Acorda Therapeutics, Inc. v. Roxane Laboratories, Inc. , 903 F.3d 1310 ( 2018 )

United States Court of Appeals
for the Federal Circuit
______________________
ACORDA THERAPEUTICS, INC.,
Plaintiff-Appellant
ALKERMES PHARMA IRELAND LIMITED,
Plaintiff-Appellee
v.
ROXANE LABORATORIES, INC., MYLAN
PHARMACEUTICALS INC., TEVA
PHARMACEUTICALS USA, INC.,
Defendants-Cross-Appellants
______________________
2017-2078, 2017-2134
______________________
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.
______________________
Decided: September 10, 2018
______________________
BRUCE 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,
2 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
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, Washing-
ton, DC, argued for defendants-cross-appellants. Defend-
ants-cross-appellants Roxane Laboratories, Inc., Teva
Pharmaceuticals USA, Inc. also represented by ANDREW
CURTIS NICHOLS; BRYCE COOPER, GEORGE C. LOMBARDI,
REID SMITH, Chicago, IL.
ROBERT FLORENCE, Parker Poe Adams & Bernstein
LLP, Atlanta, GA, for defendant-cross-appellant Mylan
Pharmaceuticals Inc. Also represented by MICHEAL L.
BINNS, KAREN L. CARROLL.
SARAH ANNE KAGAN, Banner and Witcoff, Ltd., Wash-
ington, DC, for amicus curiae Biotechnology Innovation
Organization. Also represented by MELISSA A. BRAND,
LISA MEREDITH HEMMENDINGER; HANSJORG SAUER, Bio-
technology Innovation Organization, Washington, DC.
SCOTT E. KAMHOLZ, Covington & Burling LLP, Wash-
ington, 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.
______________________
Before NEWMAN, DYK, and TARANTO, Circuit Judges.
Opinion for the court filed by Circuit Judge TARANTO.
Opinion dissenting filed by Circuit Judge NEWMAN.
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 3
TARANTO, Circuit Judge.
Before 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. Pa-
tent 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.
One 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 administer-
ing 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.
4 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
Roxane Laboratories, Inc.; Mylan Pharmaceuticals,
Inc.; and Teva Pharmaceuticals USA, Inc., have submit-
ted Abbreviated New Drug Applications seeking FDA
approval to market generic versions of Ampyra. In July
2014, Acorda and Alkermes sued those entities (“defend-
ants”) 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, 2018.
Acorda appealed the invalidity ruling regarding the
Acorda patents. The defendants cross-appealed the
validity ruling regarding the Elan patent and the result-
ing injunction. We now affirm the judgment that the
asserted Acorda patent claims are invalid. We dismiss
the cross-appeal as moot.
I
A
In view 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 obvious-
ness issue is an understanding of the prior art.
4-AP, 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.). Belong-
ing to a class of compounds that function as potassium-
channel blockers, 4-AP “has been found to slow the potas-
sium 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
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 5
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. Even-
tually, 4-AP research led to the development, patenting,
and FDA approval of Ampyra.
1
In the 1980s, researchers at the Rush Medical School
conducted a study on 12 patients with multiple sclerosis,
and 5 without, to determine whether intravenous admin-
istration 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 Scle-
rosis, 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 im-
provement 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 ef-
fects 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
6 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
many of our patients were of sufficient magnitude
to represent a functionally noteworthy therapeutic
benefit. Studies are currently in progress to de-
termine the clinical usefulness of oral 4-AP as a
symptomatic treatment.
J.A. 6701; accord J.A. 6697.
In 1990, an overlapping group of researchers pub-
lished 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 im-
provements occurred in all of the 15 [multiple sclerosis]
patients given 4-AP.” J.A. 6329; accord J.A. 6327. “Im-
provements developed gradually with doses as low as
10 mg 4-AP, usually beginning within 60 minutes after
drug administration.” J.A. 6329. Motor function im-
proved 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 appar-
ent with both simple function tests and the performance
of complex motor tasks such as gait and repetitive move-
ments.” J.A. 6329. Finally, Davis notes, no “serious or
bothersome side effects,” including seizures, were ob-
served at single oral doses up to 25 mg. J.A. 6332.
A few 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
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 7
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 Clini-
cal 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 improve-
ments 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 sei-
zures).
Soon thereafter, some of the same researchers pub-
lished 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
8 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
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 demon-
strated a significant improvement in EDSS score.
J.A. 6656.
Overall, 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 func-
tions, it increased their capability to perform the activi-
ties 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. 1 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 sub-
sequent 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]. Im-
provements in fatigue and ambulation were men-
tioned quite often by the patients as being
responsible for the favorable overall effect . . . .
J.A. 6657. The paper thus reports improvements in
specific measures, while few patients experienced a
significant change in EDSS, the overall composite meas-
ure. Id. As for adverse effects, two patients experienced a
1 By comparison, only 5 reported an improvement
in visual function; 4 in cognitive function/concentration;
and 1 in diplopia (double vision), speech, spasticity, and
urinary and fecal incontinence. J.A. 6656 tbl.1; see
J.A. 6654.
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 9
seizure—one on the second day of treatment and the other
after 18 months of treatment. J.A. 6656–57. 2 Otherwise,
the subjective side effects reported by the patients “never
were reported to be very troublesome.” J.A. 6657.
Polman 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 [multi-
ple 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].” Id.Around 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, concentra-
tion-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, concentra-
tion-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 result-
2 A third patient was presumptively diagnosed with
a case of 4-AP-induced hepatitis. J.A. 6657.
10 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
ing 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 en-
cephalopathy 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 ambula-
tion) in both the low- and high-serum concentration
ranges, although no significant changes were seen in
EDSS scores or ambulation index (AI) scores. 3 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)”).
Bever I concludes that the therapeutic response was
not concentration-related as between the two ranges
tested and, therefore, that “[t]he lower serum concentra-
tion 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
3 See Stephen L. Hauser et al., Intensive immuno-
suppression in progressive multiple sclerosis, 308 New
Eng. J. Med. 173, 174, 180 (1983) (ambulation index is a
rating scale to assess mobility by measuring the time and
degree of assistance needed to walk 25 feet).
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 11
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 prospec-
tively defined neurologic deficits or adjust significance
levels to compensate for multiple comparisons.” Id. at
1058. Bever I then observes that another study “ad-
dressed 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.The 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 Amino-
pyridines 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 treat-
ment 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 amino-
pyridines may provide a new approach to the symptomat-
ic treatment of [multiple sclerosis].” Id. at S118. 4 As to
4 Although criticizing a few 4-AP studies as involv-
ing a small sample size or lacking a double-blinded or
randomized design, Bever II also looked at “[l]arger
randomized, double-blind, placebo-controlled crossover
trials of” 4-AP with treatment periods as long as three
months. J.A. 6172; accord Bever II at S118 (in the article
abstract, stating that “[p]reliminary studies of [4-]AP
12 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
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.
2
The foregoing studies involved immediate-release, ra-
ther 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 formu-
lations, entered into an agreement with the researchers at
Rush Medical School to obtain their work on 4-AP phar-
maceutical 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 inter-
ested 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 formula-
tion. 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.
Elan 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,
demonstrated benefit in many temperature-sensitive
patients with [multiple sclerosis], and improvement of
function was found in a large randomized double-blind,
placebo-controlled crossover trial of 3 months of oral
treatment in 68 patients with [multiple sclerosis]”).
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 13
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 Novem-
ber 1, 1991; issuance date of July 30, 1996; and expiration
date of July 30, 2018.
In 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.
Elan 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 improve-
ment in that measure. J.A. 6681. Schwid notes, however,
14 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
that the EDSS “may have been an inadequate outcome
variable for [the 1994 Elan] trial.” Id. The paper ex-
plains:
[The EDSS] is imprecise due to substantial intra-
rater and inter-rater variability, and relatively in-
sensitive 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 sensi-
tive, quantitative measures of function in [multi-
ple sclerosis].
Id. (internal references omitted).
In the 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 impres-
sion. 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. 5 In addition to that result, Schwid observes that
“most of the other outcomes showed trends favoring 4AP
5 Dr. Goodman testified at trial (for Acorda) that
the p-value would be 0.14 (greater than the customary
0.05 ceiling for “statistical significance”) if adjusted for
the fact that there were multiple outcome measures (7
total). J.A. 878; see Dist. Ct. Op. at *13 n.10.
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 15
[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 formula-
tion of 4-AP, including another study reported by Stefoski
(13 of 17 patients “showed ‘clinically important’ improve-
ments”), 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.
Schwid 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.
3
While 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., Pharmaco-
16 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
kinetic 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). Acor-
da 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.
Soon 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 treat-
ment 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 formula-
tion for use in the treatment of multiple sclerosis. Dist.
Ct. Op. at *8.
Acorda 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.
a
In 2000 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. 6 After
6 This was a Phase II study within the meaning of
the FDA’s classification of certain studies as Phase I, II,
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 17
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. 7 After the study
or III. See J.A. 870; U.S. Dep’t of Health & Human
Servs., U.S. Food & Drug Admin., The FDA’s Drug Review
Process: Ensuring Drugs Are Safe and Effective (2017),
https://www.fda.gov/drugs/resourcesforyou/consumers/uc
m143534.htm.
7 During oral argument, counsel for Acorda repeat-
edly noted the result that the placebo group actually
outperformed the 10 mg twice-daily group in 3 of the
7 weeks. E.g., Oral Arg. at 8:57–9:20; id. at 10:05–20.
But Acorda has not shown where that result was pub-
lished in the prior art. See Sept. 23, 2016 Trial Tr. at 785,
Acorda Therapeutics, Inc. v. Alkem Labs. Ltd., No. 1:14-
cv-00882-LPS (D. Del. Oct. 21, 2016), ECF No. 269 (coun-
sel for Acorda stating at trial that the MS-F201 data was
not publicly available prior art, other than the data
reported in the Goodman references). On this record, that
result could not have informed the legally relevant person
of skill in the art about whether to expect (or, as Acorda
argues, not to expect) the 10 mg twice-daily dose to suc-
ceed in improving walking.
18 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
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.Most 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 ab-
stract 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. An-
other reported result is that the 4-AP sustained-release
treatment “group showed statistically significant im-
provement from baseline compared to placebo in function-
al 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
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 19
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 “Conclu-
sions” 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 improve-
ment in measures of mobility and muscle
strength.
J.A. 6372.
The 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 ob-
served 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 indi-
viduals 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
20 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
fatigue—rather than the EDSS, because “it was not clear
whether” the EDSS “would adequately reflect this type of
improvement.” Id. (Methods section).
As to the study’s results concerning safety, the Good-
man 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 re-
quires further study and characterization[,] particularly
in the anticipated dose range.” Id.As to the results concerning efficacy, the Goodman
Poster includes a graph of a dose-response curve for the
25-foot walk:
J.A. 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
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 21
between 12 and 14 seconds for a “stable clinical effect at
20 to 40” mg/day in the “flat part of the dose response
curve”).
The results section also provides bar graphs showing
changes in individual patients’ speed on the 25-foot walk.
J.A. 6503. The upper bar graph shows, on average, im-
provements 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 pa-
tient’s speed having decreased by more than 20%. Id.22 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
The 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:
Id.In the “Results Summary,” the Goodman Poster states
that “[s]ignificant improvement in walking speed was
observed in the [4-AP sustained-release] treated group
(p=0.04*),” where the p-value reflects a “*repeated meas-
ure 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 aggre-
gated 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 specifical-
ly, 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
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 23
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*).” Id.The 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.This 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 obvious-
ness analysis in this case.
b
In 2003, after completion of the MS-F201 study, Acor-
da 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, anoth-
er 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 explain-
ing that isolating responders in the study—those patients
24 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
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).
Acorda then conducted two Phase III studies to evalu-
ate 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 suc-
cessful, with p < 0.0001. Id.Neither the results of the MS-F202 study nor the re-
sults of the Phase III studies constitute publicly available
prior art to the Acorda patents in this case.
4
On 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.
The parties treat the Acorda patents’ claims, for pur-
poses of the invalidity issue on appeal, as involving meth-
ods 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 con-
centration in order to improve walking in a hu-
man with multiple sclerosis in need thereof, said
method comprising:
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 25
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 pri-
or period of 4-aminopyridine titration, and then,
maintaining administration of 4-
aminopyridine by orally administering to said
human a sustained release composition of 10 mil-
ligrams of 4-aminopyridine twice daily; without a
subsequent period of 4-aminopyridine titration,
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 main-
tained 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, lines 58–59.
