Eli Lilly and Co. v. Teva Pharmaceuticals Usa, Inc. , 619 F.3d 1329 ( 2010 )

United States Court of Appeals
for the Federal Circuit
__________________________
ELI LILLY AND COMPANY,
Plaintiff-Cross Appellant,
v.
TEVA PHARMACEUTICALS USA, INC.,
Defendant-Appellant.
__________________________
2010-1005, -1033
__________________________
Appeals from the United States District Court for the
Southern District of Indiana in case no. 06-CV-1017,
Judge Sarah Evans Barker.
___________________________
Decided: September 1, 2010
___________________________
CHARLES E. LIPSEY, Finnegan, Henderson, Farabow,
Garrett & Dunner, LLP, of Reston, Virginia, argued for
plaintiff-cross appellant. With him on the brief were L.
SCOTT BURWELL; DAVID S. FORMAN, HOWARD W. LEVINE,
LAURA P. MASUROVSKY, MARK J. FELDSTEIN, and J. DEREK
MCCORQUINDALE, of Washington, DC. Of counsel on the
brief was GILBERT T. VOY, Eli Lilly and Company, of
Indianapolis, Indiana.
EDWARD H. RICE, Loeb & Loeb LLP, of Chicago, Illi-
nois, argued for defendant-appellant. With him on the
ELI LILLY v. TEVA PHARMA 2
brief were MARINA N. SAITO, STEVEN M. LUBEZNY and
JULIE P. SAMUELS.
__________________________
Before RADER, Chief Judge, LINN and PROST, Circuit
Judges.
RADER, Chief Judge.
Following an 11-day bench trial, defendant Teva
Pharmaceuticals USA, Inc. (“Teva”) appeals the district
court’3s permanent injunction preventing any manufac-
ture or distribution of a generic version of the drug
Evista® until the expiration of U.S. Patent Nos. 6,906,086
(the “’086 patent”); RE39,049 (the “’049 patent”);
RE38,968 (the “’968 patent) (collectively the “Bone Loss
Patents”); and RE39,050 (the “’050 patent” or the “Low
Dose Patent”). See Eli Lilly & Co. v. Teva Pharms. USA,
Inc., 657 F. Supp. 2d 967 (S.D. Ind. 2009). Plaintiff Eli
Lilly & Co. (“Lilly”) cross appeals the district court’s
ruling that certain claims of its U.S. Patent Nos.
6,458,811 (the “’811 patent”) and 6,894,064 (the “’064
patent”) are invalid for lack of written description. De-
tecting no reversible error, this court affirms.
I
A
Osteoporosis is a major debilitating disease that
causes loss of bone mass (decreased density and enlarge-
ment of bone spaces) without a reduction in bone volume.
Thus, osteoporosis makes bones porous and fragile.
Healthy human bones go through a number of
changes over time, in part due to remodeling. Bone
remodeling is the process by which a portion of the bone
called the trabecular portion is removed and then re-
placed. The first stage of remodeling is bone absorption,
3 ELI LILLY v. TEVA PHARMA
whereby certain cells essentially dig out part of the bone
and remove it. The second stage of the remodeling proc-
ess is bone formation, or resorption, during which differ-
ent cells replace the bone that was lost via absorption.
In healthy adults, the skeletal mass remains constant
throughout the remodeling process because the amount of
bone that is lost is replaced in similar amounts. With the
onset of osteoporosis, the remodeling process does not
completely replace the lost bone mass. Thus, more bone is
removed than is replaced. Accordingly, remodeling leaves
a thinner, weaker bone.
Osteoporosis is largely a consequence of a lack of suf-
ficient estrogen in the system. Before menopause, estro-
gen naturally slows the process of remodeling in women,
essentially acting as a “brake” on the process. Following
menopause, when women’s bodies lose significant levels of
systemic estrogen, the remodeling process becomes more
vigorous. Osteoporosis is a relatively common condition:
approximately one in two women beyond the age of fifty
suffers an osteoporotic fracture at some point during the
remainder of their lives.
Because osteoporosis results mainly from a lack of es-
trogen in the system following menopause, the principal
treatment, historically, for postmenopausal osteoporosis
has been estrogen replacement therapy (“ERT”). ERT
successfully prevents bone loss as well as fractures. ERT,
however, presents other problems, including increased
risk of both breast and uterine cancer. Therefore, re-
searchers sought a therapeutic remedy to treat and pre-
vent postmenopausal osteoporosis that would act like
estrogen in preventing bone loss but would not cause
damaging side effects in other tissues.
ELI LILLY v. TEVA PHARMA 4
B
Evista® treats postmenopausal osteoporosis. The ac-
tive ingredient in Evista® is raloxifene hydrochloride.
Raloxifene is part of a class of compounds known as
antiestrogens, which were originally developed for the
treatment of estrogen-dependent breast cancer. A large
number of breast cancers are estrogen dependent, which
means that estrogen stimulates their growth. Antiestro-
gens work to inhibit the growth of a cancer by binding to
estrogen receptors in breast cancer cells, thereby blocking
the action of the estrogen.
Antiestrogens, however, often carry side effects simi-
lar to the side effects of estrogen itself. Researchers
discovered that when certain antiestrogens were not
competing with estrogen for receptors (i.e., when there
was little estrogen already in the system, such as in
postmenopausal women), the antiestrogens were found to
have a stimulatory estrogenic effect in the uterus. This
effect was ultimately associated with an increased risk of
endometrial cancer.
Various antiestrogens mimic the effect of estrogen in
varying degrees, and the degree to which a particular
antiestrogen mimics estrogen is referred to as its intrinsic
estrogenicity. One of the first clinically successful anti-
estrogens used in the treatment of breast cancer, ta-
moxifen, has significant intrinsic estrogenicity.
C
Researchers at Lilly first synthesized and tested the
molecule now known as raloxifene in the late 1970s in an
effort to find a purer antiestrogen that would have posi-
tive effects in breast tissue but less damaging effects in
the uterus. Dr. C. David Jones and Mr. Larry Black, the
5 ELI LILLY v. TEVA PHARMA
ultimate inventor of the Bone Loss patents, first identified
that molecule as “LY156758.”
