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`Keith J. Miller
`Justin T. Quinn
`Michael J. Gesualdo
`ROBINSON MILLER LLC
`One Newark Center
`19th Floor
`Newark, NJ 07102
`(973) 690-5400
`
`Attorneys for Plaintiffs
`Janssen Pharmaceuticals, Inc. and
`Janssen Pharmaceutica NV
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF NEW JERSEY
`
`
`JANSSEN PHARMACEUTICALS, INC.
`and JANSSEN PHARMACEUTICA NV,
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`
`
`
`
`
`Plaintiffs,
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`v.
`
`
`MYLAN LABORATORIES LIMITED,
`
`
`Defendant.
`
`Civil Action No. 2-19-cv-16484-CCC-MF
`
`JANSSEN PHARMACEUTICALS, INC. AND JANSSEN PHARMACEUTICA NV’S
`PRELIMINARY RESPONSES TO MYLAN LABORATORIES LIMITED’S INITIAL
`INVALIDITY CONTENTIONS WITH RESPECT TO U.S. PATENT NO. 9,439,906
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`VIII.
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`JANSSEN’S RESPONSE TO MYLAN’S CONTENTIONS REGARDING
`SECONDARY CONSIDERATIONS OF OBVIOUSNESS
`‘“Objective indicia may often be the most probative and cogent evidence of non-
`obviousness in the record[,]”’ because “they ‘provide objective evidence of how the patented
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`device is viewed in the marketplace, by those directly interested in the product.’” Kinetic
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`Concepts, Inc. v. Smith & Nephew, Inc., 688 F.3d 1342, 1370 (Fed. Cir. 2012) (quoting Ortho-
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`McNeil Pharm., Inc. v. Mylan Labs., Inc., 520 F.3d 1358, 1365 (Fed. Cir. 2008); Demaco Corp. v.
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`F. Von Langsdorff Licensing Ltd., 851 F.2d 1387, 1391 (Fed. Cir. 1988)). They “serve to ‘guard
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`against slipping into use of hindsight,’ and to resist the temptation to read into the prior art the
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`teachings of the invention in issue.” Apple Inc. v. Samsung Elecs. Co., Ltd., 839 F.3d 1034, 1052
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`(Fed Cir. 2016) (en banc) (quoting Graham v. John Deere Co., 383 U.S. 1, 36 (1966)). Objective
`
`indicia of nonobviousness include, but are not limited to, long-felt but unmet need solved by the
`
`claimed invention and failure of others, commercial success of products practicing the claimed
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`invention, industry praise of the claimed invention, unexpected results of the claimed invention,
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`and copying of the claimed invention. Id.
`
`A.
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`Long-felt but unsolved need and failure of others
`
`Evidence of a long-felt but unsolved need, or failure of others, can indicate the
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`nonobviousness of a claimed invention. KSR, 550 U.S. at 406; Graham v. John Deere Co. of Kan.
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`City, 383 U.S. 1, 17-18 (1966). To determine whether there was a long-felt unmet need for the
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`invention in question, a court must analyze the problem to be solved based on the real world
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`problems that confronted skilled artisans at the time the invention was made. See, e.g., Leo Pharm.
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`Prods., Ltd. v. Rea, 726 F.3d 1346, 1359 (Fed. Cir. 2013); Tex. Instruments Inc. v. Int’l Trade
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`Comm’n, 988 F.2d 1165, 1178 (Fed. Cir. 1993).
