  United States Court of Appeals
      for the Federal Circuit
                ______________________

    LEO PHARMACEUTICAL PRODUCTS, LTD.
                Appellant,

                           v.

    Teresa Stanek Rea, ACTING DIRECTOR,
   UNITED STATES PATENT AND TRADEMARK
                   OFFICE,
                    Appellee.
             ______________________

                      2012-1520
                ______________________

    Appeal from the United States Patent and Trademark
Office, Board of Patent Appeals and Interferences in No.
95/000,153.
                 ______________________

               Decided: August 12, 2013
                ______________________

    WILLIAM E. SOLANDER, Fitzpatrick, Cella, Harper &
Scinto, of New York, New York, argued for appellant. On
the brief were ANDREW D. MEIKLE , LEONARD R. SVENSSON
and EUGENE T. PEREZ, Birch, Stewart, Kolasch & Birch,
LLP, of Falls Church, Virginia.

    AMY J. NELSON, Associate Solicitor, United States Pa-
tent & Trademark Office, of Alexandria, Virginia, argued
for appellee. With her on the brief was FRANCES M.
2                      LEO PHARMACEUTICAL PRODUCTS    v. REA

LYNCH, Associate Solicitor. Of counsel was NATHAN K.
KELLEY, Deputy Solicitor.
                ______________________

        Before RADER, Chief Judge, O’MALLEY, and REYNA,
                       Circuit Judges.
RADER, Chief Judge.
    This appeal arises from an inter partes reexamination
of U.S. Patent No. 6,753,013 (the ’013 patent). The ’013
patent is owned by Leo Pharmaceutical Products, Ltd.
(Leo Pharmaceuticals) and challenged by third party
requester Galderma R&D. While the “substantial evi-
dence” standard of review for fact findings made by the
Board of Patent Appeals and Interferences (Board) 1
makes Leo Pharmaceutical’s burden on appeal a challeng-
ing one, after careful review, this court finds that Leo
Pharmaceuticals has met that burden. Because the
Board incorrectly construed the claim term “storage
stable,” this court reverses the Board’s claim construction.
See Ex parte Leo Pharm. Prods., Ltd., No. 2012-003165
(B.P.A.I. Apr. 30, 2012). Furthermore, because the Board
incorrectly found the claimed invention would have been
obvious in view of the prior art and incorrectly weighed
the objective indicia of nonobviousness, this court reverses
the Board’s obviousness determination.
                             I.
   This case concerns pharmaceutical compositions for
the topical treatment of certain skin conditions, e.g.,



    1 Under the Leahy-Smith America Invents Act, Pub.
L. No. 112-29 § 7(a)(1), 125 Stat. 284, 313 (2011), the
Board changed its name from the Board of Patent Appeals
and Interferences to the Patent Trial and Appeal Board.
This court uses the prior designation for consistency with
the decision below.
LEO PHARMACEUTICAL PRODUCTS    v. REA                      3

psoriasis. See ’013 patent col. 1, ll. 8–10, 19–25. Psoriasis
can be a painful and socially debilitating disease. The
prior art discloses that psoriasis is commonly treated
through a combination treatment of: (1) a vitamin D
analog and (2) a corticosteroid. ’013 patent col. 1, ll. 23–
26.
     The ’013 patent teaches that simultaneous treatment
with vitamin D and corticosteroids can heal psoriasis
faster and more effectively. ’013 patent col. 9, ll. 1–11.
However, according to the ’013 patent, a storage stable
combination of vitamin D and corticosteroids in a single
formulation did not exist in the prior art. ’013 patent col.
1, ll. 29–31. The ’013 patent teaches that previous combi-
nation formulations were not storage stable because
vitamin D and corticosteroids have divergent pH re-
quirements for optimum stability. ’013 patent col. 1, ll.
31–36. Specifically, vitamin D analogs require basic
environments with a higher pH value (above 8) for opti-
mal stability, but corticosteroids are most stable in acidic
environments with a lower pH value (in the range of 4–
6). ’013 patent col. 1, ll. 48–53. Because of the storage
stability problem, physicians had to prescribe a two-drug
regimen that required patients to apply one drug in the
morning and another at night. ’013 patent col. 1, ll. 61–
67. This two-drug regimen generated patient compliance
issues.
    After recognizing the storage stability problem, Leo
Pharmaceuticals began testing formulations that com-
bined vitamin D analogs and corticosteroids. In testing
formulations from the prior art, Leo Pharmaceuticals
found that several ingredients—including almond oil,
propylene glycol, and water—did not solve the problem.
See J.A. 566–68 (aqueous alcohol-based solvents); J.A.
561–63, 570 (propylene glycol and almond oil). Leo
Pharmaceuticals then discovered that a new set of sol-
vents, including polyoxypropylene 15 stearyl ether (POP-
15-SE), solved the storage stability problem by allowing
4                      LEO PHARMACEUTICAL PRODUCTS       v. REA

