Court Opinion

ID: 4310948
Source: CourtListenerOpinion
Date Created: 2018-09-10 15:00:52.996055+00
Date Added: 2024-06-11T14:44:26.274509
License: Public Domain

United States Court of Appeals
      for the Federal Circuit
                ______________________

            OREXO AB, OREXO US INC.,
               Plaintiffs-Appellants

                           v.

             ACTAVIS ELIZABETH LLC,
                 Defendant-Appellee
               ______________________

                      2017-1333
                ______________________

    Appeal from the United States District Court for the
District of Delaware in No. 1:14-cv-00829-SLR-SRF,
Judge Sue L. Robinson.
                ______________________

              Decided: September 10, 2018
                ______________________

    ERROL TAYLOR, Milbank, Tweed, Hadley & McCloy,
LLP, New York, NY, argued for plaintiffs-appellants.
Also represented by ANNA BROOK, JORDAN P. MARKHAM,
FREDRICK ZULLOW.

    GEORGE C. LOMBARDI, Winston & Strawn LLP, Chica-
go, IL, argued for defendant-appellee. Also represented
by TYLER JOHANNES, MICHAEL KEENAN NUTTER, IVAN
MICHAEL POULLAOS; GEOFFREY P. EATON, Washington,
DC.
                 ______________________
2                        OREXO AB   v. ACTAVIS ELIZABETH LLC

    Before NEWMAN, HUGHES, and STOLL, Circuit Judges.
NEWMAN, Circuit Judge.
     Orexo AB and Orexo US Inc. (collectively “Orexo”) ap-
peal the decision of the United States District Court for
the District of Delaware, holding claims 1, 3–6, and 8–10
of U.S. Patent No. 8,940,330 (“the ’330 Patent”) invalid on
the ground of obviousness. 1 The ’330 Patent, entitled
“Abuse-Resistant Pharmaceutical Composition for the
Treatment of Opioid Dependence,” claims a product
having the brand name Zubsolv®, approved by the FDA
for treatment of opioid dependence.
    Actavis Elizabeth LLC (“Actavis”) filed an Abbreviat-
ed New Drug Application (“ANDA”) for a generic counter-
part of Zubsolv, accompanied by a Paragraph IV
certification, leading to this Hatch-Waxman litigation in
accordance with 21 U.S.C. § 355(j) and 35 U.S.C. §
271(e)(2)(A). Two Orexo patents were challenged by
Actavis, but U.S. Patent No. 8,454,996 (“the ’996 Patent”),
entitled “Pharmaceutical Composition for the Treatment
of Acute Disorders,” which was held valid in the district
court, is not involved in this appeal.
    We reverse the judgment of invalidity of the ’330 Pa-
tent, for we conclude that obviousness was not proved by
clear and convincing evidence.
                      BACKGROUND
                            A
                    The ’330 Patent
    The ’330 Patent specification explains that opioid-
based pharmaceutical products intended for the relief of
pain have become a source of addiction, dependency, and

     1  Orexo AB v. Actavis Elizabeth LLC, 217 F. Supp.
3d 756 (D. Del. 2016) (“Dist. Ct. Op.”).
OREXO AB   v. ACTAVIS ELIZABETH LLC                       3

abuse. Treatment for opioid addiction includes a protocol
called “substitution therapy,” where partial opioid ago-
nists 2 that have higher binding affinities at opioid recep-
tors but produce lowered dependency than full agonists
like heroin, can lead to cessation of addiction by relieving
the opioid craving. The prior art shows use for this pur-
pose of the partial agonist buprenorphine, administered
in sublingual tablets and in oral films.
    The ’330 Patent explains that while buprenorphine
has less narcotic effect than a full opioid, addicts were
known to dissolve the buprenorphine from the substitu-
tion therapy tablet, and inject the dissolved buprenor-
phine intravenously to achieve an enhanced opioid effect.
To counteract this abuse, it was known to combine bu-
prenorphine with the opioid antagonist 3 naloxone in
substitution therapy.
    It was known that formulations containing buprenor-
phine to naloxone at a ratio of 4:1 provide the therapeuti-
cally optimal balance for sublingual treatment. Naloxone
has poor transmucosal bioavailability so that if the mix-

