LOS ANGELES BIOMEDICAL RESEARCH INSTITUTE AT HARBOR-UCLA MEDICAL CENTER, Appellant
ELI LILLY AND COMPANY, Appellee
from the United States Patent and Trademark Office, Patent
Trial and Appeal Board, in No. IPR2014-00752.
Davison, Fenwick & West LLP, Seattle, WA, argued for
appellant. Also represented by David Keith Tellekson,
Elizabeth B. Hagan; Virginia Kay DeMarchi, Amy Hayden,
Mountain View, CA.
J. Feldstein, Finnegan, Henderson, Farabow, Garrett &
Dunner, LLP, Washington, DC, argued for appellee. Also
represented by Joshua Goldberg, Yieyie Yang; Charles E.
Lipsey, Reston, VA; Mark Stewart, Eli Lilly and Company,
Newman, Bryson, and Moore, Circuit Judges.
Bryson, Circuit Judge.
Los Angeles Biomedical Research Institute at Harbor-UCLA
Medical Center ("LAB") seeks review of a decision
of the Patent Trial and Appeal Board holding all claims of
U.S. Patent No. 8, 133, 903 ("the '903 patent")
unpatentable as obvious. We vacate the Board's order and
remand for further proceedings.
'903 patent claims a method of "arresting or
regressing" a condition known as penile fibrosis. The
method entails the long-term, daily administration of drugs
known as type 5 phosphodiesterase ("PDE5")
inhibitors. The drugs function by inhibiting the enzymatic
action of PDE5, which is found in the human penis.
See '903 patent, col. 6, line 51, through col.
7, line 15.
penis contains two cylindrical chambers called the corpora
cavernosa. Those chambers fill with blood during an erection.
The corpora cavernosa are surrounded by a membrane called the
tunica albuginea. Penile fibrosis is characterized by the
buildup of excess collagen. It includes two conditions:
penile tunical fibrosis, which results from the buildup of
excess collagen in the tunica albuginea, and corporal tissue
fibrosis, which results from a buildup of excess collagen in
the corpora cavernosa. See '903 patent, col. 68,
ll. 22-32, 37-39; see also id., col. 9, ll. 45-46.
two fibrotic conditions can cause erectile dysfunction,
although they do not always do so. Tunical fibrosis can
manifest itself as Peyronie's disease, a condition that
"usually leads to penile deformation (curved penis
during erection), pain, and quite frequently erectile
dysfunction." '903 patent, col. 1, ll. 33-34.
Corporal tissue fibrosis, which results from the death of
smooth muscle cells in the corpora cavernosa and a
corresponding buildup of collagen, can cause dysfunction of
the mechanism that retains blood in the corpora cavernosa
during an erection. In a healthy male, the relaxation of the
smooth muscle cells in the penis increases the flow of blood
to the corpora cavernosa. The flow of blood into the corpora
cavernosa in turn compresses the veins of the penis against
the tunica albuginea to block the flow of blood from the
penis. The compression of those veins is known as the
veno-occlusive mechanism. Disruption of that mechanism, known
as corporal veno-occlusive disorder ("CVOD"), can
lead to erectile dysfunction. Id., col. 2, ll.
addition to the two types of penile fibrosis, there are many
other causes of erectile dysfunction. Some causes of erectile
dysfunction, such as those of psychological origin, are
entirely unrelated to fibrosis.
early 2000s, PDE5 inhibitors such as sildenafil (Viagra) and
tadalafil (Cialis) were well known and commonly used for the
on-demand treatment of erectile dysfunction. See
'903 patent, col. 10, line 59, through col. 11, line 3.
The use of sildenafil and tadalafil for that purpose was not
restricted to cases of erectile dysfunction resulting from
penile fibrosis. Individuals with erectile dysfunction of
varying causes were instructed to take PDE5 inhibitors before
sexual activity in order to obtain an erection at the desired
time. As the '903 patent explains, that use of PDE5
inhibitors was "not addressed to the long-term cure of
underlying tissue fibrosis." Id., col. 10, line
67, through col. 11, line 3.
time, according to the patent, there was a need for adequate
non-surgical treatments for Peyronie's disease and other
fibrotic conditions. '903 patent, col. 2, ll. 2-7 (noting
that surgery was "the only option" available in
most cases of Peyronie's disease). Erectile dysfunction
resulting from those conditions could be treated
symptomatically with on-demand PDE5 inhibitors, but there was
"[n]o effective method of treatment . . . directed
towards the molecular pathways underlying excessive collagen
deposition" to address penile fibrosis. Id.,
col. 2, ll. 44-46.
