Appeals from the United States District Court for the
District of Delaware in Nos. 1:14-cv-00882-LPS,
1:14-cv-00922-LPS, 1:14-cv-00935-LPS, 1:14-cv-00941-LPS,
Chief Judge Leonard P. Stark.
M. Wexler, Paul Hastings LLP, New York, NY, argued for
plaintiff-appellant. Also represented by Stephen Blake
Kinnaird, Igor Victor Timofeyev, Washington, DC; Garrard R.
Beeney, Wenying Angela Chang, Stephen J. Elliott, Sullivan
& Cromwell LLP, New York, NY; Anthony Michael, Jane G.
Wasman, Acorda Therapeutics, Inc., Ardsley, NY.
Maryellen Noreika, Morris, Nichols, Arsht & Tun-nell LLP,
Wilmington, DE, for plaintiff-appellee. Also represented by
Jeremy A. Tigan.
Charles B. Klein, Winston & Strawn LLP, Washington, DC,
argued for defendants-cross-appellants.
Defendants-cross-appellants Roxane Laboratories, Inc., Teva
Pharmaceuticals USA, Inc. also represented by Andrew Curtis
Nichols; Bryce Cooper, George C. Lombardi, Reid Smith,
Florence, Parker Poe Adams & Bernstein LLP, Atlanta, GA,
for defendant-cross-appellant Mylan Pharmaceuticals Inc. Also
represented by Micheal L. Binns, Karen L. Carroll.
Anne Kagan, Banner and Witcoff, Ltd., Washington, DC, for
amicus curiae Biotechnology Innovation Organization. Also
represented by Melissa A. Brand, Lisa Meredith Hemmendinger;
Hansjorg Sauer, Biotechnology Innovation Organization,
E. Kamholz, Covington & Burling LLP, Washington, DC, for
amicus curiae Pharmaceutical Research and Manufacturers of
America. Also represented by Brianne Bharkhda; David Evan
Korn, Pharmaceutical Research and Manufacturers Association
of America, Washington, DC.
Newman, Dyk, and Taranto, Circuit Judges.
TARANTO, CIRCUIT JUDGE.
us are patents that claim the administration of a medication
containing the active ingredient 4-aminopyridine (4-AP) to
improve walking in individuals with multiple sclerosis.
Acorda Therapeutics, Inc., holds New Drug Application No.
022250, approved by the U.S. Food and Drug Administration
(FDA). Pursuant to that approval, Acorda markets, under the
name "Ampyra®," 10 milligram 4-AP
sustained-release tablets for twice-daily oral
administration. In the FDA's Approved Drug Products
with Therapeutic Equivalence Evaluations, or Orange
Book, Acorda has listed, as claiming methods of using Ampyra,
four patents that Acorda owns: U.S. Patent No. 8, 007, 826;
No. 8, 663, 685; No. 8, 354, 437; and No. 8, 440, 703. Those
patents ("the Acorda patents") are the main patents
at issue on appeal.
additional patent is before us. Acorda holds an exclusive
license to an earlier, broader patent, U.S. Patent No. 5,
540, 938, referred to as "the Elan patent" because
it was originally assigned to Elan Corporation, plc (whose
successor in interest is Alkermes Pharma Ireland Ltd.). The
Elan patent, listed in the Orange Book for Ampyra along with
the Acorda patents, claims methods of treating patients
having certain conditions, including multiple sclerosis, by
administering a drug containing a sustained-release
formulation of any of certain agents, one of them 4-AP. The
later Acorda patents claim species of the Elan patent's
genus claims by adding further, more specific requirements to
the Elan patent's claimed methods. While the Elan
patent's claims broadly cover administering a
sustained-release formulation of 4-AP to individuals with
multiple sclerosis, the Acorda patents' claims further
specify that such a drug must be administered (1) in a 10 mg
dose twice a day (2) at that stable dose for the entire
treatment period of at least two weeks (3) to achieve 4-AP
serum levels of 15-35 ng/ml and (4) to improve walking.
Laboratories, Inc.; Mylan Pharmaceuticals, Inc.; and Teva
Pharmaceuticals USA, Inc., have submitted Abbreviated New
Drug Applications seeking FDA approval to market generic
versions of Ampyra. In July 2014, Acorda and Alkermes sued
those entities ("defendants") in the District of
Delaware, alleging infringement of several claims in each of
the Elan and Acorda patents. The defendants stipulated to
infringement but challenged the validity of the asserted
claims. The district court held that the asserted claims in
the Acorda patents are invalid for obviousness. But the court
upheld the asserted claims of the Elan patent against
invalidity challenges and enjoined the defendants from
activity infringing that patent until it expired on July 30,
appealed the invalidity ruling regarding the Acorda patents.
