United States Court of Appeals for the Federal Circuit
2008-1282
BAYER SCHERING PHARMA AG
and BAYER HEALTHCARE PHARMACEUTICALS, INC.,
Plaintiffs-Appellants,
v.
BARR LABORATORIES, INC.,
Defendant-Appellee.
Peter B. Bensinger, Jr., Bartlit Beck Herman Palenchar & Scott LLP, of Chicago,
Illinois, argued for plaintiffs-appellants. With him on the brief was Lawrence D. Rosenberg,
Jones Day, of Washington, DC.
George C. Lombardi, Winston & Strawn LLP, of Chicago, Illinois, argued for
defendant-appellee. With him on the brief were Bradley C. Graveline, Michael K. Nutter,
Eric L. Broxterman and William P. Ferranti.
Nancy L. Tompkins, Townsend and Townsend and Crew LLP, of San Francisco,
California, for amicus curiae. With her on the brief was Mark T. Jansen. Of counsel on the
brief were Cedric C.Y. Tan and Kristin M. Cooklin, of Washington, DC.
Appealed from: United States District Court for the District of New Jersey
Judge Peter G. Sheridan
UNITED STATES COURT OF APPEALS FOR THE FEDERAL CIRCUIT
2008-1282
BAYER SCHERING PHARMA AG
and BAYER HEALTHCARE PHARMACEUTICALS, INC.,
Plaintiffs-Appellants,
v.
BARR LABORATORIES, INC.,
Defendant-Appellee.
Appeal from the United States District Court for the District of New Jersey in case no.
05-CV-2308, Judge Peter G. Sheridan.
______________________
DECIDED: August 5, 2009
_______________________
Before NEWMAN, FRIEDMAN, and MAYER, Circuit Judges.
Opinion for the court filed by Circuit Judge MAYER. Dissenting opinion filed by Circuit
Judge NEWMAN.
MAYER, Circuit Judge.
Bayer Schering Pharma AG (“Bayer”) appeals the judgment of the United States
District Court for the District of New Jersey, holding U.S. Patent No. 6,787,531 (“’531
Patent”) invalid due to obviousness. Bayer Schering Pharma AG v. Barr Labs., Inc., No.
05-CV-2308 (D.N.J March 3, 2008). Because we hold that the invention would have
been obvious to try, we affirm.
BACKGROUND
Bayer is a large pharmaceutical company that produces the daily oral
contraceptive, Yasmin®. One of the active ingredients in Yasmin, drospirenone, is a
progestin that inhibits ovulation. Each of the invalidated claims requires drospirenone
as the active ingredient. Drospirenone was known in the art at all times relevant. Its
contraceptive qualities are particularly well suited for producing an oral contraceptive
because, in addition to inhibiting ovulation, it is a diuretic which will diminish excess
water retention arising from the estrogen component of oral contraceptives, and has
anti-acne qualities to promote clear skin. These desirable qualities have led to
Yasmin’s success. Drospirenone is also acid-sensitive. When exposed to low-pH
(highly acidic) environments such as found in the human stomach, drospirenone
“isomerizes” – that is, the acid catalyzes a reaction that rearranges drospirenone’s
molecular structure while its molecular composition remains constant. The resulting
isomer is non-antimineralocorticoidal, meaning it will not act as a diuretic, removing the
desirable anti-bloating effect that sets drospirenone apart from other prior art progestins.
Therefore, scientists working with drospirenone for use in an oral contraceptive must be
aware of and work around the effects that the human stomach will have on the drug to
ensure that its “bioavailability” – the amount of the active drug absorbed into the
bloodstream and available to act on the body – is high enough to perform its
contraceptive function.
Drospirenone is also a poorly water soluble hydrophobic composition. Because it
will not easily dissolve into a volume of liquid, its bioavailability is degraded. To combat
this, pharmaceutical producers commonly employ a technique called “micronization,”
2008-1282 2
whereby the drug’s particle size is reduced, increasing its overall surface area. Often
(but not always) with a larger surface area, the dissolution rate is also increased,
ensuring that all of the poorly water soluble drug that can dissolve will dissolve in a
given volume of liquid. With more of the drug dissolved, the drug will exhibit a higher
bioavailability. Indeed, Bayer’s expert testified at trial that this would be his first choice
in attempting to increase the dissolution rate because, among the different ways to
increase the dissolution rate, micronization presents the best chance of success. All
commercially available oral contraceptives use micronized progestins and/or estrogens,
so this technique was well known in the art.
