Hoffmann-La Roche Inc. v. Apotex Inc.

United States Court of Appeals
for the Federal Circuit
______________________

HOFFMANN-LA ROCHE INC. AND
GENENTECH, INC.,
Plaintiffs-Appellants,

v.

APOTEX INC. AND APOTEX CORP.,
Defendants-Appellees.
______________________

2013-1128
______________________

-----------------------

HOFFMANN-LA ROCHE INC. AND
GENENTECH, INC.,
Plaintiffs-Appellants,

v.

DR. REDDY'S LABORATORIES, LTD. AND
DR. REDDY'S LABORATORIES, INC.,
Defendants-Appellees.
______________________

2013-1161
______________________

-----------------------
2 HOFFMANN-LA ROCHE INC. v. APOTEX INC.

HOFFMANN-LA ROCHE INC. AND
GENENTECH, INC.,
Plaintiffs-Appellants,

v.

WATSON LABORATORIES, INC., ACTAVIS, INC.,
WATSON PHARMA, INC., COBALT
PHARMACEUTICALS INC., AND COBALT
LABORATORIES, INC.,
Defendants-Appellees.
______________________

2013-1162
______________________

-----------------------

HOFFMANN-LA ROCHE INC. AND
GENENTECH, INC.,
Plaintiffs-Appellants,

v.

ORCHID CHEMICALS & PHARMACEUTICALS
LTD., ORCHID HEALTHCARE, ORCHID
PHARMACEUTICALS INC., AND ORGENUS
PHARMA INC.,
Defendants-Appellees.
______________________

2013-1163
______________________

-----------------------

HOFFMANN-LA ROCHE INC. AND
HOFFMANN-LA ROCHE INC. v. APOTEX INC. 3

GENENTECH, INC.,
Plaintiffs-Appellants,

v.

MYLAN INC., MYLAN PHARMACEUTICALS INC.,
GENPHARM ULC (formerly known as Genpharm
Inc.), AND GENPHARM, L.P.,
Defendants-Appellees.
______________________

2013-1164
______________________

Appeals from the United States District Court for the
District of New Jersey in Nos. 07-CV-4417, 08-CV-3065,
08-CV-4053 and 10-CV-6241, Judge Stanley R. Chesler.
______________________

Decided: April 11, 2014
______________________

MARK E. WADDELL, Loeb & Loeb LLP, of New York,
New York, argued for plaintiffs-appellants. With him on
the brief were WARREN K. MACRAE, PAULA K. COLBATH,
and KATHLEEN GERSH.

DEANNE M. MAZZOCHI, Rakoczy Molino Mazzochi
Siwik, LLP, of Chicago, Illinois, argued for all defendants-
appellees. With her on the brief were WILLIAM RAKOCZY,
TARA M. RAGHAVAN, and ERIC R. HUNT, for Watson Labor-
atories, Inc., et al. On the brief were STEVEN E. FELDMAN,
JAMES P. WHITE, LOUISE T. WALSH, PHILIP D. SEGREST,
DANIEL R. CHERRY, and SHERRY L. ROLLO, Husch Black-
well LLP, of Chicago, Illinois, for Apotex Inc., et al; EDGAR
H. HAUG, RICHARD E. PARKE, and RICHARD F. KURZ,
Frommer Lawrence & Haug, LLP, of New York, New
York, for Mylan Inc., et al.; STUART D. SENDER and
4 HOFFMANN-LA ROCHE INC. v. APOTEX INC.

MICHAEL CHOI, Budd Larner, P.C., of Short Hills, New
Jersey, for Dr. Reddy’s Laboratories, Ltd., et al.; WILLIAM
J. UTERMOHLEN, JAMES A. OLIFF, and JOHN W. O’MEARA,
Oliff & Berridge, PLC, of Alexandria, Virginia, for Orchid
Chemicals & Pharmaceuticals Ltd., et al. Of counsel were
JAMES E. CECCHI, Carella, Byrne, Bain, Gilfillan, Cecchi,
Stewart & Olstein, of Roseland, New Jersey, for Watson
Laboratories, Inc., et al. ARNOLD B. CALMANN, Saiber,
LLC, of Newark, New Jersey, for Mylan Inc., et al., BRUCE
D. RADIN, Budd Larner, P.C., of Short Hills, New Jersey,
for Dr. Reddy’s Laboratories, Ltd., et al. and CHARLES N.
QUINN, Fox Rothschild, LLP, of Exton, Pennsylvania, for
Orchid Chemicals & Pharmaceuticals Ltd., et al.
______________________

Before NEWMAN, LOURIE, and BRYSON, Circuit Judges.
Opinion for the court filed by Circuit Judge BRYSON.
Dissenting opinion filed by Circuit Judge NEWMAN.
BRYSON, Circuit Judge.
Plaintiff Hoffmann-La Roche, Inc., (“Roche”) appeals
from the decision of the United States District Court for
the District of New Jersey granting the defendant generic
drug companies summary judgment of invalidity as to
claims 1-8 of U.S. Patent No. 7,718,634 (“the ’634 patent”)
and claims 1-10 of U.S. Patent No. 7,410,957 (“the ’957
patent”). We affirm.
I
The patents at issue in this appeal are directed to
methods of treating osteoporosis through the once month-
ly administration of ibandronate, one of a class of com-
pounds known as bisphosphonates. Ibandronate, a salt of
ibandronic acid, is commercially available as Roche’s once
monthly Boniva®, which was approved by the United
States Food and Drug Administration (“FDA”) in 2005 for
HOFFMANN-LA ROCHE INC. v. APOTEX INC. 5

