Court Opinion

ID: 4264957
Source: CourtListenerOpinion
Date Created: 2018-04-18 15:00:49.230483+00
Date Added: 2024-06-11T14:30:43.171237
License: Public Domain

NOTE: This disposition is nonprecedential.

  United States Court of Appeals
      for the Federal Circuit
               ______________________

              ICOS CORPORATION,
                    Appellant

                          v.

      ACTELION PHARMACEUTICALS LTD,
                    Appellee
             ______________________

                2017-1017, 2017-1018
               ______________________

   Appeals from the United States Patent and Trade-
mark Office, Patent Trial and Appeal Board in Nos.
IPR2015-00561, IPR2015-00562.
                ______________________

               Decided: April 18, 2018
               ______________________

   MARK J. FELDSTEIN, Finnegan, Henderson, Farabow,
Garrett & Dunner, LLP, Washington, DC, argued for
appellant. Also represented by JASON LEE ROMRELL,
YIEYIE YANG; CHARLES E. LIPSEY, J. DEREK
MCCORQUINDALE, Reston, VA; MARK STEWART, Eli Lilly
and Company, Indianapolis, IN.

   MARK EDWARD WADDELL, Loeb & Loeb LLP, New
York, NY, argued for appellee. Also represented by
2     ICOS CORPORATION   v. ACTELION PHARMACEUTICALS, LTD.

KATHLEEN GERSH, WARREN K. MACRAE; ALEXANDRA
CAVAZOS, Los Angeles, CA.
               ______________________

     Before MOORE, LINN, and CHEN, Circuit Judges.
MOORE, Circuit Judge.
     ICOS Corporation appeals the Patent Trial and Ap-
peal Board’s inter partes review (“IPR”) decisions holding
claims 1–32 of U.S. Patent No. 7,182,958 and claims 1–11
of U.S. Patent No. 6,821,975 would have been obvious
over PCT Application WO 97/03675 (“Daugan”), PCT
Application WO 96/38131 (“Butler”), U.S. Patent
No. 4,721,709 (“Seth”), and Wadke, et al., Preformulation
Testing, in Pharmaceutical Dosage Forms (Herbert A.
Lieberman, et al., eds., 1989) (“Wadke”). Because the
Board did not err in its obviousness analysis and substan-
tial evidence supports its underlying fact findings, we
affirm.
                      BACKGROUND
    The ’958 patent is directed to pharmaceutical formu-
lations containing micronized tadalafil. Claim 1, which is
representative, reads:
    1. A pharmaceutical formulation comprising an
    active compound having the structural formula
ICOS CORPORATION   v. ACTELION PHARMACEUTICALS, LTD.     3

   wherein said compound is provided as free drug
   comprising particles wherein at least 90% of the
   particles of the said compound have a particle size
   of less than about 40 microns; about 50% to about
   85%, by weight, of a water-soluble diluent; a lub-
   ricant; a hydrophilic binder selected from the
   group consisting of a cellulose derivative, pov-
   idone, and a mixture thereof; and a disintegrant
   selected from the group consisting of croscarmel-
   lose sodium, crospovidone, and a mixture thereof.
The ’975 patent is directed to micronized tadalafil in a
free-drug particulate form. Claim 1, which is representa-
tive, recites:
   1. A free drug particulate form of a compound hav-
   ing a formula

   or pharmaceutically acceptable salts and solvates
   thereof, comprising particles of the compound
   wherein at least 90% of the particles have a parti-
   cle size of less than about 40 microns.
    Actelion Pharmaceuticals Ltd. (“Actelion”) filed two
petitions for inter partes review. The first, IPR2015-
00561, alleged claims 1–32 of the ’958 patent would have
been obvious over the combination of Daugan, Butler,
Seth, and the common pharmaceutical knowledge reflect-
ed in Wadke and two other references. The second,
IPR2015-00562, alleged claims 1–11 of the ’975 patent
would have been obvious over Daugan, Butler, Seth, and
4     ICOS CORPORATION   v. ACTELION PHARMACEUTICALS, LTD.