   2      An agonist is a chemical compound that binds to a
receptor and activates the receptor to produce a biological
response. Partial opioid agonists have opioid agonist
effects that “are less than the maximal effects of other,
‘full’ opioid agonists, such as morphine, and are limited by
a ‘ceiling’ effect. The drug thus produces a lower degree of
physical dependence than other opioid agonists, such as
heroin, morphine, or methadone, and is therefore particu-
larly useful in substitution therapy.” ’330 Patent, col. 9,
ll. 19–29.
     3    “Opioid antagonists are used to reverse the phar-
macological effects of opioids. Selective opioid antago-
nists, such as naloxone, may therefore be used to treat
drug overdose or to diagnose suspected opioid addiction.”
’330 Patent, col. 1, l. 65–col. 2, l. 1.
4                          OREXO AB   v. ACTAVIS ELIZABETH LLC

ture is taken in tablet form as directed, the buprenor-
phine will act as intended to treat opioid dependence with
little interference from the naloxone. However, if the
tablet is dissolved and injected, the naloxone will antago-
nize the effects of the buprenorphine, resulting in with-
drawal symptoms and thus deterring abuse of the
formulation.     The 4:1 ratio provides for appropriate
pharmacological amounts of naloxone to deter abuse when
injected, but does not interfere with buprenorphine when
taken in tablet form. ’330 Patent, col. 2, ll. 13–22; id., col.
9, ll. 37–50. However, naloxone’s “functional blockade of
buprenorphine’s action is also only partial and is short-
lived in its nature,” id., col. 2, ll. 23–25, and there was a
continuing need for improvement in substitution therapy
formulations.
    The ’330 Patent is for a sublingual tablet formulation
that is less subject to abuse. The formulation enhances
the agonist effectiveness of buprenorphine, permitting a
reduced amount of buprenorphine in the tablet and thus
reducing the amount available on dissolving and injecting
the product. In this formulation, microparticles of bu-
prenorphine are adhered to the surface of carrier particles
of citric acid, and the formulation also contains naloxone
in the 4:1 ratio. The ’330 Patent explains that the bu-
prenorphine in the microparticles acts with little interfer-
ence from the naloxone, but if the tablet is dissolved in
water for injection into the bloodstream, the naloxone will
also be dissolved and will antagonize buprenorphine’s
effects.
    All parties agree that the product in the ’330 Patent
provides improved treatment of opioid dependence, as
compared with the prior art. The ’330 Patent specifica-
tion includes data from clinical trials comparing the
related sublingual product Suboxone®. Patent Example 2
shows a 66% improvement in bioavailability of buprenor-
phine, and Patent Examples 7 and 8 show bioequivalent
OREXO AB   v. ACTAVIS ELIZABETH LLC                        5

results for a sublingual tablet containing 29% less bu-
prenorphine than in Suboxone tablets.
    Actavis does not dispute the improvement, or its value
in treatment of addiction. Rather, Actavis argues that
this formulation is obvious based on a combination of
references, and that improved function and use are irrele-
vant if the product is obvious. This theory is flawed, for
an unobvious improvement in properties or use is highly
relevant to patentability of a new product.
   Claims 1 and 6 were deemed representative:
   1. A tablet composition suitable for sublingual
   administration comprising:
       microparticles of a pharmacologically-effective
   amount of buprenorphine, or a pharmaceutically-
   acceptable salt thereof, presented upon the sur-
   face of carrier particles,
       wherein microparticles of buprenorphine or a
   pharmaceutically acceptable salt thereof are in
   contact with particles comprising citric acid,
       wherein the buprenorphine or pharmaceuti-
   cally acceptable salt thereof and the citric acid are
   not in the same particle;
       a pharmacologically-effective amount of na-
   loxone, or a pharmaceutically-acceptable salt
   thereof;
       and a disintegrant selected from the group
   consisting of croscarmellose sodium, sodium
   starch glycolate, crosslinked polyvinylpyrrolidone
   and mixtures thereof.
   6. The composition as claimed in claim 1, wherein
   the particles of citric acid are presented and act as
   carrier particles.
6                        OREXO AB   v. ACTAVIS ELIZABETH LLC