the treatment of osteoporosis. Once monthly Boniva®
provides a 150 milligram (“mg”) dose of ibandronate.
Osteoporosis is a disease characterized by abnormal
bone resorption. Resorption, the biological process by
which bone is broken down, causes decreased bone
strength and an increased risk of fractures. Bisphospho-
nates are “potent inhibitors of bone resorption.” ’957
patent, col. 1, ll. 39-40. They inhibit abnormal bone
destruction and enable the gradual restoration of lost
bone mineral density (“BMD”).
Bisphosphonates are generally known to have a low
bioavailability when administered orally, i.e., only a small
fraction of a given dose is absorbed into the blood. Addi-
tionally, oral administration of bisphosphonates can
result in adverse esophageal and gastrointestinal side
effects. As a result of the side effects and to improve the
bioavailability of the drug, patients taking bisphospho-
nates must adhere to a dosing regimen that requires a
bisphosphonate tablet to be taken in a fasting state at
least 30 minutes before eating or drinking. In the past,
the inconvenience of that regimen created problems of
patient compliance. Researchers in the field believed that
less-frequent dosing would result in patients continuing
the treatment for the long term, which is required for
bisphosphonate treatments to be successful.
Roche owns the ’634 patent and the ’957 patent, which
is the parent of the ’634 patent. Claims 1-8 of the ’634
patent and claims 1-10 of the ’957 patent are at issue in
this case and describe a method of treating osteoporosis
consisting of orally administering about 150 mg of iband-
ronic acid once monthly on a single day. Claim 1 of
the ’634 patent is representative of the claims on appeal:
1. A method for treating or inhibiting postmeno-
pausal osteoporosis in a postmenopausal woman
in need of treatment or inhibition of postmeno-
pausal osteoporosis by administration of a phar-
6 HOFFMANN-LA ROCHE INC. v. APOTEX INC.

maceutically acceptable salt of ibandronic acid,
comprising:
(a) commencing the administration of the
pharmaceutically acceptable salt of iband-
ronic acid by orally administering to the
postmenopausal woman, on a single day, a
first dose in the form of a tablet, wherein
the tablet comprises an amount of the
pharmaceutically acceptable salt of iband-
ronic acid that is equivalent to about 150
mg of ibandronic acid; and
(b) continuing the administration by orally
administering, once monthly on a single
day, a tablet comprising an amount of the
pharmaceutically acceptable salt of iband-
ronic acid that is equivalent to about 150
mg of ibandronic acid.
II
The defendants in this case are generic drug manu-
facturers who submitted Abbreviated New Drug Applica-
tions (“ANDAs”) to the FDA for approval to engage in the
manufacture and sale of generic versions of Boniva® prior
to the expiration of Roche’s patents. Roche sued the
defendants in the United States District Court for the
District of New Jersey alleging infringement under 35
U.S.C. § 271(e)(2) based on the defendants’ ANDA filings.
Roche moved for a preliminary injunction. The dis-
trict court denied the motion, holding that Roche had
failed to prove it was likely to succeed in defeating the
defendants’ obviousness challenge. This court affirmed
the district court’s denial of the preliminary injunction.
See Hoffmann-La Roche Inc. v. Apotex Inc., 496 F. App’x
46 (Fed. Cir. 2012).
While the appeal of the preliminary injunction deci-
sion was pending, the district court granted the defend-
HOFFMANN-LA ROCHE INC. v. APOTEX INC. 7

ants’ motion for summary judgment of invalidity of claims
1-8 of the ’634 patent due to obviousness under 35 U.S.C.
§ 103(a). As to the frequency of dosing, the court found
that once monthly oral dosing of ibandronate was estab-
lished in the prior art. As to the amount of the monthly
dose, the court found that the combination of several prior
art references suggested a dosage level of about 150 mg
per month, or at least indicated that a monthly dose of
150 mg was obvious to try.
The district court considered Roche’s evidence of ob-
jective considerations of nonobviousness but concluded
that “Roche’s objective considerations evidence does not
rise to the level of a mere scintilla, and it is not sufficient
to defeat the motion for summary judgment.” In response
to Roche’s argument that the 150 mg once monthly dose
gave results that were superior to a 2.5 mg daily dose, the
court found that Roche had “pointed to no evidence in
support of [its] claim that the skilled artisan would have
been surprised that the 150 mg once-monthly dose was
superior to the 2.5 mg daily dose.” The court refused to
consider contentions, raised at oral argument, that the
150 mg dose had a superior and unexpected level of
bioavailability, because Roche had not raised that argu-
ment in its opposition brief.
Pursuant to Federal Rule of Civil Procedure 56(f) the
court then raised, on its own motion, the issue of sum-
mary judgment of invalidity of claims 1-10 of the ’957
patent. After considering the parties’ submissions, the
court held those claims invalid for the same reasons that
applied to the claims of the ’634 patent. Roche argued
that it was unexpected that an intermittent ibandronate
regimen would be effective in reducing fractures. But the
court concluded that the evidence on which Roche relied
failed to show that a person of skill in the art would not
have had a reasonable expectation that the patented
method would succeed in reducing fractures. The court
explained that “empirical confirmation that a method for
8 HOFFMANN-LA ROCHE INC. v. APOTEX INC.

increasing bone mineral density helps increase bone
strength enough that bones break less easily would not
appear to be all that surprising.”
In its motion for reconsideration, Roche argued that
the district court had improperly failed to consider evi-
dence that the 150 mg dose of ibandronate showed an
unexpected level of bioavailability as compared with lower
doses. On the merits of that argument, the district court
found that the “evidence that the 150mg dosage was
absorbed better by the body simply has no relevance to
the core finding that the difference between the 150mg
dose and the prior art was small” and that there was a
reasonable expectation of success with the 150 mg dose.
Roche timely appealed the grants of summary judg-
ment of obviousness.
III
The issue in this case is whether it would have been
obvious at the time of invention to select a once monthly
oral dosing regimen of ibandronate to treat osteoporosis
and to set that dose at 150 mg.
A. Monthly Dosing
1. A relatively infrequent dosing schedule has long
been viewed as a potential solution to the problem of
patient compliance stemming from the inconvenience of
oral bisphosphonate regimens. Fosamax®, a prior art
bisphosphonate product sold by Merck & Co., was admin-
istered weekly, and several prior art references taught
once monthly oral dosing of ibandronate or other bisphos-
phonates.
First, an article in the trade journal Lunar News enti-
tled Update: Bisphosphonates (“Lunar News”) stated that
“[r]esearchers are seeking solutions for better compli-
ance,” including approaches that “use bisphosphonates
with high potency yet low irritability, such as . . . iband-
HOFFMANN-LA ROCHE INC. v. APOTEX INC. 9

