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OTSUKA PHARMACEUTICAL CO. v. SANDOZ, INC. (N.J. 11-15-2010)
The petition for writ of certiorari is denied.
Otsuka points out that "[a]t least seven different generic drug companies have filed ANDA applications to various aripiprazole products, including aripiprazole tablets, aripiprazole orally disintegrating tables, and aripiprazole oral solutions." (Pl.'s Post-Trial Br. at 208.) Otsuka also introduced evidence of copying beyond Defendants' ANDA filings. For example, Teva filed a patent application on December 16, 2004, claiming "methods of preparing aripiprazole crystalline forms." (PTX 612, U.S. Patent Application No. 2005-0203299 A1 (published September 15, 2005).) Another Teva patent application claiming a "process for preparing aripiprazole" was filed on February 7, 2005. (PTX 613, U.S. Patent Application No. 2005-0215791 A1 (published September 29, 2005).) Teva also filed international counterparts to these applications under the Patent Cooperation Treaty. (See PTX 620 (claiming methods of preparing aripiprazole crystalline forms); PTX 624 (claiming process for preparing aripiprazole).)
We therefore find that Otsuka has established some evidence of copying of aripiprazole. Because Defendants did not make out a prima facie case of obviousness, Otsuka does not bear the burden of rebutting the same by clear and convincing evidence on this point.
e. Unexpected Results
Unexpected results include "some superior property or advantage that a person of ordinary skill in the relevant art would have found surprising or unexpected." In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995). Aripiprazole has a number of unexpected therapeutic benefits that Otsuka contends could not have been predicted in 1988, including its broad efficacy in treating the positive symptoms of schizophrenia and low propensity to cause the serious side effects associated with typical antipsychotic drugs such as EPS, TD, sedation, weight gain or other metabolic effects, prolactin elevation, and orthostatic hypotension. (Pl.'s Post-Trial Br. at 131.) Defendants, contending that aripiprazole's increased antipsychotic activity and favorable side-effect profile could have been predicted at the relevant time based on the prior art, focus on the Hirose Declaration submitted by Otsuka to the USPTO during the 2005 reexamination proceedings. (Defs.' Post-Trial Br. at 55.)
Defendants' argument that an effective antipsychotic drug with a favorable side-effect profile would have been expected by bracketing the unsubstituted butoxy and the 2,3 dichloro propoxy to arrive at 2,3 dichloro butoxy, or aripiprazole, has already been addressed and rejected by this Court. (Defs.' Post-Trial Br. at 56.) Defendants' arguments that aripiprazole's efficacy was not unexpected because Otsuka withheld certain internal test data from the USPTO, or because data in the Hirose Declaration purporting to show "unexpected results" are unreliable due to bias and confound in the anti-apomorphine stereotypy test, are discussed below with respect to Defendants' charge of inequitable conduct and will not be repeated here. (Defs.' Post-Trial Br. at 121-23; see infra pp. 60-69.) At this juncture, we merely note that Dr. Roth testified credibly at trial that aripiprazole "has an exceedingly complex pharmacology," even as compared to other atypical antipsychotics. (Dkt. entry no. 352, Roth Tr. at 1043-51; see also PTX 406, Roth et al., "Magic Shotguns Versus Magic Bullets: Selectively Non-Selective Drugs for Mood Disorders and Schizophrenia," Nature Reviews, Vol. 3 (April 2004), at 355-56 (noting that "considerable controversy exists" regarding aripiprazole's mechanism of action, and its complex pharmacology precludes researchers from determining why it is effective).)
f. Industry Acclaim
Abilify® has received wide acclaim from others in the industry. In 2004, Frost Sullivan awarded its Product Innovation Award for the U.S. antipsychotic medications market to Otsuka for Abilify®. (Pl.'s Post-Trial Br. at 157.) The award was described as being "bestowed on the company that successfully develops and commercializes a medication which is believed to provide a unique set of benefits over existing products in the market." (Id.; PTX 357.) In its report covering the award, Frost Sullivan stated: "With a comparable efficacy and superior side effect profile, Abilify® may become the new standard against which all new antipsychotics are judged." (Id.)
Frost Sullivan is a market research firm that examines a wide range of industries, including the pharmaceutical industry. (Dkt. entry no. 367, Jarosz Tr. at 2040.)