The defendants cross-appealed the validity ruling regarding
the Elan patent and the resulting injunction. We now affirm
the judgment that the asserted Acorda patent claims are
invalid. We dismiss the cross-appeal as moot.
of our decision that the issues concerning the Elan patent
are moot, we focus on the background of the Acorda patents.
Essential to understanding the obviousness issue is an
understanding of the prior art.
also called "dalfampridine" and
"fampridine," was first identified in 1902.
Acorda Therapeutics, Inc. v. Roxane Labs., Inc., No.
1:14-cv-00882-LPS, 2017 WL 1199767, at *3, *5 (Mar. 31, 2017)
(Dist. Ct. Op.). Belonging to a class of compounds
that function as potassium-channel blockers, 4-AP "has
been found to slow the potassium flow in nerve impulse
transmission" and, by doing so, help "restor[e]
conduction in blocked and demyelinated nerves," '826
patent, col. 2, lines 5-11, i.e., nerves whose
myelin insulation has been damaged. 4-AP was first used in
human studies in the 1970s to investigate its effect on
neurological diseases resulting in muscle weakness. Dist.
Ct. Op. at *5. For several decades, 4-AP has been the
focus of research regarding the treatment of multiple
sclerosis in particular. See, e.g., id. at
*5-7 (reciting studies); J.A. 6697 (paper published in 1987
describing study of the effect of 4-AP on subjects with
multiple sclerosis). Multiple sclerosis causes the
demyelination, or loss of myelin, of nerves in the central
nervous system and results in a wide variety of symptoms,
including walking impairment, tingling or pain, brain
scarring, cognitive changes, visual impairments, and fatigue.
See '826 patent, col. 1, lines 36-42; Dist.
Ct. Op. at *2. Eventually, 4-AP research led to the
development, patenting, and FDA approval of Ampyra.
1980s, researchers at the Rush Medical School conducted a
study on 12 patients with multiple sclerosis, and 5 without,
to determine whether intravenous administration of 7 to 35 mg
of 4-AP had any therapeutic effect on multiple sclerosis.
J.A. 6697 (Dusan Stefoski et al., 4-Aminopyridine
Improves Clinical Signs in Multiple Sclerosis, 21 Annals
of Neurology 71 (1987)). According to the published paper
reporting that study (Stefoski), 10 of the 12 patients with
multiple sclerosis "showed mild to marked
improvement"; "[v]ision improved in 7 patients,
oculomotor function in 5, and motor function (power,
coordination, gait) in 5." J.A. 6697. Improvements were
seen at doses as low as 2 mg: In one patient, gait
improvement occurred within 25 minutes of administration of a
total dose of 2 mg. J.A. 6699. Stefoski also reported:
[W]e observed no serious or bothersome side effects at total
doses below 30 to 35 mg injected not less than 20 minutes
apart for aliquots up to 3 mg. Moreover, the clinical
improvements in many of our patients were of sufficient
magnitude to represent a functionally noteworthy therapeutic
benefit. Studies are currently in progress to determine the
clinical usefulness of oral 4-AP as a symptomatic treatment.
6701; accord J.A. 6697.
1990, an overlapping group of researchers published a paper
(Davis) reporting another study on 4-AP's effect on
symptoms of multiple sclerosis. J.A. 6327 (Floyd A. Davis et
al., Orally Administered 4-Aminopyridine Improves
Clinical Signs in Multiple Sclerosis, 27 Annals of
Neurology 186 (1990)). In that study, 20 patients with
multiple sclerosis were given either a single oral dose of
4-AP (15 patients) or a placebo (5 patients). J.A. 6327. Of
those in the active treatment group, 4 patients were given a
10 mg dose of 4-AP, 2 were given 12.5 mg, 4 were given 15 mg,
4 were given 20 mg, and 1 was given 25 mg. Davis at 187
tbl.1. Davis states that "[m]ild to marked improvements
occurred in all of the 15 [multiple sclerosis] patients given
4-AP." J.A. 6329; accord J.A. 6327.
"Improvements developed gradually with doses as low as
10 mg 4-AP, usually beginning within 60 minutes after drug
administration." J.A. 6329. Motor function improved in 9
of 13 patients in the active treatment group (motor function
was not measured in 2). Davis at 187 tbl.1; J.A. 6329. The
improvements were "most striking with respect to power
and coordination" and "were apparent with both
simple function tests and the performance of complex motor
tasks such as gait and repetitive movements." J.A. 6329.
Finally, Davis notes, no "serious or bothersome side
effects," including seizures, were observed at single
oral doses up to 25 mg. J.A. 6332.
years later, researchers at a university hospital in the
Netherlands published a paper (Van Diemen) reporting a
randomized, double-blind, placebo-controlled crossover study
that "demonstrated efficacy of [4-AP] in improving
disability of patients with multiple sclerosis." J.A.
