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Otsuka Pharmaceutical Co., Ltd v. Sandoz

December 14, 2010

OTSUKA PHARMACEUTICAL CO., LTD., PLAINTIFF,
v.
SANDOZ, INC., TEVA PHARMACEUTICALS USA, INC.,
TEVA PHARMACEUTICAL INDUSTRIES LTD., AMENDED BARR LABORATORIES, INC., BARR PHARMACEUTICALS, INC., APOTEX INC., APOTEX CORP., SUN PHARMACEUTICAL INDUSTRIES, LTD.,SYNTHON HOLDING BV, SYNTHON BV,
SYNTHON PHARMACEUTICALS, INC., AND SYNTHON LABORATORIES, INC., DEFENDANTS.



The opinion of the court was delivered by: Cooper, District Judge

NOT FOR PUBLICATION

Consolidated

MEMORANDUM OPINION

Otsuka Pharmaceutical Co., Ltd. ("Plaintiff" or "Otsuka") brought this action and a number of now-consolidated actions against generic drug manufacturers, Sandoz, Inc. ("Sandoz"); Teva Pharmaceuticals USA, Inc., Teva Pharmaceutical Industries Ltd. ("Teva"); Barr Laboratories, Inc., Barr Pharmaceuticals, Inc. ("Barr"); Apotex Corp., Apotex Inc. ("Apotex"); Sun Pharmaceutical Industries, Ltd. ("Sun"); Synthon Holding BV, Synthon BV, Synthon Pharmaceuticals, Inc., and Synthon Laboratories, Inc. ("Synthon") (collectively, "Defendants").*fn1 Otsuka alleges infringement of U.S. Patent No. 5,006,528 (the "'528 Patent"), which claims, inter alia, the chemical compound aripiprazole, based on Defendants' submissions of an Abbreviated New Drug Application ("ANDA") to the United States Food and Drug Administration ("FDA") for approval to engage in the commercial manufacture, use, or sale in the United States of generic aripiprazole products. Infringement is not contested in this action, as Defendants concede that their ANDA filings constitute literal acts of infringement "to the extent [the asserted] claims are valid and enforceable." (See Pl.'s Post-Trial Br. at 9.) 35 U.S.C. § 271(e)(2)(A); see also Glaxo, Inc. v. Novopharm Ltd., 110 F.3d 1562, 1569 (Fed. Cir. 1997) (noting that § 271(e)(2) provides "patentees with a defined act of infringement sufficient to create case or controversy jurisdiction to enable a court to promptly resolve any dispute concerning infringement and validity"). Defendants contend that the '528 Patent is invalid as obvious under 35 U.S.C. § 103; invalid due to obviousness-type double patenting over Otsuka's prior art U.S. Patent No. 4,734,416 (the "'416 Patent"); and unenforceable due to inequitable conduct arising from Otsuka's failure to disclose certain information to the United States Patent and Trademark Office ("USPTO"). Because this civil action arises under the United States patent laws, Title 35, United States Code, the Court exercises subject matter jurisdiction pursuant to 28 U.S.C. §§ 1331 and 1338(a).

The parties tried the case before the Court from August 5, 2010 through August 26, 2010. The parties thereafter submitted proposed findings of fact and conclusions of law. The Court heard closing arguments and received additional documentary evidence on October 21, 2010.*fn2

This Amended Memorandum Opinion constitutes the Court's findings of fact and conclusions of law on the issues of invalidity and unenforceability, pursuant to Fed.R.Civ.P. 52(a), and supersedes the Memorandum Opinion entered on November 15, 2010. (See dkt. entry no. 390, 12-14-10 Order.) For the reasons set forth herein, the Court concludes that Defendants did not show by clear and convincing evidence that '528 Patent is invalid as obvious under either 35 U.S.C. § 103 or the judicially-created doctrine of obviousness-type double patenting, or that the '528 Patent is unenforceable due to inequitable conduct. Accordingly, the Court will enter judgment in favor of Otsuka on its claims that Defendants have infringed the '528 Patent.

