By Kevin E. Noonan —

The Federal Circuit's jurisprudence
regarding obviousness as determined by the U.S. Patent and Trademark Office
continues its post-KSR development in Leo
Pharmaceutical Products, Ltd. v. Rea, which involves an obviousness
determination by the Office in an inter
partes reexamination.  The Court reversed the Office's obviousness rejection
as a matter of law as not being supported by the facts and for the Office's
failure to construe certain claims terms according to their broadest reasonable
meaning (ironic, in view of the Office's penchant to take that claim
construction rubric to extreme and unreasonable lengths).

The case involved U.S. Patent No.
6,753,013 owned by Leo Pharmaceutical Products that covers its Taclonex®
ointment product.  The product comprises
a combination of a corticosteroid and vitamin D or a vitamin D analog, used to
treat psoriasis and other skin ailments.  The prior art taught that these two drugs could be used to treat psoriasis
but prescribed individual topical application of the drugs at different times
(such as one in the morning and the other at night), a regimen that raised
patient compliance issues.  The basis of
Leo's invention was its discovery that that corticosteroids (that are stable at
a pH of about 4) and vitamin D or analogs (that are stable at a pH of about 8)
could be combined in stable, single formulation.  Leo's formulation combined the two drug
compounds with polyoxypropylene 15 stearyl ether (POP-15-SE), which was found
to provide conditions where both drug compounds were chemically stable.

Claim 1 of the '013 patent is
representative of Leo's claims at issue (emphasis added):

1.  A pharmaceutical composition for dermal use, said composition
comprising:
    a first pharmacologically active component
A consisting of at least one vitamin D analogue selected from the group
consisting of seocalcitol, calcipotriol, 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 stability 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 phenylcarbonyloxy;
        (ii) straight or branched C2-4-alkyl
esters of straight or branched C10-18-alkanoic or -alkenoic acids;
        (iii) propyleneglycol diesters with
C8-14-alkanoic
acids; and
        (iv) branched primary C18-24 alkanols,

wherein said pharmaceutical
composition is storage stable and non-aqueous.

The limitation that the pharmaceutical
composition was "storage stable and non-aqueous" was entered into the
claim during the reexamination, and the Board construed "storage stable"
to mean "non-aqueous."

Using this claim construction, the
Board found Leo's claims obvious over three references:

• U.S. Patent No. 4,083,974
(the Turi reference), which was filed in
1977 and taught pharmaceutical compositions comprising a steroid contained
within a solvent, POP-15-SE" (falling within the ambit of the excipients
in Leo's claims) but did not teach the combination with vitamin D.  This reference also expressly disclosed that the
formulations in the '974 patent did not contain "water, gels, or alcohols,"
and the benefits of using POP-15-SE to be that it "reduces exposure of
tissue to chemical compounds and reduces manufacturing costs."  There was no
disclosure regarding stability issues with a combination of corticosteroids and
vitamin D (which combinations were not disclosed) or for treating psoriasis.

• U.S. Patent No. 4,610,978 (the
Dikstein reference), which was filed in 1984 and taught topical preparations ("including
creams, ointments, and lotions") of the combination of a vitamin D analog
and a corticosteroid for treating psoriasis.  These formulations used water-based solvents including almond oil or
polypropylene glycol, and disclosed no recognition of storage stability
problems with these formulations.

• PCT WO 94/13353 (the Serup
reference), which was filed in 1994 and taught formulations ("creams,
ointments, pastes, or gels") comprising a vitamin D analog and a steroid
formulated under aqueous conditions that included almond oil, propylene glycol
or alcohols.  The reference noted
benefits of using vitamin D analogs to treat skin atrophy, which was recognized
as a side effect of steroid treatment.  There was no disclosure of storage stability issues with these
combinations in this reference.

The PTO applied the '974 patent as
the primary reference, which taught the use of POP-15-SE formulated
corticosteroids, combined with either the Dikstein or Serup references that
taught the vitamin D/corticosteroid combination.  According to the Board, the skilled artisan
would have been motivated to combine these teachings because they were directed
to compositions comprising corticosteroids and vitamin D, and the advantages of
adding vitamin D to corticosteroids for treating psoriasis was disclosed and
known in the art.  According to the
Board, any "invention" by the inventors involved merely "picking
and choosing" ingredients from a list of known ingredients and this was
obvious.  Turning to the distinction regarding stability introduced by amendment
during the reexamination, the Board found that evidence about stability was disclosed
in the '974 patent, which taught the skilled person to avoid aqueous components.  Finally, the Office rejected asserted Leo's objective
indicia of non-obviousness.  The
purported unexpected results that corticosteroids and vitamin D could be
combined was not surprising in view of '974 patent which taught formulations
comprising the component (POP-15-SE) that rendered the drug compounds
stable.  That the art did not teach
stability as a reason to use POP-15-SE didn't matter, "the Board
nonetheless conclud[ing] that 'the reason for utilizing the solvent does not
have to be the same reason [the solvent] was employed by the inventors'" (citing KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 419– 20 (2007)).  The Board also found that the compositions "ability
to resist degradation" (not, as noted by the Federal Circuit a recited
claim term) was enough to find that "that the composition is stable, i.e.,
not changing or fluctuating because it doesn't significantly
degrade."  The
Board found support for its definition of stability in one example in the '013
specification relating to a stability study performed on the claimed
formulation.