ronate (Roche). Oral agents could be given intermittently
(once/month, for example) and still be quite potent.”
Second, a 2001 article by Carey Krause in Chemical
Market Reporter (“Krause”) disclosed that Roche would
likely seek FDA approval of an “oral once-monthly” for-
mulation of ibandronate in 2003. Finally, United States
Patent No. 6,468,559 (“Chen”) disclosed coated-dosage
forms of bisphosphonic acids and methods for orally
administering those dosage forms. Ibandronic acid was
identified as one of many known bisphosphonic acids.
Chen disclosed a preferred embodiment in which “a
dosage form of the invention is administered to a pa-
tient . . . preferably once a month.” Lunar News, Krause,
and Chen therefore specifically taught the monthly ad-
ministration of ibandronate.
Similarly, the prior art contained references to the
monthly oral administration of bisphosphonates in gen-
eral. United States Patent Application No. 2003/0118634
(“Schofield”) taught dosing of “bone-active phosponate[s]”
and referred to equivalent doses that “can be given every
other day, twice a week, weekly, biweekly or monthly.”
United States Patent No. 5,616,560 (“Geddes”) disclosed a
bisphosphonate administration regimen in which “said
bisphosphonate is administered at least 1 day of every
said thirty(30)-day treatment period.”
2. Roche argues that the art taught away from once
monthly dosing because, according to Roche, it was widely
believed as of the date of invention that a bisphosphonate
regimen with a dose-free interval longer than one or two
weeks would not be effective. To support that contention,
Roche primarily relies on the alleged failure of its intra-
venous ibandronate study (“Recker”) to demonstrate
antifracture efficacy with quarterly dosing. Secondarily,
Roche relies on a prior art article by Thomas Schnitzer
(“Schnitzer”) speculating that the failure of the Recker
study was due to the long dose-free interval.
10 HOFFMANN-LA ROCHE INC. v. APOTEX INC.

The Recker study, however, showed a 26% reduction
in vertebral fractures with intravenous ibandronate
administered once every three months. The study was a
“failure” only in the sense that the 26% reduction was
statistically insignificant given the large number of
patients that would have been required to reach a statis-
tically significant conclusion about the relative rates of
fractures in the control and subject groups. With respect
to the reduction of hip fractures, for example, Recker
concluded that “a meaningful conclusion with regard to
efficacy could not be made owing to the low absolute
number of hip fractures.” Recker’s failure to generate
statistically significant results points to a fault in the
study; it does not teach that infrequent ibandronate
dosing is ineffective in treating osteoporosis.
The prior art references that interpreted Recker’s re-
sults demonstrate only that it was unknown why Recker
was unsuccessful in demonstrating statistically signifi-
cant antifracture efficacy. Schnitzer speculated that the
long drug-free interval was to blame for the inconclusive
results and that dosing intervals longer than one or two
weeks would be ineffective. On the other hand, an article
by Dr. Dennis Black (“Black”) described speculation that
the doses used in Recker were too low. In fact, Roche
itself subsequently acknowledged that the Recker study
was underdosed. Thus, Schnitzer’s speculation did not
amount to an affirmative teaching away from monthly
oral dosing of ibandronate, especially in the face of Black’s
competing explanation of the Recker results.
Any doubt about the efficacy of oral ibandronate dos-
ing that may have been created by Schnitzer’s speculation
was put to rest by an article published in 2001 by Riis et
al. entitled Ibandronate: A Comparison of Oral Daily
Dosing Versus Intermittent Dosing in Postmenopausal
Osteoporosis (“Riis”). Riis demonstrated that “intermit-
tent ibandronate is as effective as the continuous treat-
ment in terms of significantly increasing BMD at the
HOFFMANN-LA ROCHE INC. v. APOTEX INC. 11

spine and hip and suppressing markers of bone turnover.”
Riis showed that increases in BMD equivalent to those
obtained with a 2.5 mg per day treatment regimen were
obtained with a regimen of 20 mg of ibandronate every
other day for the first 24 days of every three-month peri-
od. Those results, Riis concluded, “confirm[ed] preclinical
data showing that it is the total dose over a predefined
period and not the dosing regimens that is the determin-
ing factor for effect on bone mass and architecture after
ibandronate treatment.” Riis’s teaching that a dose-free
interval of more than two months did not impact the BMD
efficacy of ibandronate was directly contrary to
Schnitzer’s speculation that such a dosing regimen would
not be effective. Therefore, even if Schnitzer’s interpreta-
tion of the Recker study were viewed as teaching away
from monthly dosing, Riis’s contrary findings substantial-
ly undermined that interpretation.
Roche argues that Riis did not overcome Schnitzer’s
interpretation because Riis was not an antifracture trial.
Roche argues that prior art focusing only on BMD and
bone-turnover improvements, instead of on antifracture
efficacy, does not bear on the obviousness analysis in this
case because such prior art does not establish a reasona-
ble expectation of success in reducing fracture risk.
While it is true that BMD improvements do not per-
fectly correlate with antifracture efficacy, it was well
established in the art that BMD is a powerful surrogate
for measuring fracture risk. For example, Roche’s own
expert explained:
Bone mineral density is directly related to frac-
ture risk. It is one of the most powerful surrogate
markers in the field of medicine. It is as powerful
an indicator of osteoporosis as blood pressure is a
predictor of stroke. For every standard deviation
reduction in bone mineral density, fracture risk is
doubled.
12 HOFFMANN-LA ROCHE INC. v. APOTEX INC.