BACKGROUND

I. Abilify®

Otsuka markets aripiprazole under the trade name Abilify®. Abilify® is approved by the FDA for the treatment of, inter alia, schizophrenia, bipolar disorder, irritability associated with autistic disorder in pediatric patients, and as an add-on treatment for depression. (Pl.'s Post-Trial Br. at 52.) The listing for Abilify® in the FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (the "Orange Book") contains references to both the '416 Patent and the '528 Patent as covering aripiprazole. (Defs.' Post-Trial Br. at 1, 11; Pl.'s Post-Trial Br. at 4.) Abilify® was first marketed in the United States in 2002 and was the result of several decades of drug development by Otsuka. (See Defs.' Post-Trial Br. at 144 ("Aripiprazole was the last episode in years of work by Otsuka.").) It has been commercially successful. By the end of 2009, sales of Abilify® were $3.3 billion annually, and from 2005 onward, sales of Abilify® have exceeded a billion dollars each year, qualifying it as a "blockbuster drug." (Pl.'s Post-Trial Br. at 124-25.)

II. Development of Antipsychotic Drugs for the Treatment of Schizophrenia

Schizophrenia is a serious and debilitating mental disease affecting approximately one percent of the human population. (Pl.'s Post-Trial Br. at 25.) Despite extensive research, the cause, mechanism, and etiology of schizophrenia were unknown in 1988 and remain unknown today. (Id. at 26.) Researchers believe that both genetic and environmental factors may play a role in the cause of the illness. (Id.)

Individuals with schizophrenia suffer from positive symptoms, negative symptoms, and cognitive deficits. (Id.) Positive symptoms include hallucinations and delusions, while negative symptoms include flat affect, poverty of speech, inability to experience pleasure, lack of desire to form relationships, and lack of motivation. (Defs.' Post-Trial Br. at 6.)

The first antipsychotic drug, chlorpromazine, was discovered by accident in the early 1950s. (Pl.'s Post-Trial Br. at 27.) After chlorpromazine was discovered, researchers determined that its antipsychotic properties were due to its antagonism, or blocking, of dopamine receptors in the brain. (Id.; Defs.' Post-Trial Br. at 6.) That key finding led to the development of other "typical" antipsychotics, including haloperidol, thiothixene, trifluoperazine, fluphenazine, thioridazine, mesoridazine, loxapine, molindone, perphenazine, and pentoxide. (Pl.'s Post-Trial Br. at 27.) Typical antipsychotic drugs treat the positive symptoms of schizophrenia, but not the negative symptoms. (Defs.' Post-Trial Br. at 6.) Typical antipsychotic drugs also have problematic side effects, including extrapyramidal symptoms ("EPS"), tardive dyskinesia, prolactin elevation (hyperprolactinemia), and sudden decrease in blood pressure (orthostatic hypotension). (Id.) Despite these various drawbacks, the typical antischizophrenic drugs are still used today. (Id.) Loxapine was the last of the typical antipsychotics to be approved by the FDA, in 1975. (PTX 79, Winston Shen, "A History of Antipsychotic Drug Development," Comprehensive Psychol., Vol. 40, No. 6 (1999), at 409.)

The adverse side effects of the first-generation typical antipsychotics led researchers to seek alternatives with a better side effect profile, particularly with regard to EPS. Clozapine, discovered in the early 1960s, was the first "atypical" antipsychotic drug in that it had diminished propensity to cause EPS. (Id.) Clozapine also differed from typical antipsychotics in that it was useful in treating both positive and negative symptoms of schizophrenia. (Shen at 409-10.) Unfortunately, clozapine has several potential adverse side effects including agranulocytosis, a life-threatening decrease in white blood cells; orthostatic hypotension; and frank hypotension. (Defs.' Post-Trial Br. at 6-7; Pl.'s Post-Trial Br. at 28-30.) Because of its side effect profile, clozapine was withdrawn from clinical trials in the 1970s and not approved by the FDA for treatment of schizophrenia until 1990, and then only for treatment-resistant or treatment-intolerant patients, subject to rigorous blood testing. (Pl.'s Post-Trial Br. at 30; dkt. entry no. 352, Roth Tr. at 1129, 1133, 1137.)

