United States Court of Appeals
for the Federal Circuit
__________________________
OTSUKA PHARMACEUTICAL CO., LTD.,
Plaintiff-Appellee,
v.
SANDOZ, INC., SUN PHARMACEUTICAL
INDUSTRIES, LTD., SYNTHON BV, SYNTHON
HOLDINGS BV, SYNTHON LABORATORIES, INC.,
AND SYNTHON PHARMACEUTICALS, INC.,
Defendants,
and
APOTEX INC. AND APOTEX CORP.,
Defendants-Appellants,
and
TEVA PHARMACEUTICALS USA, INC., BARR
LABORATORIES, INC., AND BARR
PHARMACEUTICALS, INC.,
Defendants-Appellants.
__________________________
2011-1126, -1127
__________________________
Appeal from the United States District Court for the
District of New Jersey in Case No. 07-CV-1000, Judge
Mary L. Cooper.
__________________________
Decided: May 7, 2012
OTSUKA PHARMA v. SANDOZ 2
__________________________
JAMES B. MONROE, Finnegan, Henderson, Farabow,
Garrett & Dunner, LLP, of Washington, DC, argued for
plaintiff-appellee. With him on the brief were MICHAEL J.
FLIBBERT, PAUL M. BROWNING and DENISE MAIN. Of
counsel on the brief were ROBERT L. BAECHTOLD and JOHN
D. MURNANE, Fitzpatrick, Cella, Harper & Scinto, of New
York, New York.
STEVEN E. FELDMAN, Husch Blackwell LLP, of Chi-
cago, Illinois, argued for defendants-appellants Apotex
Inc., et al. With him on the brief were DANIEL R. CHERRY
and SHERRY L. ROLLO.
ELIZABETH J. HOLLAND, Kenyon & Kenyon LLP, of
New York, New York, for defendants-appellants Teva
Pharmaceuticals USA, Inc., et al. With her on the brief
was MARIA LUISA PALMESE.
__________________________
Before LOURIE, MOORE, and REYNA, Circuit Judges.
LOURIE, Circuit Judge.
Apotex Inc., Apotex Corp., Teva Pharmaceuticals
USA, Inc., Barr Laboratories, Inc., and Barr Pharmaceu-
ticals, Inc. (collectively, the “Defendants”) appeal from the
final decision of the United States District Court for the
District of New Jersey sustaining the validity of the
asserted claims of U.S. Patent 5,006,528 (the “’528 patent)
under 35 U.S.C. § 103 and under the doctrine of nonstatu-
tory double patenting. We affirm.
BACKGROUND
Schizophrenia is a debilitating mental disease affect-
ing about one percent of the human population. Despite
3 OTSUKA PHARMA v. SANDOZ
extensive research, the cause, mechanism, and etiology of
schizophrenia remain unknown. Individuals with schizo-
phrenia suffer from positive symptoms, negative symp-
toms, and cognitive deficits. Positive symptoms include
hallucinations and delusions. Negative symptoms include
flat affect, poverty of speech, inability to experience
pleasure, lack of desire to form relationships, and lack of
motivation.
Drugs that treat schizophrenia are called antipsychot-
ics. The first antipsychotic drug, chlorpromazine, was
discovered by accident in the early 1950s. Subsequent
research revealed that chlorpromazine’s antipsychotic
properties were due to its antagonism (blocking) of dopa-
mine receptors in the brain. That finding resulted in the
development of other “typical” antipsychotics, which treat
positive symptoms but not negative symptoms and have a
number of problematic side effects, including extrapyra-
midal symptoms (“EPS”), tardive dyskinesia, prolactin
elevation (hyperprolactinemia), and sudden decrease in
blood pressure (orthostatic hypotension). The United
States Food and Drug Administration (“FDA”) last ap-
proved a typical antipsychotic in 1975. Despite their
drawbacks, typical antipsychotics are still used today.
Researchers discovered clozapine in the early 1960s.
Clozapine was the first “atypical” antipsychotic, in that it
had a diminished propensity to cause EPS and was useful
for treating both positive and negative symptoms of
schizophrenia. Clozapine had serious potential side
effects, however, including orthostatic hypotension, frank
hypotension, and agranulocytosis (a life-threatening
decrease in white blood cells). Due to those side effects
clozapine was withdrawn from clinical trials in the 1970s,
prompting scientists to seek an atypical antipsychotic
drug similar to clozapine with respect to efficacy but
lacking its toxicity and side effects. Researchers’ efforts
OTSUKA PHARMA v. SANDOZ 4
were largely unsuccessful, however, and the FDA ap-
proved no new antipsychotic drugs between 1976 and
1989. The FDA finally approved clozapine in 1990, but
only for treatment-resistant or treatment-intolerant
patients, subject to rigorous blood testing.
The FDA approved risperidone, the first post-
clozapine atypical antipsychotic, in 1994. Since then the
FDA has approved seven other atypical antipsychotics:
olanzapine (1996); quetiapine (1997); ziprasidone (2001);
aripiprazole (2002); paliperidone (2007); asenapine (2009);
and iloperidone (2009). Although clozapine remains the
“gold standard” with respect to efficacy, the other atypical
antipsychotics are considered at least as effective as
typical antipsychotics for treating positive symptoms,
while also treating negative symptoms and causing fewer
EPS side effects. Every FDA-approved atypical antipsy-
chotic has a chemical structure related either to clozapine
or risperidone, with the sole exception of aripiprazole—
the compound at issue in the present appeal.
Aripiprazole is the active ingredient in the antipsy-
chotic drug marketed by Otsuka Pharmaceutical Co., Ltd.
(“Otsuka”) under the brand name Abilify®. The culmina-
tion of several decades of drug development efforts,
Abilify® was approved in 2002 by the FDA and is mar-
keted for the treatment of schizophrenia, bipolar disorder,
irritability associated with autistic disorder in pediatric
patients, and as an add-on treatment for depression.
Abilify® has been commercially successful; since 2005 its
annual sales have exceeded a billion dollars, and in 2009
its sales were $3.3 billion.
Aripiprazole has the chemical name 7-{4-[4-(2,3-
dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-
dihydrocarbostyril and has the following chemical struc-
ture:
5 OTSUKA PHARMA v. SANDOZ
aripiprazole
Otsuka Pharm. Co. v. Sandoz, Inc., No. 3:07-cv-1000, 2010
U.S. Dist. LEXIS 132595, at *15 (D.N.J. Dec. 15, 2010).
Aripiprazole is a “carbostyril derivative,” that is, its
chemical structure contains a quinolinone fused ring
(labeled as “3,4-dihydrocarbostyril” in the structure
above). Aripiprazole’s carbostyril ring is referred to as
“3,4-dihydro” because it has two hydrogen atoms (not
shown in the structure above) connected to the 3 and 4
positions, and thus has a single bond between these two
carbon atoms. In contrast, a “carbostyril” moiety has only
one hydrogen atom at the 3 and 4 positions and a result-
ing double bond between the carbon atoms. Researchers
refer to both variants as “carbostyril derivatives.” Con-
nected to the 7-position of aripiprazole’s carbostyril core is
a “butoxy linker” consisting of four methylene (–CH2–)
units. A “propoxy linker,” in contrast, consists of only
three methylene units. Connected to aripiprazole’s bu-
toxy linker is a piperazine ring and a phenyl ring. The
terminal phenyl ring of aripiprazole is “2,3-dichloro”
substituted, meaning that it has chlorine atoms connected
to the 2 and 3 positions.
