NOTE: Pursuant to Fed. Cir. R. 47.6, this disposition
is not citable as precedent. It is a public record.
United States Court of Appeals for the Federal Circuit
05-1044
ELI LILLY AND COMPANY,
Plaintiff-Appellee,
and
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
and INTERNEURON PHARMACEUTICALS, INC.,
Involuntary Plaintiffs,
v.
TEVA PHARMACEUTICALS USA, INC.,
Defendant-Appellant.
___________________________
DECIDED: July 13, 2005
___________________________
Before MAYER, LOURIE, and BRYSON, Circuit Judges.
Opinion for the court filed by Circuit Judge BRYSON. Circuit Judge MAYER dissents.
BRYSON, Circuit Judge.
Teva Pharmaceuticals USA, Inc., seeks review of a decision by the United States
District Court for the Southern District of Indiana, in which the court found that Teva
infringed U.S. Patent No. 4,971,998 (“the ’998 patent”) and that the patent was not
invalid. Eli Lilly & Co. v. Teva Pharms. USA, Inc., IP 02-0512-C-B/S (S.D. Ind. July 29,
2004). We affirm.
I
The ’998 patent covers a method of treating premenstrual syndrome (“PMS”) by
administering fluoxetine, a drug belonging to a class of compounds known as Selective
Serotonin Re-Uptake Inhibitors (“SSRIs”). SSRIs increase the amount of the
neurotransmitter serotonin in the synaptic gaps of neurons by inhibiting the reuptake of
serotonin. Reuptake is the process by which serotonin is removed from the receiving
neuron and returned to the neuron from which it was sent. Fluoxetine causes the
serotonin from the receiving neuron to remain in the synaptic gap for longer than it
normally would, thereby increasing the chance that the serotonin will be recognized by
the receptors of the receiving neuron.
The symptoms of PMS typically occur during the two weeks before the beginning
of a woman’s menstrual period. That two-week period is commonly known as the luteal
period. Drugs relating to PMS treatment typically fall into one of two categories with
respect to dosing: (1) dosing limited to the luteal period only; or (2) continuous dosing,
which extends indefinitely beyond the luteal period.
The ’998 patent is entitled “Methods for Treating the Premenstrual or Late Luteal
Phase Syndrome.” Claim 2 of the ’998 patent is the only claim in suit. It reads:
A method of treating disturbances of mood, disturbances of appetite, or
both, associated with pre-menstrual syndrome, comprising administering
to a woman prior to the onset of her menstrual period, a composition
consisting essentially of approximately 5 mg to approximately 120 mg of
fluoxetine.
Eli Lilly and Company is the secondary licensee of the ’998 patent, which is
assigned to Massachusetts Institute of Technology (“MIT”) and licensed to Interneuron
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Pharmaceuticals. Lilly received approval from the Food and Drug Administration
(“FDA”) to market fluoxetine under the tradename Sarafem for the treatment of
Premenstrual Dysphoric Disorder, a particularly severe form of PMS. In connection with
its request for FDA approval, Lilly listed the ’998 patent in the FDA’s Orange Book as
covering Sarafem and its use. When Teva filed an Abbreviated New Drug Application
with the FDA seeking approval for the generic version of Sarafem to be administered by
continuous dosing, Lilly filed suit against Teva for infringement of the ’998 patent. Lilly
joined MIT and Interneuron Pharmaceuticals as involuntary plaintiffs. In response, Teva
raised the defenses of noninfringement and patent invalidity.
On July 21, 2003, the district court issued a claim construction order. Thereafter,
Teva stipulated to infringement of claim 2 for purposes of a trial on the issue of validity.
Following a bench trial, the district court found that the ’998 patent is not invalid for
either anticipation or obviousness. The court then entered a final judgment that the ’998
patent was not invalid and was infringed. Teva appeals, contending that the district
court erred as a matter of law in its claim construction and committed legal and factual
errors on the issue of obviousness.
II
Teva challenges the district court’s construction of the claim limitation requiring
the composition to be administered “prior to the onset of [a woman’s] menstrual period.”