7037 (Harriët A. M. Van Diemen et al.,
4-Aminopyridine in Patients with Multiple Sclerosis:
Dosage and Serum Level Related to Efficacy and Safety,
16 Clinical Neuropharmacology 195 (1993)). In the second
phase of the study lasting 12 weeks, 69 patients were orally
administered 10-20 mg 4-AP per day, split into two or three
doses. J.A. 7038, 7042. The doses were escalated during the
second week, and again during the sixth week, by 5-15 mg.
J.A. 7038-39. The paper reports improvements in certain
measures of eye functioning. J.A. 7042. And it reports that
"side effects were mild" for those patients given
oral doses of 4-AP (versus intravenous 4-AP). J.A. 7045;
see also Van Diemen at 200-01 (no seizures).
thereafter, some of the same researchers published a second
paper (Polman) about the long-term efficacy and safety of
4-AP given to patients with multiple sclerosis. J.A. 6654
(Chris H. Polman et al., 4-Aminopyridine in the Treatment
of Patients with Multiple Sclerosis, 51 Archives of
Neurology 292 (1994)). Polman reports a study of 31 patients
with multiple sclerosis, 19 of whom took a stable dose of
4-AP between 10-50 mg per day (the exact dose for each
patient is unknown), and 12 of whom initially took 10-15 mg
per day and then took increasing doses in 4 to 8 weeks. J.A.
6655; see J.A. 7042. In the first group, 18 of the
19 patients "had a favorable response to the
medication" and "reported a subjective improvement
in the ability to perform the activities of normal daily
life, which was mainly owing to improved ambulation and
reduction in severity of fatigue." J.A. 6655. In 3
patients, the subjective improvement was significant on the
Expanded Disability Status Scale (EDSS), id.-a
composite measure of function in multiple sclerosis patients,
including a walking component, that is "widely accepted
in the [multiple sclerosis] community," Dist. Ct.
Op. at *8; see id. at *30; J.A. 6681. In the
second group, 6 patients reported a "favorable
response" to 4-AP treatment, "as defined by the
ability to perform activities of normal daily life."
J.A. 6655-56. One patient demonstrated a significant
improvement in EDSS score. J.A. 6656.
23 patients (17 in the first group; 6 in the second group)
continued active treatment for 6 to 32 months, with daily
doses ranging from 15-40 mg. J.A. 6655-56. Those patients
"indicated the drug to be beneficial because, by
improving several neurologic functions, it increased their
capability to perform the activities of normal daily
life," including-for 13 of the 23 patients-a reported
improvement in ambulation and fatigue. J.A. 6656 & tbl.1;
see J.A. 6654. The paper states:
Although a placebo effect cannot be excluded, the dynamics of
the response in relation to the intake of the medication and
the deterioration and subsequent improvement in functioning
during a drug-free interval and subsequent restarting of the
therapy are, in our view, highly suggestive of a real effect
being induced by the 4-[AP]. Improvements in fatigue and
ambulation were mentioned quite often by the patients as
being responsible for the favorable overall effect . . . .
6657. The paper thus reports improvements in specific
measures, while few patients experienced a significant change
in EDSS, the overall composite measure. Id. As for
adverse effects, two patients experienced a seizure-one on
the second day of treatment and the other after 18 months of
treatment. J.A. 6656-57. Otherwise, the subjective side effects
reported by the patients "never were reported to be very
troublesome." J.A. 6657.
states several conclusions and suggestions for further
research. First, the study "demonstrates that 4-[AP]
therapy, in the majority of patients who favorably respond to
it, results in responses that can continue for periods of up
to 32 months or more without interfering with the course of
the disease." Polman at 296. Second, the fact that
"three major, though not life-threatening, side
effects" occurred (including 2 seizures) "indicates
that careful medical supervision is warranted during 4-[AP]
therapy." Id. Third, based on the study data,
the authors "suggest that approximately 30% of patients
with [multiple sclerosis] will report a significant clinical
response when they begin treatment with 4-[AP] and that 80%
to 90% of these responders will benefit from long-term
administration. More studies are needed for further
elaboration of the exact value of 4-[AP] in the long-term
treatment of patients with [multiple sclerosis]."
the same time, researchers at the University of Maryland, the
Baltimore VA Medical Center, and Elan published a paper
(Bever I) reporting the results of a randomized,
placebo-controlled, double-blind, concentration-controlled,
crossover trial in 8 patients with multiple sclerosis.
Christopher T. Bever, Jr., et al., The effects of
4-aminopyridine in multiple sclerosis patients: Results of a
randomized, placebo-controlled, double-blind,
concentration-controlled, crossover trial, 44 Neurology
1054 (1994); see J.A. 6180 (excerpt of Bever I).
