited to
treat only walking in MS patients. (See McDuff Tr. at 630) Further, it was not until after the
priority date of the Acorda Patents that published clinical trials revealed that Ampyra® was
effective in just a subset of patients who suffered from walking disabilities. (See id.) At each
stage of this process, a rational decisionmaker could have had a different estimation as to the
likely future sales of Ampyra®, as well as the costs of future development. But at any given
time, the pertinent comparison could have supported a rational decision to proceed with
development. 40
40
Defendants argue that a POSA considering whether to proceed with developing Ampyra® in
2004 would compare likely revenues to the entire cost of bringing Ampyra® to market. (See D.I.
265 at 63) At trial, Dr. McDuff further stated that a POSA would consider sunk costs in deciding
whether to proceed with drug development, because such costs would capture a drug's "full
development cost." (McDuff Tr. at 688) However, Plaintiffs did not incur all of those sunk
80
In arguing that Ampyra®'s purported economic unprofitability may have been the reason
no one attempted to develop it sooner, Defendants urge the Court to find that a rational
decisionmaker performing this analysis in 2004 would have been able to project Ampyra®'s
sales and to determine that the drug would be unprofitable. (See D.I. 265 at 63) But the record
does not support such a finding. Crucially, the record does not make clear how a rational
decisionmaker in 2004 would have projected the eventual size of the market for Ampyra® to be,
particularly given that later clinical trials demonstrated that the drug had a more limited patient
population than previously expected. Nor is it clear what remaining development costs a rational
decisionmaker would expect to incur, because Dr. McDuff did not adjust estimates of direct
expenditure, development time, or anticipated success rate to reflect the work that had been done.
Hence, even assuming that economic profitaqility calculations could in some cases undermine
the persuasive force of apparently strong sales, the Court finds that Defendants have not made a
sufficient showing to support such a finding in this case.
Given the strength of Ampyra®'s sales, and the absence of any evidence that its sales are
disappointing given its limited indication and patient population, 41 the Court finds that Ampyra®
is a commercial success.
costs; they obtained a license to the Elan Patent. It is not necessarily the case that the cost of the
license met or exceeded the amount of Elan's sunk costs in developing the Elan Patent.
41
Defendants argue that Ampyra®'s sales figures are weak in comparison to the sales of top MS
treatments. (See D.I. 265 at 63) This comparison is not particularly probative of commercial
success in this case because, unlike Ampyra®, none of the drugs to which Defendants are
comparing it is approved exclusively for the narrow indication of improving walking. (See
Goodman Tr. at 512)
81
b.
Nexus with the invention of the Acorda Patents
The Court further finds that there is a nexus between Ampyra's® commercial success and
the inventions claimed in the Acorda Patents. There is considerable evidence that the drug's
success is at least partially attributable to its unique indication: treating walking in MS patients.
In addition to being indicated exclusively for walking, Ampyra®'s marketing messaging to
physicians and patients specifically highlights the drug's ability to improve walking-related
symptoms ofMS. 42 (See D.I. 272 at 10) A large proportion of Ampyra®'s prescriptions are
renewals, indicating that the drug is successful in treating MS. (See id. at 87) Indeed, some
insurance companies require patients to demonstrate improved walking in order to be able to
renew their prescription. (See id.) These data, like consumer and physician surveys showing that
over 80% of doctors and patients are satisfied with Ampyra®, suggest that the drug's ability to
treat walking drives its commercial success. (See id.)
As Defendants point out, the record does not support a finding that Ampyra®'s success is
exclusively attributable to the Acorda Patents. For example, Ampyra®'s commercial success is
also attributable in part to the drug's sustained-release formulation (claimed in the Elan Patent)
and the 4-AP active ingredient (disclosed in the prior art). Plaintiffs did not attempt to apportion
Ampyra®'s success among its various features. Nevertheless, the proffered evidence regarding
the importance of the drug's efficacy (in treating walking in MS patients) to its sales is sufficient
for establishing a nexus between the Acorda Patents and Ampyra®'s success. See Apple Inc. v.
Samsung Elecs. Co., 839 F.3d 1034, 1068, 1073 (Fed. Cir. 2016) (indicating that nexus is
42
Notably, the record suggests that Ampyra® sales are not due to aggressive marketing: both
Ampyra® revenues and tablet sales have increased even as marketing expenditures for the drug
have declined. (Bell Tr. at 590-91)
82
established when patentee shows consumers are more likely to buy product if it includes patented
features).
c.