Roche’s patents do not themselves present data
demonstrating antifracture efficacy for a once monthly
150 mg dose. In fact, antifracture efficacy for Boniva®
was demonstrated to the FDA through a “bridging study”
that used BMD and bone turnover results—not antifrac-
ture testing—to establish the therapeutic noninferiority of
the 150 mg monthly dose relative to the previously ap-
proved 2.5 mg daily dose, for which antifracture efficacy
had been demonstrated.
Conclusive proof of efficacy is not necessary to show
obviousness. All that is required is a reasonable expecta-
tion of success. See PharmaStem Therapeutics, Inc. v.
ViaCell, Inc., 491 F.3d 1342, 1363-64 (Fed. Cir. 2007);
Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir.
2007). Riis—along with other prior art that used BMD
improvement as the primary efficacy marker for treating
osteoporosis—established at least a reasonable expecta-
tion that once monthly dosing of ibandronate could suc-
cessfully treat osteoporosis and reduce fracture risk.
B. Selecting the 150 mg Dose
1. Riis confirmed the total-dose concept whereby “the
efficacy of ibandronate depends on the total oral dose
given rather than on the dosing schedule.” Riis therefore
teaches that in setting the dosage level for an intermit-
tent ibandronate regimen, one need only scale up a
known-effective dose from a short-interval regimen—e.g.,
daily dosing—to achieve approximately the same BMD
and bone-loss efficacy with a long-interval regimen.
The prior art provided substantial guidance as to the
total dose, within a given time period, that would produce
effective results. A 1996 article by Ravn et al. (“Ravn”)
reported the results of a study that measured BMD im-
provements and bone-turnover markers for daily ibandro-
nate doses of 0.25 mg, 0.5 mg, 1.0 mg, 2.5 mg, and 5 mg.
The authors concluded that the “average change in bone
mass showed positive outcome in all regions in the groups
HOFFMANN-LA ROCHE INC. v. APOTEX INC. 13

receiving ibandronate 2.5 and 5.0 mg.” The 2.5 mg dose
exhibited a response that was “virtually equal” to the 5
mg dose, even though it contained only half the amount of
ibandronate. The 2.5 mg dose was thereby deemed the
“most effective dose.”
A person skilled in the art looking to scale to a month-
ly dose of oral ibandronate from a known-effective daily
dose was thus faced with a very limited set of possibili-
ties: Of the five daily doses tested in Ravn, only the 2.5
and 5 mg doses “showed positive outcome in all regions.”
Even though the 5 mg dose did not demonstrate greater
efficacy than the 2.5 mg dose, it was still deemed an
equivalently effective dose so that someone scaling it to a
single monthly dose of 150 mg (5 mg/day x 30 days/month)
would have anticipated equivalent success in raising
BMD and limiting bone turnover, based on Riis.
Additionally, United States Patent No. 6,432,932
(“Daifotis”) disclosed weekly doses of ibandronate “from
the group consisting of 35 mg, 40 mg, 45 mg, or 50 mg.”
The 35 mg weekly dose corresponds to the same total dose
as a 5 mg daily dose. The total-dose equivalent to 5 mg of
ibandronate per day is thus the only dose that appears in
both Ravn and Daifotis—suggesting that there was a
reasonable expectation of success with the total-dose
equivalents of the 5 mg daily dose, i.e., 150 mg per month.
Accordingly, the prior art pointed to a monthly treat-
ment of 150 mg of ibandronate. At the very least, the 150
mg dose was obvious to try: There was a need to solve the
problem of patient compliance by looking to less-frequent
dosing regimens. And, based on Ravn and Daifotis, in
light of Riis’s total-dose concept, there were only a “finite
number of identified, predictable solutions.” KSR Int’l Co.
v. Teleflex, 550 U.S. 398, 421 (2007).
2. Roche contends that findings by the FDA taught
away from further development of the 5 mg daily dose
(and its total-dose equivalents) because the FDA approved
14 HOFFMANN-LA ROCHE INC. v. APOTEX INC.

a 2.5 mg daily dose of ibandronate instead of a 5 mg daily
dose. But the FDA never made any findings contrary to
the 5 mg daily dose, because it was never asked to ap-
prove that dose. Instead, in approving the 2.5 mg daily
dose, the FDA merely restated the results of Ravn and
concluded that “the 2.5 mg daily dose of ibandronate has
the most favorable benefit – risk ratio and is the most
appropriate dose for the prevention and treatment of
postmenopausal osteoporosis.”
Roche next contends that Schofield taught away from
using anything other than the lowest effective dose of a
bisphosphonate, which, according to Roche, was estab-
lished by Ravn to be 2.5 mg for ibandronate. Schofield,
however, does not teach that the lowest effective dose is
the only dose that should be used when treating osteopo-
rosis with a bisphosphonate. Instead, Schofield merely
defined the lowest effective dose as a measure of a drug’s
potency relative to its therapeutic effects. Schofield then
described a preferred embodiment of a method for treat-
ing bone disorders in which the maintenance dose of a
“bone-active phosphonate” ranged from 2.5 to 15 mg per
day. That range clearly encompasses more than just a
lowest effective dose. Moreover, Ravn never purported to
establish a lowest effective dose. Instead, it sought to
establish a “most effective [daily] dose.”
Roche argues that the district court misinterpreted
and misapplied the total-dose concept from Riis. Accord-
ing to Roche, the district court “took a technical leap” in
finding that Riis’s total-dose concept implied only simple
multiplication to scale from an efficacious daily dose to a
monthly dose. The evidence before the district court,
however, showed that the total-dose concept can be used
as an effective rule of thumb by a person skilled in the art
deciding how to scale to an efficacious intermittent dose of
ibandronate. The Riis study, in particular, established
that the total dose concept can reliably predict that the
efficacy of an ibandronate treatment depends on the total
HOFFMANN-LA ROCHE INC. v. APOTEX INC. 15

