Friday, October 12, 2018

Teva loses appeal of invalidity of patent claims of 40mg Copaxone multiple sclerosis drug

The CAFC affirmed the decision of D. Delaware of invalidity of claims:

Plaintiffs-Appellants Teva Pharmaceuticals USA,
Inc., Teva Pharmaceutical Industries, Ltd., Teva Neuroscience,
Inc., and Yeda Research and Development Co.,
Ltd., appeal the decision of the United States District
Court for the District of Delaware invalidating all asserted
claims of patents directed to COPAXONE® 40mg/mL, a
product marketed for treatment of patients with relapsing
forms of multiple sclerosis. Because the district court
correctly held the asserted claims invalid as obvious
under 35 U.S.C. § 103, we affirm.

Footnote 1 of the case

In a companion case decided today, Yeda Research
& Development Co., v. Mylan Pharmaceuticals Inc., Nos.
17-1594, 17-1595, 17-1596 (Fed. Cir. Oct. 12, 2018), Yeda
Research and Development Co. appealed from the Patent
Trial and Appeal Board’s final written decisions finding
all claims of U.S. Patent Nos. 8,232,250, 8,399,413, and
8,969,302 unpatentable as obvious in three related inter
partes review proceedings.
[Therein: "We affirm the
Board’s decisions."]

The use of the Khan (2009) reference was of interest:

The district court admitted the Khan 2009 reference
for the limited purpose of showing the state of the art at
the time of the invention. In re Copaxone Consolidated
Cases, No. 14-1171-GMS, 2017 WL 401943, at *14 (D. Del.
Jan. 30, 2017). Khan 2009 was published three weeks
after August 20, 2009, the priority date of the Copaxone
patents, but the study began two years earlier. J.A.
23904–05. The study abstract noted that “[t]here is
considerable interest in studying a more patient friendly
dosing regimen of GA that may be as efficacious and
better tolerated than daily GA.” J.A. 23904. Following
the results of Khan 2008, which showed that alternate
day administration of GA appears to be as effective as
daily administration, Khan 2009 compared 20mg GA
administered twice a week to 20mg GA administered
daily in a pilot, prospective, randomized, and raterblinded
two-year study. J.A. 23904.


In light of these factual findings, the district court
concluded that a 40mg GA 3x/week dosage would be
obvious to try, noting that there were only two tested
dosage amounts in the prior art—20mg and 40mg—and
that researchers were pursuing less frequent dosing
regimens while recognizing there are a limited number of
days in a week on which to test frequency. See id. at *19.
The court recognized that obvious-to-try logic is not
always appropriate, but found that “[h]ere, there was
market pressure to solve a known problem—the fact that
many MS patients could not tolerate daily injections—and
there were a finite number of predictable solutions that a
person of ordinary skill in the art would have good reason
to pursue.” Id. The district court cited to Khan 2009,
Teva’s GALA study, and trial testimony as evidence of the
motivations of POSITAs at the time of the invention, and
noted evidence and testimony supporting the proposition
that a dosing schedule based on three predetermined days
each week is preferable for patients over an every other
day schedule. Id. at *20. The district court highlighted
testimony from Dr. Green that a regimen of injections on
three pre-determined days of each week is more convenient
for patients and has better patient adherence than an
every other day regimen, in which the days on which
patients inject differ depending on the week. Id.

Teva's position:

Teva contends that the district court erred in finding
the claimed 40mg GA 3x/week dosing regimen obvious.
Specifically, Teva argues that the district court impermissibly
relied on hindsight and an improper “obvious to try”
analysis, and analyzed the obviousness of individual
claim elements, rather than the invention as a whole.
Teva further maintains that the district court’s decision is
at odds with this court’s decision in In re Cyclobenzaprine
Hydrochloride Extended-Release Capsule Patent Litigation,
676 F.3d 1063 (Fed. Cir. 2012).