Scientists have been attempting since the early 1970s to discover an atypical antipsychotic treatment for schizophrenia that would be similar to clozapine in efficacy, but without the toxicity and significant side effects. (Pl.'s Post-Trial Br. at 30; see, e.g., PTX 116, Samuel Gershon, "Update on Drug Development," Psychopharmacology Bull., Vol. 16, No. 3 (1980), at 32 ("Clozapine-like drugs have provided investigators with results that were sometimes promising and sometimes disappointing. . . .").) These efforts, however, were largely unsuccessful, and the FDA approved no new antipsychotic drugs between 1976 and 1989. (Pl.'s Post-Trial Br. at 31; see also PTX 93, Leo E. Hollister, "Strategies in Clinical Psychopharmacology," Psychopharmacology Bull., Vol. 23, No. 3 (1987), at 389 ("It is most discouraging that more effective pharmacotherapy for schizophrenia has not been developed in the more than three decades since the introduction of the first effective drugs.").)

Risperidone was the first post-clozapine atypical antipsychotic approved by the FDA, in 1994. (Shen at 410.) While clozapine remains the "gold standard" with respect to efficacy, a total of nine atypical antipsychotics, including aripiprazole, have been approved by the FDA and are considered "at least as effective as typical antipsychotic drugs in treating the positive symptoms of schizophrenia while causing fewer EPS side effects . . . [and] also show superiority over typical antipsychotic drugs in improving the negative symptoms of schizophrenia." (Shen at 410, 412-13; Pl.'s Post-Trial Br. at 60.) With the exception of aripiprazole, all FDA-approved atypical antipsychotics are structurally related to either clozapine or risperidone.*fn3

III. The '416 Patent

Otsuka is the assignee of the '416 Patent covering "Pharmaceutically Useful Carbostyril Derivatives," which issued on March 29, 1988, and expired on March 29, 2005. It teaches that "[c]arbostyril derivatives having antihistamic action and central nervous controlling action are useful as antihistamic agents or central nervous controlling agents." ('416 Patent, Abstract.) The '416 Patent covers approximately nine trillion compounds. (Defs.' Post-Trial Br. at 132; Pl.'s Post-Trial Br. at 77.) It therefore discloses a broad genus of carbostyril compounds that generically encompasses aripiprazole, although aripiprazole is not specifically disclosed. (Pl.'s Post-Trial Br. at 53; see also Defs.' Post-Trial Br. at 11 (noting that Claim 1 and Claim 30 of the '416 Patent cover aripiprazole).)

The inventors of the '416 Patent included Dr. Yasuo Oshiro, who is also an inventor on the '528 Patent; Dr. Kazuyuki Nakagawa; and Dr. Kazuo Banno. (Defs.' Post-Trial Br. at 11.) The '416 Patent specification disclosed that compounds of the invention "are useful for central nervous controlling agents such as central muscle relaxing agents, sleep-inducing agents, pre-operative drugs, antischizophrenia agents, sedatives, antianxiety drugs, anti-manic depressive psychosis agents, antipyretic agents, analgetic agents and depressors, without showing side-effects such as . . . parkinsonism, and/or delayed dyscinesia [sic] which exist with conventional central nervous controlling agents." ('416 Patent at col. 3, lines 13-22.) Claim 13 of the '416 Patent is directed to the compound 7-[4-(4-phenylpiperazinyl)-butoxy]-3,4-dihydrocarbostyril, referred to at trial as the "unsubstituted butoxy" because it lacks any substituents on the phenyl ring and has a butoxy linker connecting the carbostyril core to the piperazine ring. ('416 Patent at col. 70, lines 62-63; see also Pl.'s Post-Trial Br. at 80 (noting that the term "unsubstituted butoxy" does not appear in the '416 Patent).) Claim 116 is directed to a particular use of, inter alia, the unsubstituted butoxy, by reference to Claim 50, which discloses "[a] method for producing an antihistaminic effect in a mammal." ('416 Patent at col. 84, lines 29-30, 36-37; col. 76, lines 1-2.)

