"Pharmaceutical Patents in the Age of KSR" by PRD published by the Food and Drug Law Institute, Update Magazine, Issue 4 (July/August 2009)

1. Update 2009, Issue 4
With Permission from FDLI, www.fdli.org
Pharmaceutical Patents
in the Age of KSR
by Patrick R. Delaney
T
The U.S. patent system is
designed to promote innovation
by rewarding investment in
research, such as that undertaken
within the pharmaceutical industry
in developing new drugs. Typically,
hundreds of millions of dollars are
invested to bring a single drug to
market, notwithstanding those efforts
which do not result in a marketable
product. For pharmaceutical products
and therapies, especially blockbuster
drugs, patent exclusivity is a primary
driver in building and maintaining
product revenue stream. So it is a major
concern if the patent coverage available
for any pharmaceutical becomes
more vulnerable to unforeseen legal
challenges due to a significant change
in the law.
KSR and Obviousness
In patent law, obviousness is the
concept that a supposed invention is
so similar to an earlier technology,
although not identical, that it is
unworthy of patent protection. The
U.S. Supreme Court first defined the
Mr. Delaney
is an independent
attorney practicing patent law in
Alexandria, VA.
32
UPDATE
July/August 2009
formal legal test for obviousness in the
1966 decision, Graham v. John Deere
Co. of Kansas City.1 As a general matter,
establishing obviousness involves
proffering a plurality of evidencefrom
various sources such as publications
(i.e., prior art) or expert witness
testimony.
These sources correspond to
teachings, suggestions and motivations
(TSM) which must be combined to
approximate the claimed invention. The
combination cannot be unreasonable,
but instead must have some reasonable
expectation of success. This reasonable
expectation is in the hypothetical view
of a person qualified by having ordinary
skill, education and training in the
subject matter involved.
In April 2007 the Supreme Court
decided KSR Int’l v. Teleflex, Inc.,2
introducing a major change to the legal
concept of obviousness. This change
restricts the enforceability of many
U.S. patents as they are more subject to
obviousness challenges to their validity
in court. The change also inhibits the
availability of new patents from the U.S.
Patent and Trademark Office (PTO).
Since the Graham decision in 1966, a
large number of specific legal rules had
developed in obviousness law by the
Federal Circuit3 and other courts, as to
how various TSM combinations could
be established to prove up obviousness.
In KSR, the Supreme Court rejected a
rigid application of the Federal Circuit’s
TSM tests. The Supreme Court in KSR
mandated a more flexible approach,
thus making it easier for a challenger
to invalidate a patent for obviousness.
Although KSR involved a patent
with claims drawn to a mechanical
apparatus, it affects the obviousness
analysis applied to all types of U.S.
patents. This article focuses on the effect
KSR has had upon pharmaceutical
patents.4
Has KSR Introduced
a Major Change for
Pharmaceutical Patents?
The effect of a major departure from
prior law is difficult to determine
until the change is defined through
subsequent judicial decisions. In
general, it is difficult to identify
trends in patent law, and in particular
obviousness law, as these cases tend to
be heavily fact-specific in nature. But
at this point, it is clear that KSR has
had some impact on pharmaceutical
patents, both in district court patent
litigation and in ex parte matters for
obtaining new pharmaceutical patents
from the PTO.
Shortly after KSR was announced
in 2007, a number of district
court decisions reflected a liberal
interpretation of KSR as a basis for
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2. substantial new challenges to the
validity of pharmaceutical patents based
on obviousness. The Federal Circuit,
however, has announced a series of
decisions since KSR. These appellate
decisions suggest the actual impact to
pharmaceutical Intellectual Property
(IP) portfolios is less substantial than
originally expected, albeit with some
exceptions depending upon the subject
matter of the patent claims.
Pharmaceutical
Compounds and
Obviousness Based on
Chemical Structure
Pharmaceutical patents often
have claims involving the chemical
structure of a pharmaceutically active
compound. Many of the relevant
Federal Circuit decisions since
KSR have acknowledged the highly
unpredictable nature of small molecule
chemical structures, thus rendering
this specific type of pharmaceutical
patent less vulnerable than other types
of patents to obviousness challenge
based on KSR.