Mr. Black published his findings in an abstract enti-
tled “LY156758: A Unique Antiestrogen Displaying High
Affinity for Estrogen Receptors, Negligible Estrogenic
Activity and Near-Total Estrogen Antagonism In Vivo.”
In that abstract, published in 1982, Mr. Black reported
that raloxifene produced a very minimal increase in
uterine weight in rats (one measure of a compound’s
intrinsic estrogenicity), while tamoxifen caused marked
uterine growth.
Lilly completed pharmacokinetic tests of raloxifene,
also referred to as “Phase I” tests, in September and
October of 1982. A Phase I test is a safety test used
generally in the drug development process before clinical
trials in patients can begin. The results of Lilly’s Phase I
tests on raloxifene, as reported in Lilly’s internal docu-
ments, revealed that the bioavailability of raloxifene was
low. In other words, very little of the ingested raloxifene
was detected in the human bloodstream.
The results of Lilly’s Phase I tests were similar to the
results of others published by Dr. Terry Lindstrom, an-
other Lilly scientist, in 1983 and 1984. Dr. Lindstrom
conducted various animal studies using raloxifene in
which he found that the bioavailability of raloxifene was
approximately 39% in rats, 17% in dogs, and 5% in mon-
keys. Dr. Lindstrom’s study did not test whether, despite
the bioavailability problem, raloxifene had any effect on
the animals.
Although attempts at measuring the parent raloxifene
in Lilly’s Phase I tests had been unsuccessful, the human
volunteers showed a considerable amount of raloxifene
conjugated to glucuronide in their serum. A conjugate
ELI LILLY v. TEVA PHARMA 6
forms when a molecule in the body attaches to the admin-
istered (i.e., “parent”) compound.
Unlike tamoxifen, the chemical structure of raloxifene
includes two free hydroxyl groups, which enable the liver
to rapidly metabolize the raloxifene. In the vast majority
of compounds, the process of glucuronidation serves to
deactivate the drug. At least one compound, however,
was known to be active in conjugated form (morphine-6),
and certain enzymes were known to be able to reverse the
effects of conjugation.
A number of researchers outside Lilly also published
articles that discussed raloxifene’s rapid metabolic con-
version. For example, in a 1983 article A.E. Wakeling
addressed the decreased potency of several compounds,
including raloxifene, when administered orally versus
when administered subcutaneously. Dr. Craig Jordan
also stated in a 1983 publication that an analog to
raloxifene with a similar chemical structure “should be
classified as an ultra short-acting estrogen antagonist”
when compared to tamoxifen. J.A. 9929. And in 1984,
Dr. Jordan published a review article in which he dis-
cussed the hydroxylation of compounds such as raloxifene
and stated that “[c]learly this will facilitate a rapid me-
tabolism and excretion of those compounds.” J.A. 9929.
Following the Phase I tests, Lilly concluded that “it
[was] not appropriate to go directly into breast cancer as
first line therapy with a compound so extensively conju-
gated and possibly poorly bioavailable since other forms of
therapy are available.” J.A. 9842. A clinical trial for
raloxifene was then initiated in 1985 under the direction
of Dr. Aman Buzdar for female breast cancer patients
whose cancer had not responded to tamoxifen. Dr. Buz-
dar published the results of his study in a 1988 article
titled “Phase II Evaluation of Ly156758 in Metastatic
7 ELI LILLY v. TEVA PHARMA
Breast Cancer.” In that article, Dr. Buzdar reported that,
with the exception of one minor response, raloxifene
produced no complete or partial responses. From these
results, Dr. Buzdar concluded that raloxifene “did not
show any antitumor activity . . . and no further evaluation
of this drug is recommended.” J.A. 6867. Although Dr.
Buzdar’s reports do not attribute raloxifene’s lack of
efficacy to a bioavailability problem, Lilly’s Dr. Lindstrom
testified at trial that he believed the breast cancer trials
had failed for that reason. J.A. 3091 at 366:9-367:4.
D
Shortly after completing its Phase I tests on
raloxifene, Lilly undertook an effort to determine whether
raloxifene could still have efficacy notwithstanding its
rapid conjugation. Mr. Black conducted studies on the
raloxifene conjugate that led him to two conclusions.
First, Mr. Black concluded that the lack of detectable
parent compound did not necessarily preclude efficacy.
Second, he concluded that, under physiological conditions,
the conjugate could possibly be converted back to the
parent compound. The results of these experiments,
which Mr. Black obtained before Dr. Buzdar conducted
his breast cancer trials, were not published.
After Mr. Black conducted those conjugate studies, he
conducted experiments to study the effects of raloxifene
on bone in various ovariectomized rat models. The results
of those experiments showed that raloxifene prevented
bone loss in that model. Lilly’s Project Team Approval
Committee (PTAC) then approved a human clinical trial
of raloxifene in postmenopausal women for the treatment
of postmenopausal osteoporosis in November of 1991. The
PTAC meeting, however, featured significant concerns
regarding bioavailability. Many of the members ex-
pressed reluctance to go forward with a compound that
ELI LILLY v. TEVA PHARMA 8
exhibited known bioavailability issues. According to Dr.
Thomas Bumol, a member of PTAC at the time, the
committee gave its approval for the clinical test despite
these concerns, at least in part because Lilly already had
an open Investigative New Drug (IND) approval on
raloxifene from the Food and Drug Administration (FDA).
This IND approval would permit Lilly to conduct clinical
tests within six months, rather than the usual twelve to
twenty-four months.
E
Before the results of the PTAC-approved clinical
study had been collected, Lilly filed its patent application
for what became the Bone Loss Patents. (All citations to
the three Bone Loss Patents, which share the same speci-
fication, are to the ’086 patent.) Because the study results
were still pending at that time, the Bone Loss Patents
contain no clinical human data. Example 5 in the Pat-
ents, however, set forth the blueprint for the PTAC-
approved clinical study. This example specifies doses of
200 mg and 600 mg of raloxifene per day. Example 1 of
the Bone Loss Patents explains Mr. Black’s study on
ovariectomized rats. The patent specification also dis-
closed publicly for the first time Mr. Black’s studies of the
glucoronide conjugate and explained that the rapid conju-
gation of raloxifene would not necessarily undermine its
efficacy in humans.