'903 patent, owned by LAB, claims such a treatment. Claim
1, the only independent claim, recites:
a) administering a cyclic guanosine 3',
5'-monophosphate (cGMP) type 5 phos-phodiesterase (PDE5)
inhibitor according to a continuous long-term regimen to an
individual with at least one of a penile tunical fibrosis and
corporal tissue fibrosis; and
b) arresting or regressing the at least one of the penile
tunical fibrosis and corporal tissue fibrosis, wherein the
PDE-5 inhibitor is administered at a dosage up to 1.5
mg/kg/day for not less than 45 days.
'903 patent, col. 68, ll. 23-32.
remaining four claims depend from claim 1 and concern the
type of drug (claim 2), the type of fibrotic condition (claim
3), the mode of administration (claim 4), and the duration of
treatment (claim 5). Id., col. 68, ll.
2013, LAB filed an infringement action in the United States
District Court for the Central District of California against
Eli Lilly & Company ("Lilly"), alleging that
Lilly's marketing of the drug Cialis induced infringement
of the '903 patent. Los Angeles Biomed. Research
Inst. v. Eli Lilly & Co., No. 2:13-cv-08567-JAK-JCG
(C.D. Cal. filed Nov. 20, 2013). Lilly subsequently filed
multiple petitions requesting that the Patent Trial and
Appeal Board conduct inter partes review of the
'903 patent. The Board instituted inter partes
review on the petition in which Lilly contended that all the
claims of the '903 patent were unpatentable as obvious in
light of three references. The cited references were:
Francesco Montorsi et al., The Ageing Male and Erectile
Dysfunction, 20 World J. Urology 28-53 (2002)
("Montorsi"); International Patent Application No.
WO 01/80860 (published Nov. 1, 2001) (John S. Whitaker et
al., applicants) ("Whitaker"); and Hartmut Porst et
al., Daily IC351 Treatment of ED, 12 Int'l J.
Impotence Research (Supp. 3) S76, B13 (2000)
'903 patent claims priority from Provisional Application
No. 60/420, 281, which was filed on October 22, 2002.
'903 patent, col. 1, ll. 12-15. The Board rejected
LAB's argument for the earlier priority date and
determined that the specification of the provisional
application did not disclose the dosage limitation of
"up to 1.5 mg/kg/day, " i.e., a dosage of up to 1.5
milligrams of PDE5 inhibitor per kilogram of the
patient's body weight each day.
Board also construed several claim limitations that are now
at issue on appeal. First, the Board construed the phrase
"an individual with at least one of penile tunical
fibrosis and corporal tissue fibrosis" to mean an
"individual hav[ing] symptoms that may be associated
with penile fibrosis, such as [erectile dysfunction], but not
that the patient be specifically diagnosed as having penile
tunical fibrosis or corporal tissue fibrosis."
the Board construed the phrase "arresting or regressing
the at least one of the penile tunical fibrosis and corporal
tissue fibrosis" as having no limiting role, but merely
stating the intended result of administering a PDE5 inhibitor
at a dosage of up to 1.5 mg/kg/day for at least 45 days.
in the Decision on Institution, the Board construed the term
"continuous long-term regimen" to mean "the
administration of drug over a certain period of time without
intermission such that the treatment is therapeutically
effective." In its final decision, the Board concluded
that the claim limitation requiring the delivery of a dosage
of up to 1.5 mg/kg/day for at least 45 days "would meet
the claim requirement of a continuous, long-term
Board then addressed the three prior art references:
Montorsi, Whitaker, and Porst.
is a review article that addresses the treatment of erectile
dysfunction in the aging male population. Montorsi states
that male erectile dysfunction is associated with aging; that
atherosclerosis (the buildup of plaque in the arteries) is
common in the elderly; and that atherosclerosis is associated
with CVOD and corporal fibrosis, which can cause erectile
dysfunction. Montorsi at 28, 30-31. Montorsi concludes that
"it seems reasonable to hypothesise that the [erectile
dysfunction] from ageing is the result of
atherosclerosis-induced cavernosal ischaemia leading to
cavernosal fibrosis and [CVOD]." Id. at 31.
discusses several relevant studies of erectile dysfunction.