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`Schizophrenia is a debilitating illness that affects about 1% of the world’s population. See
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`Matthew T. Morris and Sandip P. Tarpada, Long-Acting Injectable Paliperidone Palmitate: A
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`Review of Efficacy and Safety, 47 Psychopharmacology Bull. 42 (2017) (“Morris”) at 42-43,
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`JANUS01707770-780 at 770-771; Kane at 56, MYLANPP_0130226-237 at 227. It is widely
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`recognized as a burdensome and devastating illnesses. See Kane at 56, MYLANPP_0130226-237
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`at 227. Antipsychotics were introduced in the mid-20th century to treat the symptoms of
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`schizophrenia and related psychotic disorders, but the first generation agents carried considerable
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`side effects, including EPS such as akathisia, pseudoparkinsonism, and dystonia. See Morris,
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`JANUS01707770-780 at 771; American Psychiatric Association, Practice Guideline for the
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`Treatment of Patients with Schizophrenia (2d ed. 2004) (“2004 APA Guidelines”) at 41,
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`JANUS01707381-564 at 421 (“first-generation antipsychotic medications … could cause severe
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`sedation and extrapyramidal side effects”). Newer medications—i.e., second generation or
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`“atypical” antipsychotics—reduced the incidence and severity of EPS. See Morris at 43,
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`JANUS01707770-780 at 771.
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`Oral antipsychotics for both generations, however, were associated with poor rates of
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`patient compliance, and this problem was widely recognized. See, e.g., Robin Emsley and Sanja
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`Kilian, Efficacy and Safety Profile of Paliperidone Palmitate Injections in the Management of
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`Patients with Schizophrenia: An Evidence-Based Review, 14 Neuropsychiatric Disease &
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`Treatment 205 (2018) (“Emsley”), JANUS01707646-664 at 647 (“[T]he newer oral antipsychotics
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`failed to substantially improve adherence and reduce relapse rates.”). In fact, the Clinical
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`Antipsychotic Trials of Intervention Effectiveness study—conducted from October 2001 to
`
`December 2004—revealed that the oral medication discontinuation rate was as high as 74% (1061
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`out of 1432 patients). Jeffrey A. Lieberman. et al., Effectiveness of Antipsychotic Drugs in Patients
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`with Chronic Schizophrenia, 353 New Eng. J. Med. 1209 (2005) (“Lieberman”),
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`JANUS01707748-762 at 748. Medication noncompliance for patients suffering from psychotic
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`disorders, such as schizophrenia, can lead to disease relapse and re-hospitalization, placing a large
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`burden on patients, families, the healthcare system, and society. Morris at 42-43,
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`JANUS01707770-780 at 770-771.
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`Accordingly, there was “an urgent need” within the psychiatric community to develop a
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`long-acting injectable treatment that would eliminate the need for daily oral administration, thereby
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`helping “patients to achieve symptom control in a convenient and effective manner.” Samuel J.
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`Keith and John M. Kane, Partial Compliance and Patient Consequences in Schizophrenia: Our
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`Patients can do Better, 64 J. Clinical Psychiatry 1308 (2003) (“Keith”) at 1312, JANUS01707732-
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`739 at 736. Stated plainly, “the need for a long-acting injectable formulation of the antipsychotic
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`agents could not [have been] more compelling” prior to the date of the invention. Id. at 1313,
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`JANUS01707732-739 at 737.
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`For over 50 years, skilled artisans sought ways to develop a safe and effective long-acting
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`injectable alternative to oral antipsychotics. However, there were shortcomings with every attempt.
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`Long-acting injectable antipsychotic agents (“LAIs”) of the first generation (e.g., fluphenazine
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`decanoate and haloperidol decanoate) carry risk of significant injection site reaction and pain due
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`to their oil-based formulations, and are associated with serious extrapyramidal symptoms. Id. at
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`1312, JANUS01707732-739 at 736; Morris at 42-43, JANUS01707770-780 at 770-771 (“[T]h[e]
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`first generation of antipsychotics carry considerable side effects, most notably extrapyramidal
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`symptoms (EPS), including akathisia, pseudoparkinsonism, and dystonia.”). LAIs were also “not
`
`usually prescribed for acute psychotic episodes because [those] medications [could] take months to
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`reach a stable steady state and [were] eliminated very slowly.” 2004 APA Guidelines at 30,
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`JANUS01707381-564 at 410. Consequently, the treating physician had “little control over the
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`amount of medication the patient [was] receiving, and it [was] difficult to titrate the dose to control
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`side effects and therapeutic effects.” Id.