While micronizing a poorly water soluble composition may result in increased
bioavailability, micronizing an acid-sensitive composition may also increase its
sensitivity to the acid. A drug that isomerizes when exposed to acid thus may isomerize
at a faster rate if it is micronized.
One method pharmaceutical companies use to surmount an acid-sensitivity
problem with a drug to be taken orally is to deliver the drug via an enteric-coated pill, as
opposed to an immediate release pill, also called a “normal pill.” An enteric coating is a
pH-sensitive film that protects the drug from stomach acid, and only releases the drug
when it has passed into the less acidic duodenum and small intestine. However, enteric
coatings are not without drawbacks themselves. Coated tablets including enteric
coated tablets present an obstacle to absorption, and thus reduce the drug’s exhibited
bioavailability. Additionally, as was known in the art at the time, they introduce a
significant delay in the onset of therapeutic response while creating a considerable
patient-to-patient variation of that onset. In fact, even for an individual taking the drug at
2008-1282 3
different times, the response time may vary considerably from dose to dose. Bayer
scientists noticed these intra- and inter-individual bioavailability differences in practice in
their studies on beagles and women. This presented a further complication because
Bayer required the drug to be 99% effective, and work on all women at a single dose –
“one dose must fit all.” A normal pill may not present such variations, but will expose its
contents to the stomach’s highly acidic environment.
Dr. Johannes Tack, a Bayer scientist, began work in 1983 to develop
drospirenone into an oral contraceptive. At the time, Bayer had been working with a
related compound, spirorenone, as a diuretic. When consumed, spirorenone
metabolizes into drospirenone, which is still a diuretic, but was found to have
progestogenic (contraceptive) effects. Spirorenone itself had some contraceptive
effects that Bayer concluded were the result of the appearance of drospirenone when it
metabolized. Bayer decided to harness the diuretic effect of isolated drospirenone to
create the new contraceptive. Tack consulted prior Bayer work with drospirenone
including in vitro isomerization studies performed by a fellow Bayer scientist, Dr.
Werner Krause. Krause had also performed in vivo studies with spirorenone, about
which he published three articles. These studies, Krause I, II, and III, included the
knowledge that drospirenone was a metabolite of spirorenone. Tack decided, however,
that these in vivo studies garnered little information on the practice of drospirenone in
vivo.
Tack tested the stability of drospirenone in acid at pH 1 to simulate the conditions
of the stomach. He found that after 10 minutes, 21% of the drospirenone had
2008-1282 4
isomerized in the acid, and after 45 minutes, half had isomerized. He came to a critical
conclusion:
If the results obtained in vitro are applied to in vivo conditions, it can
be presumed that, with an assumed gastric juice volume of 100ml, the
majority of the dose (solubility of drospirenone 5-10 mg/l) passes into
solution during passage through the stomach and consequently
undergoes rapid isomerization. A clear reduction in the bioavailability of
the unchanged active substance is to be expected as a result.
The planned studies on the progestogenic efficacy of
[drospirenone] should therefore be performed with an enteric-coated
formulation.
Tack then moved into clinical studies with an enteric-coated formulation of
drospirenone. For five years, Bayer used this coated pill in its studies, even
reconfirming in 1988 that drospirenone needed an enteric coating because it isomerized
quickly in a pH 1 acidic solution.