It begins by reviewing a group of studies on sildenafil as a
treatment for erectile dysfunction in elderly patients. The
patients in that study were instructed to take up to 100 mg
of sildenafil on demand (one hour before sexual activity) but
no more than once daily over a 12 week to 6 month period.
Those studies showed that sildenafil was well tolerated and
that it ameliorated the treated condition. Montorsi at 32-33.
Another study reported that administering a 100 mg dose of
sildenafil at bedtime to male patients between 40 and 68
years old with erectile dysfunction produced an increase in
nocturnal erections. Id. at 31 (citing Francesco
Montorsi et al., Sildenafil Taken at Bedtime
Significantly Increases Nocturnal Erections: Results of a
Placebo-Controlled Study, 56 Urology 906, 907 (2000)).
Montorsi concludes that this study "opened the door to
further study investigating the possible dosage of sildenafil
to be administered daily at bedtime to prevent or treat
[erectile dysfunction] in the elderly patient." Montorsi
is an abandoned patent application that claims the chronic
use of low-dose PDE5 inhibitors to treat erectile
dysfunction. Whitaker defines "chronic" as
"the regular administration of the [PDE5 inhibitor] in
intervals unrelated to the onset of sexual activity, "
and states that "chronic administration generally refers
to regular administration for an extended period, preferably
daily for three or more days, and still more preferably daily
for as long as the patient suffers from erectile dysfunction
(in the absence of therapy)." Whitaker at 7. Whitaker
defines "daily" as "administration of the
[PDE5 inhibitor] one or more times, generally one to three
times, still more preferably one time, per about 24-hour
6 of Whitaker combines data from five clinical studies to
show that chronic administration of low doses (5 mg or 10 mg)
of tadalafil improved erectile function in a population of
patients with male erectile dysfunction. Whitaker at 34. The
study population included four subgroups, in which tadalafil
was taken (1) less than 30% of the time, (2) 30-50% of the
time, (3) 50-70% of the time, and (4) more than 70% of the
time. Id. Example 6 states that tadalafil "was
administered 'daily' to [these] patients."
Id.; accord id. at 35 ("The Study Drug
was administered in 5 mg and 10 mg doses, 'daily' and
not more than once every 24 hours."). Whitaker notes
"a trend toward better response with increased frequency
of dose." Id. at 36 (referring to results
showing better erectile function in subgroups 3 and 4 than in
subgroups 1 and 2). In Example 7, tadalafil was administered
daily for three weeks to men 21-72 years old with erectile
dysfunction, in subgroups receiving either a placebo or one
of four dosages (10, 25, 50, and 100 mg). The results showed
that "[a]dverse events [side effects] were dose-related,
and attenuated with continued daily treatment."
Id. at 38.
states that "[t]he enhanced efficacy demonstrated by low
daily dosing of a PDE5 inhibitor in treating erectile
dysfunction . . . results from improved vascular
responsiveness when the PDE5 inhibitor is present
continuously, or essentially continuously, in plasma."
Whitaker at 12. Whitaker terms that effect "vascular
conditioning, " an effect that had not been reported or
observed in treatments with PDE inhibitors generally, nor
more specifically in the case of on-demand dosing of PDE5
inhibitors. Id. Whitaker concludes that "[i]t
is expected that vascular conditioning occurs after chronic
administration of the PDE5 inhibitor, for example, after
about three daily doses of up to 10 mg, preferably after five
days of daily dosing, and more preferably after seven days of
daily dosing. In addition, after about three days of daily
dosing, intermittently missing one chronic dose may lead to a
reduction in vascular conditioning, but not a complete loss
of conditioning." Id. at 13. Whitaker then
posits: "It is theorized, but not relied upon herein,
that vascular conditioning is caused by a partial or complete
reversal of circulatory dysfunctions in penile circulation
arising from conditions such as diabetes, atherosclerosis,
smoking, hypertension, or a combination of such
factors." Id. at 13.
is a published abstract of a study showing that 100 mg of
tadalafil administered daily for three weeks to men with
erectile dysfunction having a mean age of 52.4 years was safe
and well tolerated, and that it improved erectile function.