The U.S. Patent Office (PTO) rejected the original
parent application to the Bone Loss Patents, based on an
article published by Dr. Jordan, et al., in 1987 entitled
“Effects of anti-estrogens on bone in castrated and intact
female rats” (the “Jordan Reference”). Following these
rejections, Lilly scientist Dr. Henry Bryant submitted a
declaration in which he attacked the methodology behind
and the credibility of the conclusions in the Jordan Refer-
9 ELI LILLY v. TEVA PHARMA
ence. The PTO subsequently allowed the parent applica-
tion to the Bone Loss Patents.
Claim 1 of the ’086 patent is representative and pro-
vides:
A method of inhibiting post-menopausal bone loss
in a post-menopausal woman in need of treatment
to prevent or treat post-menopausal osteoporosis
comprising administering a single daily oral dose
to said woman of an effective amount of
[raloxifene] hydrochloride.
F
In May 1992, enrollment began for Lilly’s Phase II,
proof-of-concept study, referred to as the “GGGB” study,
to test raloxifene’s efficacy in humans as described in
Example 5 of the ’086 patent. Dr. Michael Draper con-
ducted that study. The results of that study unequivo-
cally demonstrated activity in humans at both the 200 mg
and the 600 mg doses of raloxifene.
After the results of the GGGB study showed activity
in humans, Dr. Draper designed and conducted a “GGGC”
study to further characterize the dose response curve of
raloxifene. The GGGC study was the first of a number of
dose-ranging studies conducted by Lilly in order to deter-
mine the minimal effective dose of raloxifene. Dr. Draper
chose 10, 50, and 200 mg/day doses for the GGGC study.
Based on the results of the GGGC study, Lilly filed its
application for what became the Low Dose Patent on May
2, 1994, naming Dr. Draper and Mr. Black as the inven-
tors. Claim 14 of the Low Dose Patent is representative
and reads as follows (emphasis added):
ELI LILLY v. TEVA PHARMA 10
A method of preventing post-menopausal osteopo-
rosis in a post-menopausal woman in need of
treatment to prevent post-menopausal osteoporo-
sis comprising administering to said woman a hy-
drochloride salt of . . . [raloxifene] in an amount of
60 mg/day.
G
The core concept of Lilly’s ’811 and ’064 patents (col-
lectively the “Particle Size Patents”) is to process
raloxifene particles until their size falls “within a speci-
fied narrow range.” ’811 patent, col.3 ll.15-18. (All refer-
ences to the two Particle Size Patents, which share the
same specification, are to the ’811 patent.) The Particle
Size Patents disclose that, within the claimed particle size
range, the raloxifene particles provide “surprisingly
consistent in vivo absorption/bioavailability characteris-
tics.” Id. at col.29 ll.17-20. The patents also teach that
restricting raloxifene’s particle size to the claimed limits
results in manufacturing benefits. Representative claim 1
of the ’811 patent recites (emphasis added):
A compound of formula I . . . [raloxifene] and
pharmaceutically acceptable salts and solvates
thereof, characterized in that the compound is in
particulate form, said particles having a mean
particle size of less than about 25 microns, at least
about 90% of said particles have a size of less than
about 50 microns.
II
Teva filed Abbreviated New Drug Application
(“ANDA”) No. 78-193 with the FDA for raloxifene hydro-
chloride 60 mg tablets for the prevention of osteoporosis
in postmenopausal women. Under 21 U.S.C. §
11 ELI LILLY v. TEVA PHARMA
355(j)(2)(A)(vii)(IV), Teva’s ANDA included a “Paragraph
IV Certification” to Lilly’s patents for Evista®, certifying
that each of those patents is invalid, unenforceable, or
would not be infringed by Teva’s manufacture, use, or sale
of its generic raloxifene product. After receiving notice of
the Paragraph IV Certification, Lilly brought this patent
infringement suit on the Bone Loss Patents, the Low Dose
Patent, and the Particle Size Patents.
Following trial, the district court ruled that Teva did
not show that the Bone Loss Patents or the Low Dose
Patent would have been obvious to one of skill in the art
or that those patents were invalid for lack of enablement.
The district court concluded that the Particle Size Pat-
ents, however, did not comply with the written description
requirement of § 112. This court has jurisdiction under
28 U.S.C. § 1295(a)(1).
III
Under 35 U.S.C. § 103, a patent claim is invalid “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.” An accused infringer must prove invalidity by
clear and convincing evidence. Robotic Vision Sys., Inc. v.
View Eng’g, Inc., 189 F.3d 1370, 1377 (Fed. Cir. 1999).
“On appeal from a bench trial, the ultimate determination
of whether an invention would have been obvious under
35 U.S.C. § 103 is a legal conclusion that we review de
novo.” Id. at 1376. An obviousness determination, how-
ever, is based on underlying factual inquiries including:
(1) the scope and content of the prior art; (2) the level of
ordinary skill in the art; (3) the differences between the
claimed invention and the prior art; and (4) objective
evidence of nonobviousness. Id.; see KSR Int’l Co. v.
ELI LILLY v. TEVA PHARMA 12
Teleflex Inc., 550 U.S. 398, 405 (2007). This court reviews
those underlying factual determinations for clear error.
Ruiz v. A.B. Chance Co., 234 F.3d 654, 663 (Fed. Cir.
2000).
A
The district court concluded that the widely reported
bioavailability concerns would have precluded a person of
ordinary skill in the art from reasonably expecting to
successfully treat postmenopausal osteoporosis with
raloxifene. On appeal, Teva primarily relies on three
prior art references to argue that the Bone Loss Patents
would have been obvious notwithstanding the published
concerns regarding raloxifene’s bioavailability: (1) U.S.