dose administered to a patient over a given period, not on
the amount administered at any single point in time. In
light of that evidence, it was reasonable to expect that a
once monthly dose of 150 mg would have roughly the
same efficacy as a daily dose of 5 mg.
C. Safety of the 150 mg Dose
Roche next contends that there are disputed issues of
fact as to whether it would have been obvious to adminis-
ter once monthly doses of 150 mg in light of alleged safety
concerns about the adverse gastrointestinal effects of
ibandronate and other bisphosphonates.
First, Roche argues that Ravn taught away from fur-
ther development of the 5 mg daily dose, and thereby its
total-dose equivalents, because Ravn taught that the 2.5
mg daily dose was more effective than the 5 mg daily dose
and had fewer side effects. Ravn, however, concluded that
“the responses in the groups receiving 2.5 and 5 mg
ibandronate were virtually equal,” not that the 2.5 mg
dose was more effective. And although patients on the 5
mg daily dose dropped out of the study at a higher rate
than patients on lower doses, Ravn did not conclude that
the higher drop-out rate was statistically significant.
Instead, the authors merely noted that a higher frequency
of diarrhea was experienced with the 5 mg dose. A higher
frequency of diarrhea does not necessarily teach away
from the 5 mg daily dose or its equivalents, however, as
the prior art indicated that modest gastrointestinal side
effects must be weighed in light of the benefits of the
drug. Indeed, Ravn itself concluded that “[i]n the present
study, the side effect profile of ibandronate seemed to be
safe” and that “[i]n general, the safety evaluation did not
reveal any differences between ibandronate and placebo
treated groups.”
Moreover, even if the higher incidence of diarrhea and
the larger number of dropouts in the Ravn study were
initially enough to teach away from further development
16 HOFFMANN-LA ROCHE INC. v. APOTEX INC.

of the 5 mg daily dose and its total dose equivalents, any
such teaching away would have been overcome by Riis’s
finding that an oral administration of 20 mg of ibandro-
nate every other day for 24 days, followed by a nine-week
rest phase, resulted in the same rate of side effects as a
2.5 mg daily regimen.
Aside from Ravn, Roche does not point to any refer-
ences suggesting that there were safety concerns associ-
ated with the 150 mg dose. Nor was Roche’s expert, Dr.
Harris, aware of anything that taught that a once month-
ly, 150 mg dose of ibandronate would be unsafe.
To the contrary, the prior art establishes that doses
even higher than 150 mg were considered safe. United
States Patent No. 6,143,326 (“Möckel”) stated that rapid-
release ibandronate formulations showed “no significant
side effects . . . in clinical studies using ibandronate even
at high dosages” and disclosed single-dose units up to 250
mg. Defendants’ expert, Dr. Yates, testified that the
disclosures in Möckel would have led a person of ordinary
skill in the art to understand that ibandronate doses up to
250 mg would be well tolerated. Likewise, Daifotis dis-
closed that “[f]or human oral compositions comprising
ibandronate . . . a unit dosage typically comprises from
about 3.5 mg to about 200 mg of the ibandronate com-
pound.”
There is thus no genuine issue of fact concerning
whether the prior art taught away from the 150 mg dose
based on safety concerns.
D. Unexpected Results
Roche argues that the district court erred by granting
summary judgment of obviousness because the evidence
of record showed that the 150 mg monthly dose was more
effective than the 2.5 mg daily dose and that the superior
effectiveness of the 150 mg monthly dose was unexpected.
Roche also contends that ibandronate’s nonlinear bioa-
HOFFMANN-LA ROCHE INC. v. APOTEX INC. 17

vailability at the 150 mg dosage level was an unexpected
result.
Roche’s MOBILE study, published in 2005, demon-
strated that a 150 mg monthly dose is more effective than
a 2.5 mg daily dose with respect to BMD improvement in
the lumbar spine and most hip sites. The MOBILE study
demonstrated, for example, a mean BMD improvement in
the lumbar spine of 4.9% after one year for patients
taking the 150 mg monthly dose and 3.9% after one year
for patients taking the 2.5 mg daily dose. Another study
published in 2005 showed that the extent of ibandronate’s
bioavailability is nonlinear with increasing dosages:
Increasing the oral dose by 50 percent, from 100 mg to
150 mg, resulted in a nearly 150 percent increase in the
amount of the drug absorbed by the blood.
While the evidence would support a finding of superi-
or efficacy of the 150 mg monthly dose in raising BMD
levels, as compared to a 2.5 mg daily dose, that improved
efficacy does not rebut the strong showing that the prior
art disclosed monthly dosing and that there was a reason
to set that dose at 150 mg. See In re Merck & Co., 800
F.2d 1091, 1099 (Fed. Cir. 1986). The evidence of superior
efficacy does nothing to undercut the showing that there
was a reasonable expectation of success with the 150 mg
monthly dose, even if the level of success may have turned
out to be somewhat greater than would have been ex-
pected.
For the same reasons, the nonlinear bioavailability of
ibandronate does not rebut the prima facie showing of
obviousness of a once monthly dose of 150 mg. The in-
creased level of bioavailability has not been shown to be
responsible for the improved osteoporosis treatment
efficacy of the 150 mg dose. A study by Ravn et al. in
2002 showed, for example, that a near doubling of the
blood-serum concentration of ibandronate with a 5 mg
daily dose, compared to a 2.5 mg daily dose, produced no
18 HOFFMANN-LA ROCHE INC. v. APOTEX INC.

further BMD increase and no further reduction in bone
turnover. Other record evidence confirms that “[d]ue to
strong binding to the bone surface, the effects of the
systemically available amount of a bisphosphonate are
almost exclusively related to its concentration in bone
rather than [blood] serum level.” The evidence regarding
bioavailability is therefore of little relevance to the obvi-
ousness inquiry.
Accordingly, we uphold the judgment of the district
court that claims 1-8 of the ’634 patent and claims 1-10 of
the ’957 patent would have been obvious in light of the
prior art and are therefore invalid.
AFFIRMED
United States Court of Appeals
for the Federal Circuit
______________________

HOFFMANN-LA ROCHE INC. AND
GENENTECH, INC.,
Plaintiffs-Appellants,

v.

APOTEX INC. AND APOTEX CORP.,
Defendants-Appellees.
______________________

2013-1128
______________________

-----------------------

HOFFMANN-LA ROCHE INC. AND
GENENTECH, INC.,
Plaintiffs-Appellants,

v.

DR. REDDY'S LABORATORIES, LTD. AND
DR. REDDY'S LABORATORIES, INC.,
Defendants-Appellees.
______________________

2013-1161
______________________

-----------------------
2 HOFFMANN-LA ROCHE INC. v. APOTEX INC.

HOFFMANN-LA ROCHE INC. AND
GENENTECH, INC.,
Plaintiffs-Appellants,

v.