Noting that 4-AP has a "narrow toxic-to-therapeutic
range," the study aimed to evaluate the toxicity and
efficacy of 4-AP when the resulting peak concentration in
blood was low (30-59 ng/ml) versus when it was high (60-100
ng/ml). Bever I at 1055. Regarding toxicity, the report
states that "[a]ll patients experienced side
effects" when serum concentration was high, with two
serious adverse events: a seizure when serum 4-AP peaked at
104 ng/ml, and an episode of encephalopathy when serum 4-AP
peaked at 114 ng/ml. Id. at 1054, 1056. Regarding
efficacy, "[i]mprovements were seen in lower extremity
strength," including significant improvement in mean
videotape scores of lower extremity strength (scoring muscle
strength, reflexes, and ambulation) in both the low and
high-serum concentration ranges, although no significant
changes were seen in EDSS scores or ambulation index (AI)
scores. Id. at 1056-57 & tbl.4;
but see id. at 1058 (commenting that the increased
side effects from the short treatment duration "may have
contributed to the lack of improvement in overall function
(EDSS and AI scores)").
concludes that the therapeutic response was not
concentration-related as between the two ranges tested and,
therefore, that "[t]he lower serum concentration range
of 30 to 59 ng/ml may . . . be adequate for inducing
improvement of some neurologic deficits." Bever I at
1058; see id. ("Because the
high-serum-concentration arm produced much greater toxicity
than the low without any obvious therapeutic advantage, it
seems likely that clinically useful serum concentrations
would be in the 30 to 59 ng/ml range."). Bever I also
states that the "rates of treatment-related improvements
in visual and lower extremity motor function . . . were
similar to those reported in similar short-term trials of
[4-AP]," including Stefoski and Davis. Bever I at
1057-58. The article notes the limitations of the earlier
trials' designs, including "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." Id. at 1058. Bever I then
observes that another study "addressed some of the
design weaknesses in earlier studies and suggested that not
only can AP treatment improve specific residual deficits, but
it can also improve overall function." Id.
same year as Bever I appeared, Dr. Bever, with the University
of Maryland and the Baltimore VA Medical Center, published a
review article on studies of the effect of 4-AP on multiple
sclerosis (Bever II). Christopher T. Bever, Jr., The
Current Status of Studies of Aminopyridines in Patients with
Multiple Sclerosis, 36 Annals of Neurology S118 (1994);
see J.A. 6172 (excerpt of Bever II). The article
states: "Recently completed randomized, double-blind,
placebo-controlled trials show that treatment with the
potassium channel blockers 4-aminopyridine (AP) or 3,
4-diaminopyridine (DAP) can improve residual neurological
deficits in some multiple sclerosis (MS) patients."
Bever II at S118; accord id. at S120. As to
efficacy, "[t]hese studies suggest that aminopyridines
may provide a new approach to the symptomatic treatment of
[multiple sclerosis]." Id. at
S118. As to toxicity, "seizures are common
at higher doses," but 4-AP "rarely cause[s]
seizures at the doses used in [multiple sclerosis]
trials." Id. at S120; see also id. at
S118 ("Both agents [4-AP and DAP] have rarely caused
seizures."). The paper notes that one 4-AP study
"showed that side effects correlated with peak serum
concentrations, while efficacy correlated with total drug
exposure, suggesting that controlled release formulations may
be useful in minimizing toxicity." Id. at S120.
foregoing studies involved immediate-release, rather than
sustained-release, formulations of 4-AP. See Dist. Ct.
Op. at *4; J.A. 761, 763, 767, 769, 774 (testimony of
Acorda's expert, Dr. Andrew Goodman). By 1990, Elan,
which was known for its work on sustained-release
formulations, entered into an agreement with the researchers
at Rush Medical School to obtain their work on 4-AP
pharmaceutical formulations. Dist. Ct. Op. at *4.
According to Dr. Michael Myers, who worked at Elan at that
time and is a named inventor on the Elan patent, Elan was
interested in developing a sustained-release formulation of
4-AP to "potentially reduce or eliminate some of th[e]
side effects" associated with the immediate-release
formulation. Sept. 19, 2016 Trial Tr. at 149, 155-56,
Acorda Therapeutics, Inc. v. Alkem Labs. Ltd., No.
1:14-cv-00882-LPS (D. Del. Oct. 21, 2016), ECF No. 266.
developed a 4-AP sustained-release formulation in
approximately a month's time. Dist. Ct. Op. at
*4. The inventors then filed for what became the Elan patent,
which claims, among other things, administration of a
sustained-release formulation of 4-AP once or twice daily for
the treatment of neurological diseases, including multiple
sclerosis. Elan patent, col. 22, lines 16-25, 29- 30, 50-51
(independent claim 1 and dependent claims 3 and 8). The Elan
patent has a priority date of November 1, 1991; issuance date
of July 30, 1996; and expiration date of July 30, 2018.