Abilify® has won a number of other awards throughout the world over the years. Among those awards, Abilify® won the Prix Galien award in 2006 (France) for being the most innovative pharmaceutical product on the market, the Pharmaceutical Executive Magazine Central Nervous System Compound of the Year for 2004 (United States), and a variety of other awards in Germany, Japan, France, and Spain. (Id.; PTX 375.) These awards are indicative of the acclaim that aripiprazole has received in the pharmaceutical industry. See Zenith Goldline, 364 F.Supp.2d at 853 (observing that olanzapine won the Prix Galien award in 1997 and noting that "[a]lthough the inventor of risperidone received the Prix Galien Award in 1996, . . . that fact does not vitiate the industry acclaim held by olanzapine.").
B. Obviousness-Type Double Patenting
Defendants contend that the asserted claims disclosing aripiprazole and its uses are not patentably distinct from unsubstituted butoxy, which is disclosed by Claim 13 of the `416 Patent. (Defs.' Post-Trial Br. at 88, 92-96.)
We have already found that the unsubstituted butoxy compound disclosed in Claim 13 of the `416 Patent does not render aripiprazole obvious. The `416 Patent teaches that unsubstituted butoxy is useful as an antihistamine, and contains no data or other information that would lead a person of ordinary skill in the art to conclude that the unsubstituted butoxy, out of the nine trillion compounds covered by the `416 Patent and the hundreds of examples listed, would be an effective antipsychotic. In considering the claim of the earlier patent, the Court is to consider its meaning and utility in the context of the entire patent. Sun Pharm. Indus. Ltd. v. Eli Lilly Co., 611 F.3d 1381, 1388 (Fed. Cir. 2010) (observing "`fundamental rule' that claim terms `are construed with the meaning with which they are presented in the patent document'") (citing Phillips v. AWH Corp., 415 F.3d 1303, 1316 (Fed. Cir. 2005)). To the extent that the `416 Patent claims that all compounds of the invention have both antihistaminic and central nervous system controlling activity, it does not follow that all compounds of the invention are useful specifically as antipsychotics or antischizophrenics. (`416 Patent at col. 2, lines 50-52 ("The compounds of the present invention . . . have antihistaminic and central nervous controlling effects"); id. at col. 3, lines 13-19 (listing ten examples of uses for central nervous controlling agents, including antischizophrenia agents); cf. Defs.' Post-Trial Br. at 92-93.) Cf. Janssen, 456 F.Supp.2d at 657-58 (rejecting generic manufacturers' proposed lead compound, pirenperone, in § 103 obviousness analysis, on basis that prior art taught that pirenperone had potential as an anti-anxiety drug, not an antipsychotic); U.S. Patent No. 4,342,870, "Novel 3-(1-piperidinylalkyl)-4H-pyrido[1,2-A]pyrimidin-4-one Derivatives" (issued to Janssen on August 3, 1982) (covering,inter alia, pirenperone, and disclosing in specification that compounds of the invention as "useful as cardiovascular agents and to act on the central nervous system" but not specifically mentioning either antianxiety or antipsychotic effects).
Aripiprazole is distinct from unsubstituted butoxy in that it has chlorine atoms at the 2 and 3 positions of the phenyl ring, whereas unsubstituted butoxy has hydrogen atoms. The Court has already found that the prior art, including the Nakagawa Declaration, the DE `105 Patent, the SE `945 application, OPC-4392, and the Wise Poster 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. (See Defs.' Post-Trial Br. at 94 (referring to these prior art references in support of their obviousness-type double patenting argument).) Because Defendants have failed to prove that the `528 Patent covering aripiprazole was obvious in light of the `416 Patent and the prior art references cited by Defendants, it has also failed to prove that aripiprazole was obvious in light of Claim 13 of the `416 Patent. See Sanofi-Synthelabo v. Apotex Inc., 492 F.Supp.2d 353, 393 (S.D.N.Y. 2007); accord Eli Lilly Co. v. Zenith Goldline Pharms., Inc., 364 F.Supp.2d 820, 910-12 (S.D. Ind. 2005) (rejecting claim of obviousness-type double patenting where court had already found that earlier genus patent generically claiming class of compounds including the claimed invention and specifically disclosing homolog of claimed invention did not render claimed invention obvious), aff'd, 471 F.3d 1369 (Fed. Cir. 2006).