The district court found that all the ingredients in the
claims were generally known, and held that although the
specific formulation was not shown or suggested in any
reference, the new combination would have been obvious
to a person of ordinary skill. However, the prior art does
not show or suggest the claimed combination, and does
not show or suggest that this combination would achieve
enhanced therapeutic effect while being less subject to
abuse.
                            B
                     The Prior Art
    1. Suboxone® and Subutex®
    The buprenorphine and naloxone combination in the
4:1 ratio has been used for substitution therapy at least
since 2002. The prior art Suboxone sublingual tablets are
a homogeneous combination made by mixing the ingredi-
ents of buprenorphine, naloxone, citric acid, sodium
citrate, and sublingual excipients. Dist. Ct. Op. at 769
n.17 (citing Physicians’ Desk Reference, 58th ed. 2004).
Subutex® is the same formulation as Suboxone, but
without the naloxone. WO2008/152347 (“Cairns”), cited
by the examiner during prosecution, describes the tablet
formulation as a wet granulation process where bupren-
orphine, citric acid, and sodium citrate are dissolved
together and then mixed with excipients. See Orexo Br.
at 14 & n.2 (“Cairns provides the manufacturing process
for Subutex® tablets, a product with essentially the same
formulation as Suboxone® tablets, but without nalox-
one.”).
   Orexo attributes the improvements achieved by the
Zubsolv product to the microparticles of buprenorphine
adhered to the surface of citric acid carrier particles.
Orexo states that the 66% higher bioavailability is not
suggested or reasonably predictable from the prior art.
We have been directed to no reference to show or suggest
OREXO AB   v. ACTAVIS ELIZABETH LLC                        7

otherwise. Orexo stresses the Examiner’s statement in
allowing the ’330 Patent, that the improvement is due to
the ingredients and the structure:
   [T]he mere presence of citric acid in the sublin-
   gual tablets formulated according to the prior art
   (e.g. Cairns) is insufficient to achieve the superior
   pharmacokinetic profile exhibited by the instant
   invention. Applicant has persuasively demon-
   strated that the instant tablet exhibits unexpect-
   edly     superior      sublingual     buprenorphine
   bioavailability due to the ingredients as well as
   the structural characteristics recited in the in-
   stant claims.
Notice of Allowability at 5 (emphasis original), Applica-
tion No. 14/127,470 (issued as the ’330 Patent) (Nov. 4,
2014); see also Orexo Br. at 29 (quoting Notice of Allowa-
bility at 5).
   2. Suboxone® Film
     U.S. Patent No. 8,475,832 (“the ’832 Patent”) de-
scribes an orally dissolvable film that cannot be easily
removed once placed inside the mouth. The film contains
the buprenorphine/naloxone combination in the 4:1 ratio,
and is described as bioequivalent to Suboxone sublingual
tablets. The ’832 Patent teaches that optimum bioavaila-
bility of buprenorphine and naloxone from the film is
achieved at pH 3–3.5, with citric acid included in the film
to lower the pH. The district court relied on this presence
of citric acid to render obvious the citric acid carrier
particles in the Zubsolv formulation.
    However, the ’832 Patent does not reduce the amount
of buprenorphine needed to provide an effective substitu-
tion therapy dose. And the use of film in substitution
therapy presents recognized problems, as stated in the
’330 Patent, for the film does not dissolve quickly and a
maximum of only two films may be administered simul-
8                        OREXO AB   v. ACTAVIS ELIZABETH LLC