In 1988, Bayer also planned a study to determine how effectively its enteric-
coated tablet delivered a formulation as compared to an intravenous injection of the
same formulation. This study would thus measure the “absolute bioavailability” of the
drug. Bayer added what it terms a “non-routine” element to the study, by which it added
an unprotected (normal) drospirenone tablet and compared its bioavailability to that of
the enteric-coated formulation and the intravenous delivery. Tack expected to find that
the enteric-coated tablet would produce a lower bioavailability than an intravenous
injection, while the normal pill would produce an even lower bioavailability than the
enteric-coated tablet. However, he found that despite his observations that
drospirenone would quickly isomerize in a highly acidic environment and his belief
therefore that an enteric coating would be necessary to preserve bioavailability, the
normal pill and the enteric-coated pill resulted in the same bioavailability. Following this
2008-1282 5
study, Bayer developed drospirenone in a normal pill, for which it would eventually
receive the ’531 patent.
Bayer relied on the finding that drospirenone would absorb with a normal pill to
overcome an obviousness rejection in the Patent and Trademark Office. During
prosecution, the examiner rejected the claims as obvious in view of a De Castro
reference, which the examiner said taught to micronize poorly soluble drugs to increase
their bioavailability. Bayer responded that another piece of prior art, the Nickisch
reference, taught that micronizing drospirenone would increase its exposure to the
highly acidic environment in the stomach, which would result in increased isomerization.
The examiner allowed the claims, giving the specific reason that the prior art suggested
that micronizing drospirenone would not work: “The micronized drospirenone will be
degraded even more rapidly because the micronization of drospirenone expose [sic] the
drug particles in the stomach (acidic). Therefore, to formulate an oral dosage forms [sic]
containing the drospirenone particles, which exposed to the gastric environment upon
dissolution, would be un[o]bvious in view of the data presented . . . .”
The ’531 patent issued on September 7, 2004. Claim 1 is representative:
1. A pharmaceutical composition comprising
from about 2 mg to about 4 mg of micronized drospirenone particles,
about 0.01 mg to about 0.05 mg of 17.alpha.-ethinylestradiol, and
one or more pharmaceutically acceptable carriers,
the composition being in an oral dose form exposed to the gastric
environment upon dissolution,
and the composition being effective for oral contraception in a human
female.
Barr Laboratories (“Barr”) makes generic pharmaceuticals, and filed an
Abbreviated New Drug Application with the Food and Drug Administration seeking
approval to market a generic version of Yasmin®. Bayer promptly filed a patent
2008-1282 6
infringement suit against Barr. The parties agreed that if the ’531 patent is valid, Barr
infringes claims 1, 5, 8, 27, 29, 36, 49, and 50. Barr then alleged that these claims are
obvious, among other invalidity and unenforceability arguments. At trial, the two parties
agreed that 2-4 mg drospirenone was well known in the art, as well as its combination
with 0.01-0.05 mg 17α-ethinylestradiol, a pharmaceutically acceptable carrier, and a kit
containing 21 such tablets with active ingredients and 7 placebos, to be used as an
effective oral contraceptive in human females. Bayer claimed that its innovation was
that the drospirenone could be micronized to increase its bioavailability, and that the
micronized drospirenone would not need to be enteric coated for protection against the
highly acidic gastric environment.
The district court ruled that these claims were invalid as obvious, and rejected
Barr’s other theories. The court found that a person having ordinary skill in the art
would have considered the Krause I, II, and III studies’ results that spirorenone though
acid-sensitive would nevertheless absorb in vivo because drospirenone is closely
related to spirorenone. It also found that while the Nickisch reference did teach that
drospirenone isomerizes in vitro when exposed to acid simulating the human stomach,
a person of ordinary skill would be aware of the study’s shortcomings, and would verify
whether drospirenone absorbed or isomerized with precise in vivo and in vitro testing as
suggested by the Robert Aulton treatise, Pharmaceutrics: The Science of Dosage Form
Design (1988). It then held that under KSR International Co. v. Teleflex Inc., 550 U.S.
398 (2007), it would have been obvious to a person having ordinary skill in
pharmaceutical formulation to try a normal pill in formulating drospirenone as an oral
2008-1282 7
contraceptive. Bayer timely appeals this ruling; Barr does not cross-appeal its adverse
rulings. We have jurisdiction pursuant to 28 U.S.C. § 1295(a)(1).