Board found that Montorsi and Whitaker taught administering a
PDE5 inhibitor to an individual with erectile dysfunction, as
required by its construction of "an individual with at
least one of a penile tunical fibrosis and corporal tissue
fibrosis." The Board also found that Montorsi taught
that erectile dysfunction in the aging male is associated
with atherosclerosis, which in turn is associated with the
development of corporal fibrosis, and that Whitaker taught
that long-term treatment with a PDE5 inhibitor can cause
reversal of circulatory dysfunctions caused by diabetes,
atherosclerosis, smoking, hypertension, or a combination of
Board further found that the three references together taught
daily dosing of up to 1.5 mg/kg/day for at least 45 days, and
therefore met the "continuous long-term regimen"
limitation of the '903 patent. In particular, the Board
found that Montorsi taught dosing of up to 100 mg of
sildenafil per day. According to the '903 patent, col.
45, ll. 7-12, a dosage of 100 mg per day is roughly
equivalent to 1.5 mg/kg for an average weight adult male.
Although the Board acknowledged that Whitaker's Example 6
did not specifically disclose dosing every day, it noted that
Whitaker taught that better results are obtained with
increased frequency of dosing, that adverse effects are
attenuated with daily administration, and that treatment
should continue for as long as the erectile dysfunction
persists. Finally, the Board found that Porst taught that a
dosage of 100 mg of tadalafil per day is safe and well
response to Lilly's arguments based on the prior art
references, LAB argued that its treatment method produced
unexpected results, because at the time of the invention the
scientific community believed that PDE5 inhibitors would
exacerbate fibrosis, not treat it. That belief, according to
LAB, was based on the understanding that the enzyme
inductible nitric oxide synthase ("iNOS") and its
product, nitric oxide, which have a mechanism of action
similar to that of PDE5 inhibitors, were profibrotic. The
Board rejected that argument on the ground that the claims of
the '903 patent do not require a particular mechanism of
action and that any antifibrotic effect resulting from the
administration of PDE5 inhibitors, whether expected or not,
Board ultimately concluded that the combination of references
satisfies each of the limitations of the '903 patent, as
construed, and that the combination provides a reasonable
expectation of success in treating erectile dysfunction.
appeal, LAB argues that the Board erred (1) in denying
LAB's claim of priority to the October 2002 filing date
of the inventors' provisional application, (2) in
construing the three disputed claim terms, (3) in deciding
that claim 1 of the '903 patent would have been obvious
based on incorrect claim constructions, and (4) by failing to
adequately consider the prevailing beliefs in the field and
the unexpected results achieved by the inventors.
order for a patent to be entitled to priority based on an
earlier application or chain of applications, each previous
application in the chain must comply with the written
description requirement of 35 U.S.C. § 112(a).
Bradford Co. v. Conteyor N. Am., Inc., 603 F.3d
1262, 1269 (Fed. Cir. 2010). To satisfy the written
description requirement, the disclosure in each application
must "reasonably convey" to those skilled in the
art that as of the claimed priority date the inventor was in
possession of the later claimed subject matter. Vas-Cath
Inc. v. Mahurkar, 935 F.2d 1555, 1563 (Fed. Cir. 1991).
A disclosure in a parent application is not sufficient if it
"merely renders the later-claimed invention obvious . .
.; the disclosure must describe the claimed invention with
all its limitations." Tronzo v. Biomet, Inc.,
156 F.3d 1154, 1158 (Fed. Cir. 1998).
case, the inventors filed a provisional application in
October 2002 to which the '903 patent claims priority.
Lilly argues on appeal that the three prior art references
were published before the provisional application was filed
and are thus prior art under 35 U.S.C. § 102(a) even
with the priority date of October 2002. LAB responds that
Lilly asserted Whitaker and Montorsi as prior art only under
35 U.S.C. § 102(b) before the Board and that Whitaker
and Montorsi do not qualify as prior art under that
provision. We decline to address the question of Lilly's
waiver, as we conclude on the merits that the '903 patent
is not entitled to the priority date of the provisional
application because of a lack of adequate written
provisional application does not explicitly disclose a dosage
of "up to 1.5 mg/kg/day." LAB, however, contends
that the dosage level is disclosed by a rat study described
in the provisional application. In that study, rats were
provided with 100 mg/L (milligrams per liter) of sildenafil
in drinking water. LAB argues that a person of skill in the
art would be able to calculate the corresponding human dosage
according to a conversion method devised by E. J. Freireich,
and that the result of that computation would be a dosage of
approximately 1.5 mg/kg/day. See Emil J. Freireich,