taneously, producing inadequate dosage as well as prob-
lems of compliance and administration. ’330 Patent, col.
2, ll. 43–50.
    3. The Orexo Application
    Orexo’s U.S. Patent Application No. 2010/0129443
(“the ’443 Application”), titled “Non-Abusable Pharmaceu-
tical Composition Comprising Opioids,” was filed on
December 3, 2007, published on May 27, 2010, and issued
as U.S. Patent No. 8,470,361 on June 25, 2013. It is prior
art as of its filing date.
    The ’443 Application describes sublingual tablets
where smaller particles of opioid agonists are carried on
larger particles that include an opioid antagonist. The
’443 Application lists many opioid agonists including
buprenorphine, and many antagonists including naloxone.
However, citric acid is not mentioned or suggested as the
carrier particle.
    4.  European Patent Application No. EP
    0324725
    European Patent Application No. EP 0324725 (“the
EP ’725 Application”) lists a large number of water-
soluble carrier particles, to which smaller particles of a
pharmaceutically active substance may be adhered. The
EP ’725 Application does not mention sublingual tablets,
does not mention opioids as the active substance, and
does not mention citric acid as a carrier.
                            C
             The District Court Decision
    The district court held the asserted ’330 Patent claims
invalid, ruling that a skilled artisan would obviously have
selected these components from the prior art and reformu-
lated them as in the ’330 Patent. The district court stated
that the ’443 Application taught that “a person of ordi-
nary skill in the art would have been motivated to refor-
OREXO AB   v. ACTAVIS ELIZABETH LLC                         9

mulate Suboxone tablets as an interactive mixture to
improve bioavailability,” Dist. Ct. Op. at 773; that the
’832 Patent for an oral film “expressly taught a person of
ordinary skill that the addition of citric acid facilitated an
increased level of absorption of buprenorphine despite a
lower pH,” id. at 772–73; and that the EP ’725 Application
“described how to make such a mixture using dry mixing,”
id. at 773.
     In response to Orexo’s argument that no reference
showed the new formulation in the ’330 Patent, stressing
the unexpectedly enhanced bioavailability and its bene-
fits, the district court reasoned that a skilled artisan
“would not have excluded citric acid” as a carrier and
“would have known how to form an interactive mixture
using citric acid.” Id. The district court found that the
’832 Patent taught “the use of citric acid with an interac-
tive mixture would also improve [buprenorphine] bioa-
vailability,” id., and concluded that it would have been
obvious to use citric acid as carrier particles.
    Orexo argued that a person of ordinary skill would
have been dissuaded from using citric acid in this interac-
tive mixture because Examples 6–8 of the ’832 Patent
taught that as the pH is lowered through use of citric
acid, the buprenorphine bioavailability increase is accom-
panied by a compromised naloxone availability such that
the 4:1 ratio is lost. The district court described this
argument as irrelevant because the 4:1 ratio is an “un-
claimed feature” of the ’330 Patent, the court stating “any
problems with maintaining the ratio forecast by the ’832
patent goes to the reasonable expectation of success
requirement, not to motivation to combine; i.e., this
argument is irrelevant in this context.” Id. at 773 n.23.
    Orexo stresses that no reference teaches or suggests
using citric acid particles as a carrier for micronized
buprenorphine, and that the benefits of this formulation
were unexpected. Rejecting this argument, the district
10                        OREXO AB   v. ACTAVIS ELIZABETH LLC

court cited the testimony of Actavis’ expert that citric acid
“fits the definition of a carrier particle” and “therefore it
would act as a carrier particle, because it is in the Subox-
one tablet.” Dist. Ct. Op. at 771 (quoting testimony of Dr.
Dyar). However, no reference suggests citric acid carrier
particles.
     The district court also discussed the objective indicia
of unobviousness, responding to Orexo’s arguments of
unexpectedly increased bioavailability, long-felt need for
improved treatment of opioid dependence, copying by
Actavis, and hindsight. The court stated that “the unex-
pected result of increased bioavailability provides some
support for nonobviousness,” Dist. Ct. Op. at 776, but
found that interactive mixtures were generally known to
improve bioavailability and that the increase here was a
“‘difference in degree,’ not a difference in ‘kind.’” Id. at
774. The district court stated that Orexo’s arguments of
teaching away, long-felt need, and copying were “not
persuasive evidence.” Id. at 773 n.27, 776. The court
concluded that “Actavis has met its burden to prove, by
clear and convincing evidence, that claims 1, 3–6, and 8–
10 are obvious.” Id. at 776.
                        DISCUSSION
                  Standard of Review
    Following a bench trial, we review the district court’s
factual findings for clear error. Conclusions of law receive
de novo determination. See In re Cyclobenzaprine Hydro-
chloride Extended-Release Capsule Patent Litig., 676 F.3d
1063, 1069 (Fed. Cir. 2012) (“While we afford deference to
a district court’s factual findings, however, we retain
plenary review to determine whether, as a legal matter,
the evidence satisfies the clear-and-convincing standard
of proof.”).
    Obviousness is a question of law, based on the facts of
(1) the scope and content of the prior art, (2) the level of
OREXO AB   v. ACTAVIS ELIZABETH LLC                       11

