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 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 *1284 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 Due to those side effects clozapine was withdrawn from clinical trials in the 1970s, prompting scientists to seek an atypical antipsychotic drug similar to clozapine with respect to efficacy but lacking its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 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 Ability®. The culmination of several decades of drug development efforts, Ability® 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)-l-piperazi-nyl]-butoxy}-3,4-dihydrocarbostyril and has the following chemical structure:
*1285 [[Image here]]
aripiprazole
Otsuka Pharm. Co. v. Sandoz, Inc.,
No. 3:07-cv-1000,
Otsuka is the assignee of the '528 patent, which has a foreign priority date of October 31, 1988, was filed on 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 *4,
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
*1286
now before us on appeal.
See Otsuka,
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 *1,
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 *17,
The first of the Defendants’ alleged lead compounds is 7-[4-(4-phenylpiperazinyl)-butoxy]-3,4-dihydrocarbostyril, which has the following chemical structure:
[[Image here]]
“unsubstituted butoxy”
“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,
are useful for central nervous controlling agents such as central muscle relaxing agents, sleep-inducing 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.
*1287 Id. col.3 11.14-22. Claim 13 of the '416 patent claims the unsubstituted butoxy using its chemical name. Id. col.70 11.62-63. 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. eol.76 11.1-60, 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.8411.29-46.
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 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,
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 (“ED 60”) 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.
[[Image here]]
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 ED 50 of 0.53, has a 5-propoxy linker and an ethoxy substituent (-OCH2 CH3) at the 2-position of its phenyl ring. Compound 5, the second most potent de *1288 rivative with an ED B0 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 substituted propoxy, 2 had an ED 50 of 2.5; Compound 43, a 2-chloro substituted propoxy, had an ED B0 of 3.4; Compound 41, the unsubstituted butoxy, had an ED 50 of 5.5; Compound 6, an unsubstituted propoxy, had an ED B0 of 9.3; and Compound 16, a 4-chloro substituted pro-poxy, had an ED 50 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)-l-piperazinyl]-propoxy}3,4-dihydrocarbostyril and the chemical structure depicted below:
[[Image here]]
“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 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,
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- *1289 dimethyl substituted phenyl ring, a pro-poxy linker, and a carbostyril ring containing a double bond at the 3, 4-position:
[[Image here]]
“OPC-4392”
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-^1392 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-ÍS92, 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,
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 *27-
*1290
28,
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,
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 having ordinary skill in the pertinent art. 35 U.S.C. §§ 103(a), 282(2);
Microsoft Corp. v. 141 Ltd.,
— U.S.-,
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.,
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
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 *1291 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.
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.,
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 pri- or art compounds as lead compounds, or starting points, for further development efforts.
Eisai Co. v. Dr. Reddy’s Labs., Ltd.,
*1292
1292 678 FEDERAL REPORTER, 3d SERIES
USA, Inc.,
566 F.Bd 989, 994 (Fed.Cir. 2009);
Eisai
*1293
pound that motivates a chemist to make structurally similar compounds.”
Daiichi,
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,
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 controlling effects.” '416 patent col.2 11.50-51. As explained by Dr. Bryan Roth, whom the court credited as an expert in schizophre
*1294
nia, antipsychotic drag 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,
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.l. Arguments raised only in footnotes, however, are waived.
SmithKline Beecham Corp. v. Apotex Corp.,
Although Nakagawa’s mouse jumping data “could be indicative of potential anti-psychotic activity to the skilled artisan,”
Otsuka,
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,
Thus, neither the '416 patent nor the Nakagawa declaration supports the Defendants’ position that one of ordinary skill would have selected the prior art unsubsti *1295 tuted butoxy compound as a lead compound for further antipsychotic research.
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 *20,
The Defendants, citing
Pfizer,
Furthermore, as Otsuka points out, the Defendants’ theory that aripiprazole would have been obvious over the unsubstituted butoxy and the 2,3-dichloro propoxy rested in large part upon an asserted “bracketing
theory”
— ie., 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,
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,
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 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 ordinary 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.,
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 *1297 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.
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,
As an initial matter, the parties disagree over the legal test for non-statutory 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,
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
The Defendants rely on
Geneva Pharm., Inc. v. GlaxoSmithKline PLC,
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 non-statutory 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.
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,
*1299
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,
Finally, the nonstatutory double patenting issue in this case is not, as the Defendants argue, controlled by
In re Zickendraht,
50 CCPA 1529,
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 obvious *1300 ness-type double patenting over claim 13 of the '416 patent.
Conclusion
For the foregoing reasons, we affirm the judgment of the district court.
AFFIRMED
Notes
. The Defendants also asserted an ultimately unsuccessful inequitable conduct defense and counterclaim, which are not at issue on appeal.
. Elsewhere in its opinion the district court referred to Compound 39 as "OPC-4139.” See
Otsuka,
. 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.