The Federal Circuit decided Takeda
Chem. Indus., Ltd. v. Alphapharm
Pty., Ltd.5 in June of 2007. In Takeda,
the court interpreted KSR in a way
arguably strengthening, rather than
weakening, pharmaceutical patents
having claims directed to a chemical
structure. The drug in Takeda was
ACTOS, which contains pioglitazone,
a compound used to control blood
sugar in Type II diabetes.
In the obviousness determination,
the structural difference between
pioglitazone, the claimed chemical
compound, and the proposed chemical
compound involved replacing similar
alkyl groups (i.e., homology) displaced
between neighboring positions on a
ring structure (i.e., ring-walking).
FDLI
In Takeda, the court first
acknowledged that KSR did not involve
a radical change in the obviousness
determination in chemical structure
cases stating the test for obviousness
of chemical compounds is consistent
with earlier legal principles and that
the KSR court had merely rejected only
a rigid application of the TSM tests
in an obviousness inquiry. The court
in Takeda also emphasized that the
KSR decision had acknowledged the
importance that a challenger identify
a reason that would prompt a person
of ordinary skill in the relevant field
to combine the elements to meet the
claimed new invention.
The challenger in Takeda had
argued that the two compounds were
so close in chemical structure so as
to be obvious as a matter of law and
based this argument upon a prior
appellate decision6 that chemical
structure similarity, when very close,
is sufficient to establish obviousness
as a matter of law. The Takeda court,
however, distinguished this notion of
obviousness as a matter of law.
The court first determined that
the two compounds were shown
to have dissimilar pharmaceutical
properties which were not previously
known, and emphasized how this
established the highly unpredictable
nature of chemical structure cases.
The court then held that obviousness
had not been established without
some factual showing to support why
the differences, homology and ringwalking, would have been obvious.
The 2008 decision in OrthoMcNeil Pharmaceutical, Inc. v. Mylan
Laboratories, Inc.7 also supports the
view that pharmaceutical patents
involving a chemical structure in the
claims are not subject to any new KSR-
type obviousness challenges. OrthoMcNeil involved TOPOMAX, an
epilepsy drug containing the chemical
compound topiramate. Mylan
challenged the validity of the patent
covering topiramate citing KSR to
support the obviousness challenge. The
rationale was based on the supposed
probability of a person of ordinary
skill in the art discovering topiramate
from a finite number of choices and
being motivated merely by design need
or market pressure to solve a problem.
The court in Ortho-McNeil rejected
Mylan’s application of KSR and
countered that the discovery process
for topiramate did not present a
finite and small number of options.
The court held that KSR did not
apply as the mechanical case in KSR
posited a situation with a finite, and
in the context of the art, small or
easily traversed number of options
that would convince an ordinarily
skilled artisan of obviousness. The
court in Takeda also reinforced the
distinction for pharmaceutical patents
that even small changes in chemical
structure were highly unpredictable
when the available prior art fails to
identify predictable solutions for the
pharmaceutical activity involved.
The importance of considering
unpredictability in determining
obviousness was amplified by the
court in Eisai Co. Ltd. v. Dr. Reddy’s
Labs., Ltd.8 The Eisai case involved
ACIPHEX, which contains the
proton pump inhibitor rabeprazole,
a compound for the treatment of
duodenal ulcers and heartburn.
The structural difference between
rabeprazole and the proposed
compound for comparison,
lansoprazole, involved a change in
only a single lipophilicity-conferring
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UPDATE
33

3. fluorinated substituent of the proposed
lansoprazole molecule.
The challenger cited KSR as a basis
for challenging the validity of the patent
covering ACIPHEX but proffered
no factual evidence to support why
one of ordinary skill in the art would
be motivated to make the proposed
substitution. In line with both Takeda
and Ortho- McNeil, the court in Eisai
determined that the record contained
no reasons a skilled artisan would have
considered modification of lansoprazole
by removing the lipophilicityconferring fluorinated substituent
from the proposed compound as an
identifiable, predictable solution and as
such, the record did not support a case
of obviousness.