C. Conclusion on Obviousness
We find that Defendants failed to carry their burden of proving by clear and convincing evidence that Claim 12, Claim 17, or Claim 23 of the `528 Patent are invalid as obvious over the prior art references or constitute an impermissible double patenting of Claim 13 of the `416 Patent.
Defendants challenged the utility of the `528 Patent in the Final Pretrial Order, but mentioned the issue only tangentially in their post-trial brief. (Dkt. entry no. 328, Final Pretrial Order at 124-25, 164 ("Defendants' Legal Issues . . . 3. Whether claims 12, 17, and 23 are invalid under 35 USC sections 101 and/or 112 because the disclosure in the specification of the `528 patent is not adequate to support the use of aripiprazole as antischizophrenic"; cf. Defs.' Post-Trial Br. at 113.) In light of the Court's findings that the `528 Patent is commercially successful, not obvious, and infringed by Defendants, Defendants have not proven lack of utility or enablement, and we will not invalidate the `528 Patent on that basis. See Raytheon Co. v. Roper Corp., 724 F.2d 951, 959-60 (Fed. Cir. 1983) ("If a party has . . . infringed, proof of that device's utility is thereby established. People rarely, if ever, appropriate useless inventions.").
III. Enforceability of Patent — Inequitable ConductDefendants contend that Otsuka breached its duty of candor to the USPTO, rendering the `528 Patent unenforceable, by (1) withholding the Nakagawa Declaration during the prosecution of the `528 Patent, (2) withholding internal Otsuka data that was inconsistent with the data presented in the Hirose Declaration during the `528 Patent reexamination proceedings, and (3) making false statements regarding the experimental methodology used in the anti-apomorphine stereotypy test for the Hirose Declaration, in that the protocol stated that stereotyped behavior would be evaluated by "an observer blind to the treatment received by the mice," but two observers were actually involved. (Defs.' Post-Trial Br. at 148-53.)
A. Alleged Withholding of the Nakagawa Declaration and Representations Concerning Superiority of `528 Compounds over Prior Art Compounds
Defendants allege that Otsuka failed to disclose the Nakagawa Declaration during the prosecution of the `528 Patent, and that the Nakagawa Declaration was highly material because Otsuka argued to the Examiner during the reexamination proceedings that there was no evidence that the five exemplary prior art compounds had been identified as useful for treating schizophrenia, yet the Nakagawa Declaration indicated that some of those compounds, including the unsubstituted butoxy and the 2,3 dichloro propoxy, "perform[ed] excellent" in the mouse jumping test. (DTX 214 at 14; Defs.' Post-Trial Br. at 155.) Defendants conclude that therefore Otsuka must have known that its statement during the reexamination that the five exemplary prior art compounds had not been shown to exhibit antipsychotic activity was false and misleading because Dr. Oshiro, at least, had been aware of the mouse jumping data for the unsubstituted butoxy in the prosecution of the `416 Patent, and he was involved in the `528 Patent reexamination proceedings. (Defs.' Post-Trial Br. at 157-58.)
As previously stated, the Nakagawa Declaration was part of the prosecution history of the `416 Patent. (See n. 9 supra accompanying text.)
We note that Defendants do not appear to contend that the 1987 Nakagawa Declaration should have been brought to the attention of the USPTO during the initial prosecution of the `528 Patent in the early 1990s, but only that it should have been raised during the reexamination proceedings that took place in 2004-2005.
Otsuka's argument on reexamination that a butoxy linker led to an unexpected result of increased antipsychotic activity relied on data in the Hirose Declaration. (DTX 399.) The Hirose Declaration, like the `528 Patent itself, provides data for an anti-apomorphine stereotypy test, whereas the Nakagawa Declaration provided data for the mouse jumping test described by Lal. et al. in 1975. (DTX 375; DTX 214; DTX 399.) Otsuka introduced credible evidence at trial that these two tests are different, the anti-apomorphine stereotypy test being a relatively specific test for compounds that antagonize postsynaptic D2 dopamine reception; the mouse jumping test is not commonly used in antipsychotic drug discovery, while the anti-apomorphine stereotypy test has been very successful as a screen for potential antipsychotic activity; and results from the two types of tests cannot be correlated. (Dkt. entry no. 354, Roth Tr. at 1243-51; see also dkt. entry no. 346, Press Tr. at 253; dkt. entry no. 351, Castagnoli Tr. at 851-52.) Whereas the Nakagawa Declaration claimed that the inhibition of mouse jumping was "excellent" in all nine test compounds, including the unsubstituted butoxy, later test data for the unsubstituted butoxy in the anti-apomorphine stereotypy test showed that the unsubstituted butoxy was "virtually inactive" at antagonizing postsynaptic D2 receptor activity, further compelling the conclusion that the mouse jumping test and the anti-apomorphine stereotypy test cannot and should not be correlated. (Pl.'s Post-Trial Br. at 234; PTX 564, Oshiro et al., "Novel Antipsychotic Agents with Dopamine Autoreceptor Agonist Properties: Synthesis and Pharmacology of 7-[4-(4-Phenyl-1-piperazinyl)butoxy-3,4-dihydro-2(1 H)-quinolinone Derivatives," J. of Medicinal Chem., Vol. 41, No. 5 (1998), at 661 (showing ED50 value of 28, with the notation, "inactive at below given dose").)