IV. The '528 Patent-in-Suit

The '528 Patent, entitled "Carbostyril Derivatives," was issued in 1991, but has a foreign application priority date of October 31, 1988, pursuant to 35 U.S.C. § 119. (See Defs.' Post-Trial Br. at 2; Pl.'s Post-Trial Br. at 31.) The exclusivity engendered by the '528 Patent, including a six-month pediatric exclusivity period, will expire on April 20, 2015. (Defs.' Post-Trial Br. at 4.)*fn4

Otsuka asserts infringement of Claim 12, Claim 17, and Claim 23 of the '528 Patent. (Pl.'s Post-Trial Br. at 8.) Claim 12 of the '528 patent is directed to the compound aripiprazole, which has the chemical name 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydrocarbostyril. ('528 Patent at col. 19, lines 18-19.) Claim 17 of the '528 patent is directed to a pharmaceutical composition for treating schizophrenia containing, as the active ingredient, aripiprazole or a pharmaceutically acceptable salt thereof. ('528 Patent at col. 20, lines 4-7.) Claim 23 of the '528 patent is directed to a method of treating schizophrenia comprising the administration of a pharmaceutical composition containing, as an active ingredient, aripiprazole or a salt thereof. ('528 Patent at col. 20, lines 17-20.)

The structure of aripiprazole is shown below:

Aripiprazole is a carbostyril derivative with a butoxy linker at the 7-position of the carbostyril core. (Pl.'s Post-Trial Br. at 47.) The butoxy linker consists of four methylene (CH2) units, whereas a propoxy linker consists of three methylene units. Because aripiprazole has two hydrogens at positions 3 and 4 of the carbostyril ring, it is referred to as a "dihydrocarbostyril." (Id.) Researchers commonly refer to both dihydrocarbostyrils and carbostyrils as "carbostyril derivatives." (Id.) A dihydrocarbostyril has a single bond between positions 3 and 4 whereas a carbostyril has a double bond. (Id.)

Aripiprazole has a piperazine ring connected to the butoxy linker. (Id.) The other side of the piperazine ring is connected to a phenyl ring. (Id.) The phenyl ring includes chlorine substituents attached at both the 2 position and 3 position of the phenyl ring. (Id. at 47-48.) This substitution of chlorine at the 2 position and the 3 position of the phenyl ring may be referred to as a "2,3 dichloro substitution" or a "2,3 dichlorophenyl substitution." (Defs.' Post-Trial Br. at 10-11.)

V. Reexamination of the '528 Patent

Otsuka filed a Request for Ex Parte Reexamination Proceedings on August 11, 2004, with regard to the '528 Patent. (Pl.'s Post-Trial Br. at 53; DTX 121.) In the reexamination proceedings, Otsuka endeavored to distinguish aripiprazole from certain structurally similar prior art references, including unsubstituted butoxy, which had been disclosed in the '416 Patent as well as Otsuka's German Patent No. 2,912,105 ("the DE '105 Patent"); 2,3 dichloro propoxy, a homolog of aripiprazole that had been disclosed in the DE '105 Patent; and OPC-4392, a compound developed by Otsuka having the chemical name 7-{3-[4-(2,3-dimethylphenyl)-1-piperazinyl]-propoxy}-carbostyril and disclosed in various references, including the DE '105 Patent. (Pl.'s Post-Trial Br. at 53-54.)*fn5 Otsuka also referred the Examiner to an article published by one of the inventors of the '416 Patent, Dr. Kazuo Banno, "Studies of 2(1H)-Quinolinone Derivatives as Neuroleptic Agents, I, Synthesis and Biological Activities of (4-Phenyl-1-piperazinyl)-propoxy-2(1H)-quinolinone Derivatives," Chem. Pharm. Bull., Vol. 36, No. 11 (Nov. 25, 1988), at 4377-4388 (the "Banno Article"), which contained references to these three compounds.*fn6 Otsuka stated in its request for reexamination that it could be argued that the cited documents raised a substantial new question of patentability. See 35 U.S.C. §§ 302-307. Otsuka additionally explained that, with respect to the '416 patent, "it can be argued that the use of the described compounds as antischizophrenia agents is specifically contemplated." (Pl.'s Post-Trial Br. at 54-55.)