The Federal Circuit has been
consistent in advancing unpredictability
as a basis for non-obviousness in
other recent cases involving closely
related chemical structures. Chemical
enantiomers are two chemical
compounds that are nearly the same
with the exception that they are mirror
images of each other. For example,
a left-hand image and a right-hand
image. As such, enantiomers polarize
light in opposite directions.
The drug Plavix contains clopidogrel,
a dextrorotatory (i.e., clockwise
polarizing) enantiomer compound
for inhibiting the aggregation of
blood platelets and used to treat or
prevent blood-thrombotic events.
Clopidogrel is therapeutically effective
and completely without certain bad
side effects which were all found
to be associated with the opposite
levorotatory enantiomer (i.e., counterclockwise polarizing) of clopidogrel. In
addition, this undesirable enantiomer
had no therapeutic efficacy. In SanofiSynthelabo v. Apotex, Inc.,9 the court
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UPDATE
July/August 2009
affirmed the validity of the Plavix
patent. The court determined the two
enantiomeric chemical structures were
not obvious variants to each other due
to the highly unpredictable finding of
completely opposite pharmaceutical
properties in the two separate
enantiomeric compounds.
Similarly, in Proctor & Gamble v.
Teva Pharmaceuticals USA, Inc.,10
the court’s decision involved the
obviousness of ACTONEL containing
the bisphosphonate compound
risedronate, a drug for the treatment
of osteoporosis. On appeal, Teva
contended that, under KSR, the
structural similarities between
risedronate and another compound,
2-pyr EHDP, rendered the challenged
claims of the patent covering
ACTONEL obvious. Risedronate and
2-pyr EHDP are positional isomers
in that they each contain the same
atoms arranged in a slightly different
way. The court did not agree with
Teva and found the patent to be
valid on the basis that there was no
credible evidence that the structural
modification was routine.
Altana Pharma AG and Wyeth v. Teva
Pharmaceuticals USA, Inc., et al.11 is
somewhat of an exception to this line
of cases. In Altana, the drug Protonix
was involved. It contains the compound
pantoprazole, which is another proton
pump inhibitor and used to treat
gastric acid disorders in the stomach.
The challenger made only a preliminary
and partial showing that pantoprazole
might be an obvious variant of a
proposed chemical compound and the
court agreed that the patent might be
vulnerable to a validity challenge based
on obviousness. However, in Altana,
there was no final determination as
to the validity of the patent covering
Protonix because the underlying legal
context involved only a preliminary
injunction, not a full trial on the merits.
A preliminary injunction involves
only showing the mere potential for a
finding of invalidity.
So KSR appears to have had only a
marginal impact on pharmaceutical
patents involving claims directed to a
chemical structure. That is, when the
chemical structure itself is the object
of the obviousness inquiry. The same,
however, cannot be said for other types
of pharmaceutical patents.
Therapeutic Methods
and Pharmaceutical
Compositions or Salts
For the purposes of this article,
pharmaceutical patents directed to
therapeutic methods and compositions
involve something other than a small
molecule pharmaceutical compound in
the patent claims, such as a cell or an
additive. It is the cell or additive which
is involved in the obviousness inquiry.
In general, this type of subject matter
involves properties or characteristics
which are relatively more predictable
and pharmaceutical patents in this
category are more susceptible to an
obviousness challenge under KSR. Not
surprisingly, the Federal Circuit has
confirmed that these types of patents
can be successfully challenged under
KSR and found invalid.
In PharmaStem Therapeutics, Inc.
v. Viacell, Inc.,12 the court found two
patents to be invalid precisely due to
a predictably reasonable expectation
of success when combining the
separate teachings disclosed in the
prior art. The challenger proffered
prior art publications which suggested
a possibility but did not confirm
whether human stem cells are found in
cord blood. An expert testified in the
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4. patentee’s defense, opining there was
no reasonable expectation of success
to combine the prior art teachings
to arrive at the claimed invention.