DISCUSSION
Obviousness under 35 U.S.C. § 103 is the sole issue in this appeal. Whether an
invention would have been obvious at the time the invention was made is a question of
law, which we review de novo, based on underlying facts, which we review for clear
error. Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492 F.3d 1350, 1355 (Fed.
Cir. 2007). A district court's finding is clearly erroneous when, despite some supporting
evidence, we are “left with the definite and firm conviction that a mistake has been
committed.” Forest Labs., Inc. v. Abbott Labs., 339 F.3d 1324, 1328 (Fed. Cir. 2003)
(quoting United States v. U.S. Gypsum Co., 333 U.S. 364, 395 (1948)).
A patent may not be obtained if the differences between the subject matter
sought to be patented and the prior art are such that the subject matter as a whole
would have been obvious at the time the invention was made to a person having
ordinary skill in the art to which the subject matter pertains. 35 U.S.C. § 103(a). An
obviousness analysis is based on several factual inquiries. A court must examine the
scope and content of the prior art, the differences between the prior art and the claims
at issue, and the level of ordinary skill in the pertinent art. Graham v. John Deere Co.,
383 U.S. 1, 17-18 (1966). At that point, a court may consider secondary objective
evidence of non-obviousness, such as commercial success, long felt but unsolved
need, failure of others, and the like. Id.
In KSR, the Supreme Court stated that an invention may be found obvious if it
would have been obvious to a person having ordinary skill to try a course of conduct:
2008-1282 8
When there is a design need or market pressure to solve a problem and
there are a finite number of identified, predictable solutions, a person of
ordinary skill has good reason to pursue the known options within his or
her technical grasp. If this leads to the anticipated success, it is likely the
product not of innovation but of ordinary skill and common sense. In that
instance the fact that a combination was obvious to try might show that it
was obvious under § 103.
550 U.S. at 421. This approach is consistent with our methodology in In re O’Farrell,
853 F.2d 894 (Fed. Cir. 1988). See Procter & Gamble Co. v Teva Pharms. USA, Inc.,
566 F.3d 989, 996-97 (Fed. Cir. 2009); In re Kubin, 561 F.3d 1351, 1359, (Fed. Cir.
2009). O’Farrell observed that most inventions that are obvious were also obvious to
try, but found two classes where that rule of thumb did not obtain.
First, an invention would not have been obvious to try when the inventor would
have had to try all possibilities in a field unreduced by direction of the prior art. When
“what would have been ‘obvious to try’ would have been to vary all parameters or try
each of numerous possible choices until one possibly arrived at a successful result,
where the prior art gave either no indication of which parameters were critical or no
direction as to which of many possible choices is likely to be successful” an invention
would not have been obvious. O’Farrell, 853 F.2d at 903. This is another way to
express the KSR prong requiring the field of search to be among a “finite number of
identified” solutions. 550 U.S. at 421; see also Procter & Gamble, 566 F.3d at 996;
Kubin, 561 F.3d at 1359. It is also consistent with our interpretation that KSR requires
the number of options to be “small or easily traversed.” Ortho-McNeil Pharm., Inc. v.
Mylan Labs., Inc., 520 F.3d 1358, 1364 (Fed. Cir. 2008).
Second, an invention is not obvious to try where vague prior art does not guide
an inventor toward a particular solution. A finding of obviousness would not obtain
2008-1282 9
where “what was ‘obvious to try’ was to explore a new technology or general approach
that seemed to be a promising field of experimentation, where the prior art gave only
general guidance as to the particular form of the claimed invention or how to achieve it.”
O’Farrell, 853 F.2d at 903. This expresses the same idea as the KSR requirement that
the identified solutions be “predictable.” 550 U.S. at 421; see also Procter & Gamble,
566 F.3d at 996-97; Kubin, 561 F.3d at 1359-60.
Because the use of drospirenone with 17α-ethinylestradiol as an oral
contraceptive was known prior art, Bayer represented that the innovation was to
micronize the drospirenone to increase its bioavailability, and that the micronized
drospirenone would absorb with a normal pill, against the teachings of the prior art. The
district court analyzed the prior art and determined that micronizing drospirenone was
taught, and that using a normal pill would have been obvious to try.