Otsuka is the assignee of the ’528 patent, which has a
foreign priority date of October 31, 1988, was filed on
OTSUKA PHARMA v. SANDOZ 6
October 20, 1989, and issued on April 9, 1991. The exclu-
sivity afforded by the ’528 patent, including a five-year
patent term extension and a six-month period of pediatric
exclusivity, will expire on April 20, 2015. Id. at *14.
Claim 12 of the ’528 patent claims aripiprazole using its
chemical name. ’528 patent col.19 ll.18–19. Claim 16
claims “[a] pharmaceutical composition for treating
schizophrenia containing, as the active ingredient, a
carbostyril compound . . . ,” id. col.19 l.16–col.20 l.3, and
claim 17 claims “[t]he pharmaceutical composition of
claim 16 wherein the carbostyril compound” is aripipra-
zole, id. col.20 ll.4–7. Claim 23, which was added during
re-examination of the ’528 patent, claims a method of
treating schizophrenia comprising administering a phar-
maceutical composition containing aripiprazole as an
active ingredient. Ex Parte Reexamination Certificate,
’528 patent col.2 ll.13–16.
The Defendants and several other companies submit-
ted Abbreviated New Drug Application (“ANDA”) filings
to the FDA for approval to engage in the commercial
manufacture, use, or sale of generic aripiprazole products.
Otsuka brought actions against these generic drug manu-
facturers for patent infringement; most of those actions
were consolidated into the case now before us on appeal.
See Otsuka, 2010 U.S. Dist. LEXIS 132595, at *3–5.
Otsuka asserted that the Defendants infringed claims 12,
17, and 23 of the ’528 patent under 35 U.S.C.
§ 271(e)(2)(A). The Defendants conceded that their ANDA
filings constituted literal infringement but asserted in
defense and counterclaimed that the claims were invalid
for obviousness and obviousness-type double patenting. 1
1 The Defendants also asserted an ultimately un-
successful inequitable conduct defense and counterclaim,
which are not at issue on appeal.
7 OTSUKA PHARMA v. SANDOZ
The district court held a bench trial from August 5
through August 26, 2010, and heard closing arguments on
October 21, 2010. The court entered its Amended Memo-
randum Opinion on December 15, 2010. See id. at *5.
On the issue of obviousness under § 103, the court
concluded that the Defendants failed to prove by clear and
convincing evidence that the asserted claims would have
been obvious to one of ordinary skill. In its analysis, the
court considered the known carbostyril derivatives, with
particular emphasis on the three purported “lead com-
pounds” asserted by the Defendants. Id. at *53.
The first of the Defendants’ alleged lead compounds is
7-[4-(4-phenylpiperazinyl)-butoxy]-3,4-dihydrocarbostyril,
which has the following chemical structure:
“unsubstituted butoxy”
Br. Defs.-Appellants Apotex, at 12. The parties refer to
this compound as the “unsubstituted butoxy,” because its
phenyl ring is unsubstituted and it has a butoxy linker
connecting the 7-position of its carbostyril core to its
piperazine ring.
The unsubstituted butoxy is disclosed and claimed in
Otsuka’s earlier U.S. Patent 4,734,416 (the “’416 patent”),
which the parties agree is prior art to the ’528 patent.
The ’416 patent issued on March 29, 1988, and expired on
March 29, 2005. Entitled “Pharmaceutically Useful
Carbostyril Derivatives,” the ’416 patent teaches a broad
genus encompassing “approximately nine trillion com-
pounds.” Otsuka, 2010 U.S. Dist. LEXIS 132595, at *12.
OTSUKA PHARMA v. SANDOZ 8
The ’416 patent discloses that “[c]arbostyril derivatives
having antihistaminic action and central nervous control-
ling action are useful as antihistaminic agents or central
nervous controlling agents.” ’416 patent abstract. The
patent further discloses that the compounds:
are useful for central nervous controlling agents
such as central muscle relaxing agents, sleep-
inducing agents, pre-operative drugs, antischizo-
phrenia agents, sedatives, antianxiety drugs, anti-
manic depressive psychosis agents, antipyretic
agents, analgetic agents and depressors, without
showing side-effects such as the feeling of thirst,
constipation, tachycordia [sic], parkinsonism,
and/or delayed dyscinesia [sic] which exist with
conventional central nervous controlling agents.
Id. col.3 ll.14–22. Claim 13 of the ’416 patent claims the
unsubstituted butoxy using its chemical name. Id. col.70
ll.62–63. Claim 50 claims “[a] method of producing an
antihistaminic effect in a mammal comprising the step of
administering to the mammal for producing said antihis-
taminic effect a pharmaceutical composition containing a
suitable amount of a carbostyril derivative” having a
general chemical formula, id. col.76 ll.1–60, and claim 116
claims “[t]he method of claim 50, wherein the carbostyril
derivative is selected from the group consisting of” nine
specific carbostyril derivatives, including the unsubsti-
tuted butoxy, id. col.84 ll.29–46.
The unsubstituted butoxy is also disclosed in a decla-
ration submitted during the prosecution of the ’416 patent
by one of that patent’s co-inventors, Dr. Kazuyuki Naka-
gawa (the “Nakagawa declaration”). J.A. 3792–3807. The
Nakagawa declaration discloses three sets of test data
comparing certain carbostyril derivatives. The first two
measure the compounds’ antihistaminic activity. The
9 OTSUKA PHARMA v. SANDOZ
third involves a test for “Activity for inhibiting jumping
behavior in mouse induced by Methamphetamine and L-
DOPA.” J.A. 3803. Although the Nakagawa declaration
nowhere mentions schizophrenia or antipsychotic activity,
and despite conflicting evidence regarding the use of
mouse jumping test data in antipsychotic drug discovery,
the district court found that Dr. Nakagawa’s mouse
jumping data “could be indicative of potential antipsy-
chotic activity to the skilled artisan.” Otsuka, 2010 U.S.
Dist. LEXIS 132595, at *34.
The Nakagawa declaration provides mouse jumping
test data for nine carbostyril derivative test compounds
and two prior art reference compounds. The potency of
the compounds is indicated with an effective dosage
(“ED50”) value measured in milligrams per kilogram,
wherein a lower value indicates greater potency in the
mouse jumping test. The following table summarizes the
data for the test compounds.
Compound
Chemical Name ED50
No.