The district court construed that phrase to mean treatments administered “prior to the
onset of a woman’s menstrual period, including those that go on continuously
thereafter.” Teva argues that the district court erred by construing the claim to include
dosing regimens “that go on continuously thereafter.” Instead, Teva contends, the
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district court should have construed the term to refer to dosing “limited to administration
during part or all of the 14 days prior to her menstrual period and up to 3 days after,”
i.e., dosing limited essentially to the luteal phase only.
We disagree with Teva’s proposed claim construction. The district court’s
interpretation is consistent with both the claim and the specification, which do not limit
the dosing to the luteal phase. The claim language does not provide that dosing should
take place within a certain time frame. Rather, the claim simply states that the recited
composition should be administered “prior to the onset of [the woman’s] menstrual
period.” ’998 patent, col. 7, line 10. The specification also does not suggest a discrete
time period for dosing, but states only that dosing should begin “prior to the expected
onset of [a woman’s] menstrual period.” Id., col. 5, ll. 14-15; see id., col. 6, ll. 51-52
(providing, as an example, the administration of fluoxetine “starting two weeks prior to
the expected onset of a subject’s menstrual period”).
In support of its argument that the dosing period is limited to the luteal phase.
Teva relies on language from the specification stating that the dosing period for
fluoxetine “will generally begin 1 to 14 days prior to menstruation and may continue for
several days (e.g., 3 days) after onset of menstruation.” Id., col. 2, ll. 47-49; see id., col.
5, ll. 17-19. That statement, however, is preceded by the statement that “[t]he length of
time during which [fluoxetine] will be given varies on an individual basis.” Id., col. 2, ll.
45-46; see id., col. 5, ll. 15-16. Hence, the specification is not as restrictive as Teva
suggests and does not support limiting the dosing scheme to exclude any regimen that
includes administration of the drug outside the luteal phrase.
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Teva argues that the prosecution history supports construing the claim to permit
dosing only during the luteal phase. Teva points to the prosecution history of a parent
patent application, U.S. Patent Serial No. 111,771 (“the ’771 application”), and asserts
that the applicants added a luteal phase dosing limitation to the claims in that
application in order to overcome a rejection. Teva’s argument lacks merit because the
prosecution history merely reflects the applicant’s statement that dosing should occur
“prior to and during the late luteal phase.” That characterization of the timing
requirement indicates that dosing should take place during the luteal phase, but it does
not suggest that administration of the drug must terminate at any time. Hence, the
prosecution history does not carry the weight Teva attributes to it.
Finally, Teva argues that the district court’s claim construction is incorrect
because in the case of continuous dosing no monthly treatment regime can be said to
“begin prior to the onset of [a woman’s] menstrual period.” The claim language is
broad, and we agree with the district court that it does not exclude a regime of
continuous dosing. The language of the claim would plainly cover a treatment regime
that began, for example, 20 days before the onset of the woman’s menstrual period and
continued for eight days after the end of the period, with a two-day hiatus before the
beginning of the next treatment cycle. That being so, it would be highly artificial to hold
that the claim would cease to apply if the treatment regime were extended to include
administration of the composition during the two-day hiatus period. Although it is
awkward to characterize a continuous treatment regime as having a beginning point
each month, the claim by its terms merely requires that the treatment occur “prior to” the
onset of menses, and that plainly occurs in the case of continuous treatment. We
05-1044 5
therefore affirm the district court’s construction of the disputed claim term, at least
insofar as it applies to a regime of continuous coverage. Teva does not contest a
finding of literal infringement under the district court’s claim construction. Accordingly,
we affirm the judgment of infringement.
III
Teva challenges the district court’s conclusion that the ’998 patent is not invalid
for obviousness. Teva’s argument is based on three main assertions: (1) there was
evidence of contemporaneous invention; (2) two prior art publications would have
motivated persons of ordinary skill in the art to use fluoxetine to treat PMS; and (3) a
person of ordinary skill in the art would have had a reasonable expectation of success in
using fluoxetine to treat PMS. Teva also argues that the district court applied the wrong
legal standard in its obviousness analysis.