Patent No. 5,075,321 (the “Schreiber Patent”); (2) the
Jordan Reference, and (3) U.S. Patent No. 4,418,068 (the
“Jones Patent”). Teva also argues that Lilly’s own actions
demonstrate that the district court’s bioavailability find-
ings were clearly erroneous. To the contrary, Teva points
to no evidence from before the time of invention that
would teach, suggest, or motivate or supply any common
sense reason for a person of ordinary skill in the art to
reject the bioavailability concerns and routinely, simply,
or easily arrive at the inventive result.
1
In 1988, Dr. Alan Schrieber from the University of
Pennsylvania filed an application for a patent claiming
the use of raloxifene to treat human autoimmune disor-
ders. As a result of that application, the Schrieber Patent
issued on December 24, 1991. The Schrieber Patent is a
continuation-in-part of an application that Dr. Schrieber
filed in March of 1987. The Schreiber Patent suggests
clinical uses for raloxifene, namely, the treatment of
autoimmune diseases. The Schreiber Patent relies solely
on animal studies.
13 ELI LILLY v. TEVA PHARMA
The year before he filed his application for the Schrie-
ber Patent, Dr. Schrieber visited Lilly to propose develop-
ing raloxifene for the treatment of autoimmune diseases.
A group of Lilly scientists who had been associated with
the Phase I clinical trial convened to discuss Dr. Schrie-
ber’s proposal. On October 5, 1987, shortly before Dr.
Buzdar published his Phase II Study results with respect
to breast cancer, Lilly informed Dr. Schrieber that it had
decided to reject his proposal, stating, “Not insignificant
in our consideration of [raloxifene] are [sic] the disap-
pointing bioavailability results observed during our Phase
I clinical trial.” J.A. 10022.
At trial, Dr. Schreiber, testified that Lilly disclosed
the adverse bioavailability findings of the Phase I clinical
trial to him during his visit. In a subsequently published
article, Dr. Schreiber referenced that disclosure and
acknowledged that raloxifene “appears to have a short
serum half-life, which may be a result of rapid biotrans-
formation.” J.A. 6880. Nonetheless, the publication
stated that antiestrogens such as raloxifene “may repre-
sent an alternative therapeutic approach” for autoim-
mune disorders. Id.In 2003, Lilly filed reissue patent applications for two
of the Bone Loss Patents in light of the Schrieber Patent.
Lilly sought to clarify that the claims of its patents were
directed strictly to the treatment of postmenopausal bone
loss and did not also encompass the treatment of autoim-
mune disorders. The PTO reissued the two Bone Loss
Patents in 2006.
As noted, the district court concluded that one of skill
in the art would have been dissuaded from using
raloxifene to treat postmenopausal osteoporosis in light of
published bioavailability data. Teva argues that this
conclusion was clearly erroneous because the Schrieber
ELI LILLY v. TEVA PHARMA 14
Patent’s disclosure that raloxifene could be used for
autoimmune disorders would have suggested to one of
skill in the art that raloxifene’s low bioavailability in
humans could be ignored when looking for a treatment for
postmenopausal osteoporosis.
The record, however, does not leave this court with a
“definite and firm conviction” that the district court made
a mistake. Ruiz, 234 F.3d at 663 (internal quotation
marks omitted). The record simply does not contain
sufficient evidence that would allow this court to conclude
that Dr. Schrieber’s decision to continue to suggest
raloxifene as a treatment for autoimmune disorders in the
face of bioavailability concerns would influence a person
of ordinary skill to pursue a treatment for postmeno-
pausal osteoporosis.
As an initial matter, the record does not indicate that
autoimmune disorders can cause osteoporosis. Although
some evidence suggests that a person of ordinary skill
might appreciate a connection between osteoporosis and
autoimmune disorders―such as Lilly’s decision to seek to
reissue its patents due to the Schrieber Patent―Teva
itself appears less certain. See Teva Post-trial Brief (Dist.
Ct. Dkt # 645) at 13 (noting that autoimmune diseases
only “arguably include some forms of osteoporosis”).
The record shows that Teva was not able to show a
credible connection between the type of osteoporosis at
issue in this case―postmenopausal osteoporosis―and
autoimmune diseases. Contrary to Teva’s assumption,
the record indicates that raloxifene combats the two
diseases differently. Dr. Schrieber’s article explains that
raloxifene treats autoimmune disorders by disrupting the
effect that estrogen has on immunoglobulin G-coated
erythrocytes (IgC-coated cells). On the other hand,
raloxifene treats postmenopausal osteoporosis by dupli-
15 ELI LILLY v. TEVA PHARMA
cating the effect that estrogen has on the bone-remodeling
process. Without a closer relationship, Teva cannot show
that an ordinarily skilled artisan would have expected Dr.
Schrieber’s article to have relevance for the treatment of
postmenopausal osteoporosis.
Instead, Teva suggests that “the bioavailability issue
has nothing to do with bone loss specifically; it simply
addresses whether raloxifene is biologically active in
humans at all.” Appellant’s Reply Br. at 4; see id. (“If
people in the art at the time reasonably believed that
raloxifene might be active in humans, then raloxifene’s
ability to treat human bone loss would have been obvi-
ous.”). And Teva separately highlights that Dr. Schrie-
ber―and Lilly when it rejected Dr. Schrieber’s
proposal―cited the same bioavailability concerns that
were thought to preclude raloxifene’s efficacy as a treat-
ment for breast cancer.
These arguments and proposed inferences cannot
overcome the dual problems with the Schreiber Patent.
In the first place, as discussed, a person of ordinary skill
would not have drawn a connection between Dr. Schrei-
ber’s proposed treatment of autoimmune diseases in
humans and a treatment for a very different condition.
This new use of raloxifene would not have been readily
apparent as a likely successful application for a compound
that might fight autoimmune diseases. Beyond that, Dr.
Schrieber’s bare proposal to use raloxifene in humans to
treat autoimmune diseases, based only on animal studies,
is insufficient to require a finding that an ordinary skilled
artisan would have expected that a compound with known
bioavailability issues―and known clinical failures―would
successfully treat any human condition.