Claim 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 dur-
ing said time period.
’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,
26 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
lines 55–57. The parties have not distinguished the
claims for purposes of the invalidity issue before us. 8
5
Acorda 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.
According to the approved FDA label, Ampyra “‘is in-
dicated 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 (cita-
tion omitted). “Improvement in walking in MS patients is
[the] only approved use” of Ampyra. Id. The “Descrip-
tion” section of the label states that “‘Ampyra (dal-
fampridine) 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 addi-
tional benefit was demonstrated at doses greater than 10
mg twice daily and adverse reactions and discontinua-
tions because of adverse reactions were more frequent at
higher doses.’” Id. (capitalization altered).
Between 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
8 Although the ’826 patent’s claim 7 does not re-
quire a regimen of at least two weeks, asserted claim 39
does (claim 39 requires 12 weeks), as do the ’437 patent’s
asserted claims 1, 2, 5, 22, 32, 36, and 37; the ’685 pa-
tent’s asserted claims 3 and 5; and the ’703 patent’s
asserted claims 36, 38, and 45.
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 27
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 Ampy-
ra outside the United States; it has collected at least $135
million from those licenses. Id.Commercial opportunity, however, is constrained be-
cause Ampyra is indicated only for improvement of walk-
ing. 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 patients who experience walking diffi-
culties, 15–20% of those patients are prescribed Ampyra.
Id.On the other hand, Ampyra is the first and only drug
approved for improving walking in multiple sclerosis
patients. Id. When Sanofi-Aventis in 2008 conducted a
Phase III study to test whether a different potassium-
channel blocker, nerispirdine, would improve walking in
patients with multiple sclerosis, it did not find evidence of
a “specific significant difference between the responders
[and] non-responders that received nerispirdine or place-
bo” in a timed 25-foot walk. J.A. 726–28 (testimony of
Acorda’s expert Dr. Fred Lublin); see Dist. Ct. Op. at *17.
B
In 2014, the defendants notified Acorda and Alkermes
of the defendants’ submission of Abbreviated New Drug
Applications seeking FDA approval to market generic
versions of Ampyra. In mid-July 2014, Acorda and Alk-
ermes filed suits against Roxane, Mylan, and Teva,
among others, in the District of Delaware for the alleged
infringement of several claims in each of the Elan and
Acorda patents under 35 U.S.C. § 271(e). The cases were
consolidated in 2015.
28 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
The defendants stipulated to infringement of the as-
serted claims—claims 3 and 8 of the Elan patent; 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. Dist.
Ct. Op. at *9–12, *18. The defendants, however, chal-
lenged the validity of the asserted claims of all five pa-
tents for obviousness under 35 U.S.C. § 103. 9 The
defendants also challenged the validity of the asserted
claims of the Elan patent for insufficient written descrip-
tion and enablement under 35 U.S.C. § 112, ¶ 1.
After a bench trial held in September 2016, the district
court determined that the defendants had not proven
invalidity of the Elan patent. Dist. Ct. Op. at *20–29.
But the court held that the defendants had proven that
the asserted claims of the Acorda patents are invalid for
obviousness. Id. at *29–41. As to the Acorda patents:
Based on the publications discussed above, as well as
expert testimony, the court found that, as of 2004 (the
priority date), a relevant skilled artisan would have been
motivated to administer a stable dose of 10 mg of 4-AP
twice daily and had a reasonable expectation of success in
the objective of improving the walking ability of multiple
sclerosis patients. Id. at *30–35. The court also found
that the Acorda patents’ claim limitations regarding
serum levels (the pharmacokinetic limitations) were
inherent in the dosing claimed. Id. at *35–36. Finally,
the court, while finding certain facts in Acorda’s favor
regarding objective indicia of obviousness, ultimately
discounted such indicia, relying on the fact that the Elan
9 Because the effective filing date of the claims of
the Acorda patents are before March 16, 2013, the version
of § 103 preceding the enactment of the Leahy-Smith
America Invents Act, Pub. L. No. 112-29, 125 Stat. 284(2011), governs this case.
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 29
patent was a “blocking patent” for the claimed methods of
the Acorda patents: any marketer of a drug for uses
practicing those methods would need a license to the Elan
patent—to which Acorda, for years preceding the 2004
priority date, had an exclusive license from Elan. Id. at
*36–40. 10
On April 25, 2017, the court entered final judgment in
favor of the defendants as to the Acorda patents and in
favor of Acorda as to the Elan patent. The court set the
effective date of any final FDA approval of the defendants’
Abbreviated New Drug Applications no earlier than the
expiration date of the Elan patent—July 30, 2018—and
enjoined the defendants from any infringing activity
before that date.
Acorda and the defendants timely appealed and cross-
appealed, respectively. We have jurisdiction under 28
U.S.C. § 1295(a)(1).
II
Acorda makes essentially three arguments on appeal
regarding the district court’s ruling that the Acorda
patent claims are invalid for obviousness. First, Acorda
contends, on a number of grounds, that the district court
10 In inter partes reviews initiated by a petitioner
not included among the defendants here, the Patent Trial
and Appeal Board considered challenges to the Acorda
patents that did not involve Schwid or the Goodman
references but, instead, depended on whether a particular
filing with the Securities and Exchange Commission was
prior art to the patents. The Board concluded that it was
not. Coalition for Affordable Drugs (ADROCA) LLC v.
Acorda Therapeutics, Inc., Nos. IPR2015-01850, -01853, -
01857, -01858, 2017 WL 950736, at *9–20 (P.T.A.B. Mar.
9, 2017). That ruling does not change the analysis in this
case.
30 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
erred in finding that a person of skill would have had a
motivation to combine the prior art to arrive at the Acor-
da invention and a reasonable expectation of success in
doing so. Second, Acorda challenges the court’s determi-
nation that the claim limitations relating to pharmacoki-
netics—i.e., achieving 4-AP serum levels of 15–35 ng/ml—
are inherent in the claimed invention and therefore
obvious. Third, Acorda argues that the court improperly
applied a categorical rule that a blocking patent (the Elan
patent) negates any findings in favor of Acorda on the
objective indicia of commercial success, failure of others,
and long felt but unmet need. 11
Under 35 U.S.C. § 103(a), obviousness is a question of
law based on underlying questions of fact, including the
level of ordinary skill in the art, the scope and content of
the prior art, the differences between the claims and the
prior art, motivation to modify or combine with a reason-
able expectation of success, and objective indicia of non-
obviousness. See KSR Int’l Co. v. Teleflex Inc., 550 U.S.
398, 406 (2007); In re Stepan, 868 F.3d 1342, 1345–46
(Fed. Cir. 2017); PAR Pharm., Inc. v. TWI Pharm., Inc.,
773 F.3d 1186, 1193–94, 1196–97 (Fed. Cir. 2014). We
review the district court’s determination of obviousness de
11 Acorda also argues that the district court failed to
analyze the claimed inventions as a whole. We see no
methodological error. The court did nothing other than
follow the parties’ own breakdown of what aspects of the
claimed inventions, alone or together, a skilled artisan at
the priority date would have been motivated to adopt with
a reasonable expectation of success and, more generally,
would have found obvious. The court did not overlook any
meaningful argument by Acorda that certain aggregations
of claim elements, including the whole, required analysis
beyond the analysis of the walking-benefit, dosage, stabil-
ity, and serum-level aspects of the claims.
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 31
novo and its underlying factual findings for clear error.
In re Cyclobenzaprine Hydrochloride Extended-Release
Capsule Patent Litig., 676 F.3d 1063, 1069 (Fed. Cir.
2012).
A
Acorda challenges the district court’s findings about
the relevant skilled artisan’s motivations and expecta-
tions regarding the administration of a stable 10 mg 4-AP
dose twice daily to improve walking. It presents two
relatively focused arguments: that Schwid teaches away
from the claimed invention; and that the prior art teaches
the administration of sustained-release 4-AP in a titrated-
dosing regimen rather than a stable-dosing regimen.
More broadly, Acorda argues that neither the Goodman
Poster nor the prior art collectively teaches the efficacy of
a stable 10 mg twice-daily dose or indicates that such a
dose is among the small number of options that a skilled
artisan would have been motivated to test with a reason-
able expectation of success to improve walking. We reject
these challenges.
1
Acorda contends that Schwid “affirmatively teaches
away from Acorda’s invention.” Acorda Br. 36. The
district court considered Schwid, as Acorda urged, among
the teachings of the overall art available at the 2004
priority date, and it made findings as to the motivation
and expectations of a relevant skilled artisan at that date
regarding a stable 10 mg dosage of 4-AP to improve
walking. Dist. Ct. Op. at *30–31. Acorda has not shown
that Schwid renders the court’s findings on those issues
clearly erroneous.
Schwid supports a motivation to test, with a reasona-
ble expectation of success, a 10 mg twice-daily dose of
sustained-release 4-AP to improve walking in multiple
sclerosis patients. Schwid itself used a 17.5 mg twice-
32 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
daily dose, but it found success with that dosage: as stated
in Schwid, “[t]he results of this double-blind crossover
study provide evidence that 4AP [sustained release] had a
therapeutic effect on neurologic deficits from [multiple
sclerosis].” J.A. 6684. In particular, there was a statisti-
cally significant improvement for the 17.5 mg 4-AP versus
placebo in timed gait (i.e., in walking ability); and the
improvements in other outcomes, while not statistically
significant, “showed trends favoring 4AP [sustained
release].” J.A. 6681, 6684. Schwid expressly concludes
that the study shows “4AP [sustained release] improved
motor function in [multiple sclerosis] patients.” J.A. 6681.
And, stressing toxicity concerns with high doses, Schwid
provides affirmative reason to investigate low doses. See
J.A. 6681 (“4AP can provoke seizures and acute encepha-
lopathy”—episodes that “tend to occur when serum 4AP
levels peak, suggesting that lower peak levels may in-
crease safety.”); J.A. 6684 (“[F]uture studies of 4AP [sus-
tained release] will need to examine long-term efficacy
and tolerability as well as further refine dosing regimens
to optimize delivery despite a relatively narrow therapeu-
tic window.”).
Schwid makes certain observations that its study
showed favorable results in some outcome measures at
high serum levels of 4-AP (60 ng/ml)—levels that, accord-
ing to evidence emphasized by Acorda, may require the
administration of 4-AP doses higher than 10 mg twice a
day. See J.A. 445–48 (defendant’s expert’s testimony that
17.5 mg twice-daily or 25 mg twice-daily could result in
serum levels at or above 60 ng/ml); J.A. 823 (Acorda’s
expert’s testimony: similar). But Acorda overstates the
significance of this serum-level observation to the issue of
a reasonable expectation of success for walking improve-
ment.
Schwid found no statistically significant difference be-
tween the 4-AP and placebo groups as to patients’ subjec-
tive global impression of their condition, one of seven
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 33
outcome measures in the Schwid study. J.A. 6683. As to
that outcome measure, Schwid states that “[n]one of the
patients with a serum level less than 60 ng/mL felt better
(according to their global impressions) on 4AP [sustained
release] than placebo.” Id. But efficacy in patients’ global
impression is not the issue—efficacy in timed gait is.
Schwid made no such finding as to timed gait. Schwid
also observes, as a general matter, that “[t]reatment [with
4AP sustained release] appeared particularly efficacious
in subjects who achieved serum 4AP levels above 60
ng/mL, with everyone improving in timed-gait testing and
grip strength, and five of six improving by MVICT [maxi-
mum voluntary isometric contraction, measured quantita-
tively] and their own subjective assessment [global
impression].” J.A. 6684. But Schwid’s measured im-
provement in timed gait was not limited to patients with
high serum levels. See J.A. 6683 (9 of 10 patients im-
proved in timed gait, and only 6 patients achieved serum
levels greater than 60 ng/ml).
In short, high serum levels were not required, and a
dose of 17.5 mg sustained-release 4-AP twice-daily was
sufficient, for improvement in timed gait in Schwid.
Meanwhile, Acorda has pointed to nothing in Schwid
declaring that doses lower than 17.5 mg twice-daily would
not be effective in improving walking. Schwid therefore
supports a finding that a person of skill would have had a
reasonable expectation of success regarding the admin-
istration of 17.5 mg of 4-AP twice-daily—or perhaps even
a lower dose since 17.5 mg was sufficient—to improve
walking in multiple sclerosis patients. And in light of
Schwid’s warning that seizures may occur at higher doses,
the district court did not clearly err in finding that a
person of skill would look to lower doses rather than
higher ones. See Dist. Ct. Op. at *32 (“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
34 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
plausible doses because it suggested that higher doses of
4-AP were more likely to cause adverse events.”).