Insofar as the `528 Patent and Otsuka's statements during the reexamination thereof relied on anti-apomorphine activity data to show the usefulness and superiority of the claimed invention as an antipsychotic, the mouse jumping data in the Nakagawa Declaration cannot be correlated. We will not infer a contradiction, or falsity of Otsuka's representation that the superiority of butoxy-linked compounds over propoxy-linked compounds was unexpected, based on a comparison of these two different tests. Even if we were to compare the two, however, we have already found that the Nakagawa Declaration did not teach the superiority of butoxy-linked compounds. Otsuka's contention that the superiority of butoxy-linked compounds was unexpected is not undermined by the Nakagawa Declaration. Additionally, the evidence indicates that the mouse jumping data in the Nakagawa Declaration would not have been material to the Examiner during the reexamination proceedings. Otsuka submitted the Banno article during the reexamination proceedings, which contained mouse jumping data for several of the compounds at issue here, including unsubstituted butoxy, unsubstituted propoxy, and OPC-4392. (See supra p. 10; DTX 84.) The Examiner did not cite to any of these mouse jumping data in the reexamination proceedings, confirming that these data, which were distinct from the stereotypy data disclosed in the `528 Patent and presented in the Hirose Declaration, were not relevant to the patentability of the `528 Patent claims. (Pl.'s Post-Trial Br. at 236; PTX 121.)
We find that Defendants have not shown by clear and convincing evidence that Otsuka's failure to disclose the Nakagawa Declaration during the `528 Patent reexamination proceedings was either material or made with intent to deceive the USPTO. Star Scientific, Inc. v. R.J. Reynolds Tobacco Co., 537 F.3d 1357, 1365 (Fed. Cir. 2008).
B. Hirose Declaration and `528 Patent Reexamination Proceeding; Alleged Withholding of "Internal Otsuka Data"
During the reexamination proceedings for the `528 Patent, the Examiner rejected the claims of the `528 Patent as unpatentable over compounds claimed by the `416 Patent, specifically looking to five exemplary prior art compounds in the same genus as aripiprazole that the Examiner stated the `416 Patent taught as being useful in "central nervous system disorders in which anti schizophrenia [sic] is also disclosed." (Defs.' Post-Trial Br. at 71; DTX 121, `528 Reexamination History, at OPC 1324-27.) In seeking reconsideration of the Examiner's final rejection, Otsuka represented to the Examiner that the prior art did not teach that the exemplary compounds had the recited property of treating schizophrenia, and submitted the Hirose Declaration to support its argument that the selection of a butoxy linker over a propoxy linker led to unexpected superiority of the butoxy-linked compound. (DTX 399, Hirose Decl.; Defs.' Post-Trial Br. at 71.) The Examiner ultimately found that the claims of the `528 Patent were allowable because the change from a propoxy to a butoxy linker showed "a clear unexpected result in the ED50 values." (DTX 121 at OPC 1411-12.)
To the extent Defendants broadly characterize Otsuka's representation as encompassing all prior art, the full statement makes clear that Otsuka was arguing that the `416 Patent, `840 Patent, and DE `105 Patent specifically did not contain evidence that the five prior art compounds had the property of treating schizophrenia, a point that has already been addressed herein. (See Pl.'s Post-Trial Br. at 238-39.) We concur with Otsuka that this statement indicated only that the `416 Patent and DE `105 Patent lacked test data concerning antipsychotic activity. (DTX 459 at 12.)