ordinary skill in the field, (3) the differences between the
claimed invention and the prior art, and (4) any objective
indicia of nonobviousness. Graham v. John Deere Co., 383
U.S. 1, 17–18 (1966). To invalidate a patent on the
ground of obviousness, the challenger has the burden of
proving that the subject matter as a whole would have
been obvious to a person of ordinary skill in the field of
the invention. 35 U.S.C. § 103(a). A party seeking to
invalidate a patent on obviousness grounds must demon-
strate by clear and convincing evidence that a person of
ordinary skill would have selected and combined and
modified the subject matter of the references in the man-
ner of the claimed invention, with a reasonable expecta-
tion of success.     E.g., InTouch Techs., Inc. v. VGO
Commc’ns, Inc., 751 F.3d 1327, 1347 (Fed. Cir. 2014).
     Judicial hindsight must be avoided. See KSR Int’l Co.
v. Teleflex Inc., 550 U.S. 398, 421 (2007) (“A factfinder
should be aware, of course, of the distortion caused by
hindsight bias and must be cautious of arguments reliant
upon ex post reasoning.”). It is inappropriate to use the
template provided by the inventor, to render the inven-
tor’s contribution obvious. See Interconnect Planning
Corp. v. Feil, 774 F.2d 1132, 1138 (Fed. Cir. 1985) (“The
invention must be viewed not with the blueprint drawn by
the inventor, but in the state of the art that existed at the
time. The invention must be evaluated not through the
eyes of the inventor, who may have been of exceptional
skill, but as by one of ‘ordinary skill’.”).
                       Obviousness
    In holding the ’330 Patent’s claims invalid for obvi-
ousness, the district court cited the ’832 Patent to show
that “the use of citric acid with an interactive mixture
would also improve bioavailability.” Dist. Ct. Op. at 773.
The ’832 Patent is for a film that includes citric acid to
lower the pH of the film. Example 7 of the ’832 Patent
shows that a lowering of pH to 5.5 increases buprenor-
12                         OREXO AB   v. ACTAVIS ELIZABETH LLC

phine bioavailability, but also compromises the desired
4:1 ratio of buprenorphine to naloxone. ’832 Patent, col.
21, ll. 17–26. Example 8 of the ’832 Patent shows that a
further decrease in pH to 3.5 using citric acid maintained
the 4:1 ratio but did not increase buprenorphine bioavail-
ability. Id., col. 23, ll. 1–11. The ’832 Patent is directed to
replacing sublingual tablets with oral film, for possible
advantage in administration. There is no suggestion of
the different structure of the Zubsolv tablet and its ad-
vantage in deterring abuse. The Zubsolv structure is
achieved solely upon the hindsight knowledge of the
structure and benefits described in the ’330 Patent.
    The district court cited the Orexo ’443 Application for
its disclosure of particles of buprenorphine adhered to
carrier particles. However, the ’443 Application does not
mention citric acid in its extensive list of carriers, and
does not suggest that citric acid carrier particles may
provide benefits compared with the prior art. These
benefits were not predicted or suggested in any reference.
     The district court cited the EP ’725 Application for its
general description of interactive mixtures as pharmaceu-
tical formulations. This reference does not mention
opioids, does not mention sublingual tablets, does not
mention citric acid in its extensive list of carrier particles,
and does not suggest the formulation in the ’330 Patent or
its unexpected benefits.
    The product herein is admittedly new. The district
court acknowledged the undisputed testimony of Orexo’s
co-founder, Mr. Thomas Lundqvist, and Orexo’s global
chief medical officer, Dr. Michael Sumner. The district
court wrote:
     Lundqvist testified that the first clinical results
     showed that Zubsolv had a 66% improvement in
     bioavailability. (D.I. 202 at 58:9–15; D.I. 211 at
     36) According to a bioequivalence study, Zubsolv
     increases the bioavailability of buprenorphine,
OREXO AB   v. ACTAVIS ELIZABETH LLC                         13