Wadke, and additionally in view of U.S Patent No.
4,344,934. The Board instituted IPR of all claims.
    Daugan discloses a compound having the structural
formula depicted in the claims, i.e., tadalafil, and the
excipients included in claim 1 of the ’958 patent.
J.A. 3811. Butler discloses that tadalafil is poorly water
soluble and teaches a process of preparing a solid disper-
sion of tadalafil and a pharmaceutically acceptable carrier
or excipient. J.A. 3873-74. Seth discloses that when
poorly soluble hydrophobic drugs are used in solid dosage
forms, their rate of dissolution is often slow, and a “fre-
quently used method to overcome such problems is to
finely grind or ‘micronize’ drug substances to reduce their
particle-size.” J.A. 3918. Wadke discloses that “[i]t is
now generally recognized that poorly soluble drugs show-
ing a dissolution-rate-limiting step in the absorption
process will be more readily bioavailable when adminis-
tered in a finely subdivided state than as coarse materi-
al,” and “[g]rinding should reduce coarse material to,
preferably, the 10- to 40- [micron] range.” J.A. 4004–05.
    In the ’958 IPR, the Board found a motivation to com-
bine Butler’s teaching that tadalafil has poor solubility
with Seth’s teaching that compounds with low solubility
generally also have a slow dissolution rate, and with Seth
and Wadke’s teachings that reducing particle size through
micronization can increase dissolution rate. It found
ICOS had not shown that a preformulation analysis
would have deterred an ordinarily skilled artisan from
pursuing micronization. It found that, while Seth recog-
nizes disadvantages to micronization, those disad-
vantages would not have stopped ordinarily skilled
artisans from using the technique. It found there was a
reasonable expectation of success in combining the teach-
ings of these references, and rejected ICOS’ claim of
unexpected results. It found Daugan teaches the specific
required excipients in claim 1 in a limited number of
examples.
ICOS CORPORATION   v. ACTELION PHARMACEUTICALS, LTD.        5

    In the ’975 IPR, the Board found Daugan, Butler,
Seth, and Wadke disclose every limitation of the chal-
lenged claims. It found the general knowledge that
tadalafil is poorly water soluble would have motivated an
ordinarily skilled artisan to micronize it to improve its
absorption and an ordinarily skilled artisan would have
had a reasonable expectation of success in doing so. It
found Daugan, Butler, Seth, and Wadke do not teach
away from micronization.
    Based on these facts, in each instance, the Board con-
cluded that the claims would have been obvious. ICOS
appeals. It argues the Board improperly substituted its
own obviousness arguments for those in the petition and
improperly shifted the burden to ICOS to show nonobvi-
ousness. It argues the references do not provide a motiva-
tion to combine or a reasonable likelihood of success. We
have jurisdiction under 28 U.S.C. § 1295(a)(4)(A).
                        DISCUSSION
     We review the Board’s determination of obviousness
de novo and its underlying factual findings for substantial
evidence. Belden Inc. v. Berk-Tek LLC, 805 F.3d 1064,
1073 (Fed. Cir. 2015). Board decisions must be set aside
if they are “arbitrary, capricious, an abuse of discretion, or
otherwise not in accordance with law.” 5 U.S.C. § 706.
                              I
    As discussed above, the Board made several fact find-
ings in support of its conclusions of obviousness. On
appeal, ICOS challenges the Board’s findings that there
was a motivation to micronize tadalafil, that a skilled
artisan would have had a reasonable expectation of suc-
cess in doing so, and that Daugan teaches the claimed
combination of excipients. Substantial evidence supports
each of these findings.
    Substantial evidence supports the Board’s findings
that the prior art discloses the compound tadalafil, the
6      ICOS CORPORATION   v. ACTELION PHARMACEUTICALS, LTD.

micronization of drugs to less than about 40 microns, and
a motivation to combine these teachings. Daugan disclos-
es tadalafil. Wadke teaches the micronization of drug
particles, stating, “[g]rinding should reduce coarse mate-
rial to, preferably, the 10- to 40- [micron] range.” J.A.
4004–05. Butler teaches tadalafil is poorly water soluble,
and Seth teaches that poorly water soluble drugs often
also have slow dissolution. Both Seth and Wadke further
disclose that micronization solves dissolution problems.
J.A. 3918 (A “frequently used method to overcome such
problems is to finely grind or ‘micronize’ drug substances
to reduce their particle-size.”); J.A. 4004–05. In light of
this prior art, substantial evidence supports the finding
that one of ordinary skill would have been motivated to
micronize tadalafil to less than about 40 microns.
    Substantial evidence also supports the Board’s find-
ings that a skilled artisan would have had a reasonable
expectation of success in combining these teachings to
micronize tadalafil. Actelion’s expert testified that even if
tadalafil’s absorption was solubility-limited, a skilled
artisan would still have considered particle size reduction
useful for increasing dissolution rate and improving
absorption.
    While ICOS argues the prior art taught away from
micronization, substantial evidence supports the Board’s
finding that it did not. Although Butler discloses co-
precipitation as a solution to tadalafil’s poor solubility,
the Board credited Actelion’s expert’s testimony that
Butler does not suggest that micronization would not
work but instead simply chooses another possible solu-
tion. While Seth recognized problems with agglomeration
when micronizing, the Board similarly credited Actelion’s
expert’s testimony that there were recognized solutions in
the art. The Board determined Wadke does not teach a
sequential approach that favors coprecipitates over mi-
cronization but instead describes two alternative ap-
ICOS CORPORATION   v. ACTELION PHARMACEUTICALS, LTD.     7