ELI LILLY v. TEVA PHARMA 16
2
The same year that Lilly rejected Dr. Schrieber’s pro-
posal, Dr. Jordan conducted a study on intact and ovariec-
tomized 9-month-old retired breeder rats to determine the
effects of tamoxifen and raloxifene (then called “ke-
oxifene”) on bone density. The research community
sought additional insight to address the concern that
long-term tamoxifen treatment in breast cancer patients
could lead to premature bone loss. In October 1987, the
results of that study were published in the Jordan Refer-
ence.
The Jordan Reference reported that both tamoxifen
and raloxifene inhibited bone loss in overiectomized rats.
The study went on to report that raloxifene had a mini-
mal estrogenic response in the uterus. Dr. Jordan con-
cluded that these results “may have important
implications for the clinical [human] applications of
antiestrogens.” J.A. 6852. He further stated that “[i]t is
possible . . . that in the future, tamoxifen could be consid-
ered to be used as a substitute for estrogen [for the pre-
vention of osteoporosis in postmenopausal women].” Id.(emphasis added). Dr. Jordan called for clinical work on
tamoxifen to extend the rat studies to humans:
These contrasting pharmacological actions of an-
tiestrogens suggest that patients receiving long-
term adjuvant tamoxifen therapy for breast can-
cer should be evaluated to determine whether ta-
moxifen can retard the development of
osteoporosis.
J.A. 6849. The Jordan Reference did not propose further
development of raloxifene to treat or prevent postmeno-
pausal osteoporosis. At the time, the FDA had only
approved tamoxifen for clinical use in humans.
17 ELI LILLY v. TEVA PHARMA
According to the district court, the Jordan Reference
exemplified the bioavailability concerns because, after
reporting successful tests with both tamoxifen and
raloxifene, it “suggested that tamoxifen could possibly be
considered for the prevention of osteoporosis in postmeno-
pausal women, but included no specific suggestion that
raloxifene could have such clinical use.” Eli Lilly, 657 F.
Supp. 2d at 1005. The Jordan Reference’s preference for
tamoxifen, coupled with “the extensive evidence adduced
at trial regarding bioavailability concerns associated with
raloxifene in humans and the fact that Dr. Jordan himself
had published at the time regarding the rapid metabolism
of compounds with free hydroxyl groups, such as
raloxifene, suggesting its unsuitability for this purpose,”
led the district court to conclude that a person of skill
“would not have had a reasonable expectation of success
in using raloxifene to treat human postmenopausal osteo-
porosis.” Id. at 1005-06. This court detects no error in
these findings or conclusions.
On appeal, Teva relies on the results of the study de-
scribed in the Jordan Reference, which showed that
raloxifene, as well as tamoxifen, inhibited bone loss. Teva
also relies on Dr. Jordan’s conclusion that those results
“may have important implications for the clinical [i.e.,
human] applications of antiestrogens.” Teva argues that
a person of ordinary skill in the art would have relied on
Dr. Jordan’s results and conclusion to consider raloxifene
as a treatment for postmenopausal osteoporosis. To
bolster its argument, Teva points to an internal Lilly
communication from 1989 in which the Chairman of
Lilly’s Bone Biology Group acknowledged that “Craig
Jordan has already published a paper relating to
[raloxifene’s] potential in bone related disorders.” J.A.
7046. Teva also points to a statement, made by Dr.
Russell Turner in 1997 during an FDA advisory meeting
ELI LILLY v. TEVA PHARMA 18
for raloxifene, that Dr. Jordan’s study was “very, very
good at predicting the actions of pharmacological agents
on the skeleton at least regarding estrogen deficiency
induced bone loss.” J.A. 7209-10. Teva also highlights
that when the PTO rejected the Bone Loss Patents in
light of the Jordan Reference, Lilly attacked the method-
ology underlying Dr. Jordan’s experiments rather than
relying on bioavailability concerns.
The district court did not clearly err in relying on the
Jordan Reference to support its conclusion that the Bone
Loss Patents would not have been obvious. The reference
itself clearly supports the district court’s conclusion that
Dr. Jordan preferred tamoxifen over raloxifene. Teva’s
reliance on the statement by Lilly’s Bone Biology Group
Chairman is unavailing because he had more knowledge
than one of ordinary skill in the art, namely, the results of
Black’s unpublished conjugate studies, which demon-
strated that raloxifene was effective notwithstanding its
rapid conjugation. Thus, he would have likely viewed the
Jordan Reference differently. Similarly, Teva mischarac-
terizes Dr. Turner’s 1997 statement, which stands for
nothing more than the unremarkable conclusion that Dr.
Jordan’s rat models turned out to accurately predict what
happened in humans. Dr. Turner’s statement does not
suggest that five years earlier one of ordinary skill in the
art would have understood the Jordan Reference to have
overcome the bioavailability concerns associated with
raloxifene. Finally, that a patentee used one argument to
successfully overcome an office action rejection in light of
a piece of prior art does not, by itself, diminish the
strength of other arguments that otherwise effectively
reduce the significance of that prior art. This court,
therefore, perceives that this record does not show that
the prosecution history of the Bone Loss Patents creates a
difficulty for the trial court’s finding of nonobviousness.
19 ELI LILLY v. TEVA PHARMA
3
Dr. Jones applied for the Jones Patent in 1981,
shortly after Lilly first synthesized raloxifene. The Jones
Patent, which issued in 1983, covers a class of compounds
that includes raloxifene. The Jones Patent teaches that
the claimed compounds have less inherent estrogenicity
and that “use in human subjects is preferred.” Col.34
l.26. Teva argues that the Jones Patent discloses using
raloxifene for the treatment of breast cancer, which
indicates that raloxifene’s proclivity for conjugation was
not a deterrence.
The Jones Patent does not help Teva overcome con-
cerns about bioavailability that would have prompted one
of ordinary skill in the art to look elsewhere for a post-
menopausal osteoporosis treatment. The Jones Patent
was filed before Lilly had published its failures in testing
raloxifene as a treatment for breast cancer and before
publications by Dr. Jordan, Dr. Lindstrom, and others
that highlighted the bioavailability problems associated
with raloxifene. The record does not contain any reason
that a person of ordinary skill would have ignored those
later publications.