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`And although newer second-generation LAIs eliminated the need for oil-based formulations
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`and carried less risk of EPS, disadvantages associated with dosing, administration, and side-effect
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`profiles persisted. For instance, skilled artisans had developed a risperidone sustained release
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`microsphere formulation for the treatment of schizophrenia and bipolar disorder, but this second
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`generation LAI required oral antipsychotic supplementation for at least three weeks after initial
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`injection (due to a three-week lag phase after first dose) and required twice-monthly dosing. See
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`Risperdal Consta Label (2003) at 22-23, JANUS01707348-380 at 348, 370-371; Ward Lawrence et
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`al., Therapeutic Advances, Paliperidone Palmitate: A New Long-Acting Injection for
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`Schizophrenia, Progress in Neurology & Psychiatry, Supplement (2011) (“Lawrence”) at 3,
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`JANUS01707918-925 at 920 (discussing disadvantages of risperidone LAI). Skilled artisans had
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`also developed a crystalline salt formulation consisting of olanzapine and pamoic acid for the
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`treatment of schizophrenia, but this second generation LAI required twice-monthly dosing at
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`certain doses. It also carried a potentially serious risk of post-injection delirium/sedation syndrome
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`for the patient. This risk of “severe CNS [central nervous system] depression” was significant
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`enough that FDA refused to approve olanzapine LAI until Eli Lilly did “additional work . . . to
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`better understand the risk and underlying mechanism for” CNS depression. Letter, FDA Center for
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`Drug Evaluation and Research to Eli Lilly & Co., re: NDA 22-173 Not Approvable (Feb. 25, 2008)
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`at 1, JANUS01707726-731 at 727.
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`The inventors of the 906 Patent conceived a solution to address the long-felt need for a LAI
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`therapy regimen that eliminated the need for oral run-in or supplementation, minimized the
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`frequency of drug administration, and maintained safe and efficacious results for patients. See,
`
`e.g., Mark Kreston and Peter Briscoll, Thinking Globally about Treatment Success, Insights on
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`Paliperidone Palmitate, Paliperidone Palmitate Thinklink Newsletter (2009) (“Kreston”),
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`JANUS01707937-943 at 938 (“Kreston & Briscoll”) (“Paliperidone Palmitate offers a way to
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`better meet patient needs and redefine success in the treatment of schizophrenia.”); Cynthia A.
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`Bossie et al., Paliperidone Palmitate Once-Monthly Treatment in Recent Onset and Chronic Illness
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`Patients With Schizoaffective Disorder, 205 J. Nervous & Mental Disease 324 (2017) (“Bossie”) at
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`327, JANUS01707630-634 at 633 (concluding that the once-monthly paliperidone palmitate
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`“significantly improved symptoms and reduced relapse in subjects with schizoaffective disorder”);
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`Emsley at 211, JANUS01707646-664 at 652 (listing advantages of once-monthly paliperidone
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`palmitate over risperidone); Lawrence at 4-6, JANUS01707918-925 at 921-923 (discussing
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`benefits of paliperidone palmitate LAI administered according to the claimed dosing regimen over
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`other second generation LAIs).
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`Specifically, the inventors solved the problems associated with past antipsychotic
`
`medications by pioneering a novel dosing regimen for the intramuscular (i.m.) administration of a
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`second-generation antipsychotic, paliperidone palmitate. That innovative dosing regimen utilizes
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`two loading doses of paliperidone palmitate in a sustained release formulation at specific doses
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`(about 150 mg-eq. for the first dose and about 100 mg-eq. for the second dose), specific times, and
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`specific sites of administration, in order to attain rapid therapeutic effect following i.m.