2
Acorda’s second argument is that the prior art teaches
administering sustained-release 4-AP only in a titrated-
dosing regimen to avoid the risk of seizure, and therefore
that the district court could not properly find that a
person of skill would have been motivated to pursue, or
had a reasonable expectation of success concerning, a
stable-dosing regimen. We reject this argument.
The prior art is not limited to titrated dosing (where
doses start low and move higher) but rather contains
evidence of stable dosing (where the dose starts and stays
at the claimed level). As the district court noted, Polman
is evidence of safe and effective long-term oral admin-
istration of a stable dose of immediate-release 4-AP. Dist.
Ct. Op. at *34; see J.A. 6655. Schwid also provides evi-
dence of a stable-dosing regimen of 4-AP, if only for a
week. As for the studies that used escalating doses, some
of those studies began with 10 mg as the lowest dose
before titrating upwards to doses that may increase the
risk of seizure. E.g., Davis at 187 tbl.1; see also Dist. Ct.
Op. at *8 (1994 Elan study began with 12.5 mg 4-AP twice
daily); id. at *9 (10 mg twice daily was the lowest dose
used in the Acorda MS-F202 study); cf. J.A. 6647 (trial in
patients with other conditions began with dose of 10 mg 4-
AP twice daily and titrated up to 200 mg daily); J.A. 6434
(Acorda’s trial in patients with spinal cord injury began
with 10 mg twice daily as the lowest dose). Significantly,
the most important prior art, the Goodman references,
report a start dose of 10 mg twice daily. J.A. 6370, 6372,
6502.
Even if many earlier studies used a titrated-dosing
scheme to avoid adverse effects caused by starting at
higher doses, those studies do not, as the district court
found, undermine the other evidence in the prior art that
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 35
a person of skill would have a reasonable expectation of
success for a stable-dosing scheme at low doses. Dist. Ct.
Op. at *34. The Bever II prior-art review article reports
that while “seizures are common at higher doses,” 4-AP
“rarely cause[s] seizures at the doses used in [multiple
sclerosis] trials.” Bever II at S120. Other published
studies say the same: seizures were seen at higher doses,
but not lower ones like 10 mg. E.g., J.A. 6651 (trial in
patients with Eaton-Lambert syndrome, congenital myas-
thenia, and myasthenia gravis starting at dose of 10 mg
4-AP twice daily and escalating to 200 mg daily found
that all of the patients who experienced seizures during
the study “were receiving 80 mg or more of 4-AP daily”);
J.A. 6504 (Goodman Poster “Results Summary”: “At doses
above 40 mg/day, more severe adverse events were re-
ported, including two cases of seizure (at 60 and 70
mg/day)”). And in Schwid, the authors advise that future
studies pursue lower doses for long-term tolerability. See
J.A. 6681 (“4AP can provoke seizures and acute encepha-
lopathy,” but those episodes “tend to occur when serum
4AP levels peak, suggesting that lower peak levels may
increase safety.”); J.A. 6684 (“[F]uture studies of 4AP
[sustained release] will need to examine long-term effica-
cy and tolerability as well as further refine dosing regi-
mens to optimize delivery despite a relatively narrow
therapeutic window.”).
Expert testimony supports the district court’s finding
that a person of ordinary skill in the art would have been
motivated to pursue, and had a reasonable expectation of
success in pursuing, a stable-dosing regimen of 10 mg 4-
AP twice daily. According to Dr. Peroutka, “the general
goal of drug development [is] to provide a stable dosing
regimen.” J.A. 414. He testified that stable dosing was
particularly desirable for treating multiple sclerosis
because, as a chronic disease that requires long-term
treatment, a stable oral dose is much easier to administer.
See Sept. 19, 2016 Trial Tr. 110 (“Obviously, it’s a lot
36 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
easier simply to take one pill, the same pill twice a day
than to have to figure out, well, this morning I need this
much, that much. But with pills, it is almost impossible
to titrate easily.”). Even Dr. Goodman conceded that “it
would be desirable” to have a stable-dosing regimen
where “the patient would be prescribed [some dose] to
take on a regular basis.” J.A. 868. And titration was not
required given such a low starting dose: Acorda founder
Dr. Cohen testified that, upon recognizing the efficacy of
the 10 mg twice-daily dose, “we realized we didn’t have to
titrate anymore.” J.A. 614. Finally, Dr. Peroutka ex-
plained that nothing in the prior art suggested that 4-AP
could not be used for long-term treatment for a chronic
condition. Sept. 19, 2016 Trial Tr. 104.
3
Acorda’s most general argument is that the district
court improperly found that a relevant skilled artisan
“would have formed a reasonable expectation of success
based on Schwid and Goodman [in particular, the Good-
man Poster], in light of the totality of the prior art,”
regarding a 10 mg twice-daily dose of 4-AP to improve
walking. Dist. Ct. Op. at *31. We reject Acorda’s argu-
ment.
As described above, Schwid reports a statistically sig-
nificant improvement in timed gait for patients given
17.5 mg 4-AP twice-daily versus placebo. Also as de-
scribed above, the Goodman Poster reports a statistically
significant improvement in walking speed and in lower
extremity strength for patients given 10–40 mg 4-AP
twice daily versus placebo; an average improvement in
walking speed during the low-dose period (10–25 mg 4-AP
twice daily) of more than 20% for 9 of 25 subjects; and
“more severe adverse events,” including seizures, at doses
above 20 mg 4-AP twice daily. J.A. 6504. The Goodman
Poster also reports a dose response in the timed walk at
doses in the range of 10–20 mg 4-AP twice daily. See Dist.
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 37
Ct. Op. at *33 (“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.”).
The district court did not clearly err in finding that a
person of skill would have looked to both of those refer-
ences, considered their limits, and had a reasonable
expectation of success as to the efficacy of 10–20 mg 4-AP
twice daily to improve walking. Despite certain identified
“shortcomings” in the principal references, “the combined
message a [person of skill in the art] would have dis-
cerned from Schwid together with the Goodman refer-
ences was a reasonable expectation of success in treating
walking with 4-AP.” Id. at *31. Other prior art was
consistent with that message. Id. As to dosages, the
disclosures of Schwid and the Goodman Poster regarding
relevant benefits at doses including or near to the Acorda-
claimed range (recounted above), together with the re-
ported concerns about high doses, support the further
finding that a relevant skilled artisan would have “con-
sider[ed] 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.” Id. at *33(footnote attached citing further partial support from
testimony of Acorda’s Dr. Goodman). In a finding reflect-
ing both motivation and reasonable expectation of suc-
cess, the district court stated: “As the lowest of the range
of encouraging doses, 10mg/twice daily would have been
an attractive starting point for a [person of skill in the
art].” Id. These findings not only have adequate eviden-
tiary support but comport with the guidance of KSR to
“take account of the inferences and creative steps that a
38 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
person of ordinary skill in the art would employ.” 550
U.S. at 418. 12
Expert testimony further supports the district court’s
findings. The defendants’ expert Dr. Peroutka explained
that Schwid showed that the claimed formulation was
effective at a 17.5 mg twice-daily dose and that the result
was statistically significant. J.A. 406–07, 410. Dr.
Peroutka also stated that the Goodman abstracts “said
that dose response curves showed an increasing benefit in
both measures in the 20 to 50 milligram a day range [10–
25 mg twice-daily range], meaning timed walking or lower
extremity strength.” J.A. 414. According to Dr. Peroutka,
the study presented in the Goodman abstracts was a dose-
ranging study where “the goal” is “to find the most effica-
cious dose without adverse events.” Id.; accord J.A. 869
(Acorda’s expert Dr. Goodman: “[W]hat we really want to
find is the most effective dose that can be given safely.”).
The additional information provided in the bar graph in
the Goodman Poster showed that people taking 10–25 mg
twice daily did better in walking speed than placebo, and
the dose-response curve showed improvement in walking
speed at the 10 mg twice-daily dose—a level of improve-
ment that was maintained at higher doses. See J.A. 416;
Sept. 19, 2016 Trial Tr. 102 (“They got the 10 milligrams
to work at this level and that level of efficacy was main-
tained through the dose ranges.”); id. at 103 (“[I]t’s cer-
tain stable clinical effect at 20 to 40” milligrams per day
12 In its formulation describing the narrow set of
choices facing the relevant artisan in 2004 in this case,
the district court quoted KSR’s discussion of obviousness
where the claimed invention was “obvious to try.” Dist.
Ct. Op. at *32 (quoting 550 U.S. at 421). But the court
fully applied the familiar standards focused on the rele-
vant artisan’s motivation to make the claim-required
combinations with a reasonable expectation of success.
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 39
(doses of 10 mg, 15 mg, and 20 mg twice-daily).). Dr.
Peroutka testified that he would have included the 10 mg
dose in a Phase III study because there are “very serious”
side effects at higher doses so “you would take the lowest
effective dose that was safe.” Id. at 104. He also testified
that a person of skill might even want to try a lower dose,
but “based on the [Goodman] data, 10 is the lowest effec-
tive dose.” Id. Acorda’s expert Dr. Goodman himself
stated that the Goodman Poster “suggest[s]” “that the
range for further testing would be the 20 to 40 milligrams
per day [10 to 20 mg twice-daily] range.” J.A. 844–45; see
also J.A. 874 (Dr. Goodman stating during his deposition
that “a person of ordinary skill in the art in December
2003 would have been motivated based on the 201 study
to design a study along the lines of what became the 202
study,” which tested the 10 mg twice-daily dose). Ulti-
mately, the court found, based on the prior art and expert
testimony, that a person of skill before the 2004 priority
date would have looked (1) to the 10–20 mg twice-daily
dose range for effective doses that would be reasonably
expected to improve walking in multiple sclerosis patients
and (2) to the low end of that range to avoid adverse
effects. Dist. Ct. Op. at *32–33.
Acorda’s core argument appears not to be that the ev-
idence fails to support the finding of a motivation to
combine. Rather, it appears to be that the evidence
cannot support a finding of a reasonable expectation of
success (in 2004) in the absence of publications showing a
statistically significant difference in walking tests be-
tween the specific dose of 10 mg 4-AP taken twice daily
versus placebo. See Acorda Br. 41–42; Acorda Reply Br.
20–21; Oral Arg. at 6:10–30. We reject this contention.
To the extent that Acorda’s contention is a legal one,
asserting a law-required minimum for what can support a
“reasonable” expectation of success, Acorda has offered no
support for the contention. This court has long rejected a
requirement of “[c]onclusive proof of efficacy” for obvious-
40 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
ness. See, e.g., Hoffman-La Roche Inc. v. Apotex Inc., 748
F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeu-
tics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir.
2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364,
1367–68 (Fed. Cir. 2007) (reasoning that “the expectation
of success need only be reasonable, not absolute”). And
Acorda has cited no authority from the Supreme Court or
this court requiring as a matter of law, for reasonableness
of an expectation of success, testing of specific doses
versus placebo that shows the relevant result with statis-
tical significance. Acorda has furnished no basis for
treating the question in this case as anything but one of
context-specific fact based on evidence.
In some cases, of course, the evidentiary basis for an
inference of reasonable expectation of success may be
inadequate. See, e.g., In re Cyclobenzaprine, 676 F.3d at
1070–71. Here, though, as we have discussed, expert and
other evidence indicates that a person of skill in the
present context can draw reasonable inferences about the
likelihood of success even without a perfectly designed
clinical trial showing a statistically significant difference
in efficacy between a specific dose and placebo. See also
J.A. 6657 (Polman: “Although a placebo effect cannot be
excluded, the dynamics of the response in relation to the
intake of the medication and the deterioration and subse-
quent 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.”). We see no
clear error in the district court’s finding to that effect.
We are not persuaded by Acorda’s reasons for a con-
trary finding. To begin with, “Elan’s failure in the only
large-scale and properly statistically powered trial of
sustained-release 4-AP that deflated expectations for the
drug,” Acorda Reply Br. 28, is not particularly relevant to
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 41
the expectations of success for the Acorda invention. The
record shows that the Elan trial was unpublished and is
only cursorily discussed in the introduction in Schwid,
limiting any “deflat[ing]” effect on expectations in the
field. Sept. 19, 2016 Trial Tr. 143–44 (Dr. Peroutka
noting that, even in the short discussion of the 1994 Elan
study in Schwid, there is very little detail and no mention
of the dose of 4-AP that was used). Moreover, the abbre-
viated discussion of that trial in Schwid distinguishes the
aggregate outcome measure (EDSS) and results in the
Elan study from the Schwid study’s measure of particular
functionalities (e.g., timed gait). J.A. 6681 (noting the
failure of the Elan study but stating that “[t]he EDSS . . .
may have been an inadequate outcome variable for this
trial,” as EDSS measures several outcomes and could
“overlook” significant but lesser improvements in walk-
ing). And the 1994 Elan study preceded the successes
reported later in Schwid and the Goodman references,
which were a sound basis for altering earlier expectations.
