One of the
most helpful concepts in contemplation of legal opinions is “Everything I know
is wrong.” That is because logic which appears infallible in a non-legal
context is often at odds with the law’s own internal logic. Often, but
not always.
On August
12, 2013 the Court of Appeals of the Federal circuit (CAFC) decided LEO
PHARMACEUTICAL PRODUCTS, LTD. v TeresaStanek Rea, ACTING DIRECTOR (USPTO)
[Opinion]
The case was
an appeal to the CAFC by LEO following a finding of obviousness by the Board of
Patent Appeals and Interferences (BPAI) of the USPTO during inter partes
re-examination of U.S. Patent No. 6,753,013. The ‘013 patent has a priority
date of Apr 23, 1999.
Claim 1,
despite it’s length, is relatively simple (emphases 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-secopregna-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, R1in
each of the x units is CH3, R2is 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.
In non-legal
terms this means that the claimed invention is a composition including at
least one vitamin D analogue and at least one corticosteroid
in at least one solvent. The
entire composition must be storage stable and non-aqueous despite
the fact that the difference between the maximum stability pH of the vitamin
D analogue and the maximum stability pH of the corticosteroid differ
by at least 1. The solvent described as an embodiment in the ‘013 patent is Polyoxyproplyene 15 Stearyl Ether (POP-15-SE).
The claimed
composition is useful in the treatment of skin conditions such as psoriasis.
It was previously
known that both vitamin D analogues and corticosteroids
were useful in the treatment of these skin conditions. However, the two
ingredients were traditionally administered separately (e.g. one in the morning
and the other in the evening).
The CAFC
considered whether the various combinations of the three reference would have been obvious to
make.
Here are the
facts as the CAFC explains them:
Turi, filed
in 1977, discloses pharmaceutical compositions comprising a steroid contained
within a
solvent,
POP-15-SE, but does not teach the use of vitamin D. 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
specifically discloses that the claimed invention does not contain water, gels, or alcohols.
Turi addresses neither stability concerns from combining vitamin D analogs and
corticosteroids, nor the use of POP-15-SE or corticosteroids for the treatment
of psoriasis.
Dikstein, filed
in 1984, discloses dermatological compositions, including creams, ointments,
and lotions, comprising a vitamin D analog and a corticosteroid. Dikstein teaches
that vitamin D can treat psoriasis and that corticosteroids have side effects,
but it does not teach using vitamin D to treat the side effects of
corticosteroids. Every example composition in Dikstein contains almond oil or
propylene glycol and several also contain water. Dikstein does not disclose or
recognize 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.
Serup, filed
in 1993, describes a composition containing a vitamin D analog and a steroid
and teaches the use of vitamin D analogs to treat skin atrophy, a well-known side
effect of steroid treatment. 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 may
include “creams, ointments, pastes, or gels,” every example composition
disclosed in Serup is aqueous, containing
either purified or hot water. Every example also contains almond oil, propylene
glycol, or alcohol. 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.
The Board
decision under review by the CAFC relied on Turi as the primary reference
because Turi disclosed a category B corticosteroid and a category C solvent. The
Board then used Serup or Dikstein with Turi to reject various dependent claims
concerning different vitamin D analogs.
The Board
followed the Examiner’s reasoning for combining Turi with Serup: “…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.’” The Board felt that “…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 therapeutic purpose.”” The Board added that adding vitamin D to Turi “would have been
obvious to address the well-known side effects of topical steroid treatment.”
In addition, the Board held that since 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.
As regards combination
of Turi with Dikstein, the Board found that Dikstein “teaches the benefit of
combining 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. The Board indicated that the analysis for Serup also
applied to Dikstein.
The Board
admitted that Leo had submitted “extensive experimental evidence” that water, alcohol,
and propylene glycol cause unacceptable degradation of vitamin D and steroid
compositions. However, the Board felt that Turi provided explicit guidance to
exclude these ingredients. Specifically,
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.