The Hirose Declaration compared four butoxy-linked compounds representative of the invention claimed in the `528 Patent, numbered Test Compounds 1, 5, 6, and 8, to four homologous propoxy-linked prior art compounds claimed in, e.g., the DE `105 Patent and the `416 Patent, labeled Test Compounds A, B, C, and D. (DTX 399 at 2-5.) Test Compound 1 was aripiprazole, and Test Compound A was the 2,3 dichloro propoxy. (DTX 399 at 3-5.)
Two tests were conducted on each group of compounds. The first was an antiapomorphine stereotypy test, to indicate the "compound's ability to block neurotransmission of dopaminergic D2-receptors, i.e., its antipsychotic activity." (DTX 399 at 5.) The second was the anti-epinephrine lethality test, to indicate the "compound's ability to block neurotransmission of -receptors, i.e., its cardiovascular side effects such as orthostatic hypotension." (DTX 399 at 6.)
The anti-apomorphine stereotypy test indicated an ED50 value of 0.28 for aripiprazole, and an ED50 value of 6.47 for the 2,3 dichloro propoxy. (DTX 399 at 6.) Thus, Otsuka represented to the Examiner that the fact that aripiprazole was twenty-three times more potent than its 2,3 dichloro propoxy homolog was indicative of the unexpected superiority of the butoxy-linked compound.
Defendants contend that this 23-fold difference is at odds with "internal Otsuka data" wherein an anti-apomorphine stereotypy test comparing, inter alia, aripiprazole with 2,3 dichloro propoxy resulted in a mere 6-fold difference, with aripiprazole having an ED50 of 0.4 and 2,3 dichloro propoxy having an ED50 of 2.5. (DTX 59-T, Synthesis Research Group Year 1987 Research Presentation: Development of Brain Function Improvement Drug, Table 4, "Effect of Side Chain Length," at OPC 717014; Defs.' Post-Trial Br. at 150.)
We note that Defendants did not present evidence concerning the test conditions underlying the 1987 internal Otsuka test data or whether these test data may be validly compared with the 2005 Hirose Declaration test data. (See dkt. entry no. 366, Oshiro Tr. at 1901-03.) Rather, Defendants improperly attempt to shift their burden of proving the elements of inequitable conduct to Otsuka: "Neither Dr. Oshiro, nor any other Otsuka witness, offered an explanation as to why [the allegedly contradictory internal Otsuka data] would not be material, or why it was not disclosed to the PTO." (Defs.' Post-Trial Br. at 151.) Otsuka's alleged failure to explain why the internal Otsuka test data were not submitted in connection with the reexamination proceedings does not satisfy Defendants' burden of proving inequitable conduct by clear and convincing evidence.
Defendants contend that the internal Otsuka data contained in the 1987 year-end presentation contradict Otsuka's representations during the reexamination proceedings regarding the "unexpected" superiority of butoxy-linked compounds based on Dr. Oshiro's testimony regarding a different report and different compounds. Dr. Oshiro testified at trial regarding a December 1986 monthly report discussing post-OPC-4392 research efforts. (PTX 35-T.) The December 1986 report compared OPC-4310, a propoxy-linked compound thought to have a 2-chloro, 6-methyl substitution on the phenyl ring, to OPC-14542, the butoxy-linked homolog of OPC-4310, and observed that extending the methylene chain from 3 to 4 caused a "dramatic 15-fold increase in the dopamine blocking action" that was "totally unexpected." (PTX 35-T at OPC 768540-41.) Dr. Oshiro testified that his research group decided to make this same structural modification to OPC-4392, but that it did not result in the same "15-fold activity increase" he had seen in comparing OPC-4310 to OPC-14542: A: As I indicated earlier, when the propoxy in 4310 was changed to butoxy, such as in 14542, the activity increased 15-fold. And so we wanted to confirm as to whether or not the OPC-4392 which was undergoing clinical testing would have the same activity increase, which is the 15-fold activity increase, if the propoxy was changed to butoxy. So we decided to synthesize the compound. Q: And what did you find? A: We did not find a considerable increase in the activity such as when we saw from 4310 to OPC-14542. In other words, even if the propoxy was changed to butoxy, we did not see a surprising increase, such as the 15-fold increase. (Dkt. entry no. 365, Oshiro Tr. at 1772-73.)