The expert took the position that,
based upon the prior art proffered
by the challenger, it would have been
unpredictable to a person of ordinary
skill at the time of the invention that
stem cells were actually present in
cord blood.
The court in PharmaStem did not
accept the expert’s position as tenable.
Instead, the court reconsidered the
prior art and relying on KSR found
both patents to be invalid based on
obviousness. The court determined
the inventors had merely used routine
research methods to prove what was
already believed to be the case. The
court further held that scientific
confirmation of what was already
believed to be true may be a valuable
contribution, but it does not give rise
to a patentable invention.
Although decided one month
prior to KSR, the decision in Pfizer,
Inc. v. Apotex, Inc.,13 also illustrates
how a pharmaceutical patent
might be found invalid under KSR.
The Pfizer case involved the drug
NORVASC, containing amlodipine, a
dihydropyridine compound used for
treating hypertension. The obviousness
determination, however, only involved
the choice of the salt, and not the
active agent amlodipine compound.
In the new drug application
(NDA) history for NORVASC, the
Pfizer scientists had performed the
early toxicity and efficacy testing
for amlodipine using the maleate
salt of amlodipine. However, when
tablet manufacturing difficulties
became apparent for the maleate,
Pfizer switched to the besylate salt of
FDLI
amlodipine for final FDA approval of
the tablet product.
Pfizer had obtained an initial
patent covering, in general, both
amlodipine salts. This initial patent
specifically disclosed the maleate salt
of amlodipine, but not the besylate
salt. Pfizer subsequently sought
an improvement patent directed
specifically to amlodipine besylate. The
improvement patent was challenged
as invalid based on the maleate and
besylate salts of amlodipine being
obvious variants. The earlier Pfizer
patent had disclosed amlodipine
maleate and the challenger established
that besylate salts, per se, were known
in the prior art.
Pfizer had countered that it had been
unpredictable whether amlodipine
would form a stable salt with besylate
having good tablet manufacturing
properties. Pfizer further argued
that one of ordinary skill in the art
had no reasonable expectation of
success by combining amlodipine
with besylate because there was no
reliable way to predict the influence
of a particular salt species on an
active pharmaceutical compound.
Pfizer also furnished evidence that
the combination of amlodipine with
besylate resulted in favorable tablet
manufacturing properties.
The court in Pfizer came to a
conclusion completely in line with
KSR. The Pfizer court held that the
unpredictability of mere salt formation
did not reach the level of having an
unreasonable expectation of success
to a pharmaceutical chemist. The
court emphasized that besylate
was already known in the art and
that one of ordinary skill in the art
would have had some expectation of
successfully forming a stable besylate
salt with amlodipine having good
tablet manufacturing properties. At
the same time, while finding Pfizer’s
improvement patent to be invalid
as obvious, the Pfizer court did not
discount that other pharmaceutical
salts might still be patentable and
not obvious if the salt formulation
were not well-known in the prior
art or could be shown to affect the
therapeutic effectiveness of the
pharmaceutically active compound.
Biologicals
Biologicals often involve
macromolecular chemical structures
such as DNA sequences or a
structurally-related protein coded
by a DNA sequence. KSR was relied
upon by the court in the recent In re
Kubin14 decision involving this type of
biological. The case in Kubin involved
a patent application that had been
denied a patent grant at the PTO due
in part to obviousness.15
The patent applicant appealed
the case to the Federal Circuit. The
claims in the appealed application
were directed to new DNA sequences
having a chemical structure
corresponding to coding for a known
protein. The court first found that the
specification in the patent application
used a conventionally known method
of molecular cloning to derive the
claimed DNA sequences from the
known protein.
In relying on KSR, the court in
Kubin affirmed the PTO’s conclusion of
obviousness. In the decision, the court
noted that the protein was known in
the prior art and that the method of
molecular cloning was a conventional
method often used by a molecular
biologist as a person of ordinary skill
in this area. Given these preliminary
findings, the court held there was a
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UPDATE
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5. reasonable expectation of success
in developing the claimed DNA
sequences from the known protein
using a method of molecular cloning
which, at the time of the invention,
had been merely a conventional
method in the art.