the vitamin D analog and the corticosteroid to coexist in a
single pharmaceutical product.
    The ’013 patent claims a pharmaceutical composition
comprising three components: a category A component
(vitamin D analog); a category B component (corticoster-
oid); and a category C solvent. ’013 patent col. 12, ll. 23–
53. As amended during reexamination, independent
claim 1 is representative:
    1. A pharmaceutical composition for dermal use,
    said composition comprising:
    a first pharmacologically active component A con-
    sisting of at least one vitamin D analogue selected
    from the group consisting of seocalcitol, calcipotri-
    ol, calcitriol, tacalcitol, maxacalcitol, paricalcitol,
    falecalcitriol,    1α,24S-dihydroxy-vitamin        D2,
    1(S),3(R)-dihydroxy-20(R)-[((3-(2-hydroxy-2-
    propyl)-phenyl)-methoxy)-methyl]-9,10-seco-
    pregna-5(Z),7(E),10(19)-triene      and     mixtures
    thereof; and
    a second pharmacologically active component B
    consisting of at least one corticosteroid, wherein
    the difference between the maximum stability pH
    of said first component A and the maximum sta-
    bility pH of said second component B is at least 1;
    and
    at least one solvent component C selected from the
    group consisting of:
        (i) compounds of the general formula
        R3(OCH2C(R1)H)xOR2 (I) wherein x is in
        the range of 2-60, R1 in each of the x units
        is CH3, R2 is straight chain or branched
        C1-20 alkyl or benzoyl, and R3 is H or phe-
        nylcarbonyloxy;
        (ii) straight or branched C2-4-alkyl esters
        of straight or branched C10-18-alkanoic or -
        alkenoic acids;
LEO PHARMACEUTICAL PRODUCTS    v. REA                      5

        (iii) propyleneglycol diesters with C8-14-
        alkanoic acids; and
        (iv) branched primary C18-24 alkanols,
    wherein said pharmaceutical composition is stor-
    age stable and non-aqueous.
J.A. 3867 (emphases added).
    Among other changes, Leo Pharmaceuticals amended
claim 1 during reexamination to include the phrase
“wherein said pharmaceutical composition is storage
stable and non-aqueous.” J.A. 3867. Leo Pharmaceuti-
cals also added new claims 24–148, and amended and
canceled other claims. Leo Pharmaceuticals contends
that the commercial embodiment of the ’013 patent, as
amended, is the Taclonex® ointment.
    The Board construed the term “storage stable” and
“non-aqueous.” J.A. 6. Then the Board—relying on the
examiner’s findings—rejected the claims of the ’013
patent as obvious over three prior art references: U.S.
Patent No. 4,083,974 (Turi); U.S. Patent No. 4,610,978
(Dikstein); and WO 94/13353 (Serup). J.A. 9.
    Turi was filed in 1977 and is titled “Topical Steroidal
Anti-Inflammatory Preparations Containing Polyoxypro-
plyene 15 Stearyl Ether.” Turi discloses pharmaceutical
compositions comprising a steroid contained within a
solvent, POP-15-SE, but it does not teach the use of
vitamin D. Turi col. 1, ll. 58–63. Turi specifically disclos-
es that the claimed invention does not contain water, gels,
or alcohols. Turi col. 1, ll. 24–38. Instead, Turi discloses
the use of POP-15-SE as “well known to those skilled in
the art of formulating and compounding topical ointment
like compositions and preparations.” Turi col. 4, ll. 5–9.
Turi teaches that POP-15-SE is antifungal, antibacterial,
nonirritating, and lubricating. Turi col. 2, ll. 12–16. Turi
further teaches that while these properties are not suffi-
cient to provide therapeutic value, they are useful because
they render additional preservatives unnecessary. Turi
6                      LEO PHARMACEUTICAL PRODUCTS     v. REA

col. 2, ll. 18–30. Turi’s claimed invention thereby reduces
exposure of tissue to chemical compounds and reduces
manufacturing costs. Turi col. 2, ll. 18–30. Turi address-
es neither stability concerns from combining vitamin D
analogs and corticosteroids, nor the use of POP-15-SE or
corticosteroids for the treatment of psoriasis.
    The second prior art reference, Dikstein, was filed in
1984 and is titled “Compositions Containing 1α-
Hydroxycholecalciferol for Topical Treatment of Skin
Disorders and Methods Employing Same.”               Dikstein
discloses dermatological compositions, including creams,
ointments, and lotions, comprising a vitamin D analog
and a corticosteroid. Dikstein col. 3, ll. 4–48. Dikstein
teaches that vitamin D can treat psoriasis and that corti-
costeroids have side effects, but it does not teach using
vitamin D to treat the side effects of corticosteroids.
Dikstein col. 1, ll. 26–36; col. 2, ll. 55–60. Every example
composition in Dikstein contains almond oil or propylene
glycol and several also contain water. Dikstein col. 9, l.
40–col. 11, l. 60. Yet, Dikstein does not disclose or recog-
nize the storage stability problems associated with using
water, almond oil, or propylene glycol in the combination
formulations. Nor does Dikstein disclose the use of POP-
15-SE or any other solvent that could solve the storage
stability concerns.
     The third prior art reference, Serup, was filed in 1993
and is titled “Hydroxy Vitamin D3 Compounds for Treat-
ing Skin Atrophy.” Serup describes a composition con-
taining a vitamin D analog and a steroid. Serup col. 1, ll.
7–13. Serup further teaches the use of vitamin D analogs
to treat skin atrophy, a well-known side effect of steroid
treatment. Serup col. 1, ll. 14–15; col. 2, ll. 8–10. Atrophy
is associated with reduced skin thickness—vitamin D can
prevent atrophy and normalize skin thickness. Serup col.
3, ll. 3–6. Although Serup describes the benefits of using
vitamin D to treat steroid-induced atrophy, Serup does
not address any storage stability concerns associated with
this combination. While Serup teaches that preparations
LEO PHARMACEUTICAL PRODUCTS     v. REA                      7