The Federal Circuit reversed, in an
opinion by Chief Judge Rader, joined by Judges O'Malley and Reyna.  The Court found fault with the Board's claim
construction related to the term "storage stable":

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.  . . .  The
Board erred by narrowing the definition of "storage stable" to something far
short of its broadest reasonable meaning.  The plain meaning of "storage stable"
is broader than the disclosure in example two.

This error was enough for the Court
to reverse the obviousness determination (although the opinion expressly
declines to independently construe the term), but went on to overturn the Board's
obviousness rejection.

The Court's opinion found fault with
the Board's application of the facts to the claims in its obviousness
assessment, and its disregard for the objective indicia of
non-obviousness.  Substantively, the
Court disagreed with the Board because the claims were "not simply a
combination of elements found in the prior art" because "[t]he
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."  This recognition of the problem to be solved
can be sufficient to be the invention
("As an initial matter, an invention can often be the recognition of a
problem itself," citing Cardiac Pacemakers, Inc. v. St. Jude Med., Inc.,
381 F.3d 1371, 1377 (Fed. Cir. 2004)).  In this case, "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 combination" in the Court's opinion.  Moreover, "several medical research
articles published as early as 1995 discourag[ed] the combination of a vitamin
D analog with a corticosteroid because of the stability problems of vitamin D
analogs at lower pHs," and "[t]hese articles taught away from mixing topical vitamin
D formulations with other drugs."  While the prior art taught that it would be "only
natural" for vitamin D to be combined with other drugs for treating
psoriasis, the prior art "warned that vitamin D should not be combined
with other drugs requiring a low pH (e.g., corticosteroids)."  The Court found that neither the Dikstein nor
Serup references recognized, disclosed, or addressed the stability problems that
arose using the formulations disclosed in those references that were identified
by patentee, which disclosure included experimental evidence that the prior art
references taught combinations that were not stable under storage conditions.  Because the prior art did not appreciate the stability
issues, it provided "no reason for one of ordinary skill in the art to
attempt to improve upon either [the formulations disclosed in] Dikstein or
Serup using [the teachings of the] Turi [reference]."

The primary deficiency noted by the
Court is that "[t]he ordinary artisan would first have needed to recognize
the problem, i.e., that the formulations disclosed in Dikstein and Serup were
not storage stable."  This would
take "several months [of] storage stability test[ing]" to establish,
and "[o]nly 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" (emphasis in opinion).  That isn't what happened; as noted by the
Court, recognition of the problem was not achieved "within months" of
the Dikstein or Serup references (which the Court says would be expected "[i]f
these discoveries and advances were routine and relatively easy"), but
instead took "more than a decade."  In view of this evidence, it was apparent to the Court that what the
Board viewed as a straightforward combination of the cited references was
instead a "hindsight-guided combination of elements."

The Court found that the record did
not support the Board's obviousness determination, based on the facts used by
the Board to support its position.  For
example, 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."  In the Court's view this was hindsight,
because "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."  "[E]ven 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," according to the opinion, even when Serup "targeted the
precise side effects that the Board believed would have motivated the addition
of a vitamin D analog to Turi's corticosteroid composition"; even Serup "did not seek to improve Turi
by adding vitamin D."  This
conclusion was further supported by evidence that the Turi reference taught
away from the combination formulations disclosed in the Serup and Dikstein
references, i.e., the aqueous formulations (which included water and propylene
glycol) those references disclose.

With regard to the disclosure in the
prior art of "broad and general disclosures" of additives ("e.g.,
diluents, buffers, thickeners, lubricants") and composition forms ("e.g.,
liniments, lotions, applicants, oil-in-water or water-in-oil emulsions such as
creams, ointments, pastes, or gels"), "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."  "To the
contrary," according to the Court, "the breadth of these choices and
the numerous combinations indicate that these disclosures would not have
rendered the claimed invention obvious to try" citing See Rolls-Royce
PLC v. United Techs. Corp., 603 F.3d 1325, 1339 (Fed. Cir. 2010).