KSR Presents a Higher
Bar to Obtaining New
Patents from the U.S. PTO
Undoubtedly, KSR has increased
the basis for validity challenges to at
least some pharmaceutical patents in
U.S. District Courts. But the overall
effect of KSR upon pharmaceutical
patent litigation is less than was
originally anticipated. On the other
hand, KSR has significantly impacted
the availability for obtaining new U.S.
patents from the PTO.
The PTO generally construes
the U.S. patent laws regarding
patentability (including obviousness)
more conservatively than the U.S.
courts. This is due to the necessary
deference the PTO, as a regulatory
agency, must show the Federal Circuit
and U.S. District Courts. It is also due
36
UPDATE
July/August 2009
to the nature of the patent application
process. The PTO puts the initial
burden of proof upon all patent
applicants to establish patentability
as part of the quid pro quo between
the applicant and the U.S. public. If
successful, the applicant obtains a
grant of exclusivity in an issued
U.S. patent.
In response to KSR, the PTO has
established patent examination
guidelines for implementing how KSR
is to be applied in the examination
of all types of patent applications,
including pharmaceuticals. These
examination guidelines call for
a range of approaches by which
applicants may respond in obtaining
the grant of a patent. As with
any obviousness inquiry, the best
approach will depend heavily on
the specific factual circumstances
involved. Explaining the many
possible approaches pharmaceutical
patent applicants might take to
successfully overcome KSR-type
obviousness issues raised in ex parte
matters at the PTO is beyond the
scope of this article. These are the
subject of a subsequent publication.
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15
Graham v. John Deere Co. of Kansas City, 383 U.S. 1,
86 S.Ct. 684, 148 U.S.P.Q. 459 (1966).
KSR Int’l Co. v. Teleflex Inc., et al., 550 U.S. 398, 127
S.Ct. 1727, 82 U.S.P.Q.2d 1385 (2007).
The Court of Appeals for the Federal Circuit (Federal
Circuit) is the only appellate circuit court having
subject matter jurisdiction for matters involving
U.S. patents. Although Supreme Court decisions
take precedence over Federal Circuit decisions, the
Supreme Court hears relatively few patent cases
which must be appealed from the Federal Circuit.
So most legal decisions of national significance
having patent issues relating to obviousness are fully
developed at the Federal Circuit level.
This article builds upon a related article published in
the (Sept./Oct. 2007) edition of Update Magazine
shortly after the decision in KSR was announced.
Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd.,
492 F.3d 1350 (Fed. Cir. (2007)).
In re Wilder, 563 F.2d 457 (CCPA (1977)).
Ortho-McNeil Pharmaceutical, Inc. v. Mylan
Laboratories, Inc., 520 F.3d 1358 (Fed. Cir. (2008)).
Eisai Co. Ltd. v. Dr. Reddy’s Labs, Ltd., 533 F.3d
1353 (Fed. Cir. (2008)).
Sanofi-Synthelabo v. Apotex, Inc., 550 F.3d 1075
(Fed. Cir. (2008)).
Proctor & Gamble v. Teva Pharmaceuticals USA,
Inc., Nos. 2008-1404, -1405, -1406 (Fed. Cir.
(May 13, 2009)).
Altana Pharma AG v. Teva Pharmaceuticals USA,
Inc., No. 2008-1039 (Fed. Cir. (May 14, 2009)).
PharmaStem Therapeutics, Inc. v. Viacell, Inc., 491
F.3d 1492 (Fed. Cir. (2007)).
Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348
(Fed. Cir. (2007)).
In re Kubin, et al., No. 2008-1184 (Fed. Cir.
(Apr. 3, 2009)).
Ex parte Kubin, Appeal No. 2007-0819, 2007 WL
2070495 (BPAI (May 31, 2007)) “Board Decision.”
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