may include “creams, ointments, pastes, or gels,” every
example composition disclosed in Serup is aqueous,
containing either purified or hot water. Serup col. 19, l.
34–col. 23, l. 15. Every example also contains almond oil,
propylene glycol, or alcohol. Serup col. 19, l. 34–col. 23, l.
15. Thus, Serup does not recognize the stability problems
associated with using water, almond oil, or propylene
glycol in the combination formulations. Nor does Serup
disclose the use of POP-15-SE or any other solvent that
could solve the storage stability concerns.
    Based on these three prior art references, the Board
rejected claims 1, 2, 4–8, 14, 16–19, 21, 23, 39–91, and
143–146 of the ’013 patent as obvious under 35 U.S.C.
§ 103(a). J.A. 19. The Board relied on Turi as the prima-
ry reference because Turi disclosed a category B cortico-
steroid and a category C solvent. J.A. 4. The Board then
used Serup or Dikstein with Turi to reject various de-
pendent claims concerning different vitamin D analogs.
J.A. 9–14, 19–22.
    Regarding the combination of Turi with Serup, the
Board found that the reason for combining them was “for
the [Turi] solvent’s advantages and ‘to obtain a more
effective preparation without the potential of causing skin
atrophy.’” J.A. 10 (quoting the examiner’s reasoning).
According to the Board, because both Serup and Turi
describe compositions with corticosteroids, an artisan
would have found the two references reasonably pertinent
for the “same type of compositions with the same thera-
peutic purpose.” J.A. 10. The Board concluded that
adding vitamin D to Turi “would have been obvious to
address the well-known side effects of topical steroid
treatment.” J.A. 10–11. The Board also found that be-
cause Serup discloses selecting ingredients that are
“compatible” and “not deleterious,” an artisan would have
been familiar with selecting components by routinely
“picking and choosing” from a list to achieve a compatible
and non-deleterious preparation. J.A. 12.
8                     LEO PHARMACEUTICAL PRODUCTS    v. REA

    Regarding the combination of Turi with Dikstein, the
Board found that Dikstein “teaches the benefit of combin-
ing a vitamin D analog with a corticosteroid to achieve
more complete skin healing,” which was a reason to add a
vitamin D analog to Turi’s corticosteroid treatment. J.A.
22. The Board further concluded that the analysis for
Serup also applied to Dikstein. J.A. 19–21.
     The Board acknowledged that Leo Pharmaceuticals
provided “extensive experimental evidence” that water,
alcohol, and propylene glycol cause unacceptable degrada-
tion of vitamin D and steroid compositions. J.A. 14.
However, the Board found that Turi provided explicit
guidance to exclude these ingredients. J.A. 13. Specifi-
cally, the Board found that Turi excluded water, alcohol,
and propylene glycol; taught that propylene glycol is
“irritating to the skin” and “a nonlubricant;” and taught
that POP-15-SE solved the problems associated with
propylene glycol. J.A. 13 (quoting Turi col. 1, ll. 55–58).
The Board also concluded that because Serup uses al-
mond oil, but does not teach that almond oil is necessary,
an artisan, at the time of the claimed invention, would
have considered both compositions excluding or including
almond oil to be obvious. J.A. 13–14, 23.
     Addressing the objective indicia of nonobviousness,
the Board found that the objective indicia did not over-
come a prima facie case of obviousness. J.A. 15–17. The
Board acknowledged that the claimed compositions were
“adequately shown to be more storage stable than compo-
sitions formulated with certain ingredients that had been
used in the prior art, such as water,” “propylene glycol,”
and “alcohol.” J.A. 15. However, the Board concluded
that the “unexpected results” claimed by Leo Pharmaceu-
ticals were not unexpected because Turi “provided explicit
reason to use POP-15-SE as a solvent.” J.A. 18–19.
Therefore, the Board found that Leo Pharmaceuticals “did
not establish that the improvement observed was unex-
pected to one of ordinary skill in the art in view of the
strong reason to have utilized POP-15-SE.” J.A. 19. Even
LEO PHARMACEUTICAL PRODUCTS        v. REA                  9