WATSON LABORATORIES, INC., ACTAVIS, INC.,
WATSON PHARMA, INC., COBALT
PHARMACEUTICALS INC., AND COBALT
LABORATORIES, INC.,
Defendants-Appellees.
______________________

2013-1162
______________________

-----------------------

HOFFMANN-LA ROCHE INC. AND
GENENTECH, INC.,
Plaintiffs-Appellants,

v.

ORCHID CHEMICALS & PHARMACEUTICALS
LTD., ORCHID HEALTHCARE, ORCHID
PHARMACEUTICALS INC., AND ORGENUS
PHARMA INC.,
Defendants-Appellees.
______________________

2013-1163
______________________

-----------------------

HOFFMANN-LA ROCHE INC. AND
HOFFMANN-LA ROCHE INC. v. APOTEX INC. 3

GENENTECH, INC.,
Plaintiffs-Appellants,

v.

MYLAN INC., MYLAN PHARMACEUTICALS INC.,
GENPHARM ULC (formerly known as Genpharm
Inc.), AND GENPHARM, L.P.,
Defendants-Appellees.
______________________

2013-1164
______________________

Appeals from the United States District Court for the
District of New Jersey in Nos. 07-CV-4417, 08-CV-3065,
08-CV-4053 and 10-CV-6241, Judge Stanley R. Chesler.
______________________

NEWMAN, Circuit Judge, dissenting.
Hoffmann-LaRoche’s once-a-month Boniva® ibandro-
nate medication for osteoporosis required twelve years of
research and clinical testing and evaluation to demon-
strate its efficacy when dosed once a month and its safety
at this high monthly dosage. The prior investigations of
intermittent dosing, and the publications describing
protocols of lesser success, missed the protocol that pro-
duced this successful method. Indeed, this prior art
weighs heavily against obviousness, for despite extensive
exploration, this successful protocol was not discovered.
Invalidation of this patent is not supported by clear
and convincing evidence. The court’s ruling of obvious-
ness violates the principles of Graham v. John Deere Co.,
383 U.S. 1 (1966) (all factors must be considered, includ-
ing commercial success, failure of others, and long-felt
need). The court’s reasoning violates the guidance of KSR
Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007) (the
4 HOFFMANN-LA ROCHE INC. v. APOTEX INC.

standard of obvious-to-try requires a limited number of
specified alternatives offering a likelihood of success in
light of the prior art and common sense), this court in-
stead invoking judicial hindsight to reconstruct the pa-
tented subject matter.
Nowhere amid the many studies of bisphosphonate
osteoporosis treatments over a wide range of dosages and
conditions, did any reference show or suggest the Boniva®
combination of a single 150 mg dose and once-a-month
administration. No reference suggested the effectiveness
and safety of this combination. Nonetheless, my col-
leagues declare this treatment obvious to them. My
colleagues’ primary reason, that 150 mg is thirty times
the daily dose of 5 mg, does not mention that the FDA
refused to approve the 5 mg dose due to its toxic side
effects. Surely this leads away from the obviousness of a
single dose thirty times larger.
I respectfully dissent.
DISCUSSION
The unexpected results of the patented method are
conceded by the panel majority. The evidence on sum-
mary judgment was that many others sought and failed to
find an efficacious intermittent treatment schedule. The
prior art relied on by my colleagues surrounded but
missed the Roche method. The prior art shows that safety
is likely to be compromised at high doses, and that effica-
cy is likely to be compromised at extended dosing inter-
vals. Nonetheless, this court now holds that it was
obvious to do what no one did or even suggested; my
colleagues simply disregard the preferences and toxicity
warnings and discard the procedures of the prior art.
The prior art shows intermittent therapies ranging
from every other day to once a week to twice a week to
twice a month to every three months plus varying initial
loading periods, in a wide range of dosages. The prior art
HOFFMANN-LA ROCHE INC. v. APOTEX INC. 5

is replete with warnings of toxicity and patient non-
compliance. The panel majority acknowledges that
Roche’s MOBILE study and the nonlinear bioavailability
data (discussed infra) demonstrate that the 150 mg
monthly treatment produced unexpected results, but
deems this irrelevant; the court now, with knowledge of
Roche’s success, deems Roche’s successful method to have
been obvious all along.
The Supreme Court recognized in KSR that a patent
challenger must “identify a reason that would have
prompted a person of ordinary skill in the relevant field”
to arrive at the patented invention. 550 U.S. at 418. My
colleagues, unable to find any suggestion of the Roche
protocol in the prior art, accept the argument that a
monthly single dose of 150 mg was obvious because a
monthly dose of 150 mg is thirty times a daily dose of 5
mg. The FDA had refused to approve a daily dose of 5 mg
due to its demonstrated heightened toxicity. The success
of a dose thirty times larger than the prohibited 5 mg dose
cannot reasonably be predicted. Neither the prior art, nor
common sense, provides the expectation that a once-a-
month treatment at a dosage of 150 mg would be safe and
effective.
A. The Prior Art
1. The Möckel Patent
My colleagues combine many references to support
their ruling of obviousness. They cite the Möckel patent 1
for the proposition that single doses of more than 150 mg
were “known.” Möckel is directed to coated tablet formu-
lations, not the concentration of active ingredients.
Möckel provides specific examples of ibandronate tablets
containing a maximum dose of 50 mg, states that the
preferred upper limit is 100 mg, and that the formula-

1 U.S. Patent No. 6,143,326 (filed Apr. 1, 1997).
6 HOFFMANN-LA ROCHE INC. v. APOTEX INC.

tions could contain up to about 250 mg. Möckel shows no
formulated dose larger than 50 mg, although the refer-
ence contains the usual expansive statements of the
patent scrivener.
Möckel states that “no significant side effects were ob-
served in clinical studies using ibandronate at high dos-
ages,” but does not state that “high” exceeds his preferred
upper limit, for at that time the FDA had determined that
“[a] single oral dose of 100 mg is the maximum tolerable
dose of ibandronate.” J.A. 8558. Yet my colleagues rely
on this reference as rendering obvious Roche’s specific
once-a-month dosage of 150 mg.
2. Lunar News
Other references also show that the field was seeking
a better bisphosphonate protocol, and that the problems
were not solved. The Lunar News article, 2 on which the
panel majority places heavy reliance, broadly states that
some osteoporosis agents can be given intermittently.
However it never directly associates ibandronate with
oral therapy. Instead, the Lunar News article states the
then-current wisdom that “[t]he projected mode for iband-
ronate is injection once every three months.” J.A. 24321.
Contrary to the panel majority, this article supports
unobviousness of the Roche therapy, not obviousness.
3. The Chen Patent
The Chen patent 3 is similarly inapt. Chen sought to
minimize the adverse effects associated with bisphosphon-
ic acids by combining the bisphosphonic acid with a
carrier that acts as a dispersing medium for the active
agent. Chen lists all of the known bisphosphonic acids,