1994, Elan conducted a double-blind, randomized,
placebo-controlled clinical trial involving 161 patients with
multiple sclerosis to study the safety and efficacy of the
sustained-release 4-AP formulation. Dist. Ct. Op. at
*8. Patients were administered 12.5 mg 4-AP twice a day,
which was later increased to 17.5 mg twice a day and finally
to 22.5 mg twice a day. Id. One of the primary
endpoints measured was the EDSS composite measure of
function. See id. For the primary endpoints and most
of the secondary endpoints, including ambulation, the trial
revealed no statistically significant improvements for 4-AP
versus placebo. Id. But it did show a statistically
significant improvement in the secondary outcome of lower
extremity motor score, a measure of muscle strength in the
legs. Id. The 1994 Elan study was not published.
also sponsored a smaller, double-blind, placebo-controlled,
crossover study in ten patients with multiple sclerosis. That
study was reported in a paper published in 1997 (Schwid), on
which Dr. Goodman, Acorda's expert at trial, was the
senior author. J.A. 6681-84 (Steven R. Schwid et al.,
Quantitative assessment of sustained-release
4-aminopyridine for symptomatic treatment of multiple
sclerosis, 48 Neurology 817 (1997)). In the background
section, Schwid reports that an earlier, 161-patient study
had been conducted to test improvement in EDSS for multiple
sclerosis patients (the unpublished 1994 Elan study), but
that it did not detect a significant improvement in that
measure. J.A. 6681. Schwid notes, however, that the EDSS
"may have been an inadequate outcome variable for [the
1994 Elan] trial." Id. The paper explains:
[The EDSS] is imprecise due to substantial intra-rater and
inter-rater variability, and relatively insensitive to change
due to its ordinal nature. For example, a patient who needed
a cane to walk 100 meters would need to improve enough to
walk without the cane before the EDSS score would change.
Lesser improvements in gait would not be reflected by the
EDSS, and notable changes in strength or other deficits could
also be overlooked. We planned the present pilot study to
assess the effect of 4AP [sustained release] on more
sensitive, quantitative measures of function in [multiple
Id. (internal references omitted).
Schwid study, ten patients were each given 17.5 mg
sustained-release 4-AP twice a day for a week and placebo for
a week. Id. The study measured (1) time to walk 8
meters (timed gait), (2) time to climb four stairs, (3)
maximum voluntary isometric contraction measured
quantitatively, (4) manual muscle testing, (5) grip strength,
(6) EDSS, and (7) the patient's global impression.
Id. Schwid reports that the administered drug
demonstrated a statistically significant improvement over
placebo for timed gait in 9 of 10 patients, with p = 0.02.
Id. In addition to that result, Schwid
observes that "most of the other outcomes showed trends
favoring 4AP [sustained-release]." J.A. 6684. Schwid
concludes that, in the reported study, "4AP
[sustained-release] improved motor function in [multiple
sclerosis] patients." J.A. 6681. The article notes that
the results of the Schwid study are consistent with
"[p]revious double-blind, placebo-controlled
studies" using an immediate-release formulation of 4-AP,
including another study reported by Stefoski (13 of 17
patients "showed 'clinically important'
improvements"), Bever I (reporting that 4-AP
"improved lower-extremity strength" and "a
composite score of leg strength, spasticity, and
ambulation"), and another study reported by Van Diemen
(improvement in neurologic deficits, as measured by the
EDSS). J.A. 6684.
also states: "The quantitative outcomes used in this
study permit more sensitive evaluation of the therapeutic
effect and promise to be useful in future trials of
symptomatic treatments for [multiple sclerosis]." J.A.
6681. It notes particularly that timed gait showed
improvement where the EDSS did not. Id.; J.A. 6684.
Schwid advises that future studies evaluate the more
sensitive outcome measures, "establish efficacy in
larger trials," and "examine long-term efficacy and
tolerability as well as further refine dosing regimens to
optimize delivery despite a relatively narrow therapeutic
window." J.A. 6684.
Elan was conducting those studies, Acorda was exploring the
use of 4-AP in patients with spinal cord injuries. Dist.
Ct. Op. at *8. In 1997, Elan granted Acor-da an
exclusive license to the Elan patent for the use of
Elan's sustained-release formulation of 4-AP in patients
with spinal cord injuries. Id. Acorda conducted two
studies to evaluate the pharmacokinetic and safety profile of
the sustained-release formulation, and the results of both
studies are reported in a paper published in 2003 (Hayes).