Commercial success and a blocking patent
Although the Court finds that Ampyra® is a commercial success and that its commercial
success has a nexus with the patents-in-suit, this evidence is oflittle probative value to the
obviousness inquiry with respect to the Acorda Patents because the earlier Elan Patent "blocked"
competitors from practicing the Acorda Patents. See Merck, 395 F.3d at 1377. Because the
Acorda Patents practice the Elan Patent, 43 no one other than the Elan patentees and their licensees
could have practiced the invention of the Acorda Patents without facing liability for patent
infringement. The risk of such liability would have provided an independent incentive for a
patentee not to develop the invention of the Acorda Patents, even if those inventions were
obvious. See Warner Chilcott Co, LLC v. Teva Pharm. USA, Inc., 37 F. Supp. 3d 731, 739 (D.
Del. 2014), aff'd, 594 F. App'x 630 (Fed. Cir. Nov. 18, 2014).
For this reason, the Court finds that Plaintiffs' evidence that Ampyra®'s commercial
success had a nexus to the Acorda Patents does not support a finding that the claims of the
Acorda Patents are non-obvious.
2.
Unexpected Results
Evidence that a "claimed invention exhibits some superior property or advantage that a
person of ordinary skill in the relevant art would have found surprising or unexpected" may
suggest that the invention is non-obvious. In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995).
Plaintiffs argue that the efficacy of a 10 mg/twice-daily dose of 4-AP would have been surprising
43
lt is undisputed that the Acorda Patents practice the Elan Patent. (See D.I. 265 at 37)
83
to a POSA, as would have been the fact that a 10 mg dose was as effective in treating walking as
higher doses. In Plaintiffs' view, these results are unexpected because "[n]one of the [prior] art,
viewed alone or in combination, supported an expectation that the 10 mg[/twice-daily] dosing
regimen of the Acorda [P]atent claims would improve walking or increase walking speed." (D.I.
274 at 6) Specifically, Plaintiffs argue that the limited and varied data in the prior art would have
prevented a POSA from developing such an expectation. (See id. at 6-9)
A showing that a drug was slightly more or less effective than the prior art would suggest
does not constitute an "unexpected result" for purposes of assessing obviousness. Galderma
Labs., L.P. v. Tolmar, Inc., 737 F.3d 731, 739 (Fed. Cir. 2013); In re Merck, 800 F.2d at 109899. As discussed above with respect to the obviousness of the 10 mg dose, the prior art, while
perhaps insufficient to prove the effectiveness of that dosage, did not render its effectiveness
unexpected. Further, although the prior art in this case suggested that larger doses of 4-AP might
be more effective than smaller doses, there was not sufficient evidence of dose-response to
render a 10 mg/twice-daily dose non-obvious under an obvious-to-try-standard.
For these reasons, the Court finds that Plaintiffs have not presented evidence of
unexpected results that militates in favor of finding that the claims of the Acorda Patents are nonobvious.
3.
Failure of Others
The "failure of others to find a solution to the problem which the patent[ s] ... purport[]
to solve" may be probative of non-obviousness because it suggests "the presence of a significant
defect [in the prior art], while serving as a simulated laboratory test of the obviousness of the
solution to a skilled artisan." Symbol Techs., Inc. v. Opticon, Inc., 935 F.2d 1569, 1578-79 (Fed.
84
Cir. 1991) (internal quotation marks omitted; brackets in original). Plaintiffs argue that the nonobviousness of the Acorda Patents is evident from the failure of others to develop a "safe and
effective therapy to improve walking in MS patients." (D.I. 274 at 24)
The record includes only minimal evidence that anyone other than the Acorda patentees
attempted to develop a "safe and effective therapy to improve walking in MS patients." (Id.)
Drs. Lublin and Goodman testified that another pharmaceutical company, Sanofi-Aventis, tried
and failed to develop a therapy to improve walking in MS patients, using as an active ingredient
a potassium channel blocker other than 4-AP. (See Lublin Tr. at 411-13; Goodman Tr. at 51315) But this failed effort is not particularly probative of a "gap" in the prior art that would render
non-obvious the invention of the Acorda Patents. Sanofi-Aventis likely did not use 4-AP
because it was blocked from doing so by the Elan Patent. (See D.I. 272 at 92) Bence, SanofiAventis' failure does not provide much evidence that the formulation of the Acorda Patents was
non-obvious.
The record also reflects that Elan failed in its attempts to develop MS therapies for
indications other than walking. (PTX-0360 at 101-02) Since Elan's failed efforts preceded the
Schwid and MS-F201 studies that demonstrated 4-AP's effects in walking- indeed, as Dr.
Goodman testified, the study documenting Elan's failure prompted those later studies (see
Goodman Tr. at 469)- Elan's failure is not particularly probative of what would have been
obvious to a POSA on the priority date of the Acorda Patents. Moreover, the Acorda Patents
themselves have also not been successful as a therapy for indications other than walking - and
Ampyra® is not FDA-approved for treatment of any other symptom of MS. (See McDuff Tr. at
630)
85
For these reasons, the Court finds that Plaintiffs have not presented evidence of "failure
of others" that militates in favor of finding that the claims of the Acorda Patents are non-obvious.