2 Update: Bisphosphonates, LUNAR NEWS, Spring,
27–29 (1999).
3 U.S. Patent No. 6,468,559 (filed Apr. 28, 2000).
HOFFMANN-LA ROCHE INC. v. APOTEX INC. 7

and states that oral dosages may be administered any-
where between once every two weeks and once every
twelve weeks, with the optimal frequency of once every
twelve weeks. Chen does not provide any example using
ibandronate, and does not suggest a specific dosage or
dosage interval for any ibandronate-containing product.
Nor does Chen state what parameters may lead to a
successful regimen.
4. The Geddes Patent
The other references on which my colleagues rely are
no more helpful to their conclusion. The Geddes patent 4
is directed to a combination therapy of a bisphosphonate
compound and a hormone, and states that the bisphos-
phonate may be dosed from every day to once a month.
Geddes does not mention ibandronate or the dosage or
suggest that it may be effective at 150 mg once a month.
5. The Schofield Patent Application
The Schofield application, 5 on which the court also re-
lies, describes a treatment regimen featuring a front-end
“loading period” of 7 to 180 days, followed by a mainte-
nance dose. The loading dose of bisphosphonate may be
given daily or every other day, while the maintenance
dose may be given anywhere from daily to monthly.
Schofield further states that the loading dose is about two
to twenty times greater than the maintenance dose.
Schofield mentions ibandronate as a possible active agent
appropriate for use in its methods, but provides no dosag-
es or specified periods for ibandronate.

4 U.S. Patent No. 5,616,560 (filed Mar. 20, 1996).
5 U.S. Patent Application Pub. No. 2003/0118634
(filed Dec. 17, 2002).
8 HOFFMANN-LA ROCHE INC. v. APOTEX INC.

6. The Riis Article
Several references address intermittent treatment,
but none suggests once-monthly administration of 150 mg
of oral ibandronate. The court relies on the Riis article, 6
which shows dosing patients with 20 mg of ibandronate
every other day for twenty-four days, followed by a 9-week
period of no treatment, then returning to 20 mg every
other day for twenty-four days, and a 9-week period of no
treatment, etc. The court characterizes this as definitive
proof of the “total dosing concept.” However, Riis makes
no suggestion that the once-a-month dosing at the high
dosage used by Roche could replace Riis’ elaborate proce-
dure.
Riis illustrates the general belief that some sort of
complex dosing is needed if daily doses are supplanted.
The simplicity of the Boniva® regimen is nowhere to be
found, although the need for a better regimen was well
recognized. See Graham, 383 U.S. at 18 (objective evi-
dence of nonobviousness includes long-felt need and
failure of others). Riis contains no suggestion that a once-
monthly dosage of 150 mg would be both safe and effec-
tive–this became known only after Roche discovered it.
7. The Recker Study
By comparison, the Recker article, 7 which sets forth in
its introduction the state of the art in 2004, states that
“oral bisphosphonates must be administered frequently

6 BJ Riis et al., Ibandronate: A Comparison of Oral
Daily Dosing Versus Intermittent Dosing in Postmenopau-
sal Osteoporosis, 16 J. BONE MIN. RES., 10, 1871–78
(1997).
7 R. Recker et al., Insufficiently Dosed Intravenous
Ibandronate Injections are Associated with Suboptimal
Antifracture Efficacy in Postmenopausal Osteoporosis, 34
BONE 890 (2004).
HOFFMANN-LA ROCHE INC. v. APOTEX INC. 9

(e.g., daily or weekly)” and in accordance with “stringent
dosing recommendations.”
Only this court reads the prior art to suggest and ren-
der obvious that which eluded the art at the time.
8. The Ravn Study
The court attempts to overcome the shortcomings of
the prior art by applying the total dose concept of Riis to
the dosage ranges in the Ravn8 reference. Ravn tested
daily treatment using a range of dosages and concluded
that 2.5 mg per day is the most effective dose. Yet the
court selects Ravn’s 5.0 mg dose, despite its increased
toxicity and Ravn’s preference for the lower dose, to scale
up to Roche’s 150 mg dose. Ravn does not suggest a once-
monthly dose of 150 mg.
It is also noteworthy that the Riis publication, which
is later in time than Ravn, selected the 2.5 mg dosage, not
the 5.0 mg dosage, as a framework for intermittent dos-
ing.
9. The Daifotis Patent
The panel majority also cites a patent issued to
Roche’s expert Dr. Daifotis9 as evidence of obviousness of
monthly oral dosing. Dr. Daifotis described dosing sched-
ules ranging from twice a week to twice a month, and
recommended once-a-week dosing of 7 mg to 100 mg, with
a preferred range of 35 mg to 50 mg per week. Daifotis
does not show or suggest any monthly dosage, or that

8 P. Ravn et al., The Effect of Bone Mass and Bone
Markers of Different Doses of Ibandronate: A New
Bisphosphonate for Prevention and Treatment of Postmen-
opausal Osteoporosis: A 1-Year Randomized, Double-
Blind, Placebo-Controlled Dose-Finding Study, 15 BONE
527–33 (1996).
9 U.S. Patent No. 6,432,932 (filed Sep. 2, 1999).
10 HOFFMANN-LA ROCHE INC. v. APOTEX INC.