4
Teva also argues that Lilly’s pursuit of raloxifene as a
treatment for both breast cancer and postmenopausal
osteoporosis indicates that a person of ordinary skill
would have had a reasonable expectation that raloxifene
would be useful in humans despite its chemical structure.
Teva argues that at the time it performed the Buzdar
study, “Lilly scientists . . . had to have a basis for rea-
sonably believing raloxifene would work in humans.”
Appellant’s Br. at 29.
ELI LILLY v. TEVA PHARMA 20
The record belies this argument for two reasons.
First, the record will not allow this court to conflate Lilly
scientists with those of ordinary skill in the art. See KSR,
550 U.S. at 420 (“The question is not whether the combi-
nation was obvious to the patentee but whether the
combination was obvious to a person of ordinary skill in
the art.”). The district court found, and the parties do not
dispute, that the level of ordinary skill in the art for the
Bone Loss Patents was a bachelor’s degree in a scientific
discipline with basic knowledge about (1) animal studies
and their usefulness in osteoporosis research and (2) how
bioavailability characteristics relate to the success of a
drug. The Lilly researchers had both knowledge and
credentials superior to the ordinary artisan. Second, and
perhaps more importantly, the record shows that the
Buzdar study failed. In light of Dr. Buzdar’s published
report describing that failure, the district court correctly
found that a person of ordinary skill would have been
discouraged from using raloxifene.
Teva argues that the Buzdar study failed for reasons
unrelated to the rapid conjugation of raloxifene. Teva
relies on three pieces of evidence to support this conclu-
sion. First, Dr. Buzdar did not mention bioavailability
issues in his published report on his study. To the con-
trary, Teva argues, the Buzdar publication says that
“[t]he toxicity of [raloxifene] was comparable to ta-
moxifen” J.A. 6867, which, Teva argues, suggests that
raloxifene is active in humans. Second, Dr. Draper, the
co-inventor of the Low Dose Patent, testified at trial that
“[t]he raloxifene in breast cancer effort was discontinued
for a variety of reasons, but it was not because the defini-
tive study had shown the drug either to be inactive . . .
and bioavailability had not been commented on in [the
Buzdar] trial.” J.A. 3188 at 749:22-750:12. Third, Teva
points to Dr. Draper’s statements to the FDA in 1991
21 ELI LILLY v. TEVA PHARMA
discussing the Buzdar study, which do not mention
bioavailability as a reason for its failure.
The record again leads to a different conclusion com-
pletely. The record indeed shows that the Buzdar study
did not expressly attribute its failure to bioavailability
concerns. The record nonetheless shows that a person of
ordinary skill would have seen the bioavailability issue as
a likely reason underlying the failure. For instance,
Lilly’s Dr. Lindstrom testified that the result of the Buz-
dar study “was consistent with the Phase I studies . . . in
the human volunteers that there was no bioavailability.”
J.A. 3091 at 366:18-21. That testimony supports the
district court’s conclusion that the results of the Buzdar
study would have suggested to a person of ordinary skill
that low bioavailability would likely interfere with
raloxifene’s efficacy.
5
The record thus amply supports the District Court’s
conclusion that the ordinary artisan would not have
considered it obvious to use raloxifene to treat postmeno-
pausal osteoporosis. This court detects no clear error in
the trial court’s findings on the underlying facts of obvi-
ousness and detects no error in its conclusion that the
record does not contain a clear and convincing showing
that the Bone Loss Patents would have been obvious at
the time of invention.
IV
Teva also challenges the validity of the Low Dose Pat-
ent in two respects, both of which fail.
First, Teva argues that the Low Dose Patent is invalid
as obvious under § 103. But its obviousness argument
hinges on the success of its attack of the Bone Loss Pat-
ents. Specifically, Teva argues that “If the district court
ELI LILLY v. TEVA PHARMA 22
erred in concluding that bioavailability questions ren-
dered the Bone Loss Patents unobvious, . . . it also err[ed]
in finding that the Low Dose Patent was unobvious[.]”
Appellant Br. at 2 (emphasis added). Because this court
affirms the district court’s conclusion that the Bone Loss
Patents would not have been obvious, it affirms its con-
clusion as to the Low Dose Patent as well.
Second, Teva contends that if the Bone Loss Patents
are valid, then the Low Dose Patent claims are invalid for
nonstatutory double patenting. Nonstatutory double
patenting was borne out of 35 U.S.C. § 101, not § 103.
Specifically, § 101 precludes more than one patent on the
same invention. This court’s predecessor, concerned that
applicants could evade that § 101 requirement by drafting
claims that “vary slightly from the earlier patent,” fash-
ioned the doctrine of nonstatutory double patenting “to
prevent issuance of a patent on claims that are nearly
identical to claims in an earlier patent.” Geneva Pharm.,
Inc. v. Glaxosmithkline PLC, 349 F.3d 1373, 1377-78 (Fed.
Cir. 2003). The primary inquiry in double patenting cases
is therefore whether the claims in the latter patent are
more than a “slight variant” from the claims in the earlier
patent. Id. (citing In re Lonardo, 119 F.3d 960, 965 (Fed.
Cir. 1997)). Nonetheless, nonstatutory double patenting
is sometimes referred to as “obviousness-type” double
patenting, id. at 967, and “prevents the extension of the
term of the original patent via the patenting of an obvious
variation.” Georgia-Pacific Corp. v. U.S. Gypsum Co., 195
F.3d 1322, 1326 (Fed. Cir. 1999).
The district court found that conducting clinical trials
to test for an optimal dose for a drug “is generally a
routine process and that Dr. Draper’s [GGGC] tests did
not incorporate any concepts or ideas that would have
been beyond the reach of a person having ordinary skill in
the art at that time.” Eli Lilly & Co., 657 F. Supp. 2d at23 ELI LILLY v. TEVA PHARMA
1014 (quotation marks omitted). Teva relies on that
uncontested finding to argue on appeal that the Low Dose
Patent is merely an obvious variant of what Lilly already
patented.
