678 F.3d 1280 (Fed. Cir. 2012), 2011-1126, Otsuka Pharmaceutical Co., Ltd. v. Sandoz, Inc.

Docket Nº:2011-1126, 2011-1127.
Citation:678 F.3d 1280, 102 U.S.P.Q.2d 1729
Opinion Judge:LOURIE, Circuit Judge.
Party Name: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 Pharmace
Attorney: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, Harpe...
Judge Panel:Before LOURIE, MOORE, and REYNA, Circuit Judges.
Case Date:May 07, 2012
Court:United States Courts of Appeals, Court of Appeals for the Federal Circuit
 
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678 F.3d 1280 (Fed. Cir. 2012)

102 U.S.P.Q.2d 1729

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.

Nos. 2011-1126, 2011-1127.

United States Court of Appeals, Federal Circuit.

May 7, 2012

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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, IL, 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, NY, 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 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

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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 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:

(Image Omitted)

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aripiprazole

Otsuka Pharm. Co. v. Sandoz, Inc., No. 3:07-cv-1000, 2010 WL 4596324, at *4-5, 2010 U.S. Dist. LEXIS 132595, at *15 (D.N.J. Nov. 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 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, 2010 U.S. Dist. LEXIS 132595 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

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now before us on appeal. See Otsuka, 2010 WL 4596324, at *1, 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

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, 2010 U.S. Dist. LEXIS 132595 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 *17, 2010 U.S. Dist. LEXIS 132595 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:

(Image Omitted)

" unsubstituted butoxy"

Br. Defs.-Appellants Apotex, at 12. The parties refer to this compound as the " unsubstituted butoxy," because its phenyl ring is...

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