Forest Laboratories, LLC v. Sigmapharm Laboratories, LLC (257 F. Supp. 3d 664, 2017)

OPINION

Sue L. Robinson, Senior District Judge

I. INTRODUCTION

This consolidated case arises out of the filing of Abbreviated New Drug Applications (“ANDAs”) by defendants Sigmap-harm Laboratories, LLC (“Sigmapharm”); Breckenridge : Pharmaceutical, Inc. (“Breckenridge”); Hikma. Pharmaceuticals, LLC, Hikma Pharmaceuticals, PLC, and West-Ward Pharmaceutical Corporation (collectively, “Hikma”); Alembic Pharmaceuticals Ltd., Alembic Global Holding S.A., and Alembic Pharmaceuticals, Inc. (collectively, “Alembic”); and Amneal Pharmaceuticals, LLC, Amneal Pharmaceuticals of New York, LLC, ancj Amneal Pharmaceuticals Co. India PVT.LTD (collectively, “Amneal”). All defendants may be collectively referred to as “defendants.” Each of the defendants, has submitted an ANDA in an attempt to market generic versions of asenapine before the expiration of U.S. Patent No. 5,763,476 (“the ’476 patent”), which claims sublingual or buccal compositions of asenapine and methods of using such compositions to treat mental disorders, including schizophrenia. Plaintiffs Forest Laboratories, LLC and Forest Laboratories Holdings, Ltd. (collectively, “Forest” or “plaintiffs”) brought patent infringement suits against each of the defendants, which suits were consolidated into the above captioned suit. In the case tried before the court, each of the defendants conceded infringement of claim' 1 of the ’476 patent and two of the four defendants (Amneal and Hikma) conceded infringement of claim 4. Therefore, the focus of the trial (conducted in the fall of 2016) was infringement of claim 4 and the validity of the ’476 patent. The court has jurisdiction over this matter pursuant to 28 U.S.C. §§ 1331 and 1338(a).. Venue is appropriate pursuant to 28 U.S.O. § 1400(b). Having considered the documentary evidence and testimony, the court makes the following findings of fact and conclusions of law, pursuant to Federal Rule of Civil Procedure 52(a).

II. FINDINGS OF FACT

A. Development of Saphris®

Saphris® is an atypical antipsychotic containing asenapine maleate approved for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. (PTX 54 at 1, 3) Saphris is the only antipsychotic, that is administered sublingually. (D J. 311 at 85:9-12; D.I. 315 at 1039:5-13) Sublingual administration requires patients to put the formulation under the tongue and wait for the formulation to dissolve. Patients taking Saphris sublingually also cannot eat or drink for ten minutes following administration. (PTX 54 at 1, 3, 37)

Asenapine was not initially developed as a sublingual tablet but, instead, as a standard conventional tablet given orally. This is shown in a series of publications by Organon, the company that first developed asenapine for use in humans. (PTX 33; PTX 37; PTX 53) One of the first publications concerning asenapine is 'Sitsen; J. M. Ad., et al., Org 5222: Preliminary Clinical Results 15-18 (Raven Press,- Ltd., 1992) (“Sitsen 1992”). (PTX 37) Sitsen 1992 explains that while- there were drugs then available for the treatment of schizophrenia, they were not satisfactory due to their debilitating side effects. (Id. at 15) In particular, the available first generation anti-psychotics caused serious movement disorders, referred to as “extrapyramidal” side effects (“EPS”), including -Parkinsonism and tardyskinesia — side effects that persisted even when the patients stopped taking the medicines. (D.I. 311- at 71:12-25, 85:20-86:5; D.I. 313 at 612:18-613:2, 618:18-619:20)

At the time of the publication of Sitsen 1992, there were two second generation or “atypical” antipsychotics available, cloza-pine and risperidone. Although clozapine caused fewer movement disorders, it caused other serious side- effects including a rare white blood cell condition, termed “agranulocytosis,” that was potentially fatal and had to be closely monitored. (D.I. 313 at 730:4-12; D.I. 315 at 1059:9-1061:23) For this reason, clozapine was used sparingly and was only approved for the most treatment-resistant of schizophrenia patients. Risperidone caused an increase in prolactin, which resulted in the serious side effect of breast , growth and lactation, even in men. (DTX 63, 955 at figure 4D, 960; D.I. 311 at 70:25-71:11; D.I. 313 at 672:3-673:18, 674:10-24; D.I. 315 at 1057:1-1058:12)