though the Board found that Turi did not teach POP-15-
SE as a solvent to allow “vitamin D and corticosteroid to
coexist,” the Board nonetheless concluded that “the reason
for utilizing the solvent does not have to be the same
reason [the solvent] was employed by the inventors.” J.A.
17 (citing KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 419–
20 (2007)).
                             II.
    This court reviews claim construction without defer-
ence. Cybor Corp. v. FAS Techs., Inc., 138 F.3d 1448,
1455–56 (Fed. Cir. 1998) (en banc). “During reexamina-
tion, as with original examination, the PTO must give
claims their broadest reasonable construction consistent
with the specification.” In re Suitco Surface, Inc., 603
F.3d 1255, 1259 (Fed. Cir. 2010).
    For claim construction, the portion of the representa-
tive claim at issue reads:
    1. A pharmaceutical composition for dermal use,
    said composition comprising . . . [components A, B,
    & C] . . . wherein said pharmaceutical composition
    is storage stable and nonaqueous.
J.A. 3867 (emphasis added) (claim 1 of the ’013 patent as
amended during reexamination).
    Although the claim term, “storage stable” is not de-
fined in the ’013 patent, the specification teaches a com-
bination composition of a vitamin D analog, a
corticosteroid, and a component C solvent, coexisting
“without degradation.” ’013 patent col. 8, ll. 1–6. The
Board construed “ability to resist degradation”—even
though “ability to resist degradation” is not a claim
term—to denote “that the composition is stable, i.e., not
changing or fluctuating because it doesn’t significantly
degrade.”       J.A.   6    (citing   http://www.merriam-
webster.com/stable).
    The Board then adopted a disclosure in the specifica-
tion to define “storage stable.” J.A. 6–7. Example two
10                      LEO PHARMACEUTICAL PRODUCTS      v. REA

discloses an accelerated chemical stability test “after
storage for one month at 40ºC and three months at 25ºC
and 40ºC, respectively.” ’013 patent col. 10, ll. 54–56.
This test “describes a specific stability test to determine
the chemical stability of a composition comprising all
three components stored for a period of time.” J.A. 6; see
also ’013 patent col. 10, l. 50–col. 11, l. 56. The Board
adopted this test because one of ordinary skill “would
have reasonably looked to the described stability test as
defining what was meant by ‘storage stable.’” J.A. 6–7.
    At the outset, the Board’s construction of “storage
stable” is impermissibly narrow because example two is
just one disclosure of an accelerated stability test. Under
its accepted and customary meaning, “storage stable”
would include a composition that maintains its stability
during its shelf life for its intended use as an approved
pharmaceutical product for sale and home use by ordinary
customers. See Appellant’s Br. 30.
    The Board erred by narrowing the definition of “stor-
age stable” to something far short of its broadest reasona-
ble meaning. The plain meaning of “storage stable” is
broader than the disclosure in example two.
    Accordingly, this court vacates the Board’s construc-
tion. Because it is unnecessary for this court to adopt a
specific alternative construction to resolve this appeal,
this court declines to do so, leaving that question to a
later forum where the issue is determinative.
                              III.
     Obviousness is a question of law based on under-
     lying findings of fact. An analysis of obviousness
     must be based on several factual inquiries: (1) the
     scope and content of the prior art; (2) the differ-
     ences between the prior art and the claims at is-
     sue; (3) the level of ordinary skill in the art at the
     time the invention was made; and (4) objective ev-
     idence of nonobviousness, if any.
LEO PHARMACEUTICAL PRODUCTS       v. REA                   11

    In re Kubin, 561 F.3d 1351, 1355 (Fed. Cir. 2009); see
also Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966).
This court reviews the Board’s fact findings for substan-
tial evidence. In re Mouttet, 686 F.3d 1322, 1330 (Fed.
Cir. 2012). Based on the underlying fact findings, wheth-
er a claimed invention would have been obvious under 35
U.S.C. § 103(a) is a question of law reviewed de novo. Id.
    As the Board acknowledges, this record does not pre-
sent unresolved issues of fact. J.A. 9. Thus, at bottom,
this court confronts a question of law: whether, in light of
the prior art references and objective indicia of nonobvi-
ousness, the claimed invention would have been obvious
to a person of ordinary skill in the art at a time just before
the time of invention.
                             A.
    Relying on Turi, Dikstein, and Serup, the Board con-
cluded that “a skilled worker familiar with a wide range
of possible ingredients to incorporate into a composition
comprising a steroid and vitamin D analog” would have
arrived at the ’013 patent’s claimed invention. J.A. 14.
    The ’013 patent, however, is not simply a combination
of elements found in the prior art. The inventors of
the ’013 patent recognized and solved a problem with the
storage stability of certain formulations—a problem that
the prior art did not recognize and a problem that was not
solved for over a decade.
    As an initial matter, an invention can often be the
recognition of a problem itself. See Cardiac Pacemakers,
Inc. v. St. Jude Med., Inc., 381 F.3d 1371, 1377 (Fed. Cir.
2004) (“There can of course arise situations wherein
identification of the problem is itself the invention.”).
Here, the prior art either discouraged combining vitamin
D analogs and corticosteroids in a single formulation, or
attempted the combination without recognizing or solving
the storage stability problems associated with the combi-
nation.
12                    LEO PHARMACEUTICAL PRODUCTS    v. REA

