IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF NEW JERSEY
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`C.A. No. 2:19-cv-16484
` (CCC) (MF)
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`))))))))))
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`JANSSEN PHARMACEUTICALS, INC. and
`JANSSEN PHARMACEUTICA NV,
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`Plaintiffs,
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`v.
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`MYLAN LABORATORIES LIMITED
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`Defendant.
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`DEFENDANT MYLAN LABORATORIES LIMITED’S INITIAL
`INVALIDITY CONTENTIONS
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`Pursuant to Local Patent Rules (L. Pat. R.) 3.3 and 3.6, and the Amended Scheduling Order
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`(ECF No. 44), Defendant Mylan Laboratories Ltd. (“Mylan”) hereby submits the following
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`invalidity contentions to Plaintiffs Janssen Pharmaceuticals, Inc. and Janssen Pharmaceutica NV
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`(collectively, “Plaintiffs”) concerning U.S. Patent No. 9,439,906 (“the ’906 patent”). In their
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`Disclosures of Asserted Claims dated November 19, 2019, Plaintiffs state that they are asserting
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`claims 1-21 of the ’906 patent.
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`a) A. Cleton, et al. Evaluation of the pharmacokinetic profile of gluteal versus
`deltoid intramuscular injections of paliperidone palmitate 100 mg equivalent
`in patients with schizophrenia. 83 Supp. 1 Clin. Pharmacol. & Therapeutics
`S31, PI-75 (Mar. 2008) (“Cleton 75”) (MYLANPP_0130025)
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`Cleton 75 published in March of 2008, prior to the earliest effective filing date of the ’906
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`patent, and lists authors distinct from the named inventors of the ’906 patent. As such, Cleton 75
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`is prior art to the ’906 patent under pre-AIA 35 U.S.C. § 102(a).3
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`Cleton 75 discloses a multiple-dose, open-label, parallel-group study of patients with
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`schizophrenia to investigate the PK profile of 100 mg eq. paliperidone palmitate administered into
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`the deltoid or gluteal muscle. Cleton 75 at Abstract. Patients with schizophrenia were randomized
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`to receive four injections into either the deltoid or gluteal muscle on days 1, 8, 36, and 64. Id. The
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`study found that the median Cmax was higher in deltoid vs. gluteal muscle after the second and
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`fourth injections. Id. Further, the median concentration-time profile was higher following deltoid
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`injection. Id. After four injections, median AUC∞ was similar for both injection sites, but Cmax and
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`AUC for paliperidone were 30% and 20% higher respectively in deltoid vs. gluteal muscle. Id.
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`Increased median predose plasma concentrations on days 8, 36, and 64 suggested subjects were
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`not completely at steady state after 4 injections. Id.
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`b) A. Cleton, et al. Assessment of the dose proportionality of paliperidone
`palmitate 25, 50, 100 and 150 mg eq; A new long-acting injectable
`antipsychotic following administration in the deltoid or gluteal muscles. 83
`Supp. 1 Clin. Pharmacol. & Therapeutics S31, PI-74 (Mar. 2008) (“Cleton
`74”)
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`Cleton 74 published in March of 2008, prior to the earliest effective filing date of the ’906
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`patent, and lists authors distinct from the named inventors of the ’906 patent. As such, Cleton 74
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`is prior art to the ’906 patent under pre-AIA 35 U.S.C. § 102(a).4
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`Cleton 74 discloses a single-dose, open-label, parallel-group study in patients with
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`schizophrenia to evaluate dose proportionality of paliperidone palmitate injections administered
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`in either gluteal or deltoid muscle. Data from the study indicated AUC∞ increased proportionally
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`with increasing paliperidone palmitate doses, regardless of gluteal or deltoid injection. Overall,
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`deltoid injection was associated with a higher Cmax and slightly earlier tmax vs gluteal injection.