monthly dosing might be effective. Nonetheless the panel
majority selects the Daifotis 35 mg per week dosage,
calculates that 35 mg times 4 weeks is about 150 mg per
month, and combines this calculation with Riis and Ravn
to find obvious the Roche combination of dosage and
schedule.
B. The Bioavailability Explanation
My colleagues agree that the results achieved with
the Boniva® product were not suggested or predicted. In
her expert report Dr. Daifotis discussed the scientific
basis that had later been found to explain the successful
treatment obtained with this protocol. Dr. Daifotis pre-
sented a published scientific article by Reginster 10 et al.
showing the disproportionate uptake of ibandronate into
the blood stream, an unpredicted and unusual result. Dr.
Daifotis testified that this explains the unexpected effica-
cy of Roche’s 150 mg dose. The record contains the follow-
ing graphical portrayal, where the mean area under the
curve (AUC) indicates the average concentration of iband-
ronate in the blood:

10 Jean-Yves Reginster et al., Monthly Oral Iband-
ronate is Well-Tolerated and Efficacious in Postmenopau-
sal Women: Results From the Monthly Oral Pilot Study,
90 J. OF CLIN. ENDOCRIN. & METAB. 5018–24 (2005).
HOFFMANN-LA ROCHE INC. v. APOTEX INC. 11

Dr. Daifotis explained that “[t]his was a surprising find-
ing concerning the disproportionate amount of ibandro-
nate that becomes available from oral administration of
amounts above about 50 mg, and it was unknown as of
May 2002.” J.A. 20726–27 ¶108. Dr. Daifotis explained
that “[t]he benefit of this surprising result was that a
patient could receive higher than thought possible
amounts of active drug to be available to inhibit osteo-
clasts, while at the time not adversely affecting the safety
profile of a 150 mg dose of ibandronate.” J.A. 20732 ¶115.
Dr. Daifotis also cited clinical trial data showing that
a 150 mg monthly dose of ibandronate is superior at
increasing bone density in the lumbar spine of postmeno-
pausal women, as compared to 100 mg given once a
month, 50 mg given on two consecutive days in a single
month (50/50) and a 2.5 mg daily dose.
The record contains other scientific articles, e.g., Paul
D. Miller et al., Monthly Oral Ibandronate Therapy in
12 HOFFMANN-LA ROCHE INC. v. APOTEX INC.

Postmenopausal Osteoporosis: 1-Year from the Mobile
Study, 20 J. BONE MINER. RES. 1315–22 (2005). Nothing
in the prior art renders the result expected, predicted, or
obvious.
C. Expert Testimony
Also of record were the reports of Roche’s experts Dr.
Bilezikian and Dr. Harris. Roche explained that each
opines that, at the time of the inventions, a person skilled
in the art would not have had any reasonable expectation
of succeeding with a safe, effective, and well-tolerated
once-monthly oral dosage of ibandronate in an amount as
large as 150 mg.
The trier of fact is “require[ed to] consider all evidence
relating to obviousness before finding a patent invalid on
those grounds.” In re Cyclobenzaprine Hydrochloride
Extended-Release Capsule Patent Litig., 676 F.3d 1063,
1075 (Fed. Cir. 2012). It is noteworthy that although the
generic producers who are defendants herein also pre-
sented expert reports, no expert provided anything other
than a personal opinion that the Roche discovery was
obvious.
The evidence of long-felt need, failure of others, and
commercial success was unrebutted, and no adverse
expert provided any evidence from which the success of
the Boniva® product could be confidently predicted. Their
only argument was that it would have been “obvious to
try” the Roche method. Of course, it is possible to specu-
late about all sorts of treatment schedules, as in the
Krause newsletter, 11 but speculation without specificity
and a plan for achieving a reasonable likelihood of success
does not provide clear and convincing evidence of obvi-
ousness on the ground of “obvious to try.”

11Carey Krause, Roche, GlaxoSmithKline in Drug
Pact, Chem. Market Reporter, December 17, 2001.
HOFFMANN-LA ROCHE INC. v. APOTEX INC. 13

D. Obvious to Try
For an invention to be obvious to try, there must be a
finite number of known choices in the prior art, and a
reasonable expectation of success for the choice that is
tried. KSR, 550 U.S. at 421. Obvious to try cannot be
found when the prior art gives no hint that a specific trial
might achieve the desired result. In re Kubin, 561 F.3d
1351, 1359 (Fed. Cir. 2009) (quoting In re O’Farrell, 853
F.2d 894, 903 (Fed. Cir. 1988)). Dr. Daifotis testified,
“monthly oral dosing of alendronate was not seen as a
feasible or desirable endeavor for investigation; if it had
been, we would have explored it.” J.A. 20717.
The law of “obvious to try” requires that there be a
limited number of defined alternatives and a suggestion
that the desired result is likely to be achieved through the
proposed trial. The Court stated:
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 ordi-
nary 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.
KSR, 550 U.S. at 421. Here, however, even my col-
leagues agree that the result was unpredicted, and that
there was no suggestion in the prior art, or in common
sense, that this procedure might produce the sought-after
result. Nonetheless, my colleagues invalidate the success-
ful treatment as “obvious to try.”
The extensive experimentation with other regimens
and dosages demonstrates that this selection was not
obvious to try. The failure to meet this long-felt need
weighs heavily against my colleagues’ finding that the
Roche protocol, although not obvious to investigators in
14 HOFFMANN-LA ROCHE INC. v. APOTEX INC.

the field, is obvious to this court. As stated in In re Soni,
54 F.3d 746, 750 (Fed. Cir. 1995), “[t]he basic principle
behind this rule is straightforward—that which would
have been surprising to a person of ordinary skill in the
particular art would not have been obvious.” As estab-
lished in KSR, absent limited alternatives and some
direction toward the successful path, “obvious to try” is
not applicable.
The prior art does not suggest the Roche protocol, or
that it might have a reasonable expectation of success.
Only with knowledge of Roche’s success, can one recon-
struct that which is not suggested in the prior art. If
anything, the large amount of study and publication adds
to the uncertainty, for it provides no direction for poten-
tial success. The court’s holding today will simply dis-
courage improvements in crowded fields, by holding that
even if such investigation should succeed, a patent is not
available.
From my colleagues’ invalidation of the patent on this
significant medical advance, I respectfully dissent.