The court first determined how the person having ordinary skill in the art of
pharmaceutical formulation would consider the correlation of in vitro and in vivo tests. It
relied principally on Robert Aulton’s pharmacologist textbook, Pharmaceutics: The
Science of Dosage Form Design, which, as the court found, teaches that “dissolution
rate data when combined with solubility . . . provide an insight to the formulator into the
potential in vivo absorption characteristics of a drug. However, in vitro tests only have
significance if they can be related to in vivo results. Once such a relationship has been
established, in vitro dissolution tests can be used as a quality control test. (Aulton, p.
9).” The court concluded that the person of ordinary skill would not accept in vitro
testing as valid without a correlation to in vivo tests.
2008-1282 10
With that knowledge, the court then turned to micronization. It found that Aulton
cut both ways on this point, because it taught both that micronizing a poorly water
soluble substance like drospirenone may increase its absorption rate, but may also
increase the rate of degradation. However, Aulton stated, and other evidence
corroborated, that “it is now generally recognized that poorly soluble drugs showing a
dissolution rate limiting step in the absorption process will be more readily bioavailable
when administered in a finely subdivided [micronized] form with larger surfaces than as
the coarse material. . . . The fine material often in micronized form with larger specific
surface dissolves at faster rates which can lead to improved drug absorption by passive
diffusion.” The district court acknowledged that the prior art suggested that there would
be concern about the dissolution of a poorly water soluble acid-sensitive drug, but found
that the prior art generally suggests that micronization could improve the dissolution of
drospirenone. It concluded that a person having ordinary skill would have seen it as a
viable option.
Bayer argues that this is clear error because the court relied on one piece of prior
art to show that micronization has been shown to work on acid-sensitive compounds.
The court reviewed the Hargrove reference, which was a study on micronizing
progesterone, concluding that “it confirms that not all acid-sensitive drugs require
enteric coating.” This is incorrect, as Barr agrees, because progesterone is not an acid-
sensitive drug. However, Bayer’s own expert, Dr. James McGinity, testified that
micronization is the first choice solution because it presents the best chance for
success. So there remains adequate support for the conclusion that micronization was
a viable option.
2008-1282 11
The district court then moved to Bayer’s second alleged non-obvious aspect of
the invention, whether the formulation should use an enteric-coated or normal tablet
delivery. The court considered Bayer’s argument that prior art taught formulation
scientists to employ an enteric coating on drospirenone, and Barr’s argument that an
enteric coating is so complicated, expensive, cumbersome to manufacture, and prone to
variability that it only would be used as a last resort by formulation scientists working
with an acid-sensitive drug. The court found neither side persuasive, and considered
the prior art as the center, again focusing on the Aulton textbook. It found that Aulton
recognizes the necessity of an enteric coating to the formulation of acid-sensitive drugs,
but that an enteric coating also introduces drawbacks, including that enteric coated
tablets have the lowest bioavailability of all drug delivery forms. Poor bioavailability of
drospirenone is the major problem that Tack sought to solve. The district court further
found that Aulton teaches that there is variability in bioavailability both intra- and inter-
subject when using enteric coated tablets, which is a significant obstacle to Bayer’s
requirement that the drug must be 99% effective for all women.
In effect, while Bayer argued that prior art teaches away from using micronized
drospirenone in a normal tablet, Barr argued that the prior art teaches away from using
an enteric coating. What the parties have done, however, is present the options
available to a pharmaceutical formulator having ordinary skill to solve the problem of
acid-sensitive but hydrophobic drospirenone.
Barr argued that the Krause series on spirorenone is controlling because of the
great similarity between spirorenone and drospirenone. The Krause series tested the
bioavailability of spirorenone in vivo in humans and monkeys to determine whether
2008-1282 12
there was need to develop a “pharmaceutical formulation resistant to gastric juice.” The
studies each found no spirorenone isomers in the subjects’ blood streams, and
concluded that spirorenone is absorbed before it isomerizes. Furthermore, an in vitro
comparison found that drospirenone isomerized in pH 1 acid with a profile similar to
spirorenone. The court found that the drugs were closely related in that they are both
(1) acid-sensitive at similar rates, (2) steroids having the same pharmacological
properties, (3) derivatives of the same drug, (4) of the same chemical composition
except for one bond, and (5) from the same family of substances. The court then
concluded that a person of ordinary skill would find the drugs closely related, and would
therefore access these studies when formulating drospirenone. He would be led to
believe that drospirenone, like spirorenone, may absorb in vivo, but isomerize in vitro.