proaches and recognizes particle size reduction was the
“most commonly employed practice.” J.A. 4022.
     Substantial evidence also supports the Board’s finding
that an ordinarily skilled artisan would have combined
the claimed excipients recited in claim 1 of the ’958 pa-
tent. Claim 1 requires: (1) about 50% to about 85%, by
weight, of a water-soluble diluent; (2) a lubricant; (3) a
hydrophilic binder selected from the group consisting of a
cellulose derivative, povidone, and a mixture thereof; and
(4) a disintegrant selected from the group consisting of
croscarmellose sodium, crospovidone, and a mixture
thereof. Each of these limitations is present in Daugan.
Examples A1 and B2 in Daugan disclose oral formulations
of tadalafil containing lactose, which Actelion’s expert
testified is a water-soluble diluent and is present in the
examples at 59.3% and 70.5%, by weight. Examples A1,
A2, B1, and B2 all disclose the use of forms of magnesium
stearate, which Actelion’s expert testified was a common-
ly used lubricant. Example B1 discloses the use of poly-
vinyl pyrollidone, which Actelion’s expert testified is
another name for providone. Daugan specifically disclos-
es tadalafil in combination with the disintegrant crosca-
mellose sodium in example B1 and with the disintegrant
crosprovidone in examples A1 and A2. In short, example
B1 discloses all of the claimed excipients except the
diluent, which is disclosed in examples A1 and B2, and
which Actelion’s expert testified was commonly used in
oral tablets. The Board’s finding that one of skill in the
art would have combined the claimed excipients with
micronized tadalafil is, therefore, supported by substan-
tial evidence.
                             II
   ICOS argues the Board improperly substituted its
own obviousness arguments in place of Actelion’s argu-
ments. For example, ICOS argues that in the ’958 IPR,
the Board improperly relied on Lawrence X. Yu, An
8      ICOS CORPORATION   v. ACTELION PHARMACEUTICALS, LTD.

Integrated Model for Determining Causes of Poor Oral
Drug Absorption, 16 Pharmaceutical Research 1883
(1999) (“Yu”), a reference that is not in the prior art, to
conclude that one of skill in the art would not necessarily
have engaged in rational formulation and preformulation
testing. ICOS argues this violates 35 U.S.C. § 316(e),
which places the burden on the petitioner to establish
unpatentability, because Actelion never cited this portion
of Yu and did not argue one skilled in the art would have
acted irrationally. It also argues this violates due process
under the APA because the Board relied on a new theory
of obviousness for the first time in its final written deci-
sion. The record, however, indicates that ICOS intro-
duced Yu as rebuttal evidence to support its theory of
rational design. The Board’s determination that, read in
its entirety, Yu does not clearly support the position for
which ICOS introduced it in rebuttal was not in error.
The Board did not use Yu to teach elements of the claim
or to supply the motivation to combine. Its findings
regarding Yu are limited to its rejection of ICOS’ argu-
ments regarding this reference.
     While ICOS argued Wadke implied a sequential prac-
tice of first trying to increase solubility and then, if that
fails, trying micronization, Actelion argued Wadke taught
micronization as a solution. The Board did not err in
resolving the parties’ dispute as to the teaching of Wadke.
The Board’s factual determination as to which interpreta-
tion to adopt does not constitute improperly raising a new
argument.
    Likewise, in the ’958 IPR, the Board did not err in cit-
ing Modern Pharmaceutics (Gilbert S. Banker & Christo-
pher T. Rhodes eds., 3d ed.) (“Banker”) in its discussion of
micronization during formulation. ICOS first raised at
the hearing the argument that Wadke is irrelevant to
formulation design because it is titled “Preformulation
Testing.” Unlike in Honeywell Int’l Inc. v. Mexichem
Amanco Holding SA, 865 F.3d 1348, 1358 (Fed. Cir.
ICOS CORPORATION   v. ACTELION PHARMACEUTICALS, LTD.      9

2017), here, the Board did not rely on a new ground of
rejection not previously raised. Although Actelion cited
Banker for a different proposition, the Board relied on
Banker to support a finding responding to ICOS’ late-
raised interpretation of Wadke.
    ICOS argues the Board raised new arguments to side-
step Seth’s teaching away from micronization. In this
case, the Board did not err in considering the testimony of
ICOS’ expert Dr. Byrn in determining that read as a
whole, Seth did not teach away. The Board was free to
consider this rebuttal evidence.
                        CONCLUSION
    Based on the Board’s findings that each limitation
was in the prior art, the prior art provided a motivation to
combine these elements in the manner claimed, and there
was a reasonable expectation of success in doing so, we
see no error in the Board’s conclusions of obviousness. We
have considered ICOS’ remaining arguments and find
them unpersuasive. We therefore affirm the Board’s
conclusion that claims 1–32 of the ’958 patent and claims
1–11 of the ’975 patent would have been obvious over
Daugan, Butler, Seth, and Wadke. The judgments of the
Board are affirmed.
                       AFFIRMED