The USPTO granted Otsuka's request for reexamination and thereafter issued an Office Action rejecting the claims of the '528 Patent as obvious over the disclosures in the '416 Patent and the DE '105 Patent of prior art compounds including unsubstituted butoxy. (Pl.'s Post-Trial Br. at 55.) Otsuka responded to this action by arguing that while the prior art references considered by the examiner "may suggest that their compounds may be useful for treating central nervous disorders, generally, there is no evidence that the five exemplary carbostyril derivatives identified by the Examiner have such properties, let alone the recited property of treating schizophrenia." (Pl.'s Post-Trial Br. at 55; DTX 121 at OPC 1274.) The USPTO again rejected the claims of the '528 Patent in a second and final Office Action on the basis that one of skill in the art would be motivated to make homologs of compounds in the prior art by changing the linker length from a propoxy to a butoxy. (Pl.'s Post-Trial Br. at 56; DTX 121 at OPC 1320-34.)

Otsuka conducted an interview with the USPTO on September 13, 2005, in response to the USPTO's second Office Action, and filed a Request for Reconsideration on September 14, 2005. (Pl.'s Post-Trial Br. at 56; DTX 121 at OPC 1340-41 and 1342-1400.) Along with its Request for Reconsideration, Otsuka submitted a declaration by Dr. Tsyoshi Hirose (the "Hirose Declaration") including test data for representative claimed compounds of the '528 Patent compared to structurally related prior art propoxy-linked compounds. (Pl.'s Post-Trial Br. at 57; DTX 121 at OPC 1344, 1365-1400.) The USPTO thus ultimately concluded that the closest prior art compounds were those tested in the Hirose Declaration, which included the 2,3-dichloro propoxy compound but not the unsubstituted butoxy compound or OPC-4392. (Pl.'s Post-Trial Br. at 57; DTX 121 at OPC 1368-69.) The Hirose Declaration reported data for an anti-apomorphine stereotypy test on mice to evaluate each "compound's ability to block neurotransmission of dopaminergic D2-receptors, i.e., its antipsychotic potency." (Hirose Decl. at 5.) With regard to this test, the Hirose Declaration argued, and the USPTO agreed in allowing the claims, that the structural difference between a butoxy and a propoxy linker chain "shows a clear unexpected result in the ED50 [50% effective dose] values." (DTX 121 at OPC 1412, Reexamination -- Reasons for Patentability/Confirmation.)*fn7 Specifically, the Hirose Declaration data indicated that the aripiprazole compound was twenty-three times more potent than the 2,3 dichloro propoxy compound. (Hirose Decl. at 6.)

The USPTO issued a Reexamination Certificate allowing all the claims of the '528 patent on June 13, 2006. (DTX 121 at OPC 1426-28.) The Reexamination Certificate also allowed the addition of three new claims, Claims 22-24, which are directed to methods of treating schizophrenia using compositions of the invention. (Id.)

DISCUSSION

I. Applicable Legal Standards

A. Presumption of Validity and Burden of Proof

A patent is presumed to be valid, and each of its claims are presumed valid independent of the validity of other claims. 35 U.S.C. § 282. An accused infringer seeking to overcome the presumption of validity bears the burden of showing by clear and convincing evidence that the patent is invalid. Robotic Vision Sys., Inc. v. View Eng'g, Inc., 189 F.3d 1370, 1377 (Fed. Cir. 1999).

B. Obviousness

"A patent may not be obtained . . . [if] 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 art to which said subject matter pertains." 35 U.S.C. § 103(a). While the ultimate determination of obviousness under § 103 is a question of law, it is based on several 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) evidence of secondary factors, also known as objective indicia of non-obviousness. Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966). "While the sequence of these questions might be reordered in any particular case, the [Graham] factors continue to define the inquiry that controls." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 407 (2007).

A party seeking to invalidate a patent based on obviousness must demonstrate 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. Procter & Gamble Co. v. Teva Pharm. USA, Inc., 566 F.3d 989, 994 (Fed. Cir. 2009).