Bayer argues now that the district court ignored key differences between
drospirenone and spirorenone, such as that the former isomerizes 40% faster than the
latter, and that drospirenone is more soluble and thus could dissolve and isomerize in
acid faster. This is irrelevant because the Krause series prior art is not an anticipatory
reference. It can be used to show that a drug formulator having ordinary skill had a
viable known option to consider with micronized, unprotected drospirenone, and a
reasonable expectation that drospirenone would perform similarly (even if not
identically) to the spirorenone in the Krause series. See O’Farrell, 853 F.2d at 903-904
(“Obviousness does not require absolute predictability of success . . . all that is required
is a reasonable expectation of success.”).
Similarly, Bayer argued that the Nickisch article teaches that drospirenone
isomerizes when exposed to acid in vitro, teaching away from allowing exposure to the
2008-1282 13
gastric environment, and thus suggesting the need for an enteric coating. Barr attacked
the merits of the study as it would apply to the practice of drospirenone in vivo, noting
that Nickisch did not test drospirenone in vivo to correlate its in vitro findings. Barr also
challenged the Nickisch reference on the grounds that drospirenone was found to
isomerize slowly and would not have isomerized before the stomach emptied, that the in
vitro environment was too extreme to be compared to an in vivo practice, and that it did
not explain its testing protocols. The court found that a person of ordinary skill in the art
would recognize that Nickisch establishes that drospirenone isomerizes in vitro, but
would be alerted to the study’s shortcomings when used in vivo.
At this point, a person having ordinary skill in the art has reached a crossroads
where he must choose between two known options: delivery of micronized drospirenone
by a normal pill following the spirorenone analogy in the Krause series, or delivery of
drospirenone by an enteric-coated pill following the Nickisch teaching that the drug
needs to be protected from the stomach. This is a finite number of identified,
predictable solutions. See KSR. 550 U.S. at 421. The prior art would have funneled the
formulator toward these two options; he would not have been required to try all
possibilities in a field unreduced by the prior art, thus avoiding the first pitfall of O’Farrell,
853 F.2d at 903. Additionally, the prior art was not vague in pointing toward a general
approach or area of exploration, but rather guided the formulator precisely to the use of
either a normal pill or an enteric-coated pill, thus avoiding the second pitfall of O’Farrell.
Id. Because the selection of micronized drospirenone in a normal pill led to the result
anticipated by the Krause series, the invention would have been obvious. See KSR,
550 U.S. at 421.
2008-1282 14
CONCLUSION
Accordingly, the judgment of the United States District Court for the District of
New Jersey is affirmed.
AFFIRMED
2008-1282 15
United States Court of Appeals for the Federal Circuit
2008-1282
BAYER SCHERING PHARMA AG
and BAYER HEALTHCARE PHARMACEUTICALS, INC.,
Plaintiffs-Appellants,
v.
BARR LABORATORIES, INC.,
Defendant-Appellee.
Appeal from the United States District Court for the District of New Jersey in Case No. 05-
CV-2308, Judge Peter G. Sheridan.
NEWMAN, Circuit Judge, dissenting.
With all respect to my colleagues, I do not share their view that it would have been
obvious to do that which was indisputably unobvious to the experienced formulation
scientists whose assignment was to formulate the known product drospirenone. The
evidence showed, without contradiction, that it was known that micronized drospirenone
rapidly degraded at the acidity of stomach acid. The evidence showed, without
contradiction, that the Bayer scientists working in this field believed that the product
required an enteric coating in order to prevent degradation in the stomach, upon ingestion
as an oral contraceptive. Yet my colleagues, employing their own expertise, hold that since
the scientists working in this field turned out to be mistaken, it would have been obvious
that it was not necessary to take steps to prevent acid degradation. The court discounts
the testimony of the scientists themselves, ignores the knowledge concerning this product
and its instability in acid, ignores the textbook teachings, and finds that this unlikely process
obviously should have been tried. That is not the law of obviousness.