Similarly, the “inconclusiveness of the exploratory
studies of 4-AP, a 102-year old drug,” Acorda Reply
Br. 28, does not speak to the more recent research relied
on by the district court—namely, Schwid and the Good-
man references. And “the rigorous 2003 Solari review of
the field dispelling any confidence in using
am[ino]pyridines to treat [multiple sclerosis],” id. at 29,
does not dispel confidence in a walking improvement;
rather, Solari, a prior-art literature review, reports a
statistically significant improvement in walking,
J.A. 7208 (reviewing three studies that “assessed the
efficacy of aminopyridines on ambulation” and reporting
that patients who received 4-AP showed a statistically
significant improvement in ambulation compared to
42 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
placebo (p<0.0001)). 13 When Acorda asserts that the
“prior art’s [Schwid’s] teaching that 4-AP had a narrow
therapeutic window where high doses and high blood
serum levels were necessary for any meaningful thera-
peutic effect,” Acorda Reply Br. 29, Acorda is incorrect, as
discussed previously: Schwid reports that a relatively low
(17.5 mg twice a day) dose showed a statistically signifi-
cant improvement in walking and that high serum levels
were not required for improvements in timed gait.
Schwid, which reports success and no seizure events with
a stable dose of 17.5 mg twice daily, also undermines
Acorda’s argument that “the prior art’s consistent use of
titration to achieve a therapeutic dose because of seizure
risk” conclusively precludes a reasonable expectation of
success even for a low dose like 10 mg twice daily that
avoids high peak serum levels. Id. In the end, Schwid,
Goodman as a whole, and expert testimony supply a
sufficient basis for the district court’s finding of a reason-
able expectation of success in this case.
In light of the record evidence, the district court did
not clearly err in finding that a person of skill at the time
of the invention would have had a motivation to combine,
and a reasonable expectation of success in combining, the
teachings of the prior art to arrive at the Acorda invention
of a stable regimen of 10 mg twice-daily sustained-release
4-AP to improve walking in multiple sclerosis patients.
B
Acorda nevertheless contends that a skilled artisan
would not have a reasonable expectation of success re-
garding the invention of the Acorda patents because the
prior art did not teach or suggest a final limitation of the
13 Alessandra Solari et al., Aminopyridines for symp-
tomatic treatment in multiple sclerosis (Review), Cochrane
Database of Systematic Reviews, Issue 4 (2002).
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 43
asserted claims—the pharmacokinetic limitation, which
requires 4-AP serum levels in the 15–35 ng/ml range.
E.g., ’826 patent, col. 27, line 29. We disagree.
The district court found that the prior art taught that
a dose of 10 mg sustained-release 4-AP twice daily would
result in serum levels within the range claimed in the
Acorda patents. Dist. Ct. Op. at *35. Hayes discloses that
when a sustained-release formulation of 4-AP is adminis-
tered in a 10 mg dose twice daily, and steady-state condi-
tions are reached, the result is a 4-AP average serum
level of 20.8 ± 5.7 ng/ml (15.1–26.5 ng/ml, which is within,
and in fact covers most of, the Acorda patents’ claimed
range). J.A. 6436, 6439 tbl.3. The Hayes study is sum-
marized—and Hayes’s table listing the pharmacokinetic
results is replicated—in the specifications of two of the
Acorda patents. ’826 patent, col. 24, line 25 through
col. 25, line 50 (Example 7 and Table 7); ’685 patent,
col. 24, line 30 through col. 25, line 54 (Example 7 and
Table 7). The district court noted that the parties did not
dispute either of two propositions: the Hayes researchers
used the Elan formulation that is claimed in the Acorda
patents and is now marketed as Ampyra; and the phar-
macokinetic results reported in Hayes are inherent prop-
erties of that formulation. Dist. Ct. Op. at *35. As
discussed in the previous subsections, the district court
also found that a person of skill would have been motivat-
ed, with a reasonable expectation of success, to administer
a dose of 10 mg sustained-release 4-AP twice daily to
improve walking in multiple sclerosis patients. Id. at
*35–36. Based on those findings, the court invoked the
principle that “an obvious formulation cannot become
nonobvious simply by administering it to a patient and
claiming the resulting serum concentrations,” Santarus,
Inc. v. Par Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir.
2012), and concluded that the pharmacokinetic limitation
could not alter the obviousness analysis.
44 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
On appeal, Acorda does not directly object to the dis-
trict court’s inherency finding about Hayes, but Acorda
suggests that a person of skill would expect that the
inherent pharmacokinetic profiles would differ between
patients with spinal cord injury (as in Hayes) and pa-
tients with multiple sclerosis (as in the Acorda patents).
But Acorda cites no support for that assumption, and
Acorda appears to have made the opposite assumption by
including the Hayes pharmacokinetic data in its own
patents on using 4-AP to treat multiple sclerosis. Acor-
da’s expert also admitted at trial that Hayes “may cer-
tainly show the pharmacokinetic profile that’s analogous
to what would be found in MS [multiple sclerosis] pa-
tients. I don’t have any dispute with that.” J.A. 825. The
defendants’ expert agreed, testifying that a person of skill
would expect the same pharmacokinetic profile in pa-
tients with either condition. J.A. 539–40. And while
Acorda argues that a person of skill in the art “would
have no basis to connect Hayes with [multiple sclerosis]
prior art,” Acorda Br. 54, Hayes’s introduction explicitly
makes that connection, stating that “[4-AP] is the first
compound shown to restore some neurologic function in
patients with chronic [spinal cord injury] or other demye-
linating conditions such as multiple sclerosis.” J.A. 6433
(internal references omitted). 14
Even if the pharmacokinetic profile is inherent in the
10 mg twice-daily administration of sustained-release 4-
AP in Hayes, Acorda complains that a person of skill may
not have known the details of the formulation used in
14 Hayes also discloses that the reported study on
the pharmacokinetics of sustained-release 4-AP was
sponsored by Acorda. J.A. 6433. That disclosure links
Hayes to the Goodman references, which also disclose an
association with Acorda in a sustained-release 4-AP
study. J.A. 6370, 6372, 6498.
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 45
Hayes (Ampyra) and therefore would not have known
whether the formulation claimed in the Acorda patents
would produce the same pharmacokinetic profile. Cf. In
re Cyclobenzaprine, 676 F.3d at 1069–71 (obviousness
analysis of patent claims to a “therapeutically effective
plasma concentration” and to particular pharmacokinetic
parameters required a factual finding regarding what a
skilled artisan would know about the serum levels needed
to produce a therapeutic effect). But Acorda, in response
to the district court’s question as to whether the pharma-
cokinetic limitation would have been obvious, conceded at
trial that a skilled artisan in 2003 would know the phar-
macokinetic data for a 10 mg twice-daily dose of sus-
tained-release 4-AP. J.A. 1108–09 (counsel for Acorda: “It
was known in the art that a sustained-release formulation
of 10 [mg] [twice daily] could achieve that PK [pharmaco-
kinetic result], not that that PK would yield any efficacy
for walking.”). Acorda itself therefore assumed that a
person of skill would know that a regimen of 10 mg twice-
daily dosing of sustained-release 4-AP—regardless of the
specifics of the rest of the formulation—would achieve
that pharmacokinetic profile. And, again, Acorda has not
pointed to any evidence to contradict that assumption,
such as evidence showing that a person of skill would
expect another sustained-release formulation containing
the same dose of 4-AP to produce a different pharmacoki-
netic profile, how that formulation would differ, or how
the associated profile would differ.
C
Acorda’s remaining argument on appeal concerns the
proper analysis of objective indicia of nonobviousness in
this case. Acorda focuses on the district court’s reliance
on the Elan patent as a blocking patent for the Acorda
patents’ claimed inventions, in determining that commer-
cial success, failure of others, and long-felt but unmet
need did not “support” or “militate in favor of” nonobvi-
ousness. Dist. Ct. Op. at *39, *40. Acorda characterizes
46 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
the district court as having applied a categorical rule that
a blocking patent defeats the significance of such objective
indicia to the obviousness determination. We think,
however, that the district court’s opinion is best read not
as invoking a categorical rule, but as drawing conclusions
on the limited factual record created in this case bearing
on the effect of a blocking patent. In any event, the court
did not err in concluding that the defendants proved
obviousness, considering the evidence on objective indicia.
1
A patent has been called a “blocking patent” where
practice of a later invention would infringe the earlier
patent. The existence of such a blocking patent may deter
non-owners and non-licensees from investing the re-
sources needed to make, develop, and market such a later,
“blocked” invention, because of the risk of infringement
liability and associated monetary or injunctive remedies.
If the later invention is eventually patented by an owner
or licensee of the blocking patent, that potential deterrent
effect is relevant to understanding why others had not
made, developed, or marketed that “blocked” invention
and, hence, to evaluating objective indicia of the obvious-
ness of the later patent. See Note, Subtests of “Nonobvi-
ousness”: A Nontechnical Approach to Patent Validity, 112
U. Pa. L. Rev. 1169, 1177 (1964) (Regarding commercial
success, “a court must be assured that the patentee’s
market domination is not attributable to monopoly power
or other economic coercion, or to other factors unrelated to
patent validity.”) (cited in Graham v. John Deere Co. of
Kansas City, 383 U.S. 1, 18, 36 (1966)).
We briefly discussed blocking patents in Merck & Co.
v. Teva Pharmaceuticals USA, Inc., 395 F.3d 1364 (Fed.
Cir. 2005) (Merck I). The Merck patent at issue, applied
for in 1998, was for the weekly administration of alendro-
nate monosodium trihydrate (Fosamax). Id. at 1366–67.
That patent was preceded by Merck’s earlier patent
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 47
(issued in 1986) covering a method of administering an
effective amount of Fosamax to treat osteoporosis, as well
as Merck’s statutory right, since obtaining FDA approval
in 1995, to the exclusive marketing of any dosage strength
of Fosamax for the next five years. 395 F.3d at 1367,
1377; Br. for Def.-Appellant Teva Pharm. USA, Inc.,
Merck I, No. 04-1005, 2003 WL 24307848, at *62–63 (Fed.
Cir. Dec. 17, 2003). We ruled that the district court had
erred in its analysis of commercial success because the
earlier patent and FDA regulatory approval depressed
incentives for others to invent the weekly-dosing scheme.
395 F.3d at 1377 (“Because market entry by others was
precluded on those bases, the inference of non-
obviousness of weekly-dosing, from evidence of commer-
cial success, is weak.”). In that context, we said, the
evidence of commercial success was “not enough to show
the claims at bar are patentably distinct from the weekly-
dosing ideas in the [invalidating prior art].” Id.In Galderma Laboratories, L.P. v. Tolmar, Inc., 737
F.3d 731 (Fed. Cir. 2013), we considered the district
court’s finding, in support of commercial success, that the
FDA-approved product “quickly gained and maintained
market share.” Id. at 740. Because earlier patents owned
by Galderma may have “blocked” competition to market
the FDA-approved product by any entity other than
Galderma, we reasoned that the commercial success of the
product was “of ‘minimal probative value’” and not suffi-
cient to justify a conclusion of nonobviousness in light of
the other evidence supporting obviousness. Id. at 741(quoting Merck I, 395 F.3d at 1376).
Recently, in Merck Sharp & Dohme Corp. v. Hospira,
Inc., 874 F.3d 724 (Fed. Cir. 2017) (Merck II), we conclud-
ed that Merck’s exclusive license to a blocking patent did
not, all by itself, justify discounting evidence of commer-
cial success. Id. at 730–31. We explained that commer-
cial success is “a fact-specific inquiry” that may involve
considering the operation of specific blocking patents on
48 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
possible competition. Id. at 731. But the mere existence
or sheer number of blocking patents does not, without
more, “necessarily detract from evidence of commercial
success of a product or process.” Id. Nevertheless, “even
giving the evidence of commercial success its full and
proper weight,” we affirmed the judgment invalidating
the claims at issue for obviousness in light of “the evi-
dence that the claimed process was substantially de-
scribed in the prior art” and that “merely ordinary
experimentation was required to arrive at the [patent at
issue].” Id.Merck II’s reasoning reflects a common-sense recogni-
tion that, as a theoretical matter, a blocking patent may
or may not deter innovation in the blocked space by
commercially motivated potential innovators other than
the owners or licensees of the blocking patent. 15 Where
the owner of the blocking patent or exclusive licensee is
different from the owner of the patent in suit, the grant-
ing of a license may be a realistic possibility. Even where,
as here, the owner of the patent in suit and the exclusive
licensee of the blocking patent are the same, such a
potential innovator might or might not think it could
successfully challenge the blocking patent. And such a
potential innovator might or might not be willing to
research in the blocked space without a license to a block-
ing patent—even if the research itself is within the safe
harbor provided by 35 U.S.C. § 271(e)(1)—and wait until
it has already developed and patented its aimed-at im-
15 We use the term “blocked space” to refer to what
would infringe given the “boundaries,” Festo Corp. v.