Of obvious to try

We have previously identified two categories of impermissible
“obvious to try” analyses that run afoul of
KSR and § 103: when what was “obvious to try” was (a) to
vary all parameters or try every available option until one
succeeds, where the prior art gave no indication of critical
parameters and no direction as to which of many possibil-
ities is likely to be successful; or (b) to explore a new
technology or general approach in a seemingly promising
field of experimentation, where the prior art gave only
general guidance as to the particular form or method of
achieving the claimed invention. See In re Kubin, 561
F.3d 1351, 1359 (Fed. Cir. 2009) (quoting In re O’Farrell,
853 F.2d 894, 903 (Fed. Cir. 1988)).
This case falls into neither of the two impermissible
categories. Here, the prior art focused on two critical
variables, dose size and injection frequency, and provided
clear direction as to choices likely to be successful in
reducing adverse side effects and increasing patient
adherence. As of the priority date, only two GA dose sizes
had been shown to be effective, safe, and well-tolerated:
20mg and 40mg. Concerning frequency, the 1996 FDA
SBOA, Flechter, and Khan 2008 all encouraged POSITAs
to pursue a less frequent than daily dosing regimen; these
references indicated that less frequent injections of GA
were just as effective as daily injections, and less frequent
injections improved patient adherence and reduced adverse


Given this motivation, a POSITA had only a limited
number of permutations of dose and frequency to explore
that were not already disclosed in the prior art. Because
a thrice-weekly 40mg injection would result in a total
weekly dose very close to that in the already-approved
daily 20mg injection—120mg/week versus 140mg/week—
the district court found a POSITA would have had a
reasonable expectation of success in pursuing the thriceweekly
dose frequency in terms of effectiveness, patient
adherence, and FDA approval.


Although the universe of potential GA doses is
theoretically unlimited
, the universe of dosages in the
prior art that had clinical support for being effective and
safe consisted of only two doses: 20mg and 40mg. Even if
there were multiple injection frequencies not yet tested in
the prior art—1x, 2x, 3x a week etc.—these still represent
a limited number of discrete permutations.

This is not a situation where the prior art gave no direction
in how to reach a successful result; the prior art
clearly indicated that less frequent doses should be explored
(i.e., moving away from the daily, “7x/week” dose
towards less frequent doses) and that higher doses, while
maintaining the same weekly dose (i.e., moving from
20mg daily to 40mg every other day), could increase
efficacy while not affecting adverse reactions.


Nor do we find merit in Teva’s argument that the district
court separately analyzed the 40mg dose limitation
and the 3x/week limitation, without considering them
together “except to conclude that the mash-up would be
obvious to try.” Appellants’ Opening Br. 55. We note that
the district court spent considerable time discussing why
the combination of a 40mg dose administered 3x/week
would be obvious to try. See In re Copaxone, 2017 WL
401943, at *19. And while “[t]he determination of obviousness
is made with respect to the subject matter as a
whole, not separate pieces of the claim,” SanofiSynthelabo
v. Apotex, Inc., 550 F.3d 1075, 1086 (Fed. Cir.
2008), this court has previously employed the same frequency-and-dosage-amount
approach to obviousness used
by the district court here. In Hoffmann-La Roche, 748
F.3d at 1329, the court considered whether it would have
been obvious at the time of invention to select a once a
month oral dosing regimen of 150mg of ibandronate to
treat osteoporosis. The court first discussed how the prior
art taught that infrequent dosing, such as monthly dosing,
was preferred. Id. at 1329–31. The court then separately
discussed why a POSITA would have selected a
150mg dose, before considering the limitations together
and concluding that “[a]t the very least, the 150mg dose
was obvious to try.” Id. at 1331–33. Teva makes no
convincing argument why a similar approach is inappropriate

Footnote 14 gets into "needle fatigue"