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`c) L. Citrome, Paliperidone: quo vadis? Int J Clin Pract, April 2007, 61, 4, 653–
`662 (“Citrome”) (MYLANPP_0130289-98)
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`Citrome published in April 2007, more than one year prior to the earliest effective filing
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`date of the ’906 patent. As such, Citrome is prior art to all claims of the ’906 patent under pre-AIA
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`35 U.S.C. § 102(b).
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`Citrome discloses that paliperidone was approved on December 20, 2006 by the US Food
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`and Drug Administration for the treatment of schizophrenia. Citrome at 653. Also known as 9-
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`hydroxy-risperidone, paliperidone is the major plasma metabolite of risperidone, an antipsychotic
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`that was launched commercially in 1994. Id. Risperidone is extensively used, and has received
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`regulatory approval for the treatments of schizophrenia, bipolar mania, and more recently,
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`irritability associated with autistic disorder in children and adolescents. Id. Risperidone was
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`demonstrated in a meta-analysis to be superior to first-generation antipsychotics for the treatment
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`of schizophrenia. Id.
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`Citrome states that several formulations of paliperidone have been tested, including an oral
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`immediate-release formulation, an oral extended-release (ER) formulation, and a depot
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`intramuscular formulation. Id. at 654. Citrome lists the clinical trials of paliperidone that were
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`registered on http://www.clinicaltrials.gov as of November 24, 2006. Id. at 656. Of the 22 studies
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`registered, 18 were with patients with schizophrenia, one with schizoaffective disorder, and three
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`in bipolar, manic or mixed episodes. Twenty Phase III studies were listed, one Phase II study and
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`one Phase I study. Fifteen studies were using the oral extended release formulation of paliperidone,
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`and seven were for the depot intramuscular formulation. Id. at 654-55. Citrone states that clinical
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`study NCT00210548 evaluated intramuscular injections of 50, 100 or 150 mg eq paliperidone
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`formulated as a depot preparation vs. placebo, on days 1, 8, 36 and 64 of therapy. Id. at Table 1.
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`Another study, NCT00210717, evaluated intramuscular injections of 25-100 mg eq every 4 weeks
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`versus risperidone depot 25–50 mg every 2 weeks. Id.; see also id. (NCT00101634 evaluating
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`intramuscular doses of 25, 50 or 100 mg eq vs. placebo and NCT00147173 evaluating
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`intramuscular doses of 50, 100 and 150 mg eq vs. placebo). Citrone states that “depot intramuscular
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`preparation of paliperidone holds greater promise if it can be demonstrated that it can be
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`administered less frequently than risperidone intramuscular microspheres and that there is little lag
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`time prior to the development of adequate blood levels, thus eliminating the need for concurrent
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`oral administration of an antipsychotic upon the initiation of the depot.” Id. 660.5
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`e) ClinicalTrials.Gov, NCT00210548 (October 10, 2006 version). (“NCT 548”)
`(MYLANPP_0130021-22)
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`NCT 548 published on October 10, 2006, more than one year prior to the earliest effective
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`filing date of the ’906 patent. As such, NCT 548 is prior art to all claims of the ’906 patent under
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`pre-AIA 35 U.S.C. § 102(b).
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`5 Mylan incorporates by reference herein the protocols of all clinical trials disclosed in
`Citrome that were publicly available as of the earliest priority date of the ’906 patent.
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`NCT 548 discloses a study to evaluate the safety and efficacy of three different doses of
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`paliperidone palmitate in treating subjects with schizophrenia. NCT 548 discloses that four
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`injections of paliperidone palmitate in either 50, 100, or 150 mg eq. doses will be administered in
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`the gluteal muscle on days 1, 8, 36, and 64 of the double-blind treatment period of the study. The
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`description of the study discloses that the hypothesis is that the 3 doses of paliperidone are each
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`more efficacious than placebo in treating subjects with schizophrenia.
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`g) U.S. Patent No. 6,555,544 to Francois et al. (Apr. 29, 2003) (“the ’544
`patent”) (MYLANPP_0130014-20)
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`The ’544 patent published in 2003, more than one year prior to the earliest effective filing
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`date of the ’906 patent. As such, the ’544 patent is prior art to all claims of the ’906 patent under
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`pre-AIA 35 U.S.C. § 102(b).