Shoketsu Kinzoku Kogyo Kabushiki Co., 535 U.S. 722, 730
(2002), or “metes and bounds,” Brenner v. Manson, 383
U.S. 519, 534 (1966), set by the blocking patent’s claims.
See Andrew Corp. v. Gabriel Electronics, Inc., 847 F.2d
819, 823 (Fed. Cir. 1988).
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 49
provement to negotiate for a cross-license with the block-
ing patent’s owner to share the profits from the improve-
ment. Besides the assessment of whether the blocking
patent can be successfully challenged, a number of varia-
bles appear generally relevant to the calculus, including:
the costliness of the project; the risk of research failure;
the nature of improvements that might arise from the
project, and whether such improvements will be entirely
covered by the blocking patent; the size of the market
opportunities anticipated for such improvements; the
costs of arriving at the improvements and getting them to
market; the risk of losing the invention race to a blocking-
patent owner or licensee; the risk that the blocking-patent
owner (making its own economic calculations, perhaps in
light of its own other products or research activities) will
altogether refuse to grant a license to the improvement or
will demand so large a share of profits that the whole
project is not worthwhile for the potential innovator—all
evaluated in light of other investment opportunities.
For such reasons, it is clear that, if all other variables
are held constant, a blocking patent diminishes possible
rewards from a non-owner’s or non-licensee’s investment
activity aimed at an invention whose commercial exploita-
tion would be infringing, therefore reducing incentives for
innovations in the blocked space by non-owners and non-
licensees of the blocking patent. Such a blocking patent
therefore can be evidence that can discount the signifi-
cance of evidence that nobody but the blocking patent’s
owners or licensees arrived at, developed, and marketed
the invention covered by the later patent at issue in
litigation. But the magnitude of the diminution in incen-
tive in any context—in particular, whether it was great
enough to have actually deterred activity that otherwise
would have occurred—is “a fact-specific inquiry.” Merck
II, 874 F.3d at 731. That inquiry, conducted within the
framework under which the challengers always retain the
burden of persuasion on obviousness, may be a difficult
50 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
one as a practical matter. In a particular case, a court
may ultimately be left, for its evaluation, with the solid
premise of diminished incentives, plus some evidence
(possibly weak or ambiguous) about the significance of the
deterrence, together with a background sense of the
general realities in the area at issue that can affect the
weight to be given to the evidence in the specific case.
2
Against this background, we review the district
court’s consideration of objective indicia of nonobvious-
ness in light of the Elan patent. Acorda licensed the Elan
patent in the late 1990s, before the period of commercial
success alleged by Acorda and found by the district court.
Here, Acorda bore the burden of producing evidence of
objective indicia, but the “ultimate burden of proving
obviousness” at all times remained with the defendants.
Galderma, 737 F.3d at 736–38. We conclude that the
district court did not err in viewing the Elan patent,
among other evidence, as evidence that discounted the
weight of Acorda’s evidence of commercial success, failure
of others, and long-felt but unmet need so that “the evi-
dence as a whole” in the case “prove[d] clearly and con-
vincingly that the Acorda Patents are invalid due to
obviousness.” Dist. Ct. Op. at *41.
The parties presented evidence on the objective indi-
cia of commercial success, failure of others, and long-felt
but unmet need. 16 In particular, the defendants present-
ed evidence of blocking by the Elan patent. See Dist. Ct.
Op. at *38 & n.43 (undisputed that invention of Acorda
patents practice the Elan patent).
16 Acorda also presented evidence of unexpected re-
sults, but the district court found the evidence unpersua-
sive. See Dist. Ct. Op. at *39. Acorda does not appeal
that finding.
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 51
As to commercial success, the district court found that
“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.”
Id. at *38. The district court therefore found that the
evidence of commercial success did not support the con-
clusion that the Acorda patent claims were non-obvious.
Id. at *39.
We will interpret the district court’s statements to-
gether as referring to domestic marketing of a product.
As discussed below, the Elan patent would not preclude
practice of the Elan invention outside the United States
or under the safe harbor provision of 35 U.S.C. § 271(e)(1)
for specified FDA-related activities. The district court’s
key finding, therefore, is that “[t]he risk of [infringement]
liability” for marketing in the United States “would have
provided an independent incentive for a patentee not to
develop the invention of the Acorda patents, even if those
inventions were obvious.” Dist. Ct. Op. at *38.
That finding is supported by the record. The defend-
ants offered unrebutted testimony from an expert in
economics and pharmaceuticals that the Elan patent
acted as a blocking patent for entities other than Acorda
(the exclusive licensee to the Elan patent) that wanted to
pursue commercial opportunities like Ampyra. J.A. 965–
66 (“[O]ther entities that might want to pursue commer-
cial opportunity like Ampyra . . . would not have access to
[the sustained-release 4-AP formulation claimed in the
Elan patent] because Acorda has that exclusive license.”).
The Elan patent issued in 1996 and was licensed exclu-
sively to Acorda in 1997 for spinal cord injury and in 1998
for multiple sclerosis treatment. J.A. 965. After that, the
exclusive license blocked others from domestic marketing
without risk of infringement.
52 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
Other evidence supports a finding that the Elan pa-
tent would have deterred entities other than Elan (holder
of the Elan patent) and Acorda (exclusive licensee) from
investing in research whose reward depended on market-
ing a drug like Ampyra. After more than a decade of
research by different groups and then issuance of the
Elan patent in 1996, clinical trial research into sustained-
release 4-AP treatment for multiple sclerosis appears,
based on the prior art introduced at trial, to have been
limited to Elan and Acorda. When seeking to use 4-AP for
multiple sclerosis, Acorda itself sought and obtained a
license to the Elan patent. There is no evidence that Elan
sought to license the Elan patent to any entity other than
Acorda, or that Acorda sought to sublicense the Elan
patent, either of which would dilute the power of the
blocking patent. J.A. 966. And what Elan granted Acor-
da was an exclusive license, suggesting the significance of
the Elan patent’s blocking power.
Acorda notes that U.S. patents do not block sales out-
side the United States. That observation is relevant, but
it is not shown to be weighty in this case by any concrete
evidence about the particular inventions at issue. Indeed,
the two international studies that Acorda highlights were
both conducted before issuance of the Elan patent in 1996.
See J.A. 6654 (1994 Polman study); J.A. 7037 (1993 Van
Diemen study).
Acorda also notes that potential innovators would not
have been blocked from practicing the Elan patent in the
ways covered by the safe harbor provision of 35 U.S.C. §
271(e)(1), which declares specified activities to be non-
infringing if undertaken “solely for uses reasonably relat-
ed to the development and submission of information” to
the FDA. See Merck KGaA v. Integra Lifesciences I, Ltd.,
545 U.S. 193, 205–08 (2005). That safe harbor is certainly
relevant, but it does not eliminate infringement liability
for the eventual reward-collecting activity of generally
marketing the product. We have no basis for finding clear
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 53
error in the district court’s finding about the explanatory
significance of the risk of such liability. Acorda did not
supply evidence to make unreasonable the implicit find-
ing that securing freedom from blocking patents in ad-
vance is likely important to pharmaceutical research
investments. 17 And amici appearing in this court on
appeal have not supplied such evidence either. 18
17 Without contrary evidence, we see nothing inher-
ently unreasonable about the implicit finding to that
effect. See Stoyan A. Radkov, Freedom to Operate (FTO)
from a large company’s perspective 3, 5, Royal Society of
Chemistry (Oct. 11, 2010), http://www.rsc.org/images/
StoyanRadkov_tcm18-192425.pdf (in a presentation by an
attorney for Novartis Pharma AG an FTO analysis of
“[t]he ability to perform a particular commercial activity
(e.g. commercialize a product, provide a service, perform a
manufacturing process or use a product) without ‘infring-
ing’ 3rd party’s valid IP [intellectual property] rights,”
explaining that “[i]dentifying possible 3rd party IP rights
posing risks as soon as possible is essential”); Saharsh
Davuluri, Generic Drugs – The Freedom to Operate,
Neutland Labs. Ltd. (Aug. 2, 2014), https://www.neuland
labs.com/blog/2014/08/02/generic-drugs-the-freedom-to-op
erate/ (“A Freedom to Operate analysis is crucial – and is
best performed before embarking down the product devel-
opment path.”). In so stating, we do not prejudge what
evidence in another case might demonstrate.
18 Amici point out that pharmaceutical improve-
ments (new formulations, new combinations, and new
indications of previously marketed drugs) are not un-
common: 23 were approved by the FDA and launched in
2016. Biotech. Innovation Org. Br. at 20 (citing A.I. Graul
et al., The year’s new drugs & biologics 2016: Part I, 53
Drugs of Today 27, 28 (2017)). But amici do not specify
whether the approved applications for those improve-
54 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
Acorda offers no more persuasive basis for challenging
the district court’s findings of the weakness of Acorda’s
evidence of the failure of others and long-felt but unmet
ments are held by the owners (or licensees) of any original
blocking patents or by competing entities. See Chie Hoon
Song & Jeung-Whan Han, Patent cliff and strategic
switch: exploring strategic design possibilities in the
pharmaceutical industry, 5 SpringerPlus 692, 698–99
(2016) (noting that some of the best ways for a pharma-
ceutical company to avoid the “patent cliff” of losing the
monopoly on its brand-name drug from patent expiration
is through a product-line extension (new formulations,
new combinations), new indications, or a follow-on prod-
uct). For example, among the examples from 2016 listed
in the Graul article are Ilaris, Ezetrol, and Inegy, see
Graul, The year’s new drugs & biologics, 53 Drugs of
Today at 56, 57, which involve improvements (new indica-
tions) on drugs previously approved for other indications
for marketing by the same company that submitted the
application for the new indication. See Product Update:
New indication for Inegy, The Pharmaceutical Journal
(Mar. 1, 2016), https://www.pharmaceutical-journal.com/
news-and-analysis/notice-board/new-indication-for-inegy/
20200796.article?firstPass=false (Merck sells the drug
Inegy (ezetimibe/simvastatin) for both old and new indica-
tions); U.S. Food & Drug Admin., U.S. Dep’t of Health &
Human Servs., FDA News Release: FDA approves expand-
ed indications for Ilaris for three rare diseases (Sept. 23,
2016), https://www.fda.gov/newsevents/newsroom/press
announcements/ucm522283.htm (Ilaris (canakinumab)
sold by Novartis for old and new indications); Joel Levy,
MHRA approves new indication for MSD’s Ezetrol, Phar-
mafile (Feb. 26, 2016), http://www.pharmafile.com/news/
503098/mhra-approves-new-indication-msd-s-ezetrol
(Merck (MSD) sells Ezetrol (ezetimibe) for both old and
new indications).
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 55
need as evidence of non-obviousness. Dist. Ct. Op. at *39–
40. As to the former, the district court found that Sanofi-
Aventis experimented with another potassium-channel
blocker and was unsuccessful, and “Sanofi-Avenits likely
did not use 4-AP because” of the blocking effect of the
Elan patent. Id. at *39. Acorda has not shown clear error
in that finding. Acorda also points to the failure of Elan’s
1994 study. But the district court reasonably found that
“Elan’s failure is not particularly probative” because the
Elan study preceded publications that would render the
invention obvious to those of skill in the art (Schwid and
Goodman) as of the 2004 priority date. Dist. Ct. Op. at
*40; see Graham, 383 U.S. at 36 (“The [1956] Scoggin
invention . . . rests upon exceedingly small and quite non-
technical mechanical differences in a device which was old
in the art. At the latest, those differences were rendered
apparent in 1953 by the appearance of the Livingstone
patent [invalidating prior art], and unsuccessful attempts
to reach a solution to the problems confronting Scoggin
made before that time became wholly irrelevant.”); see
also Note, Subtests of “Nonobviousness,” 112 U. Pa. L.