See, e.g., J.A. 4676–77 (Kolodny deposition, describing
needle fatigue associated with Copaxone
20mg/day); J.A. 4869 (Dr. Green, describing Khan 2008:
“It reveals clear and obvious patient preference for an
every-other-day dosing regimen when compared to a daily
dosing regimen given the option.”); J.A. 4857 (Dr. Green:
“As we discussed, most of the adverse events associated
with the use of glatiramer acetate, and in fact the most
troubling set of adverse events had to do with injection
site reactions or immediate post-injection reactions. Both
of those are tied to injections. So if you reduce the frequency
of injections, well, it’s clearly obvious that you
would reduce the frequency of those injection site reactions
or immediate post-injection reactions.”).

As to unknown mechanisms

Finally, this court’s decision in In re Cyclobenzaprine,
676 F.3d at 1063, does not warrant a different outcome.
Teva argues that prior to the invention, higher doses of
GA were not necessarily known to be more effective, GA’s
pharmacokinetic and pharmacodynamic (“pk/pd”) profile
was and remains unknown, GA’s mechanism of action is
still unknown, and the cause of patient’s reactions to
injections of GA is unknown. Teva contends that the
unpredictable nature of GA categorically precludes the
obvious-to-try analysis employed by the district court.
Appellants’ Opening Br. 50.
In Cyclobenzaprine, we held that bioequivalence alone
could not establish obviousness because “skilled artisans
could not predict whether any particular PK profile,
including a bioequivalent one, would produce a therapeutically
effective formulation.” 676 F.3d at 1070. The court
applied traditional motivation and reasonableexpectation-of-success
analysis, reasoning that “[w]hile it
may have been obvious to experiment with the use of the
same PK profile [from an immediate-release formulation]
when contemplating an extended-release formulation,
there [wa]s nothing to indicate that a skilled artisan
would have had a reasonable expectation that such an
experiment would succeed in being therapeutically effective.”
Id. In Cyclobenzaprine, there were no prior art
clinical studies to suggest what would be a therapeutically
effective formulation.

We do not read Cyclobenzaprine as establishing a rigid
rule categorically precluding obviousness findings
without pk/pd data.

In this case, the evidence shows that pk/pd data
was largely irrelevant to the invention.
Numerous clinical
studies in the prior art describe GA and its effects on
the human body. Although the precise mechanism of GA
is not known, it is known to be immunomodulating—i.e.,
it changes the immune system—and is not necessarily
measurable in the bloodstream and its levels are not
indicative of efficacy. See In re Copaxone, 2017 WL
401943, at *21–22; J.A. 3998–99, 4886–87. Testimony
was given at trial that pharmacokinetic studies for drugs
like GA are less appropriate than for small molecule
drugs, such as those at issue in Cyclobenzaprine. J.A.
4886–87. GA was also known to be “forgiving,” in that
occasional missed doses would not reduce efficacy, and
that fact gave POSITAs further confidence in eliminating
one dose every two weeks. J.A. 4848–49; 4884–85; 4732.
Higher doses were clinically shown to be at least as
effective as lower doses; Cohen shows, at the very least,
that 40mg is as effective and well-tolerated as 20mg, but
with a more rapid onset of action. Finally, Teva itself, in
its 1996 application to FDA, indicated that pharmacokinetic
studies “would be of limited value.” J.A. 20689.

Is invocation of "common sense" camouflage for conclusory assertions?

Teva finds fault with the district court’s reference to
“common sense” in its reliance on Dr. Green’s testimony.
During trial, Appellees’ expert Dr. Green testified that a
POSITA would expect reducing the frequency of injections
to be associated with enhanced overall tolerability of the
regimen. J.A. 4911. In its post-trial briefing, Teva argued
that Dr. Green’s testimony was conclusory and
unsupported by the prior art. The district court rejected

The bottom line for the CAFC:

In light of the foregoing, we conclude that the district
court did not err in invalidating all asserted claims of the
Copaxone patents as obvious.


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