Teva acknowledges, however, that it did not raise its
double patenting argument before the district court. Yet
Teva contends that this court should address the issue
anyway. Teva provides a number of reasons why this
court should address the double patenting issue in the
first instance, all of which boil down to the argument that
the proper resolution of the issue is beyond any doubt.
See, e.g., Appellants Br. at 49 (“Allowing Lilly to extend
its raloxifene monopoly for two years as a reward for
routine dose testing . . . would harm the general public by
depriving post-menopausal women of a cost-effective,
generic alternative to Lilly’s Evista® for nearly two years
after Lilly’s monopoly rights should have expired.”).
This court concludes that the record is insufficiently
clear for it to conclude that the proper resolution is be-
yond any doubt. For example, the district court made
findings adverse to Teva, including that a person of
ordinary skill in the art would not have had a reasonable
likelihood of success in using such a low dose of raloxifene
to treat postmenopausal osteoporosis. Further, the PTO,
in allowing the Low Dose Patent, represented that the
Bone Loss Patents taught away from the dosages claimed
in the Low Dose Patent. Thus, the record creates at least
some doubt that the dosage claimed in the Low Dose
Patent is merely a slight variant from the claims of the
Bone Loss Patents. Thus, this court declines to excuse
Teva for failing to raise the nonstatutory double patenting
issue at trial.
ELI LILLY v. TEVA PHARMA 24
V
Teva also alleges that the Bone Loss Patents and Low
Dose Patent do not meet the enablement requirement of
35 U.S.C. § 112, first paragraph. Section 112, first para-
graph, requires a patent specification to enable a person
of skill in the art to make and use the claimed invention.
The enablement requirement “incorporates as a matter of
law the requirement of 35 U.S.C. § 101 that the specifica-
tion disclose as a matter of fact a practical utility for the
invention.” Rasmusson v. SmithKline Beecham Corp., 413
F.3d 1318, 1323 (Fed. Cir. 2005) (internal quotation
marks omitted). “In the context of determining whether
sufficient utility as a drug, medicant, and the like in
human therapy has been alleged, it is proper for the
examiner to ask for substantiating evidence unless one
with ordinary skill in the art would accept the allegations
as obviously correct.” Id. (internal quotation marks
omitted).
Teva argues that if the Jordan Reference did not ren-
der the Bone Loss Patents obvious due to concerns about
raloxifene’s bioavailability, then the disclosure in the
Bone Loss Patents and the Low Dose Patent could not
have been enabling because of the prevailing view that
raloxifene would not work in humans. This contention
fails on this record because the Bone Loss Patents disclose
two sets of information not found in the prior art.
First, the Bone Loss Patents describe the results of
Mr. Black’s conjugate studies and explains that the
conjugation of raloxifene would not be detrimental to its
efficacy in treating human bone loss. Teva argues that
the results of Mr. Black’s conjugate studies do not provide
a person of skill in the art with a reasonable expectation
of success. According to Teva, scientists at Lilly knew of
those results before Dr. Buzdar concluded his failed
25 ELI LILLY v. TEVA PHARMA
breast cancer study, yet those same scientists argued at
trial that the Buzdar study was thought to have failed
due to bioavailability concerns.
The problem with Teva’s argument is that it once
again treats all bioavailability issues the same. As the
party with the burden both in the district court and in
this court, Teva must do more. The Bone Loss Patents
describe Black’s conjugation studies as specifically rele-
vant to bone loss, not breast cancer. See col.3 ll.52-60 (“ß-
Glucuronidase is fairly ubiquitous and is thought to be
active in the resorption process of bone remodeling . . . .
Therefore, conjugation of the benzothiophenes of formula
I is not considered to be necessarily detrimental to their
bioavailability as an inhibitor of bone loss.”). The record
simply does not show that the failed breast cancer tests
make the results of Black’s conjugate studies less reliable.
Second, the Bone Loss Patents describe the details of
a human clinical study, which was ongoing at the time the
application was filed. As the district court acknowledged,
the Manual of Patent Examining Procedure (MPEP)
explains that the initiation of a clinical trial has a signifi-
cant impact on the PTO’s utility inquiry:
Before a drug can enter human clinical trials, the
sponsor, often the applicant, must provide a con-
vincing rationale to those especially skilled in the
art (e.g., the Food and Drug Administration) that
the investigation may be successful. Such a ra-
tional would provide a basis for the sponsor’s ex-
pectation that the investigation may be successful.
In order to determine a protocol for phase I test-
ing, the first phase of the clinical investigation,
some credible rationale of how the drug might be
effective or could be effective would be necessary.
Thus, as a general rule, if an applicant has initi-
ELI LILLY v. TEVA PHARMA 26
ated human clinical trials for a therapeutic prod-
uct or process, Office personnel should presume
that the applicant has established that the subject
matter of that trial is reasonably predictive of hav-
ing the asserted therapeutic utility.
MPEP (2008) § 2107.03 at IV (emphasis added).
Teva does not challenge this presumption of utility,
but instead argues that it simply helps its obviousness
argument because neither Lilly nor the FDA relied on
anything more than what was in the prior art before
approving Lilly’s GGGB “proof of concept” trial. Specifi-
cally, Teva contends that the record contains no evidence
that Lilly or the FDA relied on Black’s conjugate stud-
ies―the only other piece of evidence that Teva acknowl-
edges was not in the prior art―to approve the human
clinical trials.
For the reasons discussed in Section III.4, supra, this
court rejects Teva’s argument that the Bone Loss Patents
would have been obvious based on Lilly’s own actions. To
the extent that Teva revisits this argument in the en-
ablement context, it appears to contend that Lilly’s ac-
tions provide circumstantial evidence that an ordinarily
skilled artisan would not have found helpful the facts on
which the district court relied to hold that the patents are
enabled. This court rejects that argument as well, and for
essentially the same reason: it conflates the expertise of
Lilly scientists with the knowledge of one of ordinary skill
in the art. Just because Lilly or the FDA might not have
actually relied on the results of Black’s conjugate studies
to approve the proof of concept trial does not create clear
and convincing evidence that a person of ordinary skill
would not rely on the disclosure of the human trials to
conclude that the claimed invention was useful. Indeed,
Lilly appears to have had many advantages that a person
27 ELI LILLY v. TEVA PHARMA
of ordinary skill would not have had, not the least of
which was the FDA’s prior approval of Lilly’s IND appli-
cation. Lilly’s reliance on those advantages rather than
its knowledge of Black’s conjugate studies to proceed with
human trials does not create clear and convincing evi-
dence that a person of ordinary skill would fail to find
comfort in the latter.