The statutory criterion is whether the invention would have been obvious to persons
of ordinary skill at the time of the invention, not whether it is sufficiently simple to appear
obvious to judges after the discovery is finally made, despite the years of contrary belief
among the scientists charged with the project. At the time that the Bayer scientists were
attempting to formulate drospirenone as an oral contraceptive, the textbook teaching was
that micronizing acid-sensitive products would accelerate their acid-induced degradation.
See, e.g., Aulton’s Pharmaceutics: The Design and Manufacture of Medicines (advising
against micronizing acid-sensitive drugs because it reduces the drug’s bioavailability). My
colleagues criticize these specialists, and rule that it was nonetheless obvious to conduct
experiments that they believed would not work. The court rules that the scientists should
have “tried” that which they believed would fail, and that when they eventually did try this
unlikely formulation, and it succeeded, it was obvious to do so.
The unusual physiological behavior of drospirenone in the stomach was not known;
this knowledge followed as scientific explanation; it did not precede the invention in suit.
There was no evidence to reasonably suggest that micronized drospirenone was likely to
be usable, with 99+ percent consistency of effectiveness, without any protection from
degradation by stomach acid. A usable contraceptive requires virtually complete
effectiveness, and the standard confronting the Bayer scientists was high. Unlike the
2008-1282 2
unrelated drugs cited by the panel majority, contraceptives require complete effectiveness.
Previously known oral contraceptives such as progesterone and spironolactone are not
acid sensitive, and drospirenone presented a highly specific challenge to the formulation
scientists. The Bayer scientists believed that the way of avoiding the known acid
degradation of drospirenone was to protect it from acid. My colleagues, however, find that
it would have been obvious to expose it to acid, although it was not obvious to the scientists
working on the project.
“Obviousness” requires that the subject matter was obvious to persons of ordinary
skill in the field of the invention. The law does not hold it “obvious to try” experiments that
contravene conventional knowledge, and that are not deemed reasonably likely to succeed.
The evidence in this case is a better measure of obviousness than is the hindsight science
of judges, for the scientists who eventually made this discovery testified, without dispute,
that they did not believe an uncoated micronized product would meet the demanding
criteria of contraceptive effectiveness. The Court in KSR International Co. v. Teleflex Inc.,
550 U.S. 398 (2007) explained that the standard for “obvious to try” is whether there was a
“reasonable expectation of success” at the time. It was undisputed that there was not. It
was undisputed that it was not reasonably expected that uncoated micronized drospirenone
would be 99+% effective as an oral contraceptive when ingested into the acidic stomach,
when it was known to degrade rapidly in acid.
The district court stated that micronization was a “viable” option, and that although
success was “uncertain,” the invention was obvious to try. However, “viability” is not the
standard. “Viability” implies that the experiment may or may not succeed. What the law
requires is not guesswork, not dumb luck, but a reasonable degree of predictability of
2008-1282 3
success. My colleagues depart from the statutory standard, in ruling that persons of
ordinary skill would have conducted experiments that were expected to fail. Nothing in the
prior art teaches the likelihood of success of ingestion of uncoated micronized
drospirenone; what is taught is the likelihood of failure.
The invention must be viewed as a whole. With the existing knowledge that
drospirenone is both hydrophobic and that it degrades rapidly in acid, and the existing
knowledge that micronization, although useful to counteract a drug’s hydrophobic
properties, renders the drug even more susceptible to acid degradation, it was not shown
that a person of ordinary skill in this field would have had a reasonable expectation of
achieving complete contraceptive bioavailability and effectiveness with uncoated
micronized drospirenone. The contrary view has surfaced only in this litigation-induced
argument. The exercise of judicial expertise to override the clear evidence of how persons
of skill in this field actually behaved, is inappropriate.
I respectfully dissent.
2008-1282 4