     During reexamination, Leo Pharmaceuticals present-
ed several medical research articles published as early as
1995 discouraging the combination of a vitamin D analog
with a corticosteroid because of the stability problems of
vitamin D analogs at lower pHs. See J.A. 612 (Knud
Kragballe, Vitamin D3 Analogues, 13 DERMATOLOGICAL
CLINICS 835, 838 (1995)); J.A. 6237 (Mark G. Lebwohl,
The Evolution of Vitamin D Analogs for the Treatment of
Psoriasis, ARCHIVES OF DERMATOLOGY, 285 (Nov. 1995)).
These articles taught away from mixing topical vitamin D
formulations with other drugs. See, e.g., J.A. 612. Even
though studies in the prior art compared the effectiveness
of treating psoriasis with vitamin D versus corticosteroid,
those studies did not describe combining the two into one
formulation. See id. Researchers noted that it was “only
natural” for clinicians to attempt to try combinations of
vitamin D with other ingredients, but warned that vita-
min D should not be combined with other drugs requiring
a low pH (e.g., corticosteroids). See J.A. 6237. These
researchers recognized possible advantages from combin-
ing a vitamin D treatment with topical corticosteroids,
but nevertheless they recommended a two-drug regimen
where patients applied the drugs at different times of a
day or on alternating days. See id.
    Although Dikstein and Serup attempt the combina-
tion of a vitamin D analog with a corticosteroid, neither
discloses or addresses the stability problems of combining
vitamin D analogs and corticosteroids into one pharma-
ceutical formulation. As evidenced by the experiments
Leo Pharmaceuticals conducted, the prior art does not
teach any composition that exhibits storage stable proper-
ties. Every example disclosed in Dikstein contains either
almond oil or propylene glycol. Similarly, the examples
disclosed in Serup contain not only water, but also al-
mond oil, alcohol, or propylene glycol.
    Leo Pharmaceuticals presented experimental evi-
dence to the Board that each of these ingredients harmed
the storage stability of the vitamin D analog and cortico-
LEO PHARMACEUTICAL PRODUCTS    v. REA                     13

steroid combination. See J.A. 562–64, 570 (Hoy Decls.
discussing propylene glycol and almond oil); J.A. 566–68
(Didriksen Decl. discussing aqueous alcohol-based sol-
vents). For example, the use of propylene glycol as a
solvent resulted in 100% degradation of the vitamin D
analog. J.A. 562–564, 692–702. Similarly, the use of
aqueous solvents resulted in almost complete degradation
of the vitamin D analog after three months of storage—
98.3% degradation in one formulation and 100% degrada-
tion in another. J.A. 710–16, 1025–26. And, when al-
mond oil was used as a solvent, vitamin D analogs
degraded 13–29% after three months of storage. J.A. 570,
723–24. The vitamin D analogs were not the only compo-
nents at risk for degradation. When commercial oint-
ments with vitamin D analogs or corticosteroids were
combined, one corticosteroid degraded by 10% after four
weeks and another degraded by almost 50% within 24
hours. J.A. 563; see also J.A. 723–24 (range of 5–12%
corticosteroid degradation after 6 months of storage in
combination with a vitamin D analog).
    Moreover, because neither Dikstein nor Serup recog-
nized or disclosed the stability problem, the record shows
no reason for one of ordinary skill in the art to attempt to
improve upon either Dikstein or Serup using Turi. The
ordinary artisan would first have needed to recognize the
problem, i.e., that the formulations disclosed in Dikstein
and Serup were not storage stable. To discover this
problem, the ordinary artisan would have needed to spend
several months running storage stability tests. See ’013
patent col. 10, l. 50–col. 11, l. 56; see also J.A. 545, 563–
68. Only after recognizing the existence of the problem
would an artisan then turn to the prior art and attempt to
develop a new formulation for storage stability. If these
discoveries and advances were routine and relatively
easy, the record would undoubtedly have shown that some
ordinary artisan would have achieved this invention
within months of Dikstein or Serup. Instead this inven-
tion does not appear for more than a decade.
14                    LEO PHARMACEUTICAL PRODUCTS     v. REA

     Although the Board acknowledges “compositions with-
in the scope of the [’013 patent claims] were adequately
shown to be more storage stable than compositions formu-
lated with certain ingredients that had been used in the
prior art,” the Board went on to find this evidence insuffi-
cient “to overcome the strong case of obviousness.” J.A.
15. By brushing aside the storage stability issue, the
Board erred by collapsing the obviousness analysis into a
hindsight-guided combination of elements. This record,
however, discloses several reasons that a person of ordi-
nary skill in the art would not have been motivated to try,
let alone make, the claimed invention of the ’013 patent.
    First, the Board found motivation to combine Dikstein
or Serup with Turi because one of ordinary skill would
have used vitamin D to solve the well-known side effects
of steroid treatment. However, combining Turi and
vitamin D to address the side effects of a steroid treat-
ment is only straightforward in hindsight. Turi was
publicly available in the prior art for twenty-two years
before the ’013 patent was filed, yet there is no evidence
that anyone sought to improve Turi with vitamin D.
According to the record, even when Serup published the
well-known side effects of steroid-induced atrophy in
1994, no one—including Serup—sought to improve Turi
by adding vitamin D to Turi’s corticosteroid composition.
Serup even targeted the precise side effects that the
Board believed would have motivated the addition of a
vitamin D analog to Turi’s corticosteroid composition, yet
Serup did not seek to improve Turi by adding vitamin D.
    Moreover, focusing on the “non-aqueous” claim ele-
ment, the Board found “there was a strong reason to have
made a non-aqueous composition with POP-15-SE.” J.A.
15. The Board believed an artisan would have “add[ed]
the Vitamin D analog of Serup [or Dikstein] to Turi’s
POP-15-SE containing steroid composition for the sol-
vent’s advantages and to obtain a more effective steroid
preparation.” J.A. 10 (internal quotations marks omit-
ted). However, substantial evidence does not support the
LEO PHARMACEUTICAL PRODUCTS      v. REA                      15