A February 1987 report states that Otsuka researchers realized that the chlorine positions on the phenyl ring for OPC-4310 and OPC-14542 were wrong, due to an error on the label of a starting material, in that the chlorine previously stated as being at the 6 position was actually at the 3 position; "[t]hat is, they should be 3-chloro 2-methyl instead of 2-chloro 6-methyl." (PTX 37-T at OPC 768547.)
Defendants argue that Dr. Oshiro testified here that a six-fold difference in stereotypy test results is not surprising, because test data reported in later monthly reports showed six-fold difference in the stereotypy test results for OPC-4392 versus the butoxy-linked analog. Dr. Oshiro's testimony does not support that interpretation. He merely acknowledged that the December 1986 report stated that OPC-4392 had an ED50 of 9.3 in the anti-apomorphine stereotypy test, and that the February 1987 report stated that OPC-14565, identical to OPC-4392 except that it had a butoxy linker instead of a propoxy linker, had an ED50 of 1.4 in the anti-apomorphine stereotypy test. (Dkt. entry no. 366, Oshiro Tr. at 1842-45; PTX 35-T at OPC 768541; PTX 37-T at OPC 768548.) Defendants did not directly ask Dr. Oshiro his opinion concerning a six-fold increase in stereotypy test data and further never asked Dr. Oshiro if the internal Otsuka test data was inconsistent with the test data reported in the Hirose Declaration. Moreover, his testimony regarding the six-fold increase was not particularly indicative of a full understanding of the relevant question or his agreement therewith: Q: So OPC-4392 with a butoxy linker was actually six times more active in the Anti-Apomorphine Test than OPC-4392 with a propoxy linker. Do you see that? A: The results in the Mouse Test or Mice Test is that way, yes. (Dkt. entry no. 366, Oshiro Tr. at 1845.)
Thus, the only testimony on this point was in regard to data concerning OPC-4392 and its butoxy homolog, and OPC-4310 and its butoxy homolog. None of these reports or testimony by Dr. Oshiro concerned a comparison of aripiprazole to the 2,3 dichloro propoxy. Defendants cannot now attempt to construct what answers Dr. Oshiro might have provided in response to questions Defendants never posed. Defendants' inferential interpretation of Dr. Oshiro's testimony cannot satisfy their burden of proving materiality of the "internal Otsuka data" by clear and convincing evidence.
Defendants have also not proven that any individual knowingly withheld this allegedly inconsistent data. Defendants allege that Dr. Oshiro was aware of the contents of the Hirose Declaration and therefore must have intentionally withheld the allegedly contradictory internal data with an intent to deceive the PTO. (Defs.' Post-Trial Br. at 151.) Dr. Oshiro did not affirmatively testify, however, that he was aware of the test data submitted in the Hirose Declaration. He merely testified that "most likely this draft — draft of this declaration was sent to me as an attachment to an e-mail requiring or requesting me to check the wording for the way things are worded in this document." (Dkt. entry no. 366, Oshiro Tr. at 1897.) Dr. Oshiro's testimony, which reflects his uncertain memory in this regard, does not establish that Dr. Oshiro was aware of the specific details of the test data reported in the Hirose Declaration. Because Defendants have not shown that Dr. Oshiro was aware of the specific data in the Hirose Declaration, they cannot prove that he was aware of any contradiction.
Defendants also failed to offer any evidence concerning additional details underlying their allegation that Dr. Oshiro knowingly withheld contradictory test data. Defendants never inquired as to whether Dr. Oshiro recalled in 2005 the specific stereotypy test data Defendants cite. That data was generated in 1987, 18 years earlier, and was among dozens of test results reported in Dr. Oshiro's notebooks. (DTX 59T.) It is therefore not apparent that in 2005 Dr. Oshiro would have recalled the details of the 1987 data and Defendants have not carried their burden of proof that he did. See MPEP 2001.04 (holding that the duty to disclose only applies to contemporaneously known information).
Defendants also never inquired as to whether Dr. Oshiro believed there was any contradiction between the Hirose Declaration data and the internal stereotypy data Defendants cite. On their face, data showing a six-fold improvement and data showing a 23-fold improvement are not contradictory, and Defendants have not presented any evidence that Dr. Oshiro believed to the contrary even had he been aware of these data.