C. Obviousness-Type Double Patenting

Obviousness-type double patenting is a judicially-created doctrine that prohibits "claims in a later patent that are not patentably distinct from claims in a commonly owned earlier patent." Sun Pharm. Indus., Ltd. v. Eli Lilly & Co., 611 F.3d 1381, 1384 (Fed. Cir. 2010) (quotation and citation omitted); see also Georgia-Pacific Corp. v. U.S. Gypsum Co., 195 F.3d 1322, 1326 (Fed. Cir. 1999) (obviousness-type double patenting prohibits patenting of claims that are "an obvious variation of an invention disclosed and claimed in an earlier patent by the same inventor"). Obviousness-type double patenting can apply where the earlier patent and later patent are not part of the same patent family and issue from separate parent applications. Sun Pharm., 611 F.3d at 1389 (holding the '826 patent-in-suit invalid for obviousness-type double patenting in view of the earlier '614 patent that issued from a different patent family); In re Berg, 140 F.3d 1428, 1435 n.7 (Fed. Cir. 1998) (rejecting claims for obviousness-type double patenting over claims in a patent that were "not related as by continuation, continuation-in-part, or divisional").

An obviousness-type double patenting analysis involves two steps: "First, as a matter of law the court construes the claim in the earlier patent and the claim in the later patent and construes the differences. Second, the court determines whether the differences in subject matter between the two claims render the claims patentably distinct." Eli Lilly & Co. v. Barr Labs., Inc., 251 F.3d 955, 968 (Fed. Cir. 2001) (citing Georgia-Pacific, 195 F.3d at 1326-27). Two claims are not "patentably distinct" if the later claim would have been obvious to a person of ordinary skill in the art based on the earlier claim, in light of additional prior art. In re Longi, 759 F.2d 887, 893 (Fed. Cir. 1985).

D. Inequitable Conduct

Persons involved in the preparation and prosecution of a patent application "have a duty to prosecute patent applications in the [USPTO] with candor, good faith, and honesty." Advanced Magnetic Closures, Inc. v. Rome Fastener Corp., 607 F.3d 817, 829 (Fed. Cir. 2010) (quoting Honeywell Int'l Inc. v. Universal Avionics Sys. Corp., 488 F.3d 982, 999 (Fed. Cir. 2007)).This duty of candor rests on "(1) each named inventor, (2) each attorney or agent that prepares or prosecutes the application, and (3) every other person who is substantively involved in the preparation or prosecution of the application and who is associated with the inventor or assignee." Avid Identification Sys., Inc. v. Crystal Import Corp., 603 F.3d 967, 973 (Fed. Cir. 2010) (citing 37 C.F.R. § 1.56(c)). A breach of the duty of candor constitutes inequitable conduct and renders the patent unenforceable. Bristol-Myers Squibb v. Rhone-Poulenc Rorer, Inc., 326 F.3d 1226, 1233 (Fed. Cir. 2003); Molins PLC v. Textron, Inc., 48 F.3d 1172, 1178 (Fed. Cir. 1995).

II. Validity of Patent

A. Obviousness - § 103

Defendants contend that the asserted claims are invalid as obvious over the prior art genus of carbostyril derivatives disclosed in the '416 Patent, focusing on three exemplary compounds: the unsubstituted butoxy compound, the 2,3 dichloro propoxy homolog of aripiprazole, and OPC-4392 (a 2,3-dimethyl propoxy analog of aripiprazole). (Defs.' Post-Trial Br. at 97.)

1. Level of Skill in the Art

The obviousness analysis is conducted from the perspective of a person of ordinary skill in the prior art. 35 U.S.C. § 103(a). The hypothetical person of ordinary skill "is an objective legal construct who is presumed to be aware of all the relevant prior art." Janssen Pharmaceutica N.V. v. Mylan Pharm., Inc., 456 F.Supp.2d 644, 653 (D.N.J. 2006) (citation omitted), aff'd, 233 Fed.Appx. 999 (Fed. Cir. 2007). The person of ordinary skill "is also a person of ordinary creativity, not an automaton." KSR Int'l, 550 U.S. at 421.