5-[3-(4-phenylpiperazinyl)propoxy]-
5 3,4-dihydrocarbostyril dihydrochlo- 2.1
ride
7-[3-(4-phenylpiperazinyl)propoxy]-
6 3,4-dihydrocarbostyril dihydrochlo- 9.3
ride
7-{3-[4-(4-
16 chlorophenyl)piperazinyl]propoxy}- 15.1
3,4-dihydrocarbostyril
OTSUKA PHARMA v. SANDOZ 10
7-{3-[4-(3-
39 chlorophenyl)piperazinyl]propoxy}- 2.5
3,4-dihydrocarbostyril
7-[4-(4-phenyl-1-piperazinyl)butoxy]-
41 3,4-dihydrocarbostyril (“unsubsti- 5.5
tuted butoxy”)
1-methyl-7-[3-(4-phenyl-1-
42 piperazinyl)propoxy]-3,4- 10.7
dihydrocarbostyril
7-{3-[4-(2-chlorophenyl)-1-
43 piperazinyl]propoxy}-3,4- 3.4
dihydrocarbostyril
5-{3-[4-(2-ethoxyphenyl)-1-
44 piperazinyl]propoxy}-3,4- 0.53
dihydrocarbostyril
5-{3-[4-(4-methylphenyl)-1-
45 piperazinyl]propoxy}-3,4- 8.1
dihydrocarbostyril
J.A. 3794, 3796, 3805. The two most potent carbostyril
derivatives tested in the mouse jumping study have a 5-
propoxy linker, i.e., a propoxy substituent connected at
the 5-position of the carbostyril core. Compound 44, the
most potent derivative with an ED50 of 0.53, has a 5-
propoxy linker and an ethoxy substituent (–OCH2CH3) at
the 2-position of its phenyl ring. Compound 5, the second
most potent derivative with an ED50 of 2.1, has a 5-
propoxy linker and an unsubstituted phenyl ring. Of the
7-linked carbostyril derivatives for which Dr. Nakagawa
provided mouse jumping data, Compound 39, a 3-chloro
11 OTSUKA PHARMA v. SANDOZ
substituted propoxy, 2 had an ED50 of 2.5; Compound 43, a
2-chloro substituted propoxy, had an ED50 of 3.4; Com-
pound 41, the unsubstituted butoxy, had an ED50 of 5.5;
Compound 6, an unsubstituted propoxy, had an ED50 of
9.3; and Compound 16, a 4-chloro substituted propoxy,
had an ED50 of 15.1. Thus, the best compounds in this
test were the propoxys, not the butoxy.
The second alleged lead compound considered by the
district court is a carbostyril derivative with the chemical
name 7-{3-[4-(2,3-dichlorophenyl)-1-piperazinyl]-propoxy}-
3,4-dihydrocarbostyril and the chemical structure de-
picted below:
“2,3-dichloro propoxy”
Br. Defs.-Appellants Apotex, at 9. The parties refer to
this compound as the “2,3-dichloro propoxy” because its
phenyl ring is substituted with a chlorine atom at the 2
and 3 positions and it has a propoxy linker connecting its
carbostyril core and its piperazine ring. The 2,3-dichloro
propoxy was disclosed in two prior art foreign counter-
parts to Otsuka’s ’416 patent: German Patent 2,912,105
(the “DE ’105 patent”), J.A. 3808–930, at 3926 (example
317); and Swedish Patent Publication 434,945 (the “SE
’945 application”), J.A 6396–565, at 6556 (example 134).
Like the ’416 patent, the SE ’945 application teaches that
its carbostyril derivatives “can be used as antihistamines
2 Elsewhere in its opinion the district court referred
to Compound 39 as “OPC-4139.” See Otsuka, 2010 U.S.
Dist. LEXIS 132595, at *42.
OTSUKA PHARMA v. SANDOZ 12
or agents having a regulating action in the central nerv-
ous system,” J.A. 6495, and discloses numerous examples
of agents in the latter category:
The compounds according to the present invention
are therefore useful as means of controlling the
central nervous system as muscle relaxants,
sleeping agents, presurgery drugs, antischizo-
phrenia agents, sedatives, anxiolytics, drugs for
manic-depressive psychosis, fever-lowering
agents, analgesics and “depressors” without show-
ing side effects such as thirst, constipation, tachy-
cardia, parkinsonism and/or delayed dyschezia,
which are displayed by conventional agents which
act on the central nervous system.
J.A. 6499. The SE ’945 application “discloses dozens of
carbostyril compounds,” and the 2,3-dichloro propoxy “is
just one of ninety-six different compounds disclosed in
Example 134 alone.” Otsuka, 2010 U.S. Dist. LEXIS
132595, at *37–38. The DE ’105 patent “is substantially
the same as the SE ’945 application except that the DE
’105 Patent omits any mention of potential antipsychotic
activity.” Id. at *38.
The final purported lead compound considered by the
district court is OPC-4392. This carbostyril derivative,
which has the following chemical structure, has a 2,3-
dimethyl substituted phenyl ring, a propoxy linker, and a
carbostyril ring containing a double bond at the 3,4-
position:
“OPC-4392”
13 OTSUKA PHARMA v. SANDOZ
Br. Defs.-Appellants Apotex, at 10. OPC-4392 is an
Otsuka development compound and, as of the priority
date of the ’528 patent, was the only carbostyril derivative
tested in humans as a potential antipsychotic. A prior art
article published in 1987 describes OPC-4392 as “a totally
new compound that is an anti-psychotic drug being devel-
oped.” Mitsukuni Murasaki, New Psycho-Neuro Agents,
16 Japanese J. Clinical Psychiatry 1515, 1517 (1987)
(“Murasaki 1987”); J.A. 5891–919, at 5907. The Murasaki
1987 article further notes that “the anti-psychotic action
was not strong but the strength of the activating action
stood out,” that “improvements were observed in the
negative symptoms,” and that “the extra-pyramidal
disturbances are extremely weak.” J.A. 5907. A prior art
publication from January 1988 by the same author stated
that OPC-4392 was “expected to have some advantageous
effects different from those of conventional antipsychotic
drugs,” such as chlorpromazine. Mitsukuni Murasaki,
Phase 1 Study of a New Antipsychotic Drug, OPC-4392, 12
Progress Neuro-Psychopharmacology & Biological Psy-
chiatry 793, 802 (1988) (“Murasaki 1988”); J.A. 10396–
406, at 10405. Although the article stated that OPC-4392
was “expected to have fewer side effects than conventional
drugs of the same class,” it also reported that subjects
receiving a 5-milligram dose of OPC-4392 “experienced
sleeplessness, stagger, weakness, fatigability, heavy
headedness, lack of motivation and disturbed concentra-
tion, which were so severe that they were not able to
perform daily routine work.” J.A. 10397, 10401.
Evaluating the differences between the claimed in-
vention and the prior art, the district court found that the
asserted prior art did not teach one of ordinary skill to
select the unsubstituted butoxy, the 2,3-dichloro propoxy,
or OPC-4392 as a lead compound for further antipsychotic
research. Otsuka, 2010 U.S. Dist. LEXIS 132595, at *59,
OTSUKA PHARMA v. SANDOZ 14
*64, *70. Rather, the court found that a structure like
clozapine or risperidone—both of which are structurally
dissimilar to aripiprazole—would have been an attractive
lead compound. Id. at *76. The court thus concluded that
the Defendants failed to prove by clear and convincing
evidence that one of ordinary skill would have been
motivated to combine the asserted prior art to make
aripiprazole and would have had a reasonable expectation
of success in doing so. Id. at *76–77.