J.A. 6433-40 (Keith C. Hayes et al., Pharmacokinetic
Studies of Single and Multiple Oral Doses of Fampridine-SR
(Sustained-Release 4-Aminopyridine) in Patients With Chronic
Spinal Cord Injury, 26 Clinical Neuropharmacology 185
(2003)). In the second study, Acorda tested doses of 10 mg,
15 mg, 20 mg, and 25 mg of the sustained-release formulation
of 4-AP administered twice daily in patients with spinal cord
injuries. J.A. 6434. The average serum concentration level
(at steady state) for the 10 mg twice-daily dose was 20.8
± 5.7 ng/ml. J.A. 6439; accord '826
patent, col. 25, lines 1-28 (Table 7); '685 patent, col.
25, lines 5-32 (Table 7). Acorda also conducted clinical
trials to evaluate the efficacy of that sustained-release
formulation of 4-AP in patients with spinal cord injuries,
but those studies failed.
after, Acorda learned that Elan was "no longer
interested in pursuing or supporting" research into use
of Elan's sustained-release formulation of 4-AP for
treatment of multiple sclerosis. J.A. 596 (testimony of Dr.
Ron Cohen, Acorda founder). Acorda told Elan that it wished
to take over that research. Id. In 1998, Elan agreed
to expand the earlier license to Acorda; it granted Acorda
exclusive rights over the 4-AP sustained-release formulation
for use in the treatment of multiple sclerosis. Dist. Ct.
Op. at *8.
reviewed Elan's research, including Elan's
pharmacokinetic data and clinical study reports of the 1994
Elan study. Acorda then conducted its own clinical trials.
Id. at *9.
and 2001, Acorda ran a study-the MS-F201 study-which involved
36 patients with multiple sclerosis and whose results were
published only in part. Id. After one week of a placebo
lead-in, a group of 25 patients received 10 mg 4-AP twice
daily for a week, then higher dosages, which increased weekly
in 5 mg increments up to 40 mg twice daily at week 7.
Id. The rest of the patients consistently received a
placebo. See id. The outcome measures included
fatigue, a lower extremity muscle test, a multiple sclerosis
functional composite (timed 25-foot walk; nine-hole peg test;
cognitive test), and subjective measures. Id. Only
the lower extremity muscle test showed a statistically
significant difference-"when comparing the seven week
range [4-AP] group against placebo." J.A. 604-05. The
results were not statistically significant for the timed
25-foot walk for any particular dose of 4-AP; and in 3 of the
7 weeks, the placebo group did better in the timed walk than
the 4-AP group taking 10 mg twice daily. Dist. Ct.
Op. at *9. After the study was completed, Acorda
conducted a post-hoc analysis of the data on walking
speed-which, unlike timed 25-foot walk, was not an endpoint
the study was designed to test-and identified a statistically
significant difference between the placebo and 4-AP groups
considering all doses in the aggregate. Id.
but not all of the just-described results of the MS-F201
study were published. Dr. Goodman published two nearly
identical abstracts in early 2003 (Goodman I, J.A. 6371-72,
and Goodman II, J.A. 6370) and presented a poster in
connection with those abstracts in late 2002 (Goodman Poster,
J.A. 6497-504). Goodman I explains that "[t]he primary
aim" of the randomized, placebo-controlled,
double-blinded Phase II dose-ranging study was to
"determine the safety and tolerability of escalating
doses of a sustained release (SR) formulation [of 4-AP],
given orally to patients with [multiple sclerosis]," and
that "[t]he secondary aim was to explore efficacy over a
broad dose range using measures of fatigue and motor
function." J.A. 6371; see Dist. Ct. Op. at *14.
The abstract discloses that the study involved 36 patients,
25 in the active-treatment and 11 in the placebo group, and
that the active-treatment group received 20 mg/day 4-AP, with
doses escalating 10 mg/day to reach a maximum of 80 mg/day
during week 8 of the study. J.A. 6371-72; see Dist. Ct.
Op. at *14. In the "Results" section, Goodman
I reports that five subjects withdrew as a result of adverse
effects, including two seizures, and that adverse effects
were "more severe at doses of 50 mg/day and
higher," including the two seizures that occurred at
doses of 60 and 70 mg/day. J.A. 6372; see Dist. Ct.
Op. at *14. Another reported result is that the 4-AP
sustained-release treatment "group 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). Dose-response curves showed increasing benefit in
both measures in the 20 to 50 mg/day range." J.A. 6372;
see Dist. Ct. Op. at *14. The abstract clarifies
that "[n]o other measures showed significant treatment
effects." J.A. 6372; see Dist. Ct. Op. at *14.