This court therefore affirms the district court’s ruling
on enablement.
VI
At trial, the parties contested whether Teva infringed
the Particle Size Patents. As noted, the asserted claims of
the Particle Size Patents required that the raloxifene
particles have a mean particle size of “less than about 25
microns” and that at least about 90% of the particles have
a size of “less than about 50 microns.” Following the
district court’s initial claim construction order, in which it
construed claim terms that are not relevant here, Teva
notified Lilly that it had altered its proposed drug product
by changing the particle size manufacturing specification
of its bulk raloxifene.
Lilly’s expert then conducted tests on samples of
Teva’s altered bulk raloxifene as well as samples of tab-
lets that contained the altered bulk raloxifene. The
results of those tests revealed that the particle size of
Teva’s altered bulk raloxifene, measured before formula-
tion (i.e., before it was blended with standard material
used to optimize solubility and tableted), fell outside of
the range claimed in the Particle Size Patents. Neverthe-
less, Lilly contended that Teva’s raloxifene product in-
fringed the Particle Size Patents because the raloxifene
particles contained within the tablet (i.e., measured after
formulation) fell within the claimed size range.
ELI LILLY v. TEVA PHARMA 28
According to Lilly, Teva modified its production proc-
ess in order to produce larger, more fragile raloxifene
particles in their bulk form to create the illusion of non-
infringement. Lilly alleges, however, that upon process-
ing, the artificially large particles fracture into smaller
particles that fall within the size range claimed in the
Particle Size Patents.
Thus, the district court determined that the question
of infringement turned on an issue of claim construction,
namely, “whether the particle size patents claim only size
measurements made on bulk raloxifene before it is formu-
lated or, by contrast, whether the patents also claim the
particle size of raloxifene within a formulated tablet, as
measured after extraction from the tablet.” Eli Lilly, 657
F. Supp. 2d at 1021. The district court concluded that the
limitation “in particulate form” as used in the Particle
Size Patents should be construed broadly to include
raloxifene particles both before and after formulation.
Even though Lilly won on claim construction, the dis-
trict court ruled that the breadth of the limitation ren-
dered the Particle Size Patents invalid for failure to
comply with the written description requirement of 35
U.S.C. § 112, first paragraph. The district court noted
that the Particle Size Patents did not disclose the idea of
measuring the particle size of raloxifene extracted from a
tablet, nor did the inventors perform any tests to deter-
mine how the granulation or tableting process could affect
particle size. Moreover, the district court concluded,
after reading the patent, a person of ordinary skill
in the art would not understand how to extract
raloxifene particles from a formulation in order to
determine whether they fall within the claimed
particle size range and, in fact, would have no in-
dication that size measurements on anything
29 ELI LILLY v. TEVA PHARMA
other than unformulated raloxifene would bear
any relevance to the invention.
Id. at 1027. On appeal, Lilly attacks this conclusion on
two grounds.
First, Lilly argues that the district court should have
excluded Teva’s written description argument as un-
timely. Lilly argues that it was prejudiced because Teva
failed to include its written description argument in its
final invalidity contentions before trial. The district
court, however, held that Lilly had sufficient notice of that
argument based on the testimony at trial. Id. at 1024
n.54. Lilly has failed to establish that the district court’s
decision was an abuse of discretion.
Second, Lilly argues that the district court applied an
improper test in determining whether the Particle Size
Patents comply with the written description requirement
of § 112, first paragraph. As this court recently con-
firmed, the test for written description is “whether the
disclosure of the application . . . reasonably conveys to
those skilled in the art that the inventor had possession of
the claimed subject matter as of the filing date.” Ariad
Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed.
Cir. 2010) (en banc). The district court’s decision, which
was issued before this court’s en banc decision in Ariad,
appears in some places to have been premised on a mis-
understanding of that test. Certain statements indicate
that the district court may have been focused on whether
“a person of ordinary skill in the art would . . . understand
how to extract raloxifene particles from formulation in
order to determine whether they fall within the claimed
particle size range.” Eli Lilly, 657 F. Supp. 2d at 1027.
The test for written description, however, has never been
whether the patent includes a description of the steps
that may be used to prove infringement.
ELI LILLY v. TEVA PHARMA 30
Nonetheless, the written description requirement is a
question of fact, Ariad, 598 F.3d at 1351, which this court
reviews for clear error, Ralston Purina Co. v. Far-Mar-Co,
Inc., 772 F.2d 1570, 1575 (Fed. Cir. 1985). The district
court here concluded that “a person of skill in the art
would not understand the inventors of the particle size
patents to have invented anything other than ‘a control
strategy for . . . the particle size distribution . . . of the
bulk drug substance,’ as expressly provided in the specifi-
cation.” Eli Lilly, 657 F. Supp. 2d at 1027 (quoting the
’811 patent, col.25 ll.60-61).
This court cannot characterize that finding as clearly
erroneous. The patent specification only discloses meas-
urements of bulk raloxifene. The record then features
conflicting evidence about the reading a person of ordi-
nary skill in the art would give to the passages to deter-
mine that the inventor possessed the invention of
formulated raloxifene falling within the claimed size
range. Lilly’s own expert conceded that “[o]ne reading the
[Particle Size Patent] in 1996 would not know whether
the particle size was being increased or decreased [or
remain the same] in the formulation.” J.A. 3362 at
1434:1-10. With that concession, Lilly cannot establish
that the district court made a clearly erroneous factual
finding. Thus, this court affirms the district court’s
judgment invalidating the asserted claims of the Particle
Size Patents.
VII
For the foregoing reasons, the district court’s judg-
ment is affirmed.
AFFIRMED