    such that patients require a 29% lower dose using
    Zubsolv as compared to Suboxone. (JTX 153; D.I.
    202 at 63:11–17 [Testimony of Mr. Lundqvist];
    D.I. 205 at 770:22–771:3 [Testimony of Dr.
    Sumner]; D.I. 196 at 12) Orexo’s pharmaceutical
    development report stated that “[d]ue to the antic-
    ipated improved dissolution of buprenorphine the
    selected dose of 6 mg buprenorphine is expected to
    give approximately the same systemic buprenor-
    phine exposure in humans as a Suboxone® tablet
    with 8 mg buprenorphine.” (JTX 123 at 4; JTX
    128 at 32; D.I. 203 at 352:11–22)
Dist. Ct. Op. at 760 (citations in original, bracketed
information added).
    The district court nonetheless concluded that the Zub-
solv formulation was obvious. The court cited Actavis’s
expert Dr. Dyar as showing that “citric acid is pharma-
ceutically acceptable, water soluble, and of the right size,
so therefore it would act as a carrier particle, because it is
in the Suboxone tablet.” Dist. Ct. Op. at 771 (quoting J.A.
6685, June 8, 2016 Trial Tr. at 433:12–15, ECF No. 204
(Testimony of Dr. Dyar)). Orexo points out that Dr. Dyar
cited no reference, and describes this reasoning as “hind-
sight bias,” for it recreates the prior art from the teaching
in the ’330 Patent. Orexo points out that citric acid is
nowhere used or listed or suggested as a carrier particle,
and it is not so used in the Suboxone tablet.
    At the oral argument of this appeal, Actavis conceded
that no reference teaches using citric acid as a carrier
particle, or that citric acid should be used as a carrier
particle:
    Actavis Counsel: Your Honor, I will confirm what
    counsel said before and what we’ve said in our
    briefs. There is no piece of prior art that was pre-
    sented that says citric acid is a carrier particle or
    should be used as a carrier particle.
14                         OREXO AB   v. ACTAVIS ELIZABETH LLC

Oral. Arg.      at 21:19–21:36, http://oralarguments.
cafc.uscourts.gov/default.aspx?fl=2017-1333.mp3.
     Court: If both of those things are really well
     known, then one would think that if citric acid
     were routinely or it was obvious to use it as a car-
     rier particle, you could have found some reference
     that used it. . . . Your expert didn’t even testify
     that he was familiar with this industry and that
     citric acid was routinely used as a carrier particle
     in interactive mixtures. He just said it was the
     right size and it could be used.
     Actavis Counsel: Well. You’re right Your Honor in
     terms of your characterization of the record.
     There was not citric acid used as a carrier particle
     that was in the record.
Id. at 26:12–26:50.
     Dr. Dyar did not testify that a skilled artisan would
obviously select citric acid as a carrier for buprenorphine;
he stated that if it were selected, the artisan would expect
it to work. The district court’s finding that “a person of
ordinary skill in the art would not have excluded citric
acid,” Dist. Ct. Op. at 773, is not a teaching or suggestion
to use citric acid. See In re Gordon, 733 F.2d 900, 902
(Fed. Cir. 1984) (“The mere fact that the prior art could be
so modified would not have made the modification obvious
unless the prior art suggested the desirability of the
modification.”). The record does not contain clear and
convincing evidence of a teaching or suggestion to use
citric acid particles as a carrier for this opioid product in
substitution therapy, or that the actual beneficial results
would be obtained.
    Orexo also argued that the specific formulation in the
’330 Patent preserves the 4:1 ratio of buprenorphine to
naloxone during use of the product, unlike the prior art
products. The district court stated that this benefit is
OREXO AB   v. ACTAVIS ELIZABETH LLC                        15