Board’s finding that an ordinary artisan would have
deviated from the aqueous composition of Serup or the
composition of Dikstein—plucking the vitamin D analog
from those two references and incorporating the analog
into Turi. The Board found that statements in Turi
exclude the solvents used by Serup and Dikstein. J.A. 13
(“Turi provides explicit guidance to exclude water, alcohol,
and propylene glycol . . . .”). Thus, Turi’s guidance actual-
ly teaches away from the Board’s posited combination or,
at a minimum, provides no evidence of motivation to
combine Turi with those prior solvents.
     For example, Turi distinguishes its compositions from
aqueous compositions: “The pharmaceutical compositions
of the present invention contain no water.” Turi col. 1, ll.
26–27. Indeed, all of Turi’s examples are non-aqueous.
Turi col. 8, l. 40–col. 10, l. 54. Yet, Serup’s list of prepara-
tions are all aqueous, Serup col. 19, ll. 5–9, and Serup’s
examples are all aqueous, Serup col. 19, l. 34–col. 24, l.
17. Similarly, Dikstein discloses that dermatological
creams are preferably formulated with, among other
ingredients, water. Dikstein col. 3, ll. 14–26. And, five of
Dikstein’s examples include water. Dikstein col. 9, l. 40–
col. 11, l. 21.
     Moreover, Turi specifically disclaims the use of pro-
pylene glycol because of its “very undesirable qualities
from a pharmacological point of view.” Turi col. 1, ll. 24–
61. Despite Turi’s teaching away from that solvent, four
of Dikstein’s examples, Dikstein Exs. 7, 8, 15, 16, and five
of Serup’s examples, Serup Exs. 4–8, involve propylene
glycol. Further, Dikstein discloses that propylene glycol
is a convenient solvent in the preparation of dermatologi-
cal lotions. Dikstein col. 3, ll. 14–26.
    Even with the differing solvents taught by the prior
art, the Board explained that, because Turi provided a
reason to exclude water and propylene glycol, POP-15-SE
would have been a logical non-aqueous choice to use for
improving upon Serup and Dikstein. However, Serup
“surprisingly observed that certain vitamin D analogues
16                     LEO PHARMACEUTICAL PRODUCTS     v. REA

can prevent and/or treat skin atrophy induced by topical
steroid treatment.” Serup col. 2, ll. 8–10. Similarly, when
Dikstein combined a corticosteroid and vitamin D analog,
it noted that “[s]urprisingly” the combination “led to more
complete healing.” Dikstein col. 6, ll. 48–54. With sur-
prisingly successful results, an ordinary artisan would not
have been motivated to change the solvents Serup or
Dikstein relied upon and use the different solvent dis-
closed in Turi.
    Thus, in the face of such divergent compositions with
express disclaimers of the other’s contents, the record
showing that Turi, Serup, and Dikstein describe composi-
tions for the same therapeutic purpose does not rise to the
level of a motivation to combine. Without more, and
especially in the face of such strong objective indicia of
nonobviousness discussed infra, the Board erred by using
hindsight to determine that the addition of Serup’s or
Dikstein’s vitamin D analog to Turi’s formulation would
have been obvious.
    In addition, the Board found that a person of ordinary
skill in the art would have been capable of selecting the
correct formulation from available alternatives. J.A. 12.
Specifically, the Board found more than eight different
classes of additives (e.g., diluents, buffers, thickeners,
lubricants). J.A. 12; Serup col. 19, ll. 10–15. The Board
also found more than ten different categories of composi-
tion forms (e.g., liniments, lotions, applicants, oil-in-water
or water-in-oil emulsions such as creams, ointments,
pastes, or gels). J.A. 12; Serup col. 19, ll. 5–9. “Based on
these broad and general disclosures,” the Board reasoned
that an artisan would have been able to “mak[e] choices
about what ingredients to include, and which to exclude”
in formulating a composition with a vitamin D analog and
steroid. J.A. 12. To the contrary, the breadth of these
choices and the numerous combinations indicate that
these disclosures would not have rendered the claimed
invention obvious to try. See Rolls-Royce PLC v. United
Techs. Corp., 603 F.3d 1325, 1339 (Fed. Cir. 2010)
LEO PHARMACEUTICAL PRODUCTS    v. REA                     17