The Board
concluded that Leo’s objective indicia of non-obviousness, did not
overcome the prima facie case of obviousness because the “unexpected
results” claimed by Leo Pharmaceuticals were not unexpected since Turi
“provided explicit reason to use POP-15-SE as a solvent.” so that Leo Pharmaceuticals “did not establish
that the improvement observed was unexpected to one of ordinary skill in the
art in view of the strong reason to have utilized POP-15-SE.”
The Board
cited KSR in support of the premise that “the reason for utilizing the solvent
does not have to be the same reason [the solvent] was employed by the
inventors.”
Those readers
that work in US prosecution probably don’t
see much wrong with the Board’s reasoning.
The CAFC
did.
The CAFC indicated
that the ’013 patent is not simply a combination of elements found in the prior
art. The Court credited the inventors with recognizing and solving a problem
with the storage stability of certain formulations. According to the Court, this problem was
both unrecognized and unsolved by the prior art for over a decade.
The Court
reminds us that an invention can often be the recognition of a problem itself. [Cardiac Pacemakers, Inc. v. St. Jude Med.,
Inc., 381 F.3d 1371, 1377 (Fed. Cir. 2004)]
The Court
found it relevant that during reexamination, Leo Pharmaceuticals presented 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. The prior art as a whole seemed to suggest that it was
“only natural” for clinicians to attempt to try combinations of vitamin D
with other ingredients, but warned that vitamin D should not be combined with
other drugs requiring a low pH (e.g.,
corticosteroids). The prior art recognized
possible advantages from combining a vitamin D treatment with topical
corticosteroids, but nevertheless recommended a two-drug regimen where
patients applied the drugs at different times of day or on alternating days.
The Court
noted that although Dikstein and Serup attempt the combination of a vitamin D
analog with a corticosteroid, neither discloses
or addresses the stability problems of combining vitamin D analogs and
corticosteroids into one pharmaceutical formulation.
Leo
Pharmaceuticals conducted experiments and submitted evidence to show that the prior art does not teach any composition that exhibits
storage stable properties. Every example
disclosed in Dikstein contains either almond oil or propylene glycol. Similarly, the examples disclosed in Serup
contain not only water, but also almond oil, alcohol, or propylene glycol.
Leo
Pharmaceuticals presented experimental evidence to the Board that each of these
ingredients harmed the storage stability
of the vitamin D analog and cortico-steroid combination.
The Court
suggests that since neither Dikstein nor Serup recognized or disclosed the
stability problem, there was no reason for one of ordinary skill in the art to
attempt to improve upon either Dikstein or Serup using Turi.
Now we get
to the time factor.
The Court
reasons that 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 which requires several months running storage stability tests. 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.
And here is
the antidote to KSR:
“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 invention does not
appear for more than a decade.”
It gets
better. According to the CAFC passage of time can be an indication of hindsight
(emphases added) :
“…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 treatment is only straightforward in hindsight. Turi was publicly available in the
prior art for twenty-two yearsbefore 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."
The CAFC
also finds fault with the Board’s suggestion that picking specific combinations from among
many possibilities was obvious to try in the context of time (emphases
added):
Here, the
“background of useful knowledge”—including the prior art relied on by
the Board—was published 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 predictable. Therefore, the claimed invention would not
have been obvious to try to one of ordinary skill in the art.
Even I will
admit, this is an unusual case in terms of both the amount of time between the
priority date and the publication dates on the references and in terms of the
amount of evidence the patentee presented to demonstrate that what was in some of the
references demonstrated an ignorance of the problem being solved. Nonetheless, this case suggests an
important strategy for overcoming obviousness rejections based upon old
publications. Those of you that are
considering using it should read, and re-read, the entire decision. This
strategy will work best when the claimed invention solves a problem that was
not previously recognized.
Thanks to
the enlightened panel at the CAFC for shedding new light on the meaning of the
phrase “rational underpinnings”.
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