4.
Long-Felt but Unmet Need
"Evidence of a long-felt but unresolved need can weigh in favor of ... non-obviousness
of an invention because it is reasonable to infer [that] the need would not have persisted had the
solution been obvious." Apple, 839 F.3d at 1056. The record reflects that Ampyra® satisfied a
long-felt, unmet need for a method of treating walking in MS patients. It is undisputed that
walking impairments have long been recognized as a devastating symptom of MS. The FDA's
decision to grant priority review status to Acorda's NDA for Ampyra® suggests that the industry
considered that need to be at least partially unmet. See Ferring B. V v. Watson Labs., Inc.-Fla.,
764 F.3d 1401, 1407 (Fed. Cir. 2014) (holding that fDA's decision to "fast-track" approval
supported finding oflong-felt and unmet need).
Nevertheless, this evidence of long-felt and unmet need is of limited probative value with
respect to the obviousness of the invention claimed by the Acorda Patents. As of the Acorda
Patents' priority date, a POSA would not have been able to practice the invention of the Acorda
Patents without infringing the Elan Patent. Thus, it is possible that the need for a therapy to
improve walking in MS patients remained unmet despite the obviousness of the solution claimed
in the Acorda Patents. For these reasons, the Court finds that, although Plaintiffs have presented
convincing evidence that there existed a long-felt, unmet need for a method of improving
walking in MS patients, this evidence does not militate in favor of finding that the claims of the
Acorda Patents are non-obvious.
86
F.
Conclusion as to Acorda Patents
While Defendants face a high burden in proving that the Acorda Patents are invalid as
obvious, the Court finds, after weighing all of the credible evidence, that they have met this
burden. As explained above, Defendants have adduced clear and convincing evidence that a
POSA at the priority date would have been motivated and would have had a reasonable
expectation of success to practice and combine each of the limitations of the asserted claims of
the Acorda Patents. The evidence of secondary considerations is not sufficient to overcome these
findings.
This is not to say that there is no significant evidence of nonobviousness. The Court has
explained above that there is merit in many of Plaintiffs' contentions. Of particular note, the
Court found credible th~ testimony of co-inventor (Acorda CEO) Dr. Cohen. At trial, Dr. Cohen
vividly recounted the sometimes harrowing financial risks he and his nascent company took, and
the several occasions on which it looked as if his "bet-the-company" approach had suffered a
fatal blow. (See, e.g., Cohen Tr. at 282) It may well be that Dr. Cohen's subjective experience
of the "invention story" was that the purported invention of the Acorda Patents was anything but
obvious. The Court has considered this evidence - but the law directs a different analysis. For
the reasons explained above, the evidence as a whole establishes, clearly and convincingly, and
objectively, that the asserted claims of the Acorda Patents would have been obvious to a person
of ordinary skill in the art at the priority date, notwithstanding the actual inventors' subjective
expenence.
Also, the Court agrees with Plaintiffs that, at the priority date of the Acorda Patents, the
risk of seizures "loomed over the work of exploring the use of 4-AP in MS." (D.I. 272 at 5) A
87
POSA would have known in 2004 that 4-AP was known to have the capacity to induce seizures,
and would further have known that seizures could be particularly dangerous for individuals
suffering from MS. (See id.) However, as Defendants correctly argue, a POSA can have a
motivation and reasonable expectation of success notwithstanding recognition of a substantial
risk. As Defendants further point out, even today seizure risk remains a significant concern
associated with the use of 4-AP (especially at doses greater than those of Ampyra®), but that
known and significant risk has not deterred POSAs or pharmaceutical companies - including
Plaintiffs and Defendants - from developing drugs with 4-AP as their active ingredient. (See Tr.
at 746)
In the end, there is evidence on both sides of the parties' dispute, and this was an
eminently "triable case." But the Court's assessment of the evidence as a whole is that
Defendants have proven clearly and convincingly that the Acorda Patents are invalid due to
obviousness.
CONCLUSION
Defendants have failed to prove by clear and convincing evidence that claims 3 and 8 of
the Elan Patent are invalid due to obviousness. Defendants have proven by clear and convincing
evidence that claims 1, 7, 38, and 39 of the '826 patent; claims 3 and 5 of the '685 patent; claims
1, 2, 5, 22, 32, 36, and 37 of the '437 patent; and claims 36, 38, and 45 of the '703 patent are
invalid due to obviousness.
An appropriate Order follows.
88
Disclaimer: Justia Dockets & Filings provides public litigation records from the federal appellate and district courts. These filings and docket sheets should not be considered findings of fact or liability, nor do they necessarily reflect the view of Justia.
Why Is My Information Online?