(claimed invention was not obvious to try because the
prior art disclosed a “broad selection of choices for further
investigation”).
    The ’013 patent’s claimed combination would not have
been obvious to try. “[W]here the prior art, at best gives
only general guidance as to the particular form of the
claimed invention or how to achieve it, relying on an
obvious-to-try theory to support an obviousness finding is
impermissible.” In re Cyclobenzaprine Hydrochloride
Extended-Release Capsule Patent Litigation, 676 F.3d
1063, 1073 (Fed. Cir. 2012) (internal citations and quota-
tion marks omitted). Further, “KSR did not create a
presumption that all experimentation in fields where
there is already a background of useful knowledge is
‘obvious to try,’ without considering the nature of the
science or technology.” Abbot Labs. v. Sandoz, Inc., 544
F.3d 1341, 1352 (Fed. Cir. 2008).
    Here, the “background of useful knowledge”—
including the prior art relied on by the Board—was pub-
lished decades before the ’013 patent: Turi issued in
1978, Dikstein issued in 1986, and Serup was published
in 1994. The elapsed time between the prior art and
the ’013 patent’s filing date evinces that the ’013 patent’s
claimed invention was not obvious to try. Indeed this
considerable time lapse suggests instead that the Board
only traverses the obstacles to this inventive enterprise
with a resort to hindsight. It took over a decade—after
Dikstein’s disclosure of the benefits of combining vitamin
D and corticosteroid treatments into one formulation—for
Dikstein’s formulations to be tested for storage stability.
And, until the advancement made by the inventors of
the ’013 patent, no one had proposed a new formulation
that would be storage stable. The problem was not
known, the possible approaches to solving the problem
were not known or finite, and the solution was not pre-
dictable. Therefore, the claimed invention would not have
been obvious to try to one of ordinary skill in the art.
18                     LEO PHARMACEUTICAL PRODUCTS     v. REA

Indeed ordinary artisans would not have thought to try at
all because they would not have recognized the problem.
    And, even if it was obvious to experiment with these
options, “there is nothing to indicate that a skilled artisan
would have had a reasonable expectation that such an
experiment would succeed in being therapeutically effec-
tive.” See Cyclobenzaprine, 676 F.3d at 1070. There is no
indication in the prior art which of these possible formula-
tions would be the most promising to try. And, according
to the ’013 patent, the storage stability of these formula-
tions cannot be determined based on a few days of work—
testing would likely take one to three months per formu-
lation. See ’013 patent col. 10, l. 50–col. 11, l. 55. Without
a reasonable expectation of success or clues pointing to
the most promising combinations, an artisan could have
spent years experimenting without success.
    This court and obviousness law in general recognizes
an important distinction between combining known
options into “a finite number of identified, predictable
solutions,” KSR, 550 U.S. at 421, and “‘merely throwing
metaphorical darts at a board’ in hopes of arriving at a
successful result,” Cyclobenzaprine, 676 F.3d at 1071
(quoting In re Kubin, 561 F.3d at 1359). While the record
shows that, as early as 1995, the prior art indicated that
both vitamin D analogs and corticosteroids were effective
treatments for psoriasis, see J.A. 610, 6237, that same
prior art gave no direction as to which of the many possi-
ble combination choices were likely to be successful.
Instead, the prior art consistently taught away from
combining vitamin D analogs and corticosteroids.
    This court recognizes that the record need only supply
“substantial evidence” to support the Board’s finding. In
re Gartside, 203 F.3d 1305, 1316 (Fed. Cir. 2000). In this
case, however, with no material factual disputes, this
court cannot share the Board’s analysis and application of
the law to those facts. In light of the lack of expectation of
a successful result, the failure of the prior art to provide
direction, and the substantial number of intervening
LEO PHARMACEUTICAL PRODUCTS      v. REA                  19

years between the publication of the prior art and the ’013
patent’s filing date, this invention is not simply a case of
“‘picking and choosing’ from a list in order to achieve a
compatible and non-deleterious preparation” as the Board
suggests. J.A. 12. Because the problem was not known,
the possible approaches to solving the problem were not
known or finite, and the solution was not predictable, it
would not have been obvious for a person of ordinary skill
to make the claimed invention.
                            B.
     The court now turns to the Board’s analysis of the ob-
jective indicia of nonobviousness. The Board reasoned
that “the strong case of obviousness outweighs the exper-
imental evidence and testimony about the advantages of
the claimed composition.” J.A. 17. Contrary to the
Board’s conclusion, this court finds the objective indicia,
in concert with the entire obviousness analysis, present a
compelling case of nonobviousness. In fact, the objective
indicia of nonobviousness highlight that the Board’s
analysis regarding the combination of Serup or Dikstein
with Turi was colored by hindsight.
    Whether before the Board or a court, this court has
emphasized that consideration of the objective indicia is
part of the whole obviousness analysis, not just an after-
thought. See Cyclobenzaprine, 676 F.3d at 1075–76 (A
fact finder “may not defer examination of the objective
considerations until after the fact finder makes an obvi-
ousness finding.” (quoting Stratoflex, Inc. v. Aeroquip
Corp., 713 F.2d 1530 (Fed. Cir. 1983))). When an appli-
cant appeals an examiner’s objection to the patentability
of an application’s claims for obviousness, the PTO neces-
sarily has the burden to establish a prima facie case of
obviousness which the applicant then rebuts. In re
Mouttet, 686 F.3d at 1330. However, during inter partes
reexamination, the Board is reviewing evidence of obvi-
ousness—including objective indicia—submitted by two
adversarial parties for the claims of an issued patent.
Thus, the Board should give the objective indicia its
20                    LEO PHARMACEUTICAL PRODUCTS     v. REA