The Court also did not find that
combining the '974 Turi patent with the Dikstein patent or Serup application
rendered the invention 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," said the Court, citing In re Cyclobenzaprine Hydrochloride
Extended-Release Capsule Patent Litigation, 676 F.3d 1063, 1073 (Fed. Cir.
2012).  [Further, the opinion asserts that] "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," citing Abbot Labs. v. Sandoz, Inc., 544 F.3d 1341,
1352 (Fed. Cir. 2008).

The passage of time between public
availability of the cited reference was also evidence for invention not being
obvious to try, according to the opinion:  "The length of the intervening
time between the publication dates of the prior art and the claimed invention
can also qualify as an objective indicator of nonobviousness," said the
Court, citing Ecolochem, Inc. v. S. Cal. Edison Co., 227 F.3d 1361,
1376–77 (Fed. Cir. 2000):

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.

Moreover, because the
"problem was not known, the possible approaches to solving the problem
were not known or finite, and the solution was not predictable.  Therefore, the
claimed invention would not have been obvious to try to one of ordinary skill
in the art.  Indeed ordinary artisans
would not have thought to try at all because they would not have recognized the
problem."  In addition, the Court
found there could have been no reasonable expectation of success in combining
the cited art, because in the absence of "clues pointing to the most
promising combinations, an artisan could have spent years experimenting without
success."

The opinion distinguished any
reading of the Supreme Court's KSR opinion to the contrary, stating that the
law "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).

Turning to the objective indicia,
the Court found that the Board erred in not considering evidence propounded by
patentee, citing its Cyclobenzaprine decision for the principal that "consideration of the
objective indicia is part of the whole obviousness analysis, not just an
after-thought."  The objective
indicia "play a critical role in the obviousness analysis" and are "not
just a cumulative or confirmatory part of the obviousness calculus but
constitute[] independent evidence of nonobviousness," citing Ortho-McNeil
Pharm., Inc. v. Mylan Labs., Inc., 520 F.3d 1358, 1365 (Fed. Cir. 2008).  The objective indicia "can be the most probative evidence of
nonobviousness in the record, and enables the court to avert the trap of
hindsight," citing Crocs, Inc. v. Int'l Trade Comm'n, 598 F.3d 1294, 1310
(Fed. Cir. 2010).

Here, the patentee had asserted unexpected results
over two of the cited prior art references (which had significant degradation), commercial
success, and long-felt but unfulfilled need in the art.  The Board rejected patentee's assertion of
unexpected results, on the grounds that the results obtained by Leo were not
unexpected in view of the disclosure of corticosteroid/vitamin D combinations
in the Dikstein and Serup references.  The Court disagreed, and found "'extensive
experimental evidence"" of unexpected results, including experimental
evidence reproducing the formulations disclosed in the Dikstein and Serup
references that demonstrated "significant degradation of the vitamin D
analog and corticosteroid."  These
results of instability were even found (for the corticosteroid) when the Serup
formulation was "improved" by the addition of POP-15-SE (i.e., the
combination resulting from the Board's combination of the references).

The Court cited Leo's evidence
for commercial success as being convincing for overcoming obviousness, based in
part on FDA approval (which the opinion states is "not determinative"
but can be "relevant" evidence of non-obviousness, citing Knoll
Pharm. Co., Inc. v. Teva. Pharm. USA, Inc., 367 F.3d 1381, 1385 (Fed. Cir.
2004)), as well as evidence of long-felt but unmet need.  In this regard, the length of time
intervening between the dates the various prior art references became available
to the public is relevant evidence according to the Court, because "the
researchers were aware of the benefits of using both vitamin D and
corticosteroids in the treatment of psoriasis as early as 1986" but "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 corticosteroid
was created."  This amount of time "speaks
volumes to the nonobviousness" of these claims.

The Court credited the objective
indicia strongly:

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.

This regard for the objective
indicia is in stark contrast to instances, such as the PharmaStem case shortly after the Supreme Court's KSR decision, where the objective
indicia were disregarded in view of "strong" evidence of
obviousness.  While this is just one
panel opinion, it is possible that the pendulum has begun to swing back towards
a more expansive view of non-obviousness after a more rigid application of the
doctrine immediately post-KSR.

Leo Pharmaceutical Products, Ltd. v.
Rea (Fed. Cir. 2013)
Panel: Chief Judge Rader and Circuit
Judges O'Malley and Reyna
Opinion by Chief Judge Rader