Rev. at 1174 (“In receiving evidence of unsuccessful
research, courts must take care that such research was
conducted under the same state of the art as that which
confronted the patentee. It may be that an intervening
innovation made that which the patentee accomplished
obvious even though it was not obvious to prior unsuccess-
ful researchers.” (internal reference omitted)). By 1997,
the art expressly explained why improvement of multiple
sclerosis symptoms with 4-AP was promising despite the
failed 1994 Elan study. See, e.g., J.A. 6681 (1997 Schwid
article states that the EDSS score was “an inadequate
outcome variable” for the Elan study, reports a significant
improvement in timed gait, and concludes that “4AP
[sustained-release] improved motor function in [multiple
sclerosis] patients.”).
56 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
As to long-felt but unmet need, the district court
discounted its finding of such need in light of the evidence
of blocking by the Elan patent. Dist. Ct. Op. at *40. We
see no clear error. While not dispositive, the evidence of
blocking we have discussed is pertinent, in this case, to
the factual question of long-felt but unmet need—at least
as to the period after the issuance of the Elan patent in
1996.
III
The defendants cross-appealed the district court’s
ruling that the Elan patent is not invalid and the result-
ing injunction. Because the injunction terminated by its
terms on the date of expiration of the Elan patent (July
30, 2018), and no retrospective liability is at issue, the
cross-appeal is dismissed as moot. See Fed. R. App. P.
41(b), (c); 16AA Charles A. Wright & Arthur R. Miller,
Federal Practice and Procedure § 3987 (4th ed. 2018); cf.
Defs.’ Br. 61 (“the Court need not reach the cross-appeal
unless the Court intends to issue a decision before August
2018”).
IV
We affirm the district court’s ruling that the asserted
claims of the Acorda patents are invalid and dismiss the
defendants’ cross-appeal as moot.
AFFIRMED
United States Court of Appeals
for the Federal Circuit
______________________
ACORDA THERAPEUTICS, INC.,
Plaintiff-Appellant
ALKERMES PHARMA IRELAND LIMITED,
Plaintiff-Appellee
v.
ROXANE LABORATORIES, INC., MYLAN
PHARMACEUTICALS INC., TEVA
PHARMACEUTICALS USA, INC.,
Defendants-Cross-Appellants
______________________
2017-2078, 2017-2134
______________________
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.
______________________
NEWMAN, Circuit Judge, dissenting.
The court today holds that the new Acorda treatment
for multiple sclerosis, Ampyra®, achieved after decades of
failed research, was obvious. For this discovery, where a
relatively small pharmacological difference produced long-
sought medical benefits, it is essential that the correct
law and analysis of obviousness are applied.
2 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
The district court observed that the objective indicia,
viz. commercial success, long-felt but unmet need, failure
of others, and copying, could change the result, yet dis-
counted its weight on the theory that the patentee had a
“blocking” patent. Adopting this flawed reasoning, my
colleagues hold that this new treatment for multiple
sclerosis was obvious. However, it is apparent that there
is not clear and convincing evidence of obviousness.
The consequences of this new legal theory are large,
as the amici curiae advise. Had the court’s approach to
the law of obviousness been in effect when Acorda took up
the study of 4-aminopyridine after decades of failures by
others, it is questionable whether this new treatment for
multiple sclerosis would have been discovered and pur-
sued. The loser is the afflicted public. 1
From my colleagues’ continuation of this error, and
their erroneous conclusions, I respectfully dissent.
I
The Decades of Failures
As the court reports, 4-AP has “for several decades”
been the “focus of research regarding the treatment of
multiple sclerosis.” Maj. Op. at 5. Starting in the 1980s
or earlier, scientists in several countries tried and failed
to provide safe and effective application of 4-AP. My
colleagues agree, as do the Defendants who initiated
these Hatch-Waxman proceedings, that the Acorda Pa-
tents describe novel technology, and that a safe and
effective formulation for 4-AP was not previously known.
The Acorda inventors succeeded where many others had
1 The FDA gave the Acorda product expedited ap-
proval, in view of the public need for relief of multiple
sclerosis. Appellant’s Br. at 23.
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 3
failed. The panel majority treats these past failures
simply as invalidating prior art.
The court recognizes that the Acorda Patents are di-
rected to a new, effective treatment to relieve the “walk-
ing impairment” of multiple sclerosis. 2 However, the
court holds that Acorda merely “add[ed] further, more
specific requirements to the Elan Patent’s claimed meth-
ods.” Maj. Op. at 3. The court does not mention that
Elan, after years of failures, abandoned its attempts to
use 4-AP to treat multiple sclerosis and licensed the
sustained-release patent to Acorda.
The record shows that many scientists in many insti-
tutions studied and eventually abandoned 4-AP as a
treatment prospect for multiple sclerosis. These aban-
doned studies constitute the prior art on which the dis-
trict court and my colleagues rely for obviousness of the
Acorda Patents. However, the experimentation with 4-AP
shows just the opposite – it shows that work with 4-AP
was abandoned due to the inability to balance the com-
pound’s potential effectiveness with its toxicity.
To review obviousness of the Acorda Patents, I start
with the cited references, whose chronology illustrates the
initial encouragement followed by failed attempts to apply
the neurological properties of 4-aminopyridine, and the
2 The symptoms of multiple sclerosis include “walk-
ing impairment, visual difficulty, fatigue, bladder dys-
function, tingling or pain, sexual dysfunctions, balance
problems, and cognitive changes,” with “weakness in the
legs and/or alterations in walking among the most com-
mon symptoms.” Acorda Therapeutics, Inc. v. Roxane
Labs., Inc., No. 1:14-cv-00882-LPS, 2017 WL 1199767 (D.
Del. Mar. 31, 2017) (Dist. Ct. Op.) at *2.
4 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
eventual abandonment of this product despite some
positive observations.
A. The Stefoski Study
In 1987, Stefoski et al. reported a one-day test of the
effects of 4-AP on vision and gait in twelve multiple
sclerosis patients. 3 They reported that, following intrave-
nous injection of 7 to 35 mg of 4-AP, in 1 to 5 mg doses
every ten to sixty minutes, “[v]ision improved in 7 pa-
tients, oculomotor function in 5, and motor function
(power, coordination, gait) in 5,” stating that there were
“no serious side effects,” and “transient therapeutic bene-
fit in selected patients.” Stefoski et al. at 71. My col-
leagues rely on this publication for rendering obvious
Acorda’s improvement in walking, while downplaying the
“serious side effects” including seizures reported by Bev-
er 4 and others, and the criticism of the small sample size
and the brief duration of these one-day tests.
B. The Davis Study
In 1990, Davis and Stefoski reported a study of fifteen
patients using an orally-administered formulation of 4-
AP. 5 They concluded that the results “suggest a safe and
effective therapeutic window for orally administered 4-
AP,” but they cautioned that similar studies had found
3 Dusan Stefoski et al., 4-Aminopyridine Improves
Clinical Signs in Multiple Sclerosis, 21 Annals of Neurol-
ogy 71 (1987), J.A. 6697.
4 Christopher T. Bever, Jr., The Current Status of
Studies of Aminopyridines in Patients with Multiple
Sclerosis, 36 Annals of Neurology S118 (1994) (“Bever II”),
J.A. 6172.
5 Floyd A. Davis et al., Orally Administered 4-
Aminopyridine Improves Clinical Signs in Multiple Scle-
rosis, 27 Annals of Neurology 186 (1990), J.A. 6327.
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 5
that side effects of 4-AP “precluded its clinical use,” and
that “MS patients have an increased risk of seizures.”
Davis et al. at 191.
These studies were criticized by Bever as “limited be-
cause they did not use a randomized treatment design,
were not double blinded, and relied on outcome measures
that were not widely accepted.” Bever II at S119. Alt-
hough my colleagues cite Davis’ reports of “mild to
marked improvements,” Maj. Op. at 5, they do not men-
tion the risk of seizures as warned by Davis, or Bever’s
criticisms.
While the panel majority states that Davis reported
“no serious or bothersome side effects, including seizures”
at doses up to 25 mg, id., Elan, which relied on Davis’
research team, Dist. Ct. Op. at *4, terminated its devel-
opment of 4-AP based on toxicity and seizures, and li-
censed its sustained release patent to Acorda.
Nonetheless, my colleagues hold that the Davis studies
contributed to the obviousness of the Acorda Patents,
ignoring the problems that were reported, and the aban-
donment of 4-AP by these researchers.
C. The Van Diemen study
The panel majority also relies on a study conducted in
the Netherlands and published in 1993 by Van Diemen. 6
The publication reports the effect of escalating doses of 4-
AP, measured by the Kurtzke expanded disability status
scale (EDSS) that is frequently used as a benchmark to
measure symptoms in multiple sclerosis patients. The
6 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 Neuro-
pharmacology 195 (1993), J.A. 7037.
6 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
study examined the effect on eye function of intravenous
and oral administration of 4-AP for up to 12 weeks.
My colleagues report that eye functioning was bene-
fited, but ignore the report of side effects, including nau-
sea and dizziness, at the “escalated” dosages needed to
produce improvement in eye function. Van Diemen et al.
at 200, 203.
D. The Polman study
Polman7 describes an unblinded study of the treat-
ment with 4-AP of thirty-one multiple sclerosis patients,
some of whom had been involved in an earlier study.
Twenty-three patients were treated with 4-AP for longer
than six months. The new patients were given an upward
titration dosing plan in accordance with the tolerability
by the patient, up to a maximum dose (based on patient
weight) over four to eight weeks. Polman measured
efficacy based on subjective reports from the patients
during clinic visits.
The Van Diemen and Polman references were relied
on by the district court as teaching “stable dosing,” but
they involve stable dosing only after titration to the
highest tolerable dose for each individual patient. Both
Van Diemen and Polman describe using a titration
scheme up to the maximum amount based on the patient’s
weight. Dist. Ct. Op. at *12–13. These references only
teach stable dosing after the maximum tolerable dose has
been determined for each patient, after upward titration.
Goodman, post, also reports an “increasing benefit” for
doses up to 50 mg/day if such doses can be tolerated.
These sources all show the understood need to target
7 Chris H. Polman et al., 4-Aminopyridine in the
Treatment of Patients with Multiple Sclerosis, 51 Archives
of Neurology 292 (1994), J.A. 6654.
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 7
higher doses to the extent they can be tolerated. See
Goodman Poster (reporting increasing benefit as dosage
was increased from 20mg to 50mg). 8
Polman reported that “[i]mprovements in fatigue and
ambulation were mentioned quite often by the patients.”
Polman et al. at 295. However, two patients in the Pol-
man study experienced seizures and discontinued partici-
pation. Id. at 294–5. My colleagues cite Polman’s report
of “favorable response to the medication,” Maj. Op. at 7
(citing id. at 293), but downplay Polman’s conclusion that
there was little quantifiable benefit of the therapy using
the primary EDSS benchmark, my colleagues stating that
the side effects were not troublesome, despite the reports
of seizures. Maj. Op. at 8–9.
E. Additional studies reported by Bever
The Bever II reference reports additional studies, as
follows:
Two double-blind, placebo-controlled crossover
trials of DAP have recently been completed.
Carter and associates, using 3-week treatment pe-
riods and doses up to 80 mg/day, found subjective
improvement in 48% of patients on DAP but only
24% on placebo. Although this difference was not
statistically significant, treatment-related differ-
ences were found in sensitivity to thermal chal-
lenge.
8 Dist. Ct. Op. at *14 (“The Goodman Poster is a
poster presented at the September 2002 annual meeting
of the America Committee for Treatment and Research in
Multiple Sclerosis, held in Baltimore, Maryland.”), J.A.
6497–504.
8 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
Bever II at S120 (citing JL Carter et al., A double-blind,
placebo-controlled crossover trial of 3,4-diaminopyridine
in the symptomatic treatment of multiple sclerosis, 34
Annals of Neurology 272 (1993)).
These studies further illustrate the uncertain state of
the art at that time, and the “differences” and “sensitivi-
ty” that led to abandonment of development of 4-AP.
These studies did not lead to any proposed treatment of
multiple sclerosis, despite the accumulating knowledge
concerning 4-AP. My colleagues mention the toxic effects
including seizures, encephalopathy, and hepatitis, but
skip over their importance. However, it is apparent that
others did not ignore their importance, for no proposed
product, no proposed treatment, resulted from these
studies.