Finally, Defendants suggest Dr. Hirose may have been aware of the allegedly contradictory test data because he generated test data for aripiprazole in 1987. This does not prove that Dr. Hirose was aware of the specific data Defendants cite, and Dr. Hirose testified that he did not recall whether he had seen any other comparative data concerning the compounds tested in the Hirose Declaration. (Dkt. entry no. 366, Hirose Tr. at 1968-70.)
Accordingly, Defendants have not met their burden of proof by clear and convincing evidence that any individual knowingly withheld contradictory test data. We cannot find the `528 Patent unenforceable for inequitable conduct with respect to the allegedly withheld internal Otsuka data or the representations made in the traverse during the reexamination proceedings. (DTX 459 at 12.)
C. Methodology Used in Hirose Declaration
The protocol for the anti-apomorphine stereotypy test in the Hirose Declaration indicated that "observation for stereotyped behavior will be performed by an observer blind to the treatment received by the mice." (DTX 399-A at 9.) Defendants contend that this statement indicates that only a single observer conducted all of the stereotypy testing and that this single observer would be blinded to the identity of the compound being tested, not just the doses of the compounds administered. (Defs.' Post-Trial Br. at 152.) Because two observers conducted the stereotypy experiments and because these observers were blinded to the doses administered but not the compounds, Defendants argue that Dr. Hirose did not follow his study protocol and suggest he did so with an intent to deceive. (Id. at 152-53.)
The protocol, however, does not support Defendants' interpretation. The isolated statement cited by Defendants merely indicates that individual mouse observations would be performed by a single individual. It does not state that only one individual would be involved in the overall conduct of the study, as Defendants contend. (DTX 399-A.) To the contrary, the protocol specifically identifies two individuals, Dr. Hirose and Dr. Kikuchi, as the investigators who carried out the testing. (DTX 399-A at 2.) Dr. Roth and Dr. Hirose each explained that it was therefore clear that two individuals would score the stereotypy testing. (Dkt. entry no. 352, Roth Tr. at 1100-01; dkt. entry no. 367, Hirose Tr. at 1983-86.)
Defendants did not offer any testimony in response to Dr. Roth's and Dr. Hirose's testimony in this regard. Dr. Beninger, Defendants' only witness on this issue, did not refer in any way to the listing of two investigators in the protocol and, in fact, did not provide any clear testimony in support of Defendants' position that the Hirose protocol indicated that only a single individual would perform the stereotypy testing. (Docket entry no. 351, Beninger Tr. at 958.) Accordingly, Defendants have not shown that the protocol indicates that the testing would be performed by a single individual.
Defendants also did not establish that the protocol indicated that the observers would be blinded to the identity of the compound being studied. The statement in the protocol refers to the "treatment received by the mice." (DTX 399-A at 9.) Because the observers were blinded to the dosage of compound administered to the mice, or whether the mice were instead administered the placebo, they were in fact blinded to the treatment received by the mice. As Dr. Roth explained, the statement in the protocol does not necessarily indicate that the observer was blinded to both the identity of the compound and the dose of compound administered. (Dkt. entry no. 352, Roth Tr. at 1113-14.) Dr. Hirose similarly explained that the mention of blinding in the protocol was referring to the fact that the observer was in fact blinded to the dose of test compound administered to the mice, which was in fact the treatment received by the mice. (Dkt. entry no. 367, Hirose Tr. at 1930-31.) Moreover, Dr. Roth explained that the blinding methodology used by Dr. Hirose, where the observer was blinded to the dose administered to the mice, was sufficient to effectively blind the study. (Dkt. entry no. 352, Roth Tr. at 1113-14.)
Defendants' expert Dr. Beninger, an expert in behavioral pharmacology, testified that the Hirose Declaration's anti-apomorphine stereotypy data was not capable of meaningful interpretation because the protocol introduced a confound by having different observers rating different compounds, thus "confound[ing] the compounds they are testing with the rater doing the testing." (Dkt. entry no. 351, Beninger Tr. at 931.) Dr. Beninger also testified that because the observers knew which compounds they were testing, although not the dose, the data could have been biased by the observers' expectations that the claimed compounds would be superior. (Dkt. entry no. 351, Beninger Tr. at 946-47.) Although we understand Dr. Beninger's concerns regarding the reliability of the data, we credit Dr. Roth's testimony that the raw data in fact showed "a high degree of interrater reliability" and that the blinding was adequate. (Dkt. entry no. 352, Roth Tr. at 1108-15; PTX 487-T; accord dkt. entry no. 355, Thisted Tr. at 1458-65, 1481-85.) As Dr. Hirose further explained, this blinding methodology was the standard method employed at Otsuka, and Otsuka had used this same blinding methodology in experiments conducted for generating data for submission to the FDA and for publications in peer-reviewed journal articles. (Dkt. entry no. 367, Hirose Tr. at 1931-33.)
