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 Chicago, 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 Pharmaceuticals, 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 nonstatutory double patenting. We affirm. 

BACKGROUND

Schizophrenia is a debilitating mental disease affecting 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 schizophrenia suffer from positive symptoms, negative symptoms, 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 antipsychotics. 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 dopamine 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 extrapyramidal symptoms (“EPS”), tardive dyskinesia, prolactin 

elevation (hyperprolactinemia), and sudden decrease in 

blood pressure (orthostatic hypotension). The United 

States Food and Drug Administration (“FDA”) last approved 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 approved 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 postclozapine 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 antipsychotic 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 antipsychotic drug marketed by Otsuka Pharmaceutical Co., Ltd. 

(“Otsuka”) under the brand name Abilify®. The culmination of several decades of drug development efforts, 

Abilify® was approved in 2002 by the FDA and is marketed 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 structure: 
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 resulting double bond between the carbon atoms. Researchers 

refer to both variants as “carbostyril derivatives.” Connected 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 butoxy 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 exclusivity 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 aripiprazole, 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 pharmaceutical composition containing aripiprazole as an 

active ingredient. Ex Parte Reexamination Certificate, 

’528 patent col.2 ll.13–16. 

The Defendants and several other companies submitted 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 manufacturers 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 unsuccessful 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 Memorandum 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 compounds” 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 compounds.” 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 controlling 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, sleepinducing agents, pre-operative drugs, antischizophrenia agents, sedatives, antianxiety drugs, antimanic 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 antihistaminic 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 unsubstituted butoxy, id. col.84 ll.29–46. 

The unsubstituted butoxy is also disclosed in a declaration submitted during the prosecution of the ’416 patent 

by one of that patent’s co-inventors, Dr. Kazuyuki Nakagawa (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 LDOPA.” 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 antipsychotic 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 

No. Chemical Name ED50

5 

5-[3-(4-phenylpiperazinyl)propoxy]-

3,4-dihydrocarbostyril dihydrochloride 2.1 

6 

7-[3-(4-phenylpiperazinyl)propoxy]-

3,4-dihydrocarbostyril dihydrochloride 

9.3 

16 

7-{3-[4-(4-

chlorophenyl)piperazinyl]propoxy}-

3,4-dihydrocarbostyril 

15.1 
OTSUKA PHARMA v. SANDOZ 10

39 

7-{3-[4-(3-

chlorophenyl)piperazinyl]propoxy}-

3,4-dihydrocarbostyril 

2.5 

41 

7-[4-(4-phenyl-1-piperazinyl)butoxy]-

3,4-dihydrocarbostyril (“unsubstituted butoxy”) 

5.5 

42 

1-methyl-7-[3-(4-phenyl-1-

piperazinyl)propoxy]-3,4-

dihydrocarbostyril 

10.7 

43 

7-{3-[4-(2-chlorophenyl)-1-

piperazinyl]propoxy}-3,4-

dihydrocarbostyril 

3.4 

44 

5-{3-[4-(2-ethoxyphenyl)-1-

piperazinyl]propoxy}-3,4-

dihydrocarbostyril 

0.53 

45 

5-{3-[4-(4-methylphenyl)-1-

piperazinyl]propoxy}-3,4-

dihydrocarbostyril 

8.1 

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; Compound 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 depicted 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 counterparts 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 nervous 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, antischizophrenia agents, sedatives, anxiolytics, drugs for 

manic-depressive psychosis, fever-lowering 

agents, analgesics and “depressors” without showing side effects such as thirst, constipation, tachycardia, 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 developed.” 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 Psychiatry 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 concentration, which were so severe that they were not able to 

perform daily routine work.” J.A. 10397, 10401. 