At issue in Janssen was the validity of a patent covering the atypical antipsychotic drug risperidone. The Janssen court defined the person of ordinary skill as someone having a master's degree in chemistry, medicinal chemistry, or pharmacy, or a bachelor's degree in one of those fields with at least two years of experience in researching antipsychotic drugs, but noted that its ultimate ruling that the patent in suit was nonobvious was "not contingent upon" its determination of the appropriate level of skill in the art because it would find the patent nonobvious "even were it to hold that the person of ordinary skill in the art possessed a doctorate degree." Janssen, 456 F.Supp.2d at 654 n.7. (Pl.'s Post-Trial Br. at 58-59.) Plaintiff's expert Dr. Bryan Roth, who qualified as an expert in schizophrenia, antipsychotic drug discovery, and psychopharmacology with its medicinal chemistry component, testified at trial that this definition was reasonable based on his own experience and personal knowledge of individuals actively engaged in antipsychotic drug discovery both in his lab and elsewhere. (Pl.'s Post-Trial Br. at 12, 58-59.)

Defendants propose a hypothetical person having ordinary skill in the art as "highly skilled, with a Ph.D. in organic chemistry, medicinal chemistry and/or pharmacology or in a related field and at least several years of experience designing and/or testing drug compounds." (Defs.' Post-Trial Br. at 8.) Defendants suggest that the hypothetical "person" of ordinary skill in the art in this case would have the knowledge and skill set of a team of individuals with both medicinal chemistry and pharmacology expertise, because "in 1988, research in the field of antipsychotic drug discovery and development was performed in multi-disciplinary teams." (Id.) Defendants further urge that medicinal chemists and pharmacologists would have a working knowledge of the biological tests that correlate to antipsychotic activity and pertinent side effects of antipsychotic drugs, using in vitro assays and in vivo animal models, in order to determine structure-activity relationships between changes to molecular structures of chemical compounds and corresponding effects on biological activities. (Defs.' Post-Trial Br. at 8-9.)

We find merit in Defendants' contention that the person of ordinary skill in the art would have knowledge of examining structure-activity relationships through the use of biological tests, as evidence at trial indicated the necessity of such testing in the course of antipsychotic drug development.*fn8 However, we reject the notion that the "person" of ordinary skill must possess all of the attributes of a multi-member team. The fields of medicinal chemistry and pharmacology are inherently multi-disciplinary, and it is therefore sufficient to consider the skilled artisan to be one having a degree in medicinal chemistry, pharmacology, or a related field with experience in drug research and development. See Daiichi Sankyo Co., Ltd. v. Mylan Pharm. Inc., 670 F.Supp.2d 359, 369 & n.7 (D.N.J. 2009), aff'd, 619 F.3d 1346 (Fed. Cir. 2010). Dr. David Nichols, an expert in both medicinal chemistry and pharmacology who testified on behalf of Otsuka, and Dr. Roth testified that their opinions in this case would not change if the hypothetical person of ordinary skill in the art had a Ph.D. rather than a master's degree. (Pl.'s Post-Trial Br. at 59-60.) This testimony leads the Court to conclude, however, that the hypothetical ordinarily skilled person developing atypical antipsychotic drugs in 1988 would be unlikely to have only a bachelor's degree as opposed to a master's degree.

Accordingly, the Court finds that a person of ordinary skill in the art of antipsychotic drug discovery in October 1988 would be an individual having a master's degree or Ph.D. in medicinal chemistry, pharmacology, or a related field, with experience in research and development of antipsychotic drugs such that the person would be able to evaluate pharmacological data from in vitro and in vivo screening assays to determine structure-activity relationships.