proper weight and place in the obviousness analysis, and
not treat objective indicia of nonobviousness as an after-
thought.
    Objective indicia of nonobviousness play a critical role
in the obviousness analysis. They are “not just a cumula-
tive or confirmatory part of the obviousness calculus but
constitute[] independent evidence of nonobviousness.”
Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc., 520 F.3d
1358, 1365 (Fed. Cir. 2008). This case illustrates a good
reason for considering objective indicia as a critical piece
of the obviousness analysis: Objective indicia “can be the
most probative evidence of nonobviousness in the record,
and enables the court to avert the trap of hindsight.”
Crocs, Inc. v. Int’l Trade Comm’n, 598 F.3d 1294, 1310
(Fed. Cir. 2010) (internal quotation marks omitted).
Here, the objective indicia of nonobviousness are crucial
in avoiding the trap of hindsight when reviewing, what
otherwise seems like, a combination of known elements.
    Unexpected results are useful to show the “improved
properties provided by the claimed compositions are much
greater than would have been predicted.” See In re Soni,
54 F.3d 746, 751 (Fed. Cir. 1995) (internal quotation
marks omitted). This record shows “extensive experi-
mental evidence” of unexpected results that contradict the
Board’s obviousness finding. J.A. 14. The Board conclud-
ed that the “unexpected results” claimed by Leo Pharma-
ceuticals were not surprising or unexpected. J.A. 19.
However, substantial evidence does not support the
Board’s conclusion.
    During reexamination, the inventors of the ’013 pa-
tent submitted test results that analyzed the Dikstein
and Serup formulations. The inventors found that the
formulations disclosed by Dikstein and Serup result in
significant degradation of the vitamin D analog and
corticosteroid. See J.A. 1041–46 (testing formulations in
Serup); J.A. 1625–27, 2152–2154 (testing formulations in
Dikstein). The inventors also tested an improvement of
Serup using Turi, by replacing Serup’s solvent with POP-
LEO PHARMACEUTICAL PRODUCTS    v. REA                     21

15-SE, and still found significant degradation of the
corticosteroid component. See J.A. 1045–46. These test
results are a strong indication that the ’013 patent’s
combination of known elements yields more than just
predictable results.
    In addition to evidence of unexpected results, Leo
Pharmaceuticals provided other objective indicia of non-
obviousness. For example, the commercial success of Leo
Pharmaceutical’s Taclonex® ointment is a testament to
the improved properties of the ’013 patent’s claimed
invention. Taclonex® is the first FDA-approved drug to
combine vitamin D and corticosteroids into a single for-
mulation for topical application. While FDA approval is
not determinative of nonobviousness, it can be relevant in
evaluating the objective indicia of nonobviousness. See
Knoll Pharm. Co., Inc. v. Teva. Pharm. USA, Inc., 367
F.3d 1381, 1385 (Fed. Cir. 2004). Here, FDA approval
highlights that Leo Pharmaceutical’s formulation is truly
storage stable, something that the prior art formulations
did not achieve.
    The record also shows evidence of long felt but un-
solved need, i.e., the need for a single formulation to treat
psoriasis. The length of the intervening time between the
publication dates of the prior art and the claimed inven-
tion can also qualify as an objective indicator of nonobvi-
ousness. See Ecolochem, Inc. v. S. Cal. Edison Co., 227
F.3d 1361, 1376–77 (Fed. Cir. 2000). Here, the research-
ers were aware of the benefits of using both vitamin D
and corticosteroids in the treatment of psoriasis as early
as 1986. See, e.g., Dikstein col. 1, ll. 9–16. And Turi,
upon which the Board relied to make its case, issued in
1978. Yet, it was not until the ’013 patent’s filing in
2000—twenty-two years after Turi and fourteen years after
Dikstein—that the solution to the long felt but unsolved
need for a combined treatment of vitamin D and cortico-
steroid was created. The intervening time between the
prior art’s teaching of the components and the eventual
22                    LEO PHARMACEUTICAL PRODUCTS    v. REA

preparation of a successful composition speaks volumes to
the nonobviousness of the ’013 patent.
    Here, the objective indicia—taken in sum—are the
most “probative evidence of nonobviousness . . . enabl[ing]
the court to avert the trap of hindsight.” Crocs, Inc., 598
F.3d at 1310. Viewed through the lens of the objective
indicia, as opposed to the hindsight lens used by the
Board, the ’013 patent would not have been not obvious
over Turi in combination with Dikstein or Serup. There-
fore, this court reverses the Board’s obviousness determi-
nation.
                           IV.
   For the foregoing reasons, this court reverses the
Board’s claim construction of the term “storage stable”
and its obviousness determination.
                      REVERSED