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`administration. Additionally, the claimed invention’s dosing regimen provides for once-monthly
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`administration in either the deltoid or gluteal muscle, does not require post-injection monitoring,
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`and provides for dosing windows (a dosing window of ± 2 around the second dose, and a dosing
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`window of ± 7 days around the monthly maintenance doses) that offer healthcare providers and
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`patients flexibility to accommodate real-world challenges while maintaining safe and efficacious
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`treatment. Finally, the innovative dosing strategy allows for the treatment of renally-impaired
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`patients by providing for a tailored dosing regimen that ensures safe and effective results among
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`this patient population. (As such, there is a nexus between the claimed invention and this objective
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`indicium. See Section VIII.G below.)
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`The long-felt need for a safe, convenient, and effective long-acting injectable antipsychotic
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`that could successfully address adherence challenges and improve treatment for patients with
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`psychotic disorders was satisfied by the inventions claimed in the 906 Patent, others having failed
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`beforehand. Janssen will establish the facts demonstrating long-felt need during discovery and at
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`trial and intends to rely in part on further evidence not cited herein.
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`B.
`
`Skepticism
`
`Evidence that artisans in the industry would have been skeptical of the claimed invention at
`
`the relevant time of invention can demonstrate that the invention was not obvious. See Transocean
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`Offshore Deepwater Drilling, Inc. v. Maersk Drilling USA, Inc., 699 F.3d 1340, 1352-53 (Fed. Cir.
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`2012). At the time of the invention, those in the industry were skeptical of the efficacy of high-
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`dose loading strategies (i.e., rapid neuroleptization) and had suggested that the drawbacks of such
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`therapies far outweighed the benefits. See, e.g., Goodman & Gilman at 27, MYLANPP_0130238-
`
`66 at 64 (disclosing that the “use of a loading dose . . . has significant disadvantages” and that
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`“large” loading doses can be “particularly dangerous if toxic effects occur”); Risperdal Consta
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`Label (2003) at 23, JANUS01707348-380 at 371 (“The maximum dose should not exceed 50 mg . .
`
`. No additional benefit was observed with doses greater than 50 mg RISPERDAL® CONSTA™
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`every 2 weeks; however, a higher incidence of adverse effects was observed.”).
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`Indeed, guidelines issued by the American Psychiatric Association cautioned against using
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`higher doses with first generation antipsychotics:
`
`For most patients treated with first-generation antipsychotics, a dose is recommended that is
`around the “extrapyramidal symptom (EPS) threshold” (i.e., the dose that will induce
`extrapyramidal side effects with minimal rigidity detectable on physical examination), since
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`studies indicate that higher doses are usually not more efficacious and increase the risk of
`subjectively intolerable side effects [II]. Lower doses of first-generation antipsychotic
`medications may be associated with improved adherence and better subjective state and
`perhaps ultimately better functioning.
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`2004 APA Guidelines at 13, JANUS01707381-564 at 393 (emphasis added); see also Peter Falkai
`
`et al., World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological
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`Treatment of Schizophrenia, Part 1: Acute Treatment of Schizophrenia, 6 World J. Biol. Psychiatry
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`132 (2005) (“Falkai”) at 133, JANUS01707665-725 at 667 (“Rapid dose escalation, high loading
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`doses and treatment with high doses above the mentioned dose range do not have proven superior
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`efficacy, but have been associated with increased side effects.”), id. (“First SGAs, and second-line
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`FGAs, at the lower end of the standard dose range are the preferred treatments for a person
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`experiencing a first episode of schizophrenia.”) (emphasis added) (internal citations omitted).
`
`
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`The American Psychiatric Association further warned of the dangers associated with
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`higher doses of risperidone:
`
`While the original efficacy studies comparing different doses of risperidone indicated
`optimal effectiveness at doses of around 6 mg/day, clinical investigations and subsequent
`studies indicate that for most adult patients optimal doses are between 2 and 6 mg/day, with
`a minority of patients requiring higher doses.
`
`* * *
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`Extrapyramidal side effects . . . occur to varying extents with several of the second-
`generation agents, especially higher doses of risperidone. . . . Studies using multiple doses
`of risperidone have shown that risperidone causes a dose-related increase in
`extrapyramidal side effects, with risk highest in doses greater than 6 mg/day. In any
`individual patient, it is likely that the maximally clinically effective dose of risperidone is
`lower than the dose that will cause extrapyramidal side effects.
`
`2004 APA Guidelines at 78, 86, JANUS01707381-564 at 458, 466 (emphasis added)
`
`(internal citations omitted); see also Tami R. Argo et al., Schizophrenia Treatment Algorithms,
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`Texas Medication Algorithm Project Procedural Manual (2008) (“Argo”) at 54, JANUS01707565-
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`629 at 621 (noting that EPS symptoms are “[u]sually seen with typical antipsychotics or higher
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`doses of risperidone”) (emphasis added)). Such warnings are illustrative of the industry’s
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`skepticism of using higher doses of paliperidone palmitate (since paliperidone is an active
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`metabolite of risperidone) as claimed in the 906 Patent.
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`In addition to higher loading dose regimens, skilled artisans were also skeptical of
`administering depot antipsychotics without either oral run-in or supplementation with oral therapy.
`See, e.g.,Stephen R. Marder et al., Pharmacokinetics of Long-Acting Injectable Neuroleptic Drugs:
`Clinical Implications, 98 Psychophamiacology at 433 (1989) (“Marder”), JANUS01707763-739 at
`763 (recommending that when patients are being changed horn oral to long acting injectable
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`neuroleptics, “that this conversion be done gradually over several months” because long-acting
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`injectable neuroleptics take “more time to reach a stable steady state than then oral counterparts”).
`
`The American Psychiatric Association counseled that if “a long-acting injectable medication is
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`indicated, the oral form of the same medication (i.e., fluphenazine, haloperidol, and risperidone in
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`the United States) is the logical choice for initial treatment dining the acute phase.” 2004 APA
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`Guidelines at 30, JANUS01707381-564 at 410; see also id. (“[I]f a patient experiences an
`exacerbation of psychotic symptoms while receiving long-acting injectable medications, it may be
`useful to continue the long-acting injectable medication while temporarily supplementing it with
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`oral medication.”) (internal citation omitted).
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`This skepticism specifically pertained to the claimed dosing regimens of the 906 Patent, in
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`particular the higher loading doses and the lack of required oral run-in and oral supplementation.
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`Accordingly, there is a nexus between the claimed hivention and this objective indicium. See
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`Section VIHG below. This skepticism therefore further supports the conclusion that the claimed
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`dosing regimens of the 906 Patent, which uses the higher loading doses and obviated the need for
`oral run-in and oral supplementation, were nonobvious. Janssen will establish the facts
`demonstrating skepticism during discovery and at trial and intends to rely in part on further
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`evidence not cited herein.
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`C.
`
`Commercial success
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`When a product embodying a claimed hivention is commercially successful, the
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`commercial success of that product tends to show the nonobviousness of the claimed invention.
`KSR, 550 U.S. at 406; Graham, 383 U.S. at 17-18; KBIP, LLCv. Kohler Co.,829 F.3d 1317,
`1337 (Fed. Cir. 2016). Such objective evidence is often the most probative evidence of record.
`Crocs, Inc. v. Int’l Trade Conim’n,598 F.3d 1294, 1310 (Fed. Cir. 2010).
`Invega Sustenna®, which embodies the Asserted Claims (see Section IX below), is
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`commercially successful and sales are growing. See, e.g., Janssen, Invega Sustenna Contribution
`
`2013-2017, JANUSO1709370 (showing net trade sales for hivega Sustenna®
`between 2013 and 2017); Janssen, hivega Sustenna Annual Sales 2012-2015, JANUS01707916
`(showing annual sales for Invega Sustenna
`between 2012 and 2015); Janssen,
`
`Invega Sustenna Annual Sales 2011-2018, JANUS01743309 (showing compound annual growth
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`rate over the period from 2011 to 2018 was approximately
`
`; Janssen, Invega Sustenna
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`Quarterly Sales 2009-2018, JANUS01756296 (showing approximate
`
`in sales since
`
`2009, with a a
`
`increase in sales units from 2010 to 2018, including a
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`from 2017 to 2018);
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`Janssen, IQVIA Market Sales Data, JANUSO1743072 (showing that Invega Sustenna accounted for
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`approximately
`
`share of long-acting schizophrenia treatment in Q3 2018); Michael
`
`Yang, CNS Update 2012 Managers Meeting (May 1, 2012), JANUS01707915 at 7 (“Invega
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`Sustenna continues to drive growth of JNJ’s injectable atypical franchise. The uptake of Invega
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`Sustenna once monthly atypical for schizophrenia, continues to outpace that of
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`.”), id. at 17 (“Invega® Sustenna® grew
`
`over [2011]”); Janssen, LAT
`
`Global Sales Trends, JANUS01707936 at 1 (“Invega Sustenna Continues to Drive Strong Growth
`
`of LAT Franchise: NTS up
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`in 2012 vs. 2011”). Fact and/or expert discovery is expected to
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`further show that Invega Sustenna® has been commercially successful. Moreover, the novel
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`claimed dosing regimens are the key differentiators between Invega Sustenna and competing
`therapies in the marketplace, leading to its commercial success. See, e.g., JANUS01730770, at 42-
`43 (market research showing that most physicians believe and find relevant to then practice that
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`Invega Sustenna “is dosed to achieve rapid & sustained plasma levels without the need for oral
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`supplementation”); JANUS01726815-938, at 914 (Janssen sales force emphasizing the
`“[ijmportance of stabilizing patients quickly in 12-24 horns” and that Invega Sustenna is “[d]osed
`to achieve rapid therapeutic levels without the need for oral supplementation”); JANUSO1751683-
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`696, at 683, 689, 692 (similar message directed to healthcare providers); JANUS01752855-896, at
`855-856, 872 (similar message directed to payers); JANUS01749630 (similar message directed to
`patients). Accordingly, there is a nexus between the commercial success of Invega Sustenna and
`
`the claimed dosing regimens (see Section VITT.G below), and such evidence of commercial success
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`is probative evidence of nonobviousness for the Asserted Claims.
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`Janssen will establish the facts demonstrating commercial success dining discoveiy and at
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`trial and intends to rely in part on further evidence not cited herein.
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`D.
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`Praise by others/recognition in the industry
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`Industry praise for a claimed invention can demonstrate the nonobviousness of that
`invention. See Transocean, 699 F.3d at 1351. The scientific commimity has recognized the
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`immense importance of the invention claimed in the 906 Patent and the public’s reaction has been
`
`overwhelmingly positive. As of 2017, Janssen’s Invega Sustenna® product had been approved for
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`sale in 96 countries worldwide. Janssen Research & Development, LLC, Periodic Benefit Risk
`Evaluation Report/Periodic Safety Update Report, Paliperidone Extended-Release/Paliperidone
`Palinitate 1-Month Fonnulation/Paliperidone Palmitate 3-Month Formulation (Aug. 16, 2017),
`JANUSO1707945-9369 at 961.
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`Relatedly, Xeplion® (the European counterpart to Invega Sustenna®) was “shortlisted” for the
`
`prestigious 2012 UK Prix Galien award and selected as a finalist hi the Innovative Product
`
`to Janssen EMEA subscribers, re: Janssen EMEA Newsletter
`categoiy. See Email,
`103 (May 31, 2012), JANUSO1707928-932 at 928; Email,
`to Janssen EMEA
`subscribers, re: Janssen EMEA Newsletter 114 (Aug. 16, 2012), JANUS01707933-935 at 934;
`Email, Global ENN News to Pauline SanFilippo, re: Highlight News (May 30, 2012),
`JANUSO1707926-927 at 927.
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`The claimed invention has also been touted in scientific literature, which weighs in favor of
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`nonobviousness. See, e.g., Bossie at 324, 327, JANUS01707630-634 at 630, 633 (“Paliperidone
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`palmitate once-monthly (PP1M) is an efficacious treatment for schizophrenia and schizoaffective
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`disorder” and “significantly improved symptoms and reduced relapse in subjects with
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`schizoaffective disorder.”); Emsley at 221, JANUS01707646-664 at 662 (noting that “carefully
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`conducted clinical trials and pharmacokinetic data confirmed the importance of the initial loading
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`doses” for the claimed invention and concluding that this is an “important treatment option
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`available to patients with schizophrenia and related illness”); Thomas R. Einarson et al., Economic
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`and Clinical Comparison of Atypical Depot Antipsychotic Drugs for Treatment of Chronic
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`Schizophrenia in the Czech Republic, 16 J. Med. Econ. 1089 (2013) (“Einarson”),
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`JANUS01707639-645 at 639 (comparing paliperidone palmitate, risperidone, and olanzapine
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`pamoate LAIs, and concluding that once-monthly paliperidone palmitate has “a lower overall cost
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`and superior clinical outcomes”); Lawrence, JANUS01707918-925 at 921-925 (describing the
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`“number of ways” the claimed invention will help in patient care and treatment); BMJ Journals,
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`Second-Generation Long-Acting Injectable Antipsychotic Agents: An Overview, 50 Drug &
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`Therapeutics Bull. 102 (2012), JANUS01707635-638 at 637 (“BMJ Journals”) (concluding that
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`paliperidone palmitate LAI “appears to offer some practical advantages over the other two [second
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`generation LAIs],” including that “[p]aliperidone does not require dose supplementation during
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`treatment initiation, there is some flexibility around dose administration schedules, an
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`individualised approach to dosing is feasible, no post-injection monitoring is required and it is
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`presented as a ready-to-use prefilled injection which does not require special storage conditions
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`prior to administration”).
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`178
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`Further demonstrating the industry’s strong belief in the efficacy and value of the claimed
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`invention, Invega Sustenna® is the first and only antipsychotic medication to have the United
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`States FDA recently approve the addition of real-world data to the product’s label. See Janssen
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`Press Release, Landmark Schizophrenia Data that Bring Hope in Breaking the Cycle of
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`Hospitalization and Incarceration Receive FDA Approval for Inclusion in Invega Sustenna
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`(paliperidone palmitate) Label (Jan. 3, 2018) (“Janssen Press Release 2018”), JANUS01707740-
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`747 at 740; Janssen, Comparative Efficacy Announcement Broadcast (Dec. 2017),
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`JANUS01707917 at 2 (“FDA approves new evidence demonstrating superiority of INVEGA
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`SUSTENNA® vs. commonly prescribed oral antipsychotics”). Not only does this data
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`demonstrate “[t]he superior effectiveness” of Invega Sustenna® compared to oral antipsychotics in
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`delaying time to relapse, it reveals that the “first psychiatric hospitalization or arrest and/or
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`incarceration was significantly longer” for individuals treated with Invega Sustenna® as opposed to
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`commonly prescribed oral antipsychotics. Janssen Press Release 2018, JANUS01707740-747 at
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`740. This development was recognized by the scientific community as “reason to believe that
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`Invega Sustenna may improve outcomes such as a reduction in inpatient hospitalizations or
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`arrests—the negative, real-world consequences that happen to many schizophrenia patients when
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`their medication doesn’t work.” Nick Zagorski, New Label for LAI Paliperidone Breaks FDA
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`Ground by Including Real-World Data, Psychiatry Online (Feb. 16, 2018), JANUS01707781-784
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`at 781. In addition, the FDA has repeatedly cited Invega Sustenna as a case study in the use
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`sophisticated population pharmacokinetic modeling to develop appropriate dosing regimens for
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`long-acting injectable anti-psychotics.
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`The aforementioned praise pertained to the claimed dosing regimens of the 906 Patent.
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`Accordingly, there is a nexus between the claimed invention and this objective indicium. See
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`179
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`Section VIII.G. Janssen will establish the facts demonstrating praise by others and recognition in
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`the industry during discovery and at trial and intends to rely on further evidence not cited herein.
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`E.
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`Unexpected results
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`Objective indicia of nonobviousness can be shown by evidence of unexpected results. KSR,
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`550 U.S. at 406, 416; Graham, 383 U.S. at 17-18; Sanofi-Aventis Deutschland GmbH v. Glenmark
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`Pharms., Inc., 748 F.3d 1354, 1360-61 (Fed. Cir. 2014). “To demonstrate unexpected results, a
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`party must ‘show that the claimed invention exhibits some superior property or advantage that a
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`person of ordinary skill in the relevant art would have found surprising or unexpected.’” Immunex
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`Corp. v. Sandoz Inc., 395 F. Supp. 3d 366, 402 (D.N.J. 2019) (quoting In re Soni, 54 F.3d 746, 750
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`(Fed. Cir. 1995)).
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`The claimed invention of the 906 Patent was the product of, and has yielded several,
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`unexpected results. Based on Janssen’s initial Phase I and Phase II clinical trials, the inventors
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`expected that initial injections of low doses of 50 mg-eq. of paliperidone palmitate in the patient’s
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`gluteal muscle would be therapeutically effective and clinically preferable to higher doses. Janssen
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`also initially believed that a starting dose of 25 mg-eq. would be optimal for renally impaired
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`patients. Results from Janssen’s subsequent Phase I studies and early Phase III studies, however,
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`demonstrated unexpected problems with these approaches, and illustrated that the pharmacokinetic
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`and pharmacodynamic profile of paliperidone palmitate was more complex than anticipated.19
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`Through subsequent pharmacokinetic modeling (including population pharmacokinetic modeling),
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`and clinical studies, Janssen successfully revised the dosing regimen to arrive at the claimed
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`regimen, which unexpectedly achieved the clinical success that the earlier regimens had failed to
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`achieve. Similarly, during its Phase I studies, Janssen unexpectedly discovered that its formulation
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`19 For example, the protocol for one of these studies that did not yield the anticipated results is a reference relied upon
`by Mylan as allegedly rendering the claimed inventions obvious (NCT 548).
`180
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`CONTAINS CONFIDENTIAL MATERIAL SUBJECT TO PROTECTWE ORDER
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`did not have an optimal monthly release rate or stability profile, and consequently developed a new
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`formulation with a different particle size and resuspendability profile. These unexpected results
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`relate directly to the claimed invention of the 906 Patent.
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`The claimed dosing regimens also possess the unexpected property (unlike other LAIs for
`which there is typically a trade-off between tolerability and efficacy) of being dosing regimens that
`can be used to safely and effectively treat all patient populations, regardless of age, ethnicity, or
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`body mass index (aside from renally impaired patients, for whom a separate and tailored dosing
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`regimen is provided in order to ensure safe and effective results). The claimed inventions also
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`unexpectedly achieve both rapid and long-lasting therapeutic effect, which obviates the need for
`oral run-in and oral supplementation and allow for their use in both acute and maintenance
`treatment. The claimed dosing regimens, requiring two large initial injections of paliperidone
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`palmitate into the deltoid muscle, were unexpectedly not only safe and effective, but also necessary
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`to ensure rapid therapeutic effect (compared to dosing in other sites). And, the claimed inventions
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`unexpectedly allow for safe and effective administration of paliperidone palmitate within a dosing
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`window of ± 2 days around day 8 and within a dosing window of ± 7 days around the monthly
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`maintenance dose. Janssen will establish the facts demonstrating unexpected results during
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`discoveiy and at trial and intends to rely on further evidence n