irrelevant because it “goes to the reasonable expectation
of success requirement, not to motivation to combine.”
Dist. Ct. Op. at 773 n.23. The district court found that
“there is nothing in the prior art which would have dis-
couraged a person of ordinary skill from following the
path set out in the various references.” Id. at 773. How-
ever, no reference or combination of references proposes
the path of the ’330 Patent.
    The question is not whether the various references
separately taught components of the ’330 Patent formula-
tion, but whether the prior art suggested the selection and
combination achieved by the ’330 inventors. Although the
reference ’832 Patent showed that buprenorphine bioa-
vailability in the film formulation is affected by pH, this is
not a suggestion of the sublingual tablet interactive
formulation in the ’330 Patent or a teaching of its benefit
in deterring abuse.
    The references show that the field of opioid biophar-
macology has received extensive scientific study. The ’330
Patent provides a significant improvement. Despite the
extensive study, this improvement over the then-available
treatments for addiction is not proposed or suggested in
the references. There is no suggestion that the specified
elements should be selected and combined, and that the
designated sublingual formulation would be less subject
to abuse than prior formulations for substitution therapy.
Although the need to reduce this abuse was known,
recognizing a need does not render the solution obvious.
    Here, the objective indicia guide the analysis of obvi-
ousness. See, e.g., Leo Pharm. Prods., Ltd. v. Rea, 726
F.3d 1346, 1357–58 (Fed. Cir. 2013) (“[T]his court has
emphasized that consideration of the objective indicia is
part of the whole obviousness analysis, not just an after-
thought.”). The district court stated, “the unexpected
result of increased bioavailability provides some support
for nonobviousness,” although the court also stated that
16                        OREXO AB   v. ACTAVIS ELIZABETH LLC

Orexo’s long-felt need and copying arguments “are not
persuasive evidence of such.” Dist. Ct. Op. at 776. The
court reasoned that the prior art sought to improve bioa-
vailability, that interactive mixtures were known to
improve bioavailability, and therefore that the improved
result of the ’330 Patent’s formulation was inadequate to
serve as probative evidence of unexpected results. See id.
at 774.
    Orexo states that the district court erred, for the prior
art does not teach or suggest the ’330 Patent’s formulation
as a way to improve bioavailability. Actavis responds
that the prior art is silent “about whether it would be
expected or difficult ‘to increase buprenorphine absorption
without simultaneously increasing naloxone absorption to
unacceptable levels.’” Actavis Br. at 62. Orexo counters
that silence is not a teaching or suggestion; and that the
beneficial results could not be predicted, and were indeed
unexpected. 4
     The district court erred in discounting the enhanced
bioavailability in the ’330 Patent’s formulation as “a
‘difference in degree,’ not a difference in ‘kind,’” Dist. Ct.
Op. at 774, for the clinical studies reported in the ’330
Patent show 66% improved bioavailability. Particularly
in the context of this invention, this is more than a trivial
“degree.”

     4   Actavis states that Orexo did not argue to the dis-
trict court that maintenance of the 4:1 ratio was an unex-
pected result, and thus that this argument was waived.
Actavis Br. at 61–62. Contrary to Actavis’ statement, the
record shows Orexo’s arguments that “the ’330 invention’s
novel structure and arrangement unexpectedly improves
bioavailability over the closest prior art (Cairns / Subox-
one), while maintaining the 4:1 buprenorphine to nalox-
one ratio.” Orexo’s Resp. Dist. Ct. Br. at 53, ECF No. 200;
id. at 54 (“The 4:1 ratio is unexpected and relevant.”).
OREXO AB   v. ACTAVIS ELIZABETH LLC                      17

    The district court also discounted Orexo’s evidence
that Zubsolv is less susceptible to abuse than Suboxone,
stating that “Orexo’s ‘real world evidence’ set forth above
is not compelling or unrebutted,” and that “[t]he only
objective evidence for this factor is that which was pre-
sented to, and rejected by, the FDA.” Id. at 776. Orexo
stated that evidence of Zubsolv’s effectiveness in reducing
abuse accumulated after FDA approval, and was present-
ed to the district court. Although the weight of this
evidence was disputed, the FDA deemed the product
worthy of approval for the efficacy that was established in
the clinical trials. It was established that this novel
formulation enables reduced dosage and enhanced effica-
cy in substitution therapy products, deterring abuse.
    On the entirety of the record, Actavis did not establish
obviousness by clear and convincing evidence. The judg-
ment of invalidity is reversed. We remand for appropriate
further proceedings.
             REVERSED AND REMANDED