Therefore, Defendants have not proven that the Hirose protocol inaccurately described the experimental procedures or that the testing methodology rendered the data unreliable. Because there was no misrepresentation or withholding of material information on this count, nor any intent to deceive, it cannot serve as the basis for allegedly inequitable conduct by Otsuka.
IV. Otsuka's Motion to Strike
Otsuka filed a motion to strike certain arguments made by Defendants in their post-trial brief that Otsuka contends Defendants had not included in the Final Pretrial Order or Defendants' Trial Brief, and therefore were raising for the first time post-trial. (Dkt. entry no. 372, Mot. to Strike.) Otsuka contends that Defendants' argument that (1) the 2,3 dichloro propoxy would have been selected as a lead compound for purposes of obviousness, and (2) Otsuka committed inequitable conduct before the USPTO by allegedly withholding internal anti-apomorphine stereotypy data for aripiprazole and the 2,3 dichloro propoxy, should be stricken pursuant to Rule 16(e).
The Court has considered all of the arguments made by Defendants in their post-trial brief, and determined that they lack merit. Accordingly, Otsuka's motion to strike will be denied as moot.
V. Remedies
Otsuka seeks a permanent injunction, pursuant to 35 U.S.C. § 271(e)(4)(B), enjoining Defendants and their officers, directors, employees, agents, successors, affiliates and assigns, and all persons and entities acting in concert or participation with them, from engaging in the commercial manufacture, use, marketing, sale, or offer for sale within the United States, or from importing into the United States, generic aripiprazole products, including the aripiprazole products described in Defendants' ANDA filings, until the expiration of the `528 Patent. (Pl.'s Post-Trial Br. at 241; Final Pretrial Order at 164.) See eBay Inc. v. MercExchange, L.L.C., 547 U.S. 388, 391 (2006) ("[A] plaintiff seeking a permanent injunction must . . . demonstrate: (1) that it has suffered an irreparable injury; (2) that remedies available at law, such as monetary damages, are inadequate to compensate for that injury; (3) that, considering the balance of hardships between the plaintiff and defendant, a remedy in equity is warranted; and (4) that the public interest would not be disserved by a permanent injunction.").
We find that a permanent injunction is appropriate. Infringement of the `528 patent, which the Court has found to be valid, is an irreparable injury, and remedies such as monetary damages are inadequate to compensate for that injury.Ortho-McNeil Pharm., Inc. v. Mylan Labs. Inc., No. 04-1689, 2007 WL 869545, at *1 (D.N.J. Mar. 20, 2007), aff'd, 520 F.3d 1358 (Fed. Cir. 2008). The balance of hardships as to the parties and public interest in protecting valid patents further weigh in favor of Otsuka's request for a permanent injunction. Having considered these factors, the Court concludes that Otsuka has shown that it is entitled to a permanent injunction.
Otsuka also seeks an order resetting the effective date of Defendants' AND As to a date not earlier than the expiration of the `528 Patent. (Pl.'s Post-Trial Br. at 240; Final Pretrial Order at 164.) In light of our findings as to infringement, obviousness, and enforceability, it will be so ordered. 35 U.S.C. § 271(e)(4)(A).
CONCLUSION
For the foregoing reasons, the Court holds that the `528 Patent is not invalid as obvious under 35 U.S.C. § 103; not invalid over Claim 13 of the `416 Patent pursuant to the judicially-created doctrine of obviousness-type double patenting; and not unenforceable for inequitable conduct. The Court will enter judgment in favor of Otsuka on its claims of infringement of Claim 12, Claim 17, and Claim 23 of the `528 Patent. Judgment will be entered in favor of Otsuka and against Defendants on Defendants' counterclaims seeking judgment of non-infringement, invalidity, and unenforceability of the `528 Patent. The Court will permanently enjoin Defendants from marketing their generic aripiprazole products until such time as the `528 Patent expires, and will reset the effective date for Defendants' AND As until such time. The Court will enter an appropriate order and final judgment.
Dated: November 15, 2010
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