The "Conclusions" section reads:
The safety profile of [4-AP sustained-release] was consistent
with previous experience. Doses above 50 mg [per day] added
little benefit and increased adverse effects. There was
significant improvement in measures of mobility and muscle
Goodman Poster is similar. It reproduces almost all of the
material in Goodman I in the "Abstract" section at
the upper-left-hand corner of the poster. J.A. 6502
(capitalization altered). The Poster contains more detail in
the "Background" section, which notes that
"[r]ecent clinical studies have indicated that [4-AP]
promotes improvement in motor strength, walking, fatigue, and
endurance in people with [multiple sclerosis]"; that
observed adverse events, including seizures, were associated
with higher peak plasma concentrations and rapid plasma
concentration changes caused by immediate-release 4-AP; and
that sustained-released formulations were developed to
address those problems. Id. (capitalization
altered). The study objectives were defined as: (1)
"[d]etermine 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
80mg/day)"; and (2) "[o]btain evidence of efficacy
and dose-response using several outcome measures."
Id.; accord id. (Methods section). The
Goodman Poster notes that, because individuals taking 4-AP
"frequently report" improvements in activity and
fatigue levels, the study focused on outcomes associated with
such effects-namely, timed ambulation, manual muscle testing,
and patients' self-reports of fatigue-rather than the
EDSS, because "it was not clear whether" the EDSS
"would adequately reflect this type of
improvement." Id. (Methods section).
the study's results concerning safety, the Goodman Poster
provides, in the "Results Summary," that "more
severe adverse events," including seizures, occurred
"[a]t doses above 40 mg/day." J.A. 6504
(capitalization altered). The Poster states that "the
risk of seizure requires further study and characterization[,
] particularly in the anticipated dose range."
the results concerning efficacy, the Goodman Poster includes
a graph of a dose-response curve for the 25-foot walk:
6503. The graph shows that the total time for the walk
decreased significantly between the placebo dose (run-in) and
the 20 mg/day dose. Id. The total time seems to have
plateaued at higher doses. Id. (total time remained
between approximately 12.5 and 14 seconds as doses increased
from 20 mg/day to 80 mg/day); see also Sept. 19,
2016 Trial Tr. at 102-03, 137 (testimony of defendants'
expert Dr. Peroutka, observing a walk time between 12 and 14
seconds for a "stable clinical effect at 20 to 40"
mg/day in the "flat part of the dose response
results section also provides bar graphs showing changes in
individual patients' speed on the 25-foot walk.
6503. The upper bar graph shows, on average, improvements in
speed for patients in the active-treatment group, aggregated
for doses ranging from 20-50 mg/day. Id.; see J.A.
416. It appears that a few of those patients' speed
decreased by approximately 0-10%, while more than a dozen
patients' speed increased by more than 10%-nine by more
than 20%, four by more than 40%, and one by more than 60%.
J.A. 6503. The lower bar graph shows, on average, zero or
slight improvement in speed for patients in the placebo
group, with no patient's speed having improved by more
than 20% and one patient's speed having decreased by more
than 20%. Id.
results for improvements in leg strength between the
active-treatment group (aggregating the doses of 20-50
mg/day) and placebo group showed a similar trend: (Image
"Results Summary," the Goodman Poster states that
"[significant improvement in walking speed was observed
in the [4-AP sustained-release] treated group
(p=0.04*)," where the p-value reflects a "*repeated
measure ANOVA (weeks 1-7)"-i.e., the walking
speed for the active-treatment group, aggregating the dose
levels. J.A 6504; see Dist. Ct. Op. at * 14 n. 11
(noting that Dr. Goodman explained that the p-value reflects
"the aggregated value for the treatment group as a
whole, including all dosages, and did not reflect the results
associated with any single dosage" (emphasis omitted)).
More specifically, the Goodman Poster reports that (1)
"[t]he average improvement in walking speed [in the
25-foot walk] during the low dose period (20-50 mg/day)
included > 20% increase for 9 of the 25 subjects" and
(2) "[c]hanges in the placebo-treated group were equally
distributed between increases and decreases in walking speed
and none of the 11 subjects showed increases > 18% during
the low dose period." J.A. 6504. The Poster also
reports, for the lower extremity manual muscle test (LEMMT),
a "[s]tatistically significant improvement in the [4-AP
sustained-release] treated group (p=0.01*)."
Conclusions section contains six bullet points. The first
states that the "[s]afety profile [is] consistent with
previous experience." J.A. 6503. The next few bullet
points report a "[s]ignificant benefit on timed
walking," "[s]ignificant benefit on lower extremity
strength," "[n]o evidence of benefit on overall
fatigue-susceptibility of fatigue to placebo effect,"
and "[e]vidence of dose-response in 20-40 mg/day
range." Id. Finally, there was "[l]ittle
added benefit, and increased [adverse events, ] at doses
above 50 mg/day." Id.
Goodman prior art-which post-dates Elan's transfer of the
research project to Acorda and which added significantly to
the teachings of the earlier prior art-became the most
important prior art in the obviousness analysis in this case.