Evaluating the differences between the claimed invention 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 obviousness-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 ordinary 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 between 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 mistake 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 Pharmaceuticals, 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 Defendants 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, including the 2,3-dichloro propoxy, the unsubstituted butoxy, 

and OPC-4392, were known to have antipsychotic activity, and it would have been obvious to chemically modify 

them in the ways necessary to make aripiprazole. Finally, 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 contentions, 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 conclusion 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 Graham 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 Defendants 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 contention. 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. Alphapharm 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 Pharmacal, 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 selected a prior art compound as a lead, the analysis is 

guided by evidence of the compound’s pertinent properties. 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; Yamanouchi, 231 F.3d at 1345; adverse effects such as toxicity, 

Takeda, 492 F.3d at 1358, and other relevant characteristics 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 saltforming acid). Absent a reason or motivation based on 

such prior art evidence, mere structural similarity between 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 reasoning.”). 

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 compound 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 convincing evidence that a skilled artisan would have been 

motivated to combine the teachings of the prior art references 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.” Daiichi, 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 ‘sufficiently close relationship . . . to create an expectation,’ in 

light of the totality of the prior art, that the new compound 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 identification 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 expectation 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 concluded that two compounds—clozapine and risperidone—

would have been considered viable lead compounds. Id. at 

*76. These were the only marketed antipsychotic compounds 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 relevant 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 compounds, 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 antipsychotic drug research efforts. 

B. The Unsubstituted Butoxy Compound 

In evaluating the differences between the claimed invention and the prior art, the district court first considered 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 discovery. 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 explained 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 declaration 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 particular 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. Significantly, 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 Nakagawa 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 compounds”). 

Thus, neither the ’416 patent nor the Nakagawa declaration supports the Defendants’ position that one of 

ordinary skill would have selected the prior art unsubstituted 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 obvious 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 hundreds 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 meaningful 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 sulphonate (which combines with amlodipine to form the 

besylate salt). Pfizer, 480 F.3d at 1372. This court premised 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 compound 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 compounds to arrive at aripiprazole, which shares some 

structural features of both. The district court found that 

the Defendants’ theory constituted “an improper hindsight 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 theory. Accordingly, we conclude that the Defendants failed 

to prove by clear and convincing evidence that aripiprazole would have been obvious over the 2,3-dichloro propoxy. 

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 antipsychotic 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 antipsychotic 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 positive 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] antipsychotic 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 OPC4392 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 modifications include: (1) converting OPC-4392’s carbostyril core 

into a dihydrocarbostyril; (2) changing OPC-4392’s propoxy 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 hindsight. 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) (“Patentability 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 therefore 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 OPC4392 to increase antipsychotic activity. Otsuka, 2010 U.S. 

Dist. LEXIS 132595, at *70. 

E. Conclusion 

In summary, the district court’s careful analysis exposed the Defendants’ obviousness case for what it was—

a poster child for impermissible hindsight reasoning. 

Because we agree with the district court that the Defendants 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 obviousnesstype 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 legal test for nonstatutory double patenting. Otsuka contends 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 rejection 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, however, 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 genus . . . .”). 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 compound 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 traditional obviousness analysis. 

Turning to the particulars of the district court’s decision 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 considering the Nakagawa declaration in detail, correctly concluded 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 unsubstituted 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 Nakagawa 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 demonstrating the high degree of unpredictability in antipsychotic drug discovery as of the priority date. Id. at *48, 

*61. Experts testified that the discovery of new antipsychotic 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 obviousness analysis. 550 U.S. at 421; see also Procter & 

Gamble, 566 F.3d at 996 (“[T]o the extent an art is unpredictable, 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 substitution 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 evidence 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 meaningful 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 structural changes on a compound’s antipsychotic properties, 

but also indicates that the prior art would not have provided the 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 *61, *91. Zickendraht, therefore, is distinguishable 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 unsubstituted butoxy compound, we need not examine 

Otsuka’s evidence of secondary considerations of nonobviousness. Moreover, the Defendants do not advance separate double patenting arguments for the asserted 

dependent claims of the ’528 patent. We therefore conclude 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