Teva contends that the district court confused the standard for obviousness
under section 103 with the standard for anticipation under section 102. Teva points to
the court’s statements that “one would not find a single reference[ ] suggesting the use
of fluoxetine to treat PMS” and that, prior to the ’998 patent application, “no one
suggested the use of fluoxetine or fenfluramine . . . to treat PMS.” In context, however,
those statements appear to be simply an explanation of the reasons the district court
found that Teva had failed to prove by clear and convincing evidence that the ’998
patent is invalid. In setting forth the legal standard for obviousness, the district court
made clear that a single anticipating reference is not necessary and correctly stated that
a “motivation to combine references and the reasonable expectation of success must be
05-1044 6
found in the prior art, the knowledge of one of ordinary skill in the art, or, in some cases,
from the nature of the problem to be solved.”
Teva argues that the evidence showed contemporaneous invention. Teva relies
on a study by Dr. Wilma Harrison, entitled “Treatment of Premenstrual Exacerbation of
Chronic Mild Depression with Fluoxetine: A Pilot Study,” and a study by Dr. Andrea
Stone, entitled “Assessment of Fluoxetine in the Treatment of Premenstrual Syndrome.”
Both studies proposed the use of fluoxetine to treat PMS. The Harrison proposal was
dated about four months after the filing date of the ’998 patent, and the Stone proposal
was dated about nine months after the filing date. The district court found those studies
to be “irrelevant to a § 103 obviousness analysis” based on its finding that Dr. Harrison
and Dr. Stone were not persons of ordinary skill in the art. The court ruled that the
theoretical person of ordinary skill in the art is a “physician who both treats patients [with
PMS] and is familiar with the relevant literature,” and that research clinicians, such as
Dr. Harrison and Dr. Stone, fall outside of that category because they are persons of
“extraordinary” skill in the art. Teva argues that the district court’s determination
regarding the level of skill of a person of ordinary skill in the art is incorrect and that the
district court’s error requires reversal because the two clinical studies render the ’998
patent obvious.
Even if the district court was incorrect in stating that research clinicians were not
persons of ordinary skill in the art, any error in that regard was harmless, because
notwithstanding its statement about the level of skill in the art, the district court went on
to consider the Harrison and Stone studies in its obviousness analysis and found that
they did not render the asserted claim invalid. Thus, the court explained that “[e]ven if
05-1044 7
we were to consider [both studies], it supports only an ‘obvious to try’ theory,” not a
finding of obviousness. The district court based its conclusion in part on its finding that
at the time Dr. Harrison and Dr. Stone proposed fluoxetine for treating PMS, they had
already considered or were also simultaneously considering other drugs for treating
PMS. The district court also relied on (1) the testimony of Dr. Richard Wurtman, one of
the inventors of the ’998 patent, who testified that at the time he conducted his case
study of fluoxetine, he did not know what to expect; and (2) the testimony of Dr. Jean
Endicott, one of Lilly’s expert witnesses, who testified that she had undertaken similar
studies that did not meet with success. Teva does not challenge the findings underlying
the district court’s conclusion that the studies only make fluoxetine “obvious to try.”
Because we conclude that the district court did not clearly err in making those findings,
we reject Teva’s argument on this issue.
Teva next argues that the ’998 patent is rendered obvious in view of an article by
Dr. Andrea Rapkin, entitled “Whole-Blood Serotonin in Premenstrual Syndrome,” 70
Obstetrics & Gynecology 533 (1987), and an article by Dr. Barbara Parry, entitled
“Therapeutic Effect of Sleep Deprivation in Patients With Premenstrual Syndrome,” 144
Am. J. Psychiatry 6 (1987).
The Rapkin article compared blood serotonin levels in women with PMS to blood
serotonin levels in asymptomatic women. Dr. Rapkin found a lower level of serotonin in
patients with PMS. Teva argues that the district court failed to give sufficient weight to
the teachings of the Rapkin article because the court found it was not prior art, since it
was published less than one year before the filing date of the ’998 patent. Prior art for
purposes of determining obviousness includes all publications predating the invention,
05-1044 8
which in this case is the filing date of the ’998 patent. See Richardson-Vicks Inc. v.