2. Scope and Content of Prior Art

The Court considers the scope and content of the prior art as it existed on October 31, 1988. Prior art is limited to analogous references "from the same field of endeavor" as the claimed invention; if not within the same field of endeavor, a reference may be prior art if it is reasonably pertinent to the particular problem the inventor of the claimed invention was addressing. See In re Bigio, 381 F.3d 1320, 1325 (Fed. Cir. 2004).

a. '416 Patent and Nakagawa Declaration

Defendants contend that the '416 Patent, and the declaration of Kazuyuki Nakagawa ("Nakagawa Declaration") submitted in support thereof during the patent prosecution, disclose the prior art compound unsubstituted butoxy, and that "mouse jumping" data for unsubstituted butoxy teaches toward aripiprazole, in particular a 2,3 dichloro substitution on the phenyl ring and that butoxy-linked compounds are more potent than propoxy-linked compounds. (Defs.' Post-Trial Br. at 16-23; DTX 214, Nakagawa Declaration dated 2-2-87.) The '416 Patent disclosed the unsubstituted butoxy compound as Claim 13.*fn9

Otsuka contends that the '416 Patent teaches that Claim 13, the unsubstituted butoxy, is an antihistamine and does not suggest that compound as an antipsychotic agent. Claim 13 does not disclose any specific uses for unsubstituted butoxy, but the unsubstituted butoxy is listed as an example in Claim 116, which by reference to Claim 50 is disclosed as a method for producing an "antihistaminic effect." Thus, Otsuka argues that the '416 Patent does not teach that unsubstituted butoxy is an antipsychotic; rather, the '416 Patent covers a broad genus of compounds, some of which may be useful as, inter alia, either antipsychotics or antihistamines. Dr. Roth testified that one skilled in the art would not read the '416 Patent's "laundry list" of potential central nervous system controlling effects to conclude that all carbostyril derivative compounds covered by the patent are antipsychotics, nor would that person ascertain from the '416 Patent how to screen the claimed compounds for antipsychotic activity. (Dkt. entry no. 354, Roth Tr. at 1219.)

The Court finds that Defendants overstate the scope of the '416 Patent as it pertains to teaching the uses of unsubstituted butoxy. Rather, the '416 Patent teaches that unsubstituted butoxy is an example of the invention having an antihistaminic effect.

As to the Nakagawa Declaration submitted in support of the '416 Patent application, Otsuka contends that it is not a "printed publication" form of prior art under 35 U.S.C. § 102(b) because it was not sufficiently accessible to the public prior to the October 31, 1988 priority date. (Pl.'s Post-Trial Br. at 180-87; see also DTX 333, Prosecution History for the '416 Patent.) We reject this assertion, as the Nakagawa Declaration comprises part of the prosecution history of the earlier-issued '416 Patent and is therefore deemed accessible to the public. See Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492 F.3d 1350, 1363 (Fed. Cir. 2007) (finding that district court properly considered prosecution history of earlier patent and may have committed harmless error by implying that prosecution histories are not accessible to the public). (Dkt. entry no. 377, Defs.' Reply Post-Trial Br. at 2.) Accordingly, to the extent the '416 Patent itself constitutes prior art, we find that the Nakagawa Declaration constitutes a "printed publication" under 35 U.S.C. § 102(b) and is properly considered part of the prior art for purposes of obviousness.

The Nakagawa Declaration tested certain carbostyril derivatives covered by the '416 Patent as compared to two prior art compounds for "activity for inhibiting jumping behavior in mouse induced by Methamphetamine and L-DOPA" (the "mouse jumping test"). (Nakagawa Decl. at 12.)*fn10 At trial, Otsuka argued that the mouse jumping data in the Nakagawa Declaration was not intended to provide insight to structure-activity relationships as part of an antipsychotic drug discovery effort. (Pl.'s Post-Trial Br. at 83-84; dkt. entry no. 354, Roth Tr. at 1243-48 (testifying that prior to his involvement in this case, Dr. Roth had never heard of the mouse jumping test, the mouse jumping test is not routinely used in antipsychotic drug discovery, and one skilled in the art would not be able to correlate mouse jumping data with results from the more commonly-used anti-apomorphine stereotypy test).) However, Defendants adduced evidence indicating that Otsuka itself used the mouse jumping test to predict antipsychotic activity in chemical compounds. (See Defs.' Post-Trial Br. at 18-19.)*fn11 Regardless of whether the mouse jumping test was frequently used by researchers in antipsychotic drug discovery in 1988 or whether the intention of the Nakagawa Declaration was to provide data to compare the test compounds against each other as opposed to the two prior art compounds, the Court finds that the Nakagawa Declaration does, on its face, provide comparative data for the potency of ...


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