2003, after completion of the MS-F201 study, Acorda conducted
another placebo-controlled Phase II study (MS-F202 study) to
test 4-AP's effect on walking speed. Dist. Ct.
Op. at *9. After a two-week up-titration period
beginning with a 10 mg dose, patients were administered a
stable dose of 10 mg, 15 mg, or 20 mg sustained-release 4-AP
twice daily for twelve weeks. Id. Although none of
the 4-AP groups demonstrated a statistically significant
improvement in walking speed relative to placebo, another
post-hoc analysis showed that responders were in the 4-AP
group (p < 0.0001) and that there was no meaningful
difference in efficacy among the tested 4-AP doses.
Id.; see also J.A. 612-14 (Acorda founder
Dr. Cohen explaining that isolating responders in the
study-those patients with improved walking-showed that
responders were overwhelmingly in the active treatment groups
and that there was no meaningful difference in efficacy among
the responders in those treatment groups taking 10 mg, 15 mg,
or 20 mg twice daily).
then conducted two Phase III studies to evaluate the effect
of 10 mg sustained-release 4-AP twice daily, with walking
improvement responder analysis as the primary outcome
measure. Id. Both studies were successful, with p
< 0.0001. Id.
the results of the MS-F202 study nor the results of the Phase
III studies constitute publicly available prior art to the
Acorda patents in this case.
April 9, 2004, Acorda employees filed a provisional patent
application; that date is undisputedly the priority date of
the Acorda patents. Id. at *9 n.8. The Acorda
patents issued between August 2011 and March 2014.
parties treat the Acorda patents' claims, for purposes of
the invalidity issue on appeal, as involving methods of
administering to a patient with multiple sclerosis a
sustained-release 4-AP formulation (1) in a 10 mg dose twice
daily, (2) at that stable dose for the entire treatment
period of at least two weeks, (3) maintaining 4-AP serum
levels of 15-35 ng/ml, (4) with walking improved. The parties
treat claim 7 of the '826 patent and claim 22 of the
'437 patent as representative. Claim 7 of the '826
patent depends on claim 6, which reads:
6. 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 comprising:
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
4-aminopyridine twice daily; without a subsequent period of
whereby an in vivo CmaxSS:CminSS ratio of
1.0 to 3.5 and a CavSS of 15 ng/ml to 35 ng/ml are
maintained in the human.
'826 patent, col. 27, lines 41-57. Claim 7 covers
"[t]he method of claim 6, whereby an increase in walking
speed is obtained in said human." Id., col. 27,
22 of the '437 patent depends on claim 18, which depends
on claim 1. Claim 1 of the '437 patent reads:
1. 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 4-aminopyridine 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
'437 patent, col. 27, lines 55-61. Claim 18 requires that
the sustained release composition in claim 1 be "a
tablet," id., col. 28, lines 47-48; and claim
22 requires that the tablet of claim 18 "exhibit a
release profile to obtain a CavSS of about 15 ng/ml
to about 35 ng/ml," id., col. 28, lines 55-57.
The parties have not distinguished the claims for purposes of
the invalidity issue before us.
submitted New Drug Application No. 022250 to the FDA for the
use of 10 mg 4-AP extended-release tablets (Ampyra). The FDA
granted priority review to that application and approved it
on January 22, 2010.
to the approved FDA label, Ampyra "'is indicated as
a treatment to improve walking in patients with multiple
sclerosis (MS). This was demonstrated by an increase in
walking speed.'" Dist. Ct. Op. at *4
(citation omitted). "Improvement in walking in MS
patients is [the] only approved use" of Ampyra.
Id. The "Description" section of the label
states that "'Ampyra (dalfampridine) is a potassium
channel blocker, available in a 10 mg tablet strength . . .,
formulated as an extended release tablet for twice-daily oral
administration.'" Id. (capitalization
altered). The "Dosage and Administration" section
explains that "'[t]he maximum recommended dose of
Ampyra is one 10 mg tablet twice daily, taken with or without
food, and should not be exceeded. . . . 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.'"
Id. (capitalization altered).
the time of FDA approval in 2010 and the end of 2015, total
sales of Ampyra were $1.7 billion and net income was $998.7
million. Id. at *16. Net sales of Ampyra, in
dollars, increased at an average rate of 20% per year, and
the volume of tablets sold increased at an average rate of 8%
per year, despite an increasing price per tablet over that
period (2010 to 2015). Id. Acorda also receives
royalty payments from licenses to sell Ampyra outside the
United States; it has collected at least $135 million from
those licenses. Id.
opportunity, however, is constrained because Ampyra is
indicated only for improvement of walking. Id. at
*16-17. Ampyra sales revenue is approximately 2-3% of the
total sales revenue from the top ten multiple sclerosis
drugs. Id. at *17. Not all multiple sclerosis
patients respond to Ampyra. Among multiple sclerosis ...