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`The ’544 patent discloses an “efficient, well-tolerated, sustained or delayed release (depot)
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`formulation of [paliperidone palmitate] which is therapeutically effective for at least three weeks
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`or more, in particular about one month.” ’544 patent at 2:38-43.
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`By the expression “effective for at least three weeks or more”, one
`means
`that
`the plasma
`level of
`the active
`ingredient, 9-
`hydroxyrisperidone (free alcohol liberated by hydrolysis from the
`alkanoic acid ester), should be above approximately 10 ng/ml. On the
`other hand, said plasma level should remain at all times below a
`threshold value of approximately 100 ng/ml in order for one to call the
`formulation “efficient”. The threshold value is the mean plasma level
`during a considerable period of time, e.g. for more than 15 minutes,
`above which patients may experience undesirable side effects, or
`conversely, the value of the plasma level under which the systemic
`tolerance of the formulation in question is still acceptable. The threshold
`value does not hold for transient, high plasm levels during a short period
`of time, e.g. for less than 15 minutes, which are due, for example to
`unexpected burst-release of the active ingredient.
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`Both of the foregoing features—plasma levels above a minimal
`therapeutical concentration but below a side-effect producing threshold
`value—are considered to be basic requirements that a contemporary
`depot formulation should fulfil in order to be acceptable for the intended
`patients. Limiting the number of drug administrations and the
`occurrence of undesirable side effects after each administration will
`undoubtedly improve the patients' compliance with the therapy.
`However, beyond these basic requirements, a number of further
`desiderata can be identified which would further improve patients'
`compliance; the two most notable being good local tolerance and ease
`of administration.
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`Id. at 2:43 – 3:4.
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`The disclosed paliperidone palmitate aqueous nanoparticle dispersions may be used in
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`methods of treating psychosis, schizophrenia, schizoaffective disorders, and other disorders, at a
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`frequency of every three weeks or longer intervals where possible, at dosage intervals of 2 mg/kg
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`to 4 mg/kg. Id. at 7:59-8:20; 8:44-9:44; 3:9-45. The composition discloses an aqueous nanoparticle
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`dispersion containing:
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`a)
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`from 3 to 20% (w/v) of the prodrug;
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`b)
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`from 0.5 to 2% (w/v) of a wetting agent;
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`c) one or more buffering agents sufficient to render the composition neutral to very
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`slightly basic (pH 8.5);
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`d)
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`from 0.5 to 2% (w/v) of a suspending agent;
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`e) up to 2% (w/v) preservatives; and
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`f) water q.s. ad 100%.
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`Id. at 7:45-58. The composition may contain buffering agents such as disodium hydrogen
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`phosphate; preservatives such as benzyl alcohol; isotonizing agents such as sodium chloride,
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`dextrose or mannitol; and suspending agents such as polyethylene glycols. Id. at 6:61-7:45. A
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`preferred formulation is one that contains from 3 to 20% (w/v) paliperidone palmitate, 0.5 to 2%
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`(w/v) of a wetting agent, one or more buffering agents sufficient to render the composition neutral
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`to very slightly basic (pH 8.5), from 0.5 to 2% (w/v) of a suspending agent, up to 2% preservatives,
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`and water q.s. ad 100%. Id. at 7:46-59.
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`j) Formulary Drug Reviews – Paliperidone, Hospital pharmacy 42(7):637-647
`July 2007 (“Paliperidone Formulary”) (MYLANPP_0130267-88)
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`The Paliperidone Formulary states:
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`The dose of paliperidone should be reduced in patients with moderate
`or severe renal function impairment. Elimination of paliperidone is
`reduced with declining creatinine clearance (CrCl). Total paliperidone
`clearance was reduced 32% in patients with mild renal function
`impairment (CrCl 50 to 79 mL/min), 64% in patients with moderate
`renal function impairment (CrCl 30 to 49 mL/min), and 71% in patients
`with severe renal function impