Monday, September 10, 2018

Big news in multiple sclerosis drugs: Acorda loses appeal on patent invalidity

The outcome in Acorda v. Roxane was that Acorda lost:

Roxane Laboratories, Inc.; Mylan Pharmaceuticals,
Inc.; and Teva Pharmaceuticals USA, Inc., have submitted
Abbreviated New Drug Applications seeking FDA
approval to market generic versions of Ampyra. In July
2014, Acorda and Alkermes sued those entities (“defendants”)
in the District of Delaware, alleging infringement
of several claims in each of the Elan and Acorda patents.
The defendants stipulated to infringement but challenged
the validity of the asserted claims. The district court held
that the asserted claims in the Acorda patents are invalid
for obviousness. But the court upheld the asserted claims
of the Elan patent against invalidity challenges and
enjoined the defendants from activity infringing that
patent until it expired on July 30, 2018.

Acorda appealed the invalidity ruling regarding the
Acorda patents. The defendants cross-appealed the
validity ruling regarding the Elan patent and the resulting
injunction. We now affirm the judgment that the
asserted Acorda patent claims are invalid. We dismiss
the cross-appeal as moot.

Of legal matters, the discussion of "blocking patents" is

Of background

4-AP [4-aminopyridine], also called “dalfampridine” and “fampridine,”
was first identified in 1902. Acorda Therapeutics, Inc. v.
Roxane Labs., Inc., No. 1:14-cv-00882-LPS, 2017 WL
1199767, at *3, *5 (Mar. 31, 2017) (Dist. Ct. Op.). Belonging
to a class of compounds that function as potassiumchannel
blockers, 4-AP “has been found to slow the potassium
flow in nerve impulse transmission” and, by doing
so, help “restor[e] conduction in blocked and demyelinated
nerves,” ’826 patent, col. 2, lines 5–11, i.e., nerves whose
myelin insulation has been damaged. 4-AP was first used
in human studies in the 1970s to investigate its effect on
neurological diseases resulting in muscle weakness. Dist.
Ct. Op. at *5. For several decades, 4-AP has been the
focus of research regarding the treatment of multiple
sclerosis in particular. See, e.g., id. at *5–7 (reciting
studies); J.A. 6697 (paper published in 1987 describing
study of the effect of 4-AP on subjects with multiple
sclerosis). Multiple sclerosis causes the demyelination, or
loss of myelin, of nerves in the central nervous system
and results in a wide variety of symptoms, including
walking impairment, tingling or pain, brain scarring,
cognitive changes, visual impairments, and fatigue. See
’826 patent, col. 1, lines 36–42; Dist. Ct. Op. at *2. Eventually,
4-AP research led to the development, patenting,
and FDA approval of Ampyra.

As to the mootness issue, July 30, 2018 has passed:

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.

A Kyle Bass effort is mentioned in footnote 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

Acorda's [unsuccessful] arguments:

Acorda challenges the district court’s findings about
the relevant skilled artisan’s motivations and expectations
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 titrateddosing
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 reasonable
expectation of success to improve walking. We reject
these challenges.

Of the first argument:

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
plausible doses because it suggested that higher doses of
4-AP were more likely to cause adverse events.”)

Of titrated dosing:

Acorda’s second argument is that the prior art teaches
administering sustained-release 4-AP only in a titrateddosing
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 administration
of a stable dose of immediate-release 4-AP. Dist.
Ct. Op. at *34; see J.A. 6655. Schwid also provides evidence
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,


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
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 explained
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.


Acorda’s core argument appears not to be that the evidence
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 between
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.


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 subsequent
improvement in functioning during a drug-free
interval and subsequent restarting of the therapy are, in
our view, highly suggestive of a real effect being induced
by the 4-[AP]. Improvements in fatigue and ambulation
were mentioned quite often by the patients as being
responsible for the favorable overall effect.”). We see no
clear error in the district court’s finding to that effect.

Of relevance to MS patients

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 Goodman
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
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 therapeutic 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 significant 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 reasonable expectation of success in this case.

Of relevance to patent academics, as to the concept of
"blocking patents":

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 resources
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 obviousness
of the later patent. See Note, Subtests of “Nonobviousness”:
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 alendronate
monosodium trihydrate (Fosamax). Id. at 1366–67.
That patent was preceded by Merck’s earlier patent
(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 nonobviousness
of weekly-dosing, from evidence of commercial
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 weeklydosing
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 sufficient
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 concluded
that Merck’s exclusive license to a blocking patent did
not, all by itself, justify discounting evidence of commercial
success. Id. at 730–31. We explained that commercial
success is “a fact-specific inquiry” that may involve
considering the operation of specific blocking patents on
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 evidence
that the claimed process was substantially described
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 recognition
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 granting
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 blocking
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-
provement to negotiate for a cross-license with the blocking
patent’s owner to share the profits from the improvement.
Besides the assessment of whether the blocking
patent can be successfully challenged, a number of variables
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 blockingpatent
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 exploitation
would be infringing, therefore reducing incentives for
innovations in the blocked space by non-owners and nonlicensees
of the blocking patent. Such a blocking patent
therefore can be evidence that can discount the significance
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 incentive
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
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.
Against this background, we review the district
court’s consideration of objective indicia of nonobviousness
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 evidence
as a whole” in the case “prove[d] clearly and convincingly
that the Acorda Patents are invalid due to
obviousness.” Dist. Ct. Op. at *41.
The parties presented evidence on the objective indicia
of commercial success, failure of others, and long-felt
but unmet need.16 In particular, the defendants presented
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).

Judge Newman dissented.

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 discounted
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 pursued.
The loser is the afflicted public.1



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