Sitsen 1992 explained that there was a need for an effective second generation atypical antipsychotic that could be widely used for schizophrenic patients. (PTX 37 at 3) Sitsen 1992 declared that asenapine (referred to by its internal Organon designation “Org 5222”), an atypical antipsychotic, satisfied that need. Org 5222 was described as “a new antipsychotic drug with high in vitro affinity for dopamine D1 and D2 receptors and for several types of serotonin (5-HT) receptors.” (Id. at 3) “Its behavioral pharmacology suggests antipsy-chotic properties with a relatively low propensity to induce movement disorders.” (Id.) “Org 5222 is a novel antipsychotic drug with a pharmacological profile that is different from that of the classical antipsy-chotics haloperidol[] and chlorpromazine.” (Id. at 5)

Sitsen 1992 also discussed early clinical studies with asenapine that provided promising results. The article explained that healthy male volunteers received oral doses of Org 5222 up to 30 mg, and reported that “[a]t the highest dose levels some volunteers experienced mild drowsiness and/or moderate fatigue. No other clinically significant or dose-related changes in biochemical, hematological, or urinary parameters were found.” (PTX 37 at 4) When the article referred to “oral doses,” it referred to a conventional tablet that is swallowed, passes through the' digestive system, and is subject to “first-pass metabolism,” where the drug is metabolized by the liver before it enters the blood. (D.I. 314 at 939:25-940:11) Similarly, Sit-sen 1992 reported that, in a different, clinical trial using multi-dosing • of asenapine, there was a slight elevation of liver, enzymes that were reversible after discontinuation of treatment. (PTX 37 at 4) The article reported that this side effect was considered safe, and skilled artisans understood that this sort of side effect was not considered serious,' particularly for a drug that was being used to treat schizophrenia. (D.I. 314 at 845:3-847:23, 944:1-15) Sitsen 1992 concluded that “[preliminary results of a pilot trial comparing the effects of Org 5222 ... suggest [it] is ah effective antipsychotic drug that' lacks sedative properties and extrapyramidal side effects,” and that “Org 5222 is well tolerated by healthy persons and schizophrenic patients.” (PTX 37 at 5)

In terms of efficacy, the article discussed an early clinical trial comparing the effects of Org 5222 and haloperidol in schizophrenia patients. The clinical study showed “that Org 5222 is an effective anti-psychotic drug that lacks sedative properties and extrapyramidal side effects.” (PTX 37 at 5) Although more patients dropped out of the trial who were on ase-napine than who were on haloperidol, the patients who dropped out on asenapine did so because of lack of treatment effect. (Id.) As explained by “De Boer 1993,” “[t]he main reason for patient dropout was inadequate treatment effect occurring more frequently in the Org 5222 group,” but that the asenapine arm of the study was “significantly more ill than other patients in the study.” (PTX 33 at 6) That is, the higher dropout rate observed in the asena-pine group was likely due to the fact that the patients were more difficult to treat than the patients in the haloperidol group, not that asenapine was ineffective. (D.I. 314 at 946:2-22, 947:24-948:19)

Organon published an abstract in 1993, Vrijmoed-de Vries, An Update on the Clinical Development of the Atypical Antipsy-chotic Org 5222, Schizophrenia Res. 9.2, 260-261 (1993) (“Vrijmoed 1993”). (PTX 53) This abstract again reported the same clinical study in both Sitsen 1992 and De Boer 1993. (Id. at 3) As before, the abstract reported that “Org 5222 appear[s] to be a relatively safe, atypical antipsychotic drug up to a single dose of 30 mg and multiple (14 days) oral doses of 5 mg twice daily.” (PTX 53 at 3) “Org 5222 showed similar antipsychotic effects as compared to haloperidol but in a lesser proportion of patients. Treatment with Org 5222 was safe, and induced far less extrapyramidal side-effects than haloperidol.” (Id. at 3)

Vrijmoed 1993 then stated that, based on the good results Organon had obtained so far, Organon was currently engaged in “large scale Phase II studies in (sub)chronic schizophrenic patients ... in Scandinavia.” (PTX 53 at 3) More specifically, Vrijmoed 1993 reported that two large Phase II studies of Org 5222 were ongoing to further confirm efficacy in schizophrenic patients using higher doses of asenapine (including 0.4 mg, 1.0 mg, 2.0 mg, and 4.0 mg), and that “[n]o clinically relevant adverse experiences have been reported up to date” in those studies using those doses. (PTX 53 at 3)

Taken together, skilled artisans reviewing the published early clinical studies of orally administered asenapine would understand that orally administered asena-pine was safe and clinically effective at relatively low doses. (D.I. 314 at 844:4-19, 847:24-848:11, 942:16-949:19, 955:12-16; see also D.I. 312 at 316:25-317:10, 446:4-15) Therefore, Organon continued to perform dose ranging and pharmacokinetic studies with asenapine. (PTX 23; PTX 24) One such study, conducted in December 1991, was designed to preliminarily assess the safety of and tolerance for asenapine administered intravenously (“IV”), and to obtain preliminary data on the bioavailability of orally administered asenapine in healthy male volunteers. (PTX 23 at 3) The design of the study included a controlled-rate IV infusion in two healthy volunteers. (PTX 23 at 4, 5) “Subjects receiving the highest tolerated intravenous dose were to be given a single oral dose of 30 mg of Org 5222 after a washout period of seven days.” (Id.) Because variations in metabolism among individuals can affect bioavaila-bility results, the study was designed such that the same individuals received the IV and the oral doses. (D.I. 314 at 952:12-953:9) Organon planned for eight subjects to participate in the IV study, with two subjects infused at each of four doses — 0.7 mg, 1.5 mg, 3 mg, and 4.5 mg — over 30 minutes. (PTX 23 at 4) The study, however, was terminated after the first two subjects were given the 0.7 mg IV dose. (PTX 23 at 5, 32-33,177-78)

“Subject 1,” who received the 0.7 mg IV dose, collapsed in asystole (no electrical activity in the heart), i.e., the subject’s heart had stopped beating and the patient went into cardiac arrest forty-five minutes after start of infusion while having his sitting blood pressure measured. (PTX 23 at 5, 32-33) After cardiac massage (5 ster-nal thrusts), the patient briefly gained consciousness, asked what was happening, and then lost consciousness again. (Id. at 33) The massage stimulated nodal bradycar-dia, which is a “survival mechanism,” but the heart then reverted to asystole. (Id.) Two doses of atropine, a drug used to help a patient in cardiac arrest situations, were then administered at forty-nine and fifty-four minutes. (Id. at 32) After experiencing the asystolic event, Subject 1 was sent to an independent cardiologist. (Id. at 5, 32-33,177-78) The cardiologist concluded that Subject 1, in fact, had suffered from an asystolic event. (Id. at 177) The cardiologist concluded that Subject 1 was fit and showed no evidence of any cardiac issues or cardiovascular disease. (Id.) The cardiologist concluded that the asystolic event “almost certainly has to be classed as a drug induced effect with a serious adverse effect on the conducting system of the heart.” (PTX 399 at 46-47) Accordingly, the investigators concluded that IV infusion of asenapine “was not well tolerated,” and the study was terminated. (PTX 23 at 5, 35)

Organon concluded that it could no longer conduct any further studies of asena-pine using IV administration of the drug. (D.I. 311 at 256:19-257:17) Organon then tried to determine what happened, and assessed the peak plasma levels of the parent compound, Org 5222 (asenapine), and of the metabolite, Org 30526 (desme-thyl-Org 5222). (PTX 23 at 5-6,10-11) The data demonstrated that the level of metabolite in both subjects was below the level of quantification, a finding consistent with the fact that, because the IV formulation was administered directly into the vein, the study drug did not undergo “first-pass metabolism,” that is, it was not metabolized upon initial administration. (D.I. 314 at 815:1-4, 939:5-941:4) The level of the parent compound in the blood of Subject 2 was higher than in Subject 1, demonstrating that it was the level of the parent compound and not any metabolite that caused the cardiotoxic effect. (Id. at 815:14-816:5, 963:12-24)

After the IV study, the Organon scientists focused on the conventional oral tablet formulation with which they had early success. As noted, they did so believing that the cardiotoxicity observed was due to the parent compound, not a metabolite of asenapine. (PTX 24 at 49) In June 1992, Organon designed another study to examine the pharmacokinetic profile of asena-pine and recruited twelve healthy volunteers to use asenapine both after a single oral dose (30 mg) and at steady state (5 days, 15 mg twice daily). (Id. at 4) The study planned to compare twelve subjects in two groups of six. (Id.) When another subject (again, “Subject 1”) suffered a serious adverse event, the study was terminated. Two hours and twenty-five minutes after dosing, Subject 1 was sitting up when he suddenly felt dizzy and nauseous. (Id. at 6, 42) The electrocardiogram monitor alarmed indicating asystole. (Id.) The study report indicates that the subject suffered from an asystolic episode of 8.7 seconds. (Id.) After five minutes, Subject 1 subjectively improved and, after ten minutes supine, he said that he felt normal. (Id. at 42) The subject felt dizzy again approximately two hours later. (Id.) This dizziness occurred five minutes after sitting up from supine and after food consumption. (Id.) The clinical trial team determined that Subject 1 had suffered from an asystolic event. (Id. at 42-44, 135) Subject 1 was referred to a cardiologist, who determined that he was healthy, had no evidence of cardiac disease, and that the asystolic episode was “directly related to the drug.” (Id. at 42; PTX 399 at 57)

As before, Organon examined the levels of both the parent compound and the metabolite in Subject 1 (as well as the other subjects), and determined that Subject 1 had the highest level of the parent compound in his blood stream. (D.I. 314 at 824:3-14, 964:15-965:1) Because a conventional tablet was used in this oral study, there was “first-pass metabolism” and detectable levels of metabolite in the subjects’ blood. However, Subject 4, the subject with the highest level of the metabolite, did not have a cardiotoxic event. (Id. at 824:15-825:10) When the IV data and the oral data are viewed in conjunction, they show that it was the level of the parent compound and not the metabolite that was responsible for the cardio-toxic events. (Id. at 825:1-25, 965:2-11)

Recognizing that the previously unknown serious cardiotoxic events observed during IV and oral administration of ase-napine would result in termination of the development of asenapine, Organon scientists (including the inventors of the ’476 patent, Drs. Delbressine and Wieringa) conducted a “brainstorming session” to develop possible avenues of further research. (PTX 393 at 1-4) Consistent with the data discussed above, the Organon scientists hypothesized that the plasma Cmax levels of the parent compound, asenapine, should not rise above 600 pg/ml, (Id. at 1) Orga-non then postulated several different routes of administration, including rectal, nasal, pulmonal (lungs), buccal, sublingual, plasters, and depot injections. (Id, ■ at 3-4) Of these possible routes of administration, Organon stated that ■ buccal/sublingual, plasters, and depot injections were “worth a try.” (Id.) Drs. Delbressine and Wieringa were the individuals who suggested using the buccal/sublingual route of administration, although they were not convinced that the sublingual dosage form would solve the problem. (D.I. 311 at 263:17-21, 269:17-270:18, 284:5-16)

A beagle dog study was then conducted to “compare the cardiovascular effects of orally and sublingually administered Org 5222 in the conscious dog in doses yielding similar plasma levels to determine whether sublingual Org 5222 ■ might constitute a safer route of administration.” (PTX 25 at 3-4, 9,14-19, 59) The results of the beagle dog study led to the conclusion that “Org 6222 administered sublingually has fewer cardiovascular effects than when given orally. Thus, even in doses yielding plasma levels approximately one order of magnitude higher than anticipated therapeutic levels, sublingually given Org 5222 is devoid of prohibitive cardiovascular effects.” (Id. at 4)

Based on these results, Organon determined that it could take the next incremental step in further developing asenapine using the sublingual route of administration. (D.I. 311 at 269:17-270:18) The d