F. The abandoned Elan studies
The manifestations and miseries of multiple sclerosis
are powerful, and Elan Corporation entered the field to
pursue the idea that sustained-release formulations of 4-
AP might relieve the toxic effects and provide “therapeu-
tically effective blood levels throughout a given treatment
period.” U.S. Patent No. 5,540,938 (the “Elan Patent”) at
col.2, l.15. In 1991 Elan filed the patent application
leading to the Elan Patent, which described and claimed
sustained-release formulations of 4-AP. Elan undertook
major efforts to develop a treatment for multiple sclerosis
using sustained-release formulations. Reports of these
unsuccessful efforts were published.
Schwid 9 reports a failed clinical trial in 1994, de-
scribed as a six-week, 161-patient placebo-controlled
9 Steven R. Schwid et al., Quantitative assessment
of sustained-release 4-aminopyridine for symptomatic
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 9
study of the administration of sustained-release 4-AP to
multiple sclerosis patients. The results were measured
using the EDSS benchmark, and included measures of
walking disability including gait and speed. The conclu-
sion was that there was no improvement over the placebo.
Schwid et al. at 817.
Another Elan study of ten patients, also reported by
Schwid, stated that nine of these patients showed an
improvement in speed of walking. Schwid discussed that
the mean serum level of 4-AP during the study 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.” Id. at 819–
20. The study reported 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 [sustained-release]
than placebo,” while all patients with serum levels above
60 ng/ml demonstrated improvement in timed gait, grip
strength, and five of six improving by their own subjective
impression. Id. at 819–20. In contrast, the Acorda Pa-
tents are directed to a serum range of about 15-35 ng/ml,
which Schwid described as unlikely to produce therapeu-
tic effect.
The 17.5 mg dose used by Schwid was stated to be in-
effective in a number of respects, including the EDSS
benchmark. Schwid et al. at 817. Schwid suggested that
further research should be conducted, but this does not
convert Schwid’s reported failures into a teaching of the
path to success. My colleagues state that Schwid reported
“promising” results, Maj. Op. at 55, but do not mention
Schwid’s conclusion that 4-AP was not effective at the
doses that were necessary to limit toxicity, or the lack of
treatment of multiple sclerosis, 48 Neurology 817 (1997),
J.A. 6681-84.
10 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
improvement over placebo. Instead, my colleagues sug-
gest that Schwid contributed to obviousness because
Schwid suggested that, since the EDSS benchmark had
failed, it might be useful to look at “more sensitive, quan-
titative measures.” Maj. Op. at 13–14 (quoting Schwid,
J.A. 6681). Thus the panel majority concludes that these
studies rendered obvious the Acorda success that had
eluded Schwid.
Elan also sponsored studies at the University of Mar-
yland, published by Bever et al. 10 Bever summarized that
the “lower serum concentration range of 30 to 59 ng/ml
may . . . be adequate for inducing improvement of some
neurologic deficits,” Bever I at 1058, quoted at Maj. Op.
at 10; but the panel majority ignores that the study did
not show any improvement on the EDSS benchmark or on
an ambulation benchmark, id. at 1056–57, and treats the
Bever report of “increased side effects,” including a grand
mal seizure, as a throwaway, Maj. Op. at 10.
These studies surely added to the body of knowledge,
but they did not produce a usable product. Although
these studies used Elan’s sustained-release formulations,
the effort was eventually abandoned. The record is con-
sistent in showing that Elan, like the others who had
studied 4-AP, had been unable to achieve an effective
product free of toxicity and serious side effects.
10 Christopher T. Bever, Jr. et al., The effects of 4-
aminopyridine in multiple sclerosis patients: Results of a
randomized, placebo-controlled, double-blind, concentra-
tion-controlled, crossover trial, 44 Neurology 1054 (1994)
(“Bever I”), J.A. 6180.
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 11
G. The Hayes report of early Acorda studies
Hayes 11 reports Acorda’s activity, starting in 1993 and
investigating use of 4-AP for treatment of spinal cord
injury. The first of these studies evaluated single doses of
sustained-release 4-AP in fourteen patients with spinal
cord injury, and the second study examined multiple
doses of sustained-release 4-AP in sixteen patients with
spinal cord injury. Dist. Ct. Op. at *15 (citing Hayes et al.
at 186). The Hayes publication stated that all patients in
both studies experienced at least one adverse event, such
as dizziness, hypotension, or nausea. Hayes et al. at 188,
191.
H. The Solari review article
Solari 12 is a review of medical knowledge related to 4-
AP, including reports on clinical trials conducted with MS
patients. From the studies in its analysis, Solari tabulat-
ed that 54% of the multiple sclerosis patients taking 4-AP
or diaminopyridine experienced improved motor func-
tions, compared to 7% of placebo. Solari et al., J.A. 7204.
Solari concluded that its “review of trials found there is
not enough evidence about the safety of these drugs or
whether benefits are certain.” Solari et al., J.A. 7218.
11 Keith C. Hayes et al., Pharmacokinetic Studies of
Single and Multiple Oral Doses of Fampridine-SR (Sus-
tained-Release 4-Aminopyridine) in Patients With Chronic
Spinal Cord Injury, 26 Clinical Neuropharmacology 185
(2003), J.A. 6433.
12 Alessandra Solari et al., Aminopyridines for symp-
tomatic treatment in multiple sclerosis (Review), Cochrane
Database of Systematic Reviews, Issue 4 (2002), J.A.
7204.
12 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
II
The Acorda Studies
As outlined supra, Acorda began research with 4-AP
in 1993 for treatment of spinal cord injury. As reported
by Hayes, successful results were not obtained. Dr. Ron
Cohen, the founder of Acorda, turned to study of multiple
sclerosis. Dr. Cohen testified that he took on the “daunt-
ing challenges” of seeking an effective treatment for
multiple sclerosis, with knowledge of the failures of Elan
and others. Appellant’s Br. at 13 (citing J.A. 596–97).
Acorda scientists conducted research over the ensuing
six years, and published their results as experience accu-
mulated and knowledge evolved. These publications are
treated as prior art to the Acorda Patents.
A. Acorda’s initial failures
Acorda’s initial publications reported that the multi-
ple sclerosis population receiving various experimental 4-
AP treatments showed some improvement in walking
speed and lower extremity muscle strength, but “did not
show that any individual dosage had a statistically signif-
icant effect versus placebo.” Appellant’s Br. at 15; see
Goodman Poster, n.9 ante. Dr. Goodman was the lead
clinical investigator for Acorda, and the lead author for
the published results of Acorda’s MS-F201 study, 13 a
randomized double-blind placebo-controlled study with
the aim of “determin[ing] the safety and tolerability of
escalating doses of a sustained-release (‘SR’) formulation
given orally to patients with MS.” Goodman I at S116.
13 Andrew Goodman et. al., Placebo-Controlled Dou-
ble-blinded Dose Ranging Study of Fampridine-SR in
Multiple Sclerosis, 8 Multiple Sclerosis S116 (P308) (July
2002), (“Goodman I”) J.A. 6370.
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 13
Goodman I states that the MS-F201 data “showed sta-
tistically 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).” Id. at S117. It further
states that “[d]ose response curves showed increasing
benefit in both measures in the 20 to 50 mg/day range.”
Id. However, two participants withdrew due to seizures.
Id.
The Goodman Poster reported that the MS-F201
study demonstrated “statistically significant improve-
ments in the timed 25-foot walk and manual muscle test
relative to placebo.” Dist. Ct. Op. at *15. However, the
Poster also stated that a greater improvement in fatigue
was reported by the placebo group as compared to the 4-
AP treated group, and referred to the withdrawal of two
subjects due to seizure. Goodman Poster, J.A. 6502. Dr.
Goodman testified at trial that “[a]ll of the prespecified
analyses failed except for the lower extremity manual
muscle test.” J.A. 604 (289:24–5). He stated that the
result of the timed walk “was not at all significant,” and
was consistent with the failed Elan study. J.A. 605
(290:5).
The district court found that the Goodman Poster es-
tablished that “the use 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 at the priority date of
the Acorda Patents.” Dist. Ct. Op. at *33. Acorda states
that “the district court’s conception that the Goodman
Poster teaches anything about a 10 mg BID dose of 4-AP
as the sole individual dose of an MS treatment protocol—
as opposed to merely the starting point of an escalating
dosing scheme—is impermissible hindsight.” Appellant’s
Br. at 38. Acorda is correct that the Goodman Poster does
not suggest this low-dose formulation with a reasonable
expectation of success, but reports increasing benefit as
dosage was increased from 20 to 50 mg.
14 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
Acorda correctly states that the Elan work and these
initial Acorda studies show, if anything, that 4-AP treat-
ment requires upward titration to determine the maxi-
mum tolerable dose for individual patients since efficacy
can only be achieved at higher doses, and that these
studies do not provide any reason to believe that a low
dose would be effective. Goodman I reported an “increas-
ing benefit in both measures in the 20-50 mg/day range,”
referring to mobility and lower extremity strength.
Goodman I at S117.
In 2003, Acorda conducted a 206-patient clinical
study, designated MS-F202. The study employed upward
titration to successively higher doses, starting at dosages
of 10 mg of sustained-release 4-AP twice-daily. The
highest tolerable dose was then continued for 12 weeks.
It was concluded that no treatment group showed im-
provement over placebo, over the 12-week testing period.
Dist. Ct. Op. at *9.
The low dose protocol developed by Acorda is not sug-
gested in the prior art. Although the goal was a stable
dose without individual titration, no study, no reference
reported successful results using the low dose of the
Acorda Patents, or even suggested that it should be tried.
The panel majority’s contrary theory is devoid of support.
B. Acorda’s analytical breakthrough
Acorda analyzed the MS-F202 results, focusing on
“patients in the study who, after treatment, showed a
‘meaningful difference’ from their before-treatment base-
line—i.e. the ‘responders,’” and learned that the therapeu-
tic effect of 4-AP did not increase with increase in dosage,
as prior reports and Acorda’s own research had suggested.
Appellant’s Br. at 19. Dr. Cohen testified that they “were
extremely surprised” because “[e]verything that we had
come to expect throughout the program told us that we
should be seeing more and more efficacy the higher the
dose went as long as the patients were tolerating it and
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 15
that turned out not to be the case.” J.A. 614 (299:5–9).
This contradicted the teachings of all of the earlier stud-
ies. Only the courts find it obvious.
Acorda then conducted additional clinical studies at
the lower dosages, and established that a twice-daily
sustained-release 10 mg dose produced improvement in
walking gait and speed, while avoiding the toxicity and
seizures of higher dosages. Acorda filed a provisional
patent application on April 9, 2004, directed to this
treatment. Acorda continued its studies, and after a total
of twelve years of investigation and development, Acorda
in 2010 obtained FDA approval for a product for improv-
ing the walking impairment in multiple sclerosis patients.
This product has the brand name Ampyra®. The Acorda
Patents are directed to and limited to the twice-daily
administration of 10 mg doses of sustained-release 4-AP
formulation.
The district court, affirmed by my colleagues, held the
Acorda Patents invalid on the ground of obviousness. The
district court ruled that the evidence of long-felt need,
failure of others, unexpected results, and commercial
success are irrelevant because the Elan Patent was a
“blocking” patent. However, the Elan Patent did not
block research on 4-AP, did not block other possible
treatments for multiple sclerosis, and did not affect the
Defendants’ development and copying and Hatch-
Waxman challenge to the Elan and Acorda patents. The
court’s theory of “blocking” is unrelated to whether the
Acorda product meets a long-felt need in treating multiple
sclerosis, for the Elan and Acorda patents do not block the
Defendants from developing a competitive treatment for
multiple sclerosis. The patents that support Acorda’s
eventual success do not block others from using and
learning from Acorda’s teachings, experimenting with and
comparing with Acorda’s product, and engaging in com-
petitive activity.
16 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
III
The District Court’s Analysis
The Defendants conceded infringement, and the dis-
trict court found the Acorda Patents invalid on the ground
of obviousness. The district court determined that four
claim elements were common to the Acorda Patents, then
found that each of these elements is present in a separate
reference, and held that a person of ordinary skill in this
field would obviously have selected and combined these
elements to produce the Acorda product and method.
The district court did not find any motivation or sug-
gestion in the prior art as to which elements to select and
combine, and did not find any teaching or suggestion that
such selection and combination would be likely to succeed
in treating the walking impairment of multiple sclerosis.
Acorda attributes the district court’s rulings to “hindsight
bias” and incorrect statements of law by the Defendants.
Indeed, without the hindsight knowledge of Acorda’s
success, there is no teaching or suggestion of this selection
and combination or its likelihood of success.