Upjohn Co., 122 F.3d 1476, 1480 (Fed. Cir. 1997). Accordingly, the district court erred
in finding that the Rapkin article did not qualify as prior art. That error is harmless,
however, because notwithstanding its legal error the court considered the substance of
the Rapkin article in its obviousness analysis. After considering the article, the court
found that, at most, it merely “invited those of ordinary skill in the art to explore further
the relationship of serotonin to PMS.” The court observed that the Rapkin article did not
suggest to a person of ordinary skill in the art that fluoxetine should be used to treat
PMS. Instead, the Rapkin article pointed to tryptophan and trazodone as possible
treating agents, not fluoxetine. Furthermore, the court found that the article “showed
that women with PMS had lower serotonin levels throughout the menstrual cycle, as
compared with women who did not have PMS.” The court also found, based on
evidence at trial, that fluoxetine decreases whole blood serotonin levels. Accordingly,
the court concluded that the Rapkin article taught away from the use of fluoxetine to
treat PMS, because one skilled in the art at the time “would want to increase whole
blood serotonin levels,” while fluoxetine “does the opposite; it decreases, not increases,
whole blood serotonin.” Therefore, the court concluded, “one skilled in the art who was
relying on Rapkin’s data would not have been motivated to use fluoxetine to treat PMS.”
The court’s findings with regard to the Rapkin article are not clearly erroneous,
particularly in light of the absence of any suggestion in the article to use fluoxetine in
PMS treatments and the seemingly contrary indication suggested by the data regarding
the effect of fluoxetine on serotonin blood levels. We therefore reject Teva’s argument
05-1044 9
that the district court erred in concluding that the ’998 patent would not have been
obvious in light of the Rapkin article.
The Parry article reported results showing positive, albeit temporary, effects of
total or partial sleep deprivation on PMS. The district court found that the Parry article
was not prior art because it was not published more than a year before the effective
date of the ’998 patent. Teva argues that the district court’s failure to consider the Parry
article constituted clear error because the article was relevant to the issue of
obviousness. We agree with Teva that, as in the case of the Rapkin article, the district
court erred by finding that the Parry article did not qualify as prior art. Once again,
however, that error is not fatal to the district court’s decision. The district court
recognized that the article demonstrated that Dr. Parry was “motivated to test the effect
of sleep deprivation . . . on PMS because ‘[p]remenstrual syndrome and affective
disorders may be related illnesses.’” The court made that statement in a footnote to a
paragraph in which the court found that “[a]s of October 1987, those skilled in the art
were just beginning to discover the relationship between affective disorders and PMS.”
Teva does not challenge that finding, but merely asserts that the possible link between
PMS and affective disorders, which was the subject of the Parry article, demonstrates
that “[a] person of ordinary skill in the art would likewise be motivated to use [fluoxetine]
to treat PMS” because “fluoxetine was known to be effective in the treatment of major
depressive disorder.” Teva has pointed to no evidence supporting its assertion,
however. Nor has it shown that the district court committed error in finding that the
Parry article demonstrates only a motivation to try treatments used for affective
05-1044 10
disorders on PMS patients. Accordingly, Teva has failed to show that the district court
clearly erred in finding that the Parry article fails to render the ’998 patent obvious.
Finally, Teva argues that the district court committed clear error in finding that a
person of ordinary skill in the art would not have had a reasonable expectation of
success in using fluoxetine to treat PMS. Teva maintains that a person of ordinary skill
in the art would have found the method of the ’998 patent to be obvious because the
claimed method treats particular symptoms of PMS (i.e., “disturbances of mood,”
“disturbances of appetite,” or both) as opposed to treating PMS as a whole, and
because a person of ordinary skill in the art would have known that fluoxetine has
already been demonstrated to be effective for treating depression. Teva relies too
heavily on the distinction between treating PMS as a whole and treating its symptoms.
Relying on expert testimony by Teva’s expert, Dr. Laura Miller, the district court found
that even if a person of ordinary skill in the art as of the filing date of the ’998 patent
sought to treat depression alone as a symptom, such a person would have viewed anti-
depressants as unsatisfactory to treat PMS-related depression because of the negative
side effects and perceived stigma associated with antidepressants. The district court’s
reliance on Dr. Miller’s testimony and the conclusion it reached based on that testimony
did not constitute clear error. Accordingly, we affirm the district court’s determination
that the ’998 was not invalid on the basis of obviousness.
MAYER, Circuit Judge, dissents.
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