The court then turned to the issue of nonstatutory ob-
viousness-type double patenting. The court considered
whether aripiprazole and its uses are not patentably
distinct from the unsubstituted butoxy in claim 13 of the
’416 patent. Id. at *88. Noting the structural differences
between aripiprazole and the unsubstituted butoxy, the
court found that the prior art did not teach one of ordi-
nary skill to achieve antipsychotic activity by modifying
the unsubstituted butoxy with a 2,3-dichloro substitution
on its phenyl ring to make aripiprazole. Id. at *90–91.
The court thus concluded that the Defendants failed to
prove by clear and convincing evidence that the asserted
claims were invalid for nonstatutory double patenting.
Id. at *92.
On December 15, 2010, the court entered its Amended
Order and Final Judgment in favor of Otsuka. Otsuka
Pharm. Co. v. Sandoz, Inc., No. 3:07-cv-1000 (D.N.J. Dec.
15, 2010). The Defendants timely appealed. We have
jurisdiction pursuant to 28 U.S.C. § 1295(a)(1).
DISCUSSION
A patent is invalid if an alleged infringer proves, by
clear and convincing evidence, that the differences be-
tween the claimed subject matter 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
15 OTSUKA PHARMA v. SANDOZ
having ordinary skill in the pertinent art. 35 U.S.C.
§§ 103(a), 282(2); Microsoft Corp. v. i4i Ltd., 131 S. Ct.
2238, 2242 (2011). Obviousness is a question of law with
underlying factual findings, including: (1) the scope and
content of the prior art; (2) the level of ordinary skill in
the pertinent art; (3) the differences between the claimed
invention and the prior art; and (4) objective evidence
such as commercial success, long-felt need, and the failure
of others. Graham v. John Deere Co., 383 U.S. 1, 17–18
(1966). Similarly, nonstatutory obviousness-type double
patenting is a question of law with underlying findings of
fact. In re Longi, 759 F.2d 887, 892 (Fed. Cir. 1985).
Following a bench trial, we review the district court’s
conclusions of law de novo and its findings of fact for clear
error. Golden Blount, Inc. v. Robert H. Peterson Co., 365
F.3d 1054, 1058 (Fed. Cir. 2004). A factual finding is
clearly erroneous if, despite some supporting evidence, we
are left with the definite and firm conviction that a mis-
take has been made. United States v. U.S. Gypsum Co.,
333 U.S. 364, 395 (1948).
I
We first address the Defendants’ arguments that the
district court erred by failing to hold the asserted claims
invalid for obviousness under § 103. 3
3 Defendants-Appellants Apotex Inc. and Apotex
Corp. submitted one set of appellate briefs addressing the
issues of § 103 obviousness and nonstatutory double
patenting. Defendants-Appellants Teva Pharmaceuticals
USA, Inc., Barr Laboratories, Inc., and Barr Pharmaceu-
ticals, Inc., submitted another set of briefs that addressed
only nonstatutory double patenting, but joined in full the
principal and reply briefs filed by Apotex. For purposes of
this opinion we will refer to the arguments in both sets of
briefs as the Defendants’ arguments.
OTSUKA PHARMA v. SANDOZ 16
The Defendants contend that aripiprazole would have
been obvious over the prior art carbostyril derivative
compounds at the time aripiprazole was invented. They
assert that the lead compound analysis applied by the
district court violates our precedent and “fall[s] into a
rigid obviousness analysis precluded by KSR.” Br. Defs.-
Appellants Apotex, at 35–36. In this regard, the Defen-
dants allege that the court erred by assuming that “only
the most obvious choice could serve as a lead.” Id. at 34.
According to the Defendants, prior art compounds, includ-
ing the 2,3-dichloro propoxy, the unsubstituted butoxy,
and OPC-4392, were known to have antipsychotic activ-
ity, and it would have been obvious to chemically modify
them in the ways necessary to make aripiprazole. Fi-
nally, they argue that aripiprazole’s properties and other
secondary considerations do not render aripiprazole
nonobvious.
Otsuka, in response, argues that the district court
correctly rejected the Defendants’ obviousness conten-
tions, which are based on improper hindsight bias.
Otsuka points out that no carbostyril derivative had been
shown to effectively treat schizophrenia as of the priority
date of the ’528 patent. Otsuka also contends that the
district court did not require proof that aripiprazole was
the “most obvious” compound, but rather evaluated all of
the potential choices available to one of ordinary skill and
determined that the prior art did not suggest that the
unsubstituted butoxy, 2,3-dichloro propoxy, or OPC-4392
would be suitable lead compounds. Otsuka also asserts
that secondary considerations support the court’s conclu-
sion of nonobviousness.
For the following reasons, we hold that the district
court correctly determined that the Defendants failed to
prove by clear and convincing evidence that the asserted
claims would have been obvious under § 103.
17 OTSUKA PHARMA v. SANDOZ
A. The District Court’s “Lead Compound” Analysis
In cases involving the patentability of a new chemical
compound, prima facie obviousness under the third Gra-
ham factor generally turns on the structural similarities
and differences between the claimed compound and the
prior art compounds. Daiichi Sankyo Co. v. Matrix Labs.,
Ltd., 619 F.3d 1346, 1352 (Fed. Cir. 2010). The Defen-
dants assert that the district court erred by employing a
“lead compound” analysis as part of its determination
under the third Graham factor. We reject that conten-
tion. New compounds may be created from theoretical
considerations rather than from attempts to improve on
prior art compounds. In this case, however, the parties’
arguments focus on selecting and modifying particular
prior art compounds, designated as lead compounds.
Our case law demonstrates that whether a new
chemical compound would have been prima facie obvious
over particular prior art compounds ordinarily follows a
two-part inquiry. First, the court determines whether a
chemist of ordinary skill would have selected the asserted
prior art compounds as lead compounds, or starting
points, for further development efforts. Eisai Co. v. Dr.
Reddy’s Labs., Ltd., 533 F.3d 1353, 1359 (Fed. Cir. 2008)
(“[P]ost-KSR, a prima facie case of obviousness for a
chemical compound still, in general, begins with the
reasoned identification of a lead compound.”). A lead
compound, as we have explained, is “a compound in the
prior art that would be most promising to modify in order
to improve upon its . . . activity and obtain a compound
with better activity.” Takeda Chem. Indus., Ltd. v. Al-
phapharm Pty., Ltd., 492 F.3d 1350, 1357 (Fed. Cir.
2007). As such, a lead compound is “a natural choice for
further development efforts.” Altana Pharma AG v. Teva
Pharm. USA, Inc., 566 F.3d 999, 1008 (Fed. Cir. 2009). In
recent cases involving the alleged obviousness of a new
OTSUKA PHARMA v. SANDOZ 18
chemical compound, the parties have frequently focused
upon the notion that a chemist must select one or more
lead compounds. E.g., Daiichi, 619 F.3d at 1352; Altana,
566 F.3d at 1007; Procter & Gamble Co. v. Teva Pharm.
USA, Inc., 566 F.3d 989, 994 (Fed. Cir. 2009); Eisai, 533
F.3d at 1357; Takeda, 492 F.3d at 1357; Eli Lilly & Co. v.