A. The selected claim elements
The district court selected four aspects of the Acorda
claims, as follows: (1) the use of 4-AP to improve walking
in multiple sclerosis patients; (2) the use of a 10 mg twice-
daily sustained release dose; (3) the use of stable dosing
without upward titration; and (4) the specific pharmaco-
kinetic parameters achieved. The court concluded that “a
POSA would have been motivated to combine these limi-
tations with a reasonable expectation of success.” Dist.
Ct. Op. at *29.
However, the question is not whether these four ele-
ments, if combined, would produce a successful treatment.
The question is whether the prior art contains a sugges-
tion or motivation to select these four elements from the
decades of inconclusive prior art, with a reasonable expec-
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 17
tation that the selection would eliminate the failures of
the prior art. See, e.g., In re Cyclobenzaprine Hydrochlo-
ride Extended-Release Capsule Patent Litig., 676 F.3d
1063, 1068–69 (Fed. Cir. 2012) (“a party seeking to invali-
date a patent as obvious must ‘demonstrate “by clear and
convincing evidence 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 suc-
cess from doing so.”’” (quoting Procter & Gamble Co. v.
Teva Pharms. USA, Inc., 566 F.3d 989, 994 (Fed. Cir.
2009))); In re Kubin, 561 F.3d 1351, 1359 (Fed. Cir. 2009)
(prior art does not provide a reasonable expectation of
success where the art may suggest “vary[ing] all parame-
ters or try[ing] each of numerous possible choices until
one possibly arrived at a successful result, where the prior
art gives either no indication of which parameters were
critical or no direction as to which of many possible choic-
es is likely to be successful.” (quoting In re O'Farrell, 853
F.2d 894, 903 (Fed. Cir. 1988)). The years of studies and
failures weigh heavily against the simplistic post hoc
predictability accepted by the court.
The district court analyzed the purported obviousness
of each of the four limitations, as follows.
1. Improvement in walking
The district court found that several references
showed improved walking upon treatment with 4-AP.
The court framed the question as whether a POSA would
have “a reasonable expectation that 4-AP could be suc-
cessfully used as claimed to treat (i.e., achieve therapeuti-
cally-effective blood levels in) even a single patient.” Dist.
Ct. Op. at *30. The court referred to Schwid’s analysis of
the early Acorda studies as showing “a statistically signif-
icant improvement in . . . timed gait, which was found to
be improved in nine out of 10 patients, in comparison to
the placebo group.” Id.18 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
However, the early Acorda studies all stated concern
about toxicity, particularly seizures, at the dosages that
these studies showed were needed to obtain relief. No
witness suggested that these early studies taught or
suggested that a low dosage formulation would be effec-
tive.
2. The dosage of 10 mg twice daily
The district court concluded that this dosage was an
obvious choice, because the prior art evaluated doses
ranging from 10 mg to 80 mg. Dist. Ct. Op. at *32. How-
ever, the prior art contains no suggestion, indeed no hint,
that a 10 mg twice-daily sustained-release formulation
would be effective. All of the early references demon-
strated the need for upward titration, showing that high-
er doses are needed for efficacy, with individual titration
to determine the highest tolerable dose before seizures
occurred. The district court cited the Goodman Poster as
showing that toxicity increased at higher dosages, and as
providing “[e]vidence of dose-response in [the] 20-40
mg/day range.” Dist. Ct. Op. at *32. However, the stud-
ies reported by Goodman did not provide a safe and
efficacious product, but depended on individual titration
to establish individual dosages at the highest tolerable
level.
The district court held that it was obvious to use the
10 mg dose, despite the general showing of ineffectiveness
of the 10 mg dose. Dist. Ct. Op. at *33. It is not disputed
that the general teaching was that doses higher than 10
mg were needed for therapeutic effect. It cannot reasona-
bly be viewed as obvious that a dosage that was described
in the prior art as ineffective, is in fact the optimum
dosage.
3. Stable dosing without upward titration
The district court found that the prior art, particular-
ly the Van Diemen and Polman references, taught the use
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 19
of uniform dosing of 4-AP, and “included reports of safe
and effective long-term use of stable dosing of immediate-
release 4-AP.” Dist. Ct. Op. at *34. The district court
further found that the prior art’s “consistent use of titra-
tion . . . did not undermine the other evidence in the prior
art that supports finding that a POSA would have had a
reasonable expectation of success with stable dosing.” Id.Only hindsight can construct the Acorda formulation from
these inapt teachings, for the references cited by the
district court require upward titration to select the high-
est tolerable dose, for low stable doses were ineffective.
The panel majority, seeking to fill this gap, asserts
that “[t]he prior art is not limited to titrated dosing,” Maj.
Op. at 34, citing Polman and Schwid. However, Polman
involved titration, and reported that therapeutic doses
required in excess of 40 mg for minimal quantifiable
benefit. See Polman et al. at 295 (stating that the report-
ed improvements generally did not result in significant
changes to the EDSS benchmark). In addition, Schwid
suggested the need for a far higher dose, only maintained
stable dosing for a week, and did not report meaningful
success in treating multiple sclerosis. Schwid et al. at
817.
4. Pharmacokinetic limitations
For the fourth limitation, the district court found that
the claimed pharmacokinetic serum levels were disclosed
by Hayes, for “[i]t is undisputed that the Hayes research-
ers used the Ampyra® formulation in their study.” Dist.
Ct. Op. at *35. The district court considered Acorda’s
argument that “there is nothing in the prior art identify-
ing the pharmacokinetic values recited in the claims as
being effective to improve walking or increase walking
speed in MS patients,” id., and found that “a POSA would
have been aware that a sustained-release dosage form
achieving the pharmacokinetic parameters disclosed in
20 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
Hayes III would have been associated with an improve-
ment in walking in MS patients.” Dist. Ct. Op. at *36.
The Defendants argue that even if the serum level in
the Acorda Patents is not obvious based on the Hayes
reference, the claimed range is inherent in the dosage of
4-AP, citing Santarus, Inc. v. Par Pharm., Inc., 694 F.3d
1344, 1354 (Fed. Cir. 2012), where the court held that
reciting the blood serum concentration resulting from a
dosage form did not impart patentability to known dosage
forms. Acorda responds that the prior art did not teach or
suggest that any specific blood serum levels would im-
prove walking in multiple sclerosis patients. No such
teaching or suggestion appears anywhere in the record.
Hayes does not relate its serum analysis to efficacy in
improving gait or walking speed in persons afflicted with
multiple sclerosis.
The district court referred to Acorda’s statement at
trial, that “[i]t was known in the art that a sustained
release formulation of 10 megs BID could achieve” the
claimed pharmacokinetic values. Dist. Ct. Op. at *35 n.39
(citing J.A. 1108–1109). The district court found that
there was a reasonable expectation of success with regard
to the pharmacokinetic parameters because these param-
eters are inherent in the claimed dosing. Id. The court
did not find, and the prior art does not establish, that this
pharmacokinetic range was known to have a beneficial
effect on walking speed and gait in persons afflicted with
multiple sclerosis.
B. The combination of elements
The district court found a reasonable expectation of
success on combination of the four claim elements, stating
that “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,” Dist. Ct. Op. at *33. The court concluded
that:
ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 21
Defendants have adduced clear and convincing ev-
idence that a POSA at the priority date would
have been motivated and would have had a rea-
sonable expectation of success to practice and
combine each of the limitations of the asserted
claims of the Acorda Patents.
Dist. Ct. Op. at *40.
Acorda is correct that there was no suggestion in the
prior art that the claimed combination should be tried,
and there is no hint of a reasonable expectation of success.
Acorda points to the decades of failure of others to develop
a safe and effective treatment for multiple sclerosis using
4-AP, despite its known toxicity. The district court’s
selection of separate limitations from separate sources,
and retrospectively fitting them into the Acorda template,
is achieved only with the hindsight knowledge of Acorda’s
eventual success. See Sanofi-Synthelabo v. Apotex, Inc.,
550 F.3d 1075, 1086 (Fed. Cir. 2008) (“The determination
of obviousness is made with respect to the subject matter
as a whole, not separate pieces of the claim.”). Here, only
the Acorda Patents teach the combination that successful-
ly treats this multiple sclerosis impairment while avoid-
ing toxicity and seizures.
Acorda’s path to successfully harness the neurological
benefits of 4-AP eluded the many scientists studying
multiple sclerosis. Although the district court acknowl-
edged the known adverse effects of 4-AP including sei-
zures, Dist. Ct. Op. at *41 (stating that “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”), nonetheless the court
found that a person of ordinary skill would have had a
reasonable expectation of success with the Acorda prod-
uct. The recognized need for a stable, non-toxic dosage
protocol does not render the solution obvious if it is even-
tually discovered. The record does not show any teaching
22 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
or suggestion of success of the formulation in the Acorda
Patents.
Nor does the record support a finding of “obvious to
try.” Such a finding requires that a person of ordinary
skill would not only have selected these specific elements
from various discarded experiments, but also “would have
had a reasonable expectation of success in doing so.”
Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1361 (Fed. Cir.
2007). It is clear that the prior art does not provide a
reasonable expectation of success of the Acorda Patents’
specific dosage and protocol.
IV
The Objective Indicia of Unobviousness
The objective indicia “may often be the most probative
and cogent evidence in the record . . . . It is to be consid-
ered as part of all the evidence, not just when the deci-
sionmaker remains in doubt after reviewing the art.”
Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530, 1538–39
(Fed. Cir. 1983). The district court, affirmed by the panel
majority, err in discounting the undisputed evidence of
commercial success, long-felt need, failure of others,
unexpected results, and copying.
The district court discussed the objective indicia, and
concluded that they did not “outweigh” the conclusion of
obviousness. The district court found that Ampyra® could
be considered a commercial success “[g]iven the strength
of Ampyra®’s sales, and the absence of any evidence that
its sales are disappointing given its limited indication and
patient population.” Dist. Ct. Op. at *38. However, the
court concluded that this commercial success did not
weigh heavily because “no one other than the Elan pa-
tentees and their licensees could have practiced the
invention of the Acorda Patents without facing liability
for patent infringement.” Id.ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC. 23
Commercial success is measured against the products
available for the same purpose, not against infringing
copies of the patented product. Defendants do not con-
tend that they are precluded from providing or developing
other treatments for multiple sclerosis. The Acorda
product met a long-felt need, for which the failure of
others, despite decades of experimenting with the neuro-
logical properties of 4-AP, is evidence of the unobvious-
ness of the Acorda achievement. Such evidence is an
important aid to a court that is attempting to divine
whether the patentee’s discovery was obvious in accord-
ance with law.
Concerning failure of others, the panel majority states
that Elan’s failure “is not particularly relevant to the
expectation of success.” Maj. Op. at 40–41. This is a
peculiar conclusion, for Elan had undertaken an immense
investment, including clinical trials, in the hope that its
extended-release concept would solve the problems en-
countered by others. Elan eventually gave up. Nonethe-
less, my colleagues find that Acorda’s success was obvious
to them.
The district court and my colleagues also misapply the
concept of “blocking patent,” and hold that because a
patent provides the right to exclude infringers, the indicia
of commercial success, long-felt need, failure of others,
and copying are diminished. However, as the Pharmaceu-
tical Research and Manufacturers of America, as amicus
curiae, reminds us, “a prior patent would not have cate-
gorically precluded others from further developing the
technology,” pointing to the statutory safe harbor of §
271(e)(1), the knowledge provided in the patents, and the
right to conduct research on patented subject matter. Br.
of Amicus Curiae at 4.
The objective indicia of unobviousness are measured
against the state of the science and in the commercial
context. Here the unexpected success and its human
24 ACORDA THERAPEUTICS, INC. v. ROXANE LABORATORIES, INC.
benefits are not disputed. The district court was advised
that the Patent Trial and Appeal Board sustained the
validity of the Acorda Patents in inter partes review, at
Coalition for Affordable Drugs (ADROCA), LLC v. Acorda
Therapeutics, Inc., 2017 WL 950736 (P.T.A.B. Mar. 9,
2017). Although the majority reports this event, as did
the district court, its consequences are not explored,
including issues of privity, estoppel, and finality.
CONCLUSION
Obviousness of the Acorda Patents was not estab-
lished by clear and convincing evidence. The prior art did
not provide a suggestion to select the specific elements
and limitations of the Acorda formulation, and did not
suggest that such selection and combination would have a
reasonable expectation of success in relieving the walking
impairment of multiple sclerosis. From my colleagues’
contrary holding, I respectfully dissent.