Zenith Goldline Pharm., Inc., 471 F.3d 1369, 1379 (Fed.
Cir. 2006); Yamanouchi Pharm. Co. v. Danbury Phar-
macal, Inc., 231 F.3d 1339, 1345 (Fed. Cir. 2000); cf.
Unigene Labs., Inc. v. Apotex, Inc., 655 F.3d 1352, 1362
(Fed. Cir. 2011) (“[T]he term “reference composition” is
more appropriate than “lead compound” when considering
obviousness for a chemical composition.”). In such cases
our analysis focuses on those proposed lead compounds
that the alleged infringer has attempted to prove, by clear
and convincing evidence, that the skilled artisan would
have had a reason to select from the panoply of known
compounds in the prior art. Daiichi, 619 F.3d at 1354.
In determining whether a chemist would have se-
lected a prior art compound as a lead, the analysis is
guided by evidence of the compound’s pertinent proper-
ties. See Eli Lilly, 471 F.3d at 1378; In re Lalu, 747 F.2d
703, 707 (Fed. Cir. 1984). Such properties may include
positive attributes such as activity and potency, Altana,
566 F.3d at 1008; Eli Lilly, 471 F.3d at 1379; Yama-
nouchi, 231 F.3d at 1345; adverse effects such as toxicity,
Takeda, 492 F.3d at 1358, and other relevant characteris-
tics in evidence, see Eisai, 533 F.3d at 1358 (considering a
prior art compound’s lipophilicity and low molecular
weight); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1363
(Fed. Cir. 2007) (considering the “strength, solubility, and
other known chemical characteristics” of a prior art salt-
forming acid). Absent a reason or motivation based on
such prior art evidence, mere structural similarity be-
tween a prior art compound and the claimed compound
19 OTSUKA PHARMA v. SANDOZ
does not inform the lead compound selection. See Daiichi,
619 F.3d at 1354; In re Dillon, 919 F.2d 688, 692 (Fed.
Cir. 1990) (en banc) (“[S]tructural similarity between
claimed and prior art subject matter, proved by combining
references or otherwise, where the prior art gives reason or
motivation to make the claimed compositions, creates a
prima facie case of obviousness.” (emphasis added)). Were
it otherwise, the analysis would impermissibly rely upon
ex post reasoning. See KSR Int’l Co. v. Teleflex, Inc., 550
U.S. 398, 421 (2007) (“A factfinder should be aware, of
course, of the distortion caused by hindsight bias and
must be cautious of arguments reliant upon ex post rea-
soning.”).
The second inquiry in the analysis is whether the
prior art would have supplied one of ordinary skill in the
art with a reason or motivation to modify a lead com-
pound to make the claimed compound with a reasonable
expectation of success. Takeda, 492 F.3d at 1357 (“[I]n
cases involving new chemical compounds, it remains
necessary to identify some reason that would have led a
chemist to modify a known compound in a particular
manner to establish prima facie obviousness of a new
claimed compound.”); Pfizer, 480 F.3d at 1361 (“[T]he
challenger of the patent [must] show by clear and convinc-
ing evidence that a skilled artisan would have been
motivated to combine the teachings of the prior art refer-
ences to achieve the claimed invention, and that the
skilled artisan would have had a reasonable expectation
of success in doing so.”); Dillon, 919 F.2d at 692.
In keeping with the flexible nature of the obviousness
inquiry, the reason or motivation for modifying a lead
compound may come from any number of sources and
need not necessarily be explicit in the prior art. Eisai,
533 F.3d at 1357 (citing KSR, 550 U.S. at 415); Aventis
Pharma Deutschland GmbH v. Lupin, Ltd., 499 F.3d
OTSUKA PHARMA v. SANDOZ 20
1293, 1301 (Fed. Cir. 2007). Again, pertinent properties
guide the analysis, for “it is the possession of promising
useful properties in a lead compound that motivates a
chemist to make structurally similar compounds.” Dai-
ichi, 619 F.3d at 1354 (“Potent and promising activity in
the prior art trumps mere structural relationships.”); see
also Eli Lilly, 471 F.3d at 1378 (“[P]atentability for a
chemical compound does not depend only on structural
similarity.”); In re Stemniski, 444 F.2d 581, 586 (CCPA
1971). As we have explained, “it is sufficient to show that
the claimed and prior art compounds possess a ‘suffi-
ciently close relationship . . . to create an expectation,’ in
light of the totality of the prior art, that the new com-
pound will have ‘similar properties’ to the old.” Aventis,
499 F.3d at 1301 (quoting Dillon, 919 F.2d at 692); see
also In re Wilder, 563 F.2d 457, 460 (CCPA 1977).
In the present case, in assessing whether aripiprazole
would have been prima facie obvious in view of the prior
art compounds asserted by the Defendants, the district
court summarized the applicable law as requiring inquiry
into
the hypothetical person of skill in the art’s identi-
fication of a lead compound, structural differences
between the proposed lead compound and the
claimed invention, motivation or teachings in the
prior art to make the necessary changes to arrive
at the claimed invention, and whether the person
of skill in the art would have a reasonable expec-
tation of success in making such structural
changes.
Otsuka, 2010 U.S. Dist. LEXIS 132595, at *52–53. We
discern no error in the district court’s recitation of the
applicable law. Moreover, the court did not require, as
the Defendants allege, that only “the most obvious choice”
21 OTSUKA PHARMA v. SANDOZ
could serve as the lead. Rather, the district court con-
cluded that two compounds—clozapine and risperidone—
would have been considered viable lead compounds. Id. at
*76. These were the only marketed antipsychotic com-
pounds at the time the present inventors began their
work. They were the natural and obvious lead compounds
whose structures one would have considered to modify to
obtain improved antipsychotic compounds. At the rele-
vant time, there were no carbostyril compounds that were
marketed as antipsychotics or were publicly known to
have potent antipsychotic activity with minimal side
effects. Carbostyrils were thus not plausible lead com-
pounds, except in retrospect, and the district court did not
clearly err in concluding that they were not.
As for the Defendants’ purported lead compounds, the
district court carefully considered each compound and
correctly rejected the contention that a skilled artisan
would have selected those compounds for further antipsy-
chotic drug research efforts.
B. The Unsubstituted Butoxy Compound
In evaluating the differences between the claimed in-
vention and the prior art, the district court first consid-
ered the unsubstituted butoxy compound disclosed in the
prior art ’416 patent and the Nakagawa declaration. The
Defendants contend that the court erred by finding that a
skilled artisan would not have selected the unsubstituted
butoxy as a lead compound for antipsychotic drug discov-
ery. We disagree.
As the court noted, the claims of the prior art ’416
patent explicitly disclose the unsubstituted butoxy as
producing an antihistaminic effect. This clear teaching
controls over the far more nebulous disclosure that the
trillions of carbostyril compounds encompassed by the
’416 patent “have antihistaminic and central nervous
OTSUKA PHARMA v. SANDOZ 22
controlling effects.” ’416 patent col.2 ll.50–51. As ex-
plained by Dr. Bryan Roth, whom the court credited as an
expert in schizophrenia, antipsychotic drug discovery, and
psychopharmacology, one of ordinary skill in the art
would not have understood the ’416 patent’s “laundry list”
of potential central nervous system controlling effects to
mean that every carbostyril derivative disclosed in the
’416 patent is a potential antipsychotic. Otsuka, 2010
U.S. Dist. LEXIS 132595, at *26, *31.
The Nakagawa declaration similarly fails to support
the Defendants’ contentions. As an initial matter, Otsuka
argues in a footnote to its brief that the Nakagawa decla-
ration is not eligible as prior art because the Defendants
failed to prove that a chemist seeking to develop a new
antipsychotic drug would have consulted the unindexed
file history of the prior art ’416 patent in the course of his
or her research. Br. Pl.-Appellee Otsuka, at 24 n.1.
Arguments raised only in footnotes, however, are waived.
SmithKline Beecham Corp. v. Apotex Corp., 439 F.3d
1312, 1320 (Fed. Cir. 2006). Although we may exercise
our discretion to consider improperly raised arguments,
we decline to do so here. See Becton Dickinson & Co. v.
C.R. Bard, Inc., 922 F.2d 792, 800 (Fed. Cir. 1990). We
therefore assume, without deciding, that the Nakagawa
declaration qualifies as prior art.
Although Nakagawa’s mouse jumping data “could be
indicative of potential antipsychotic activity to the skilled
artisan,” Otsuka, 2010 U.S. Dist. LEXIS 132595, at *34,
that alone does not resolve the matter. Rather, we must
consider the contents of the declaration as a whole, as the
district court correctly did. In doing so, we focus in par-
ticular on the compounds’ disclosed properties because, as
the district court found, “[g]enerally, a skilled artisan
would be attracted to the most potent compounds in
23 OTSUKA PHARMA v. SANDOZ
selecting a lead compound for development.” Id. at *54;
see also Daiichi, 619 F.3d at 1354.
Of the nine carbostyril test compounds for which the
Nakagawa declaration supplied mouse jumping data, the
unsubstituted butoxy was inferior to four other test
compounds and thus “was only of middling potency.”
Otsuka, 2010 U.S. Dist. LEXIS 132595, at *65. Signifi-
cantly, the four more potent test compounds were all
propoxy-linked, including Compound 44, which, with an
ED50 of 0.53 milligrams per kilogram, “was by far the
most potent of the compounds tested.” Id. at *54. One of
the Defendants’ own experts conceded that the activity of
Compound 44 was “striking,” and Dr. Roth testified that if
a skilled artisan were to select any compound from the
Nakagawa declaration, it would be Compound 44. Id. at
*54, *56. The Defendants do not allege obviousness over
the structurally dissimilar Compound 44, which, unlike
aripiprazole, has a propoxy linker connected at the 5-
position of its carbostyril core and a 2-ethoxy substituent
on its phenyl ring. As the district court found, the Naka-
gawa declaration would, if anything, have taught one of
ordinary skill to select a 5-linked propoxy carbostyril
derivative as a lead compound. See id. at *57 (comparing
the ED50 value of 2.1 for a 5-linked unsubstituted propoxy
and the ED50 value of 9.3 for a 7-linked unsubstituted
propoxy and finding that this “significant” difference
“would teach the skilled artisan the superiority of 5-
linked propoxy compounds over 7-linked propoxy com-
pounds”).
Thus, neither the ’416 patent nor the Nakagawa dec-
laration supports the Defendants’ position that one of
ordinary skill would have selected the prior art unsubsti-
tuted butoxy compound as a lead compound for further
antipsychotic research.
OTSUKA PHARMA v. SANDOZ 24
C. The 2,3-Dichloro Propoxy Compound
According to the Defendants, the district court erred
by failing to find that aripiprazole would have been obvi-
ous over the SE ’945 application, which taught that the
2,3-dichloro propoxy compound had antipsychotic activity.
We disagree. The Defendants’ argument “strains the
scope of the SE ’945 application.” Id. at *62. As the
district court correctly found, the SE ’945 application lists
the 2,3-dichloro propoxy compound “as one among hun-
dreds of examples that may be useful for an extensive list
of potential central nervous system controlling activities,”
id., and fails to tie the 2,3-dichloro propoxy to any mean-
ingful suggestion of antipsychotic activity.
The Defendants, citing Pfizer, 480 F.3d 1348, allege
that the SE ’945 application’s generic disclosure “is all
that is required for obviousness.” Br. Defs.-Appellants
Apotex, at 37. In Pfizer, this court held that the claimed
amlodipine besylate salt would have been obvious in view
of the known chemical structure of amlodipine and a prior
art group of salt-forming anions including benzene sul-
phonate (which combines with amlodipine to form the
besylate salt). Pfizer, 480 F.3d at 1372. This court prem-
ised its conclusion on findings that the prior art not only
provided “ample motivation to narrow the [prior art]
genus of . . . salt-forming anions . . . to a few [species],” id.
at 1363, but also “predicted the results,” id. at 1367. In
the present case, in contrast to Pfizer, the Defendants
failed to make an analogous showing. The district court
thus correctly found that one of ordinary skill in the art
would not have selected the 2,3-dichloro propoxy com-
pound as a lead compound for further antipsychotic
research.
Furthermore, as Otsuka points out, the Defendants’
theory that aripiprazole would have been obvious over the
25 OTSUKA PHARMA v. SANDOZ
unsubstituted butoxy and the 2,3-dichloro propoxy rested
in large part upon an asserted “bracketing theory”—i.e.,
that one would have combined those two asserted com-
pounds to arrive at aripiprazole, which shares some
structural features of both. The district court found that
the Defendants’ theory constituted “an improper hind-
sight analysis.” Otsuka, 2010 U.S. Dist. LEXIS 132595,
at *64. The Defendants do not on appeal challenge the
district court’s finding or re-assert their bracketing the-
ory. Accordingly, we conclude that the Defendants failed
to prove by clear and convincing evidence that aripipra-
zole would have been obvious over the 2,3-dichloro pro-
poxy.
D. OPC-4392
The Defendants also assert that the district court
erred by rejecting OPC-4392 as a lead compound. Again,
we disagree. The Defendants rely selectively on the
disclosure in Murasaki 1987 that OPC-4392 was “an anti-
psychotic drug,” J.A. 5907, and the fact that OPC-4392
proceeded to Phase II clinical trials. Taken as a whole,
however, the prior art taught away from using OPC-4392
as a starting point for further antipsychotic research.
For example, Murasaki 1987 teaches that “the anti-
psychotic action [of OPC-4392] was not strong.” Id.
Based on that teaching, together with other prior art of
record that focuses only on the effects of OPC-4392 on
schizophrenia’s negative symptoms, a skilled artisan
would have concluded that OPC-4392 did not treat posi-
tive symptoms. Otsuka, 2010 U.S. Dist. LEXIS 132595, at
*68–69. The district court also credited the testimony of
one of the Defendants’ witnesses, who stated that clinical
studies of OPC-4392 showed that it “lacked [an] antipsy-
chotic component.” Id. at *68. Furthermore, Murasaki
1987 taught that “the strength of the activating action [of
OTSUKA PHARMA v. SANDOZ 26
OPC-4392] stood out,” J.A. 5907, a property that Dr. Roth
testified would have been a “red flag” indicating that the
drug was likely to cause patients to act out on their
delusions and hallucinations. Otsuka, 2010 U.S. Dist.
LEXIS 132595, at *69. Another prior art reference,
Murasaki 1988, taught that OPC-4392, even at a “very
low dose,” id. at *41, caused “severe” side effects, J.A.
10401. In light of the totality of the evidence before the
district court, we perceive no clear error in the conclusion
that OPC-4392 was “considered a failure insofar as it did
not treat the positive symptoms of schizophrenia and was
not well-tolerated in modest doses.” Otsuka, 2010 U.S.
Dist. LEXIS 132595, at *70. The court thus did not err in
concluding that one of ordinary skill in the art would not
have selected OPC-4392 as a lead compound for further
antipsychotic research.
Even assuming that one would have selected OPC-
4392 as a lead compound, the district court found that the
Defendants failed to prove that the prior art would have
directed one to make the various modifications necessary
to convert OPC-4392 into aripiprazole. Those modifica-
tions include: (1) converting OPC-4392’s carbostyril core
into a dihydrocarbostyril; (2) changing OPC-4392’s pro-
poxy linker to a butoxy; and (3) replacing OPC-4392’s 2-
methyl and 3-methyl groups with 2-chloro and 3-chloro
substituents. On appeal, the Defendants rely in large
part on the inventors’ and Otsuka’s own development
efforts in an attempt to prove that aripiprazole would
have been obvious. E.g., Br. Defs.-Appellants Apotex, at
46–47 (arguing that Otsuka’s aripiprazole development
involved a “short timeline” and only “took a few months”).
Those arguments cannot trump the district court’s careful
fact finding, however. The inventor’s own path itself
never leads to a conclusion of obviousness; that is hind-
sight. What matters is the path that the person of ordi-
27 OTSUKA PHARMA v. SANDOZ
nary skill in the art would have followed, as evidenced by
the pertinent prior art. See 35 U.S.C. § 103(a) (“Pat-
entability shall not be negatived by the manner in which
the invention was made.”); Life Techs., Inc. v. Clontech
Labs., Inc., 224 F.3d 1320, 1325 (Fed. Cir. 2000) (“[T]he
path that leads an inventor to the invention is expressly
made irrelevant to patentability by statute.”). We there-
fore agree with the district court that the Defendants
failed to provide clear and convincing evidence that the
skilled artisan would have known how to modify OPC-
4392 to increase antipsychotic activity. Otsuka, 2010 U.S.
Dist. LEXIS 132595, at *70.
E. Conclusion
In summary, the district court’s careful analysis ex-
posed the Defendants’ obviousness case for what it was—
a poster child for impermissible hindsight reasoning.
Because we agree with the district court that the Defen-
dants failed to prove that claim 12 of the ’528 patent
would have been prima facie obvious over the asserted
prior art compounds, we need not address the court’s
findings regarding objective evidence of nonobviousness.
In addition, because the Defendants’ arguments for
obviousness of dependent claims 17 and 23 rely on a
determination of obviousness for independent claim 12,
we need not separately analyze the court’s finding that
the Defendants failed to prove invalidity for the asserted
dependent claims.
II
We now turn to the Defendants’ contention that the
district court erred by failing to hold the asserted claims
of the ’528 patent invalid for nonstatutory obviousness-
type double patenting in view of the unsubstituted butoxy
compound of claim 13 of the ’416 patent.
OTSUKA PHARMA v. SANDOZ 28
An inventor may obtain “a patent” for an invention
pursuant to 35 U.S.C. § 101; the statute thus “permits
only one patent to be obtained for a single invention.” In
re Lonardo, 119 F.3d 960, 965 (Fed. Cir. 1997). The
double patenting doctrine “precludes one person from
obtaining more than one valid patent for either (a) the
‘same invention,’ or (b) an ‘obvious’ modification of the
same invention.” Longi, 759 F.2d at 892. Nonstatutory
double patenting is a judicially created doctrine grounded
in public policy that “prevent[s] the extension of the term
of a patent, even where an express statutory basis for the
rejection is missing, by prohibiting the issuance of the
claims in a second patent not patentably distinct from the
claims of the first patent.” Id.
As an initial matter, the parties disagree over the le-
gal test for nonstatutory double patenting. Otsuka con-
tends that there is no difference between obviousness
under § 103 and obviousness-type double patenting. That
is not entirely correct. We have noted that “a double
patenting of the obviousness type rejection is analogous to
[a failure to meet] the non-obviousness requirement of 35
U.S.C. § 103.” Id. at 892 n.4 (internal quotation marks
omitted). Important differences remain, however. The
patent principally underlying the double patenting rejec-
tion need not be prior art. Id. Moreover, when analyzing
obviousness-type double patenting in cases involving
claimed chemical compounds, the issue is not whether a
skilled artisan would have selected the earlier compound
as a lead compound. That is so because the analysis must
necessarily focus on the earlier claimed compound over
which double patenting has been alleged, lead compound
or not. See Ortho Pharma. Corp. v. Smith, 959 F.2d 936,
943 (Fed. Cir. 1992) (“[I]t is the claims that are compared
when assessing double patenting.”).
29 OTSUKA PHARMA v. SANDOZ
The Defendants assert that, unlike an analysis under
§ 103, the test for obviousness-type double patenting
never asks whether the prior art would have supplied a
motivation to modify the earlier claimed compound. That
is also incorrect. Unless the earlier claim anticipates the
later claim under § 102, the question whether the two
claimed compounds are “patentably distinct” implicates
the question of obviousness under § 103, Longi, 759 F.2d
at 892, which in the chemical context requires identifying
some reason that would have led a chemist to modify the
earlier compound to make the later compound with a
reasonable expectation of success, see Takeda, 492 F.3d at
1357, 1361.
The Defendants rely on Geneva Pharm., Inc. v.
GlaxoSmithKline PLC, 349 F.3d 1373, 1377 n.1 (Fed. Cir.
2003), which states in a footnote that “[o]bviousness
requires inquiry into a motivation to modify the prior art;
nonstatutory double patenting does not.” Geneva, how-
ever, involved nonstatutory double patenting based on
anticipation, not obviousness. Id. (“This genus-species
relationship makes the claims patentably indistinct,
because the earlier species . . . anticipates the later ge-
nus . . . .”). For anticipation, of course, motivation in the
prior art is unimportant. See, e.g., Callaway Golf Co. v.
Acushnet Co., 576 F.3d 1331, 1347 (Fed. Cir. 2009) (noting
that, in an “anticipation argument, . . . motivation to
combine is not an issue”). The statement from Geneva
was later recited in dictum in Procter & Gamble Co. v.
Teva Pharm. USA, Inc., 566 F.3d 989 (Fed. Cir. 2009), in
which we concluded under § 103 that there would have
been no motivation to modify the prior art compound, id.
at 995, and then stated: “Having concluded that [the
asserted compound] was not obvious under 35 U.S.C.
§ 103, we similarly conclude that the [asserted] patent is
not invalid for obviousness-type double patenting,” id. at
OTSUKA PHARMA v. SANDOZ 30
999 (emphasis added). Contrary to the Defendants’
arguments, neither Geneva nor Procter & Gamble stands
for the proposition that, in considering whether one
compound is an obvious variant of another for purposes of
nonstatutory double patenting, analyzing the compound
of the prior claim for a reason or motivation to modify is
irrelevant.
We therefore reject the Defendants’ contention that
the district court legally erred by relying in part on its
findings under § 103 in its subsequent double patenting
analysis. The court in this case applied the correct test
for nonstatutory obviousness-type double patenting: In
the context of claimed chemical compounds, an analysis of
nonstatutory obviousness-type double patenting—like an
analysis under § 103—entails determining, inter alia,
whether one of ordinary skill in the art would have had
reason or motivation to modify the earlier claimed com-
pound to make the compound of the asserted claim with a
reasonable expectation of success. There is no other way
to consider the obviousness of compound B over compound
A without considering whether one of ordinary skill would
have had reason to modify A to make B. That is tradi-
tional obviousness analysis.
Turning to the particulars of the district court’s deci-
sion on nonstatutory double patenting, the Defendants
contend that the court improperly treated claim 13 of the
’416 patent in isolation without considering prior art, such
as the Nakagawa declaration, which would have taught a
skilled artisan to substitute a phenyl ring with chlorine
atoms at the 2- and 3-positions to make aripiprazole.
Otsuka, in response, argues that the court, after consider-
ing the Nakagawa declaration in detail, correctly con-
cluded that aripiprazole was not an obvious variant of the
unsubstituted butoxy.
31 OTSUKA PHARMA v. SANDOZ
We agree with the district court that the asserted
claims are not invalid for nonstatutory double patenting.
As we explained above, aripiprazole differs structurally
from the unsubstituted butoxy of claim 13 of the ’416
patent. Aripiprazole has chlorine substituents at the 2
and 3 positions of its phenyl ring, whereas the unsubsti-
tuted butoxy has hydrogens at those positions—i.e., it is
“unsubstituted.” In its double patenting analysis, the
court determined “that the prior art, including the Naka-
gawa Declaration, . . . did not teach the person of ordinary
skill in the art to pursue a 2,3-dichloro substitution on the
phenyl ring to achieve antipsychotic activity.” Otsuka,
2010 U.S. Dist. LEXIS 132595, at *90–91; see also id. at
*64. The evidence before the district court supports this
finding. For example, the court credited evidence demon-
strating the high degree of unpredictability in antipsy-
chotic drug discovery as of the priority date. Id. at *48,
*61. Experts testified that the discovery of new antipsy-
chotic drugs in the 1980s was “very unpredictable,” J.A.
30660, and that antipsychotic research at that time was
“notoriously unsuccessful,” J.A. 30453. As KSR makes
clear, predictability is a vital consideration in the obvi-
ousness analysis. 550 U.S. at 421; see also Procter &
Gamble, 566 F.3d at 996 (“[T]o the extent an art is unpre-
dictable, as the chemical arts often are, KSR’s focus on . . .
‘identified, predictable solutions’ may present a difficult
hurdle because potential solutions are less likely to be
genuinely predictable.” (quoting Eisai, 533 F.3d at 1359)).
As the district court correctly held, the prior art would
not have provided a skilled artisan with a reason to make
the necessary structural changes to the unsubstituted
butoxy to yield aripiprazole. Otsuka, 2010 U.S. Dist.
LEXIS 132595, at *91. The Defendants posit that substi-
tution with chlorine atoms at the 2- and 3-positions of the
phenyl ring “would have been a logical and routine modi-
OTSUKA PHARMA v. SANDOZ 32
fication.” Br. Defs.-Appellants Apotex, at 66. The evi-
dence indicates otherwise. The Nakagawa declaration
neither disclosed nor would have suggested a 2,3-dichloro
substituted antipsychotic compound. Otsuka, 2010 U.S.
Dist. LEXIS 132595, at *62; J.A. 30689. And, as we noted
above, although other prior art including the SE ’945
application disclosed 2,3-dichloro substituted compounds,
those references failed to tie that disclosure to any mean-
ingful suggestion of antipsychotic activity. Otsuka, 2010
U.S. Dist. LEXIS 132595, at *62. As Dr. David Nichols,
an expert in both medicinal chemistry and pharmacology,
testified at trial: “There was no known antipsychotic drug,
successful or otherwise, that had those two particular
[chlorine] substituents arranged in a 2,3 . . . orientation,”
and, further, “[t]here’s no teaching that suggests that a
dichlorination pattern like that would lead to a safe
atypical antipsychotic, or even an antipsychotic, period,
atypical or otherwise.” J.A. 30688–89. In short, we
perceive no clear error in the district court’s finding that
one of ordinary skill would not have been motivated to
pursue a 2,3-dichloro substitution on the phenyl ring as
would have been required to convert the unsubstituted
butoxy to aripiprazole.
Finally, the nonstatutory double patenting issue in
this case is not, as the Defendants argue, controlled by In
re Zickendraht, 319 F.2d 225 (CCPA 1963). In
Zickendraht, one of our predecessor courts reviewed a
decision of the Board of Patent Appeals and Interferences
(the “Board”) rejecting a claimed metalliferous azodyestuff
compound for nonstatutory double patenting over a
similar compound claimed in an issued patent. The two
compounds were identical but for the presence or absence
of a methyl group. Id. at 1534. In affirming the Board’s
rejection, the Zickendraht court noted that “[i]t has not
been shown that this [chemical] difference has any effect
33 OTSUKA PHARMA v. SANDOZ
on the dyeing characteristics of the compound.” Id. at
1531. The court also pointed out that the earlier “patent
disclosure would suggest to one skilled in the art” reacting
particular starting components, which “should result in
production of the dye claimed” in the pending application.
Id. at 1532. Unlike in Zickendraht, the evidence here not
only demonstrates the unpredictability of minor struc-
tural changes on a compound’s antipsychotic properties,
but also indicates that the prior art would not have pro-
vided the skilled artisan with a reason to make the neces-
sary structural changes to the unsubstituted butoxy to
yield aripiprazole. Otsuka, 2010 U.S. Dist. LEXIS
132595, at *61, *91. Zickendraht, therefore, is distin-
guishable from the present case.
Because we agree with the district court that the prior
art would not have provided one of ordinary skill with a
reason or motivation to make aripiprazole from the un-
substituted butoxy compound, we need not examine
Otsuka’s evidence of secondary considerations of nonobvi-
ousness. Moreover, the Defendants do not advance sepa-
rate double patenting arguments for the asserted
dependent claims of the ’528 patent. We therefore con-
clude that the district court correctly determined that all
of the asserted claims of the ’528 patent are not invalid for
nonstatutory obviousness-type double patenting over
claim 13 of the ’416 patent.
CONCLUSION
For the foregoing reasons, we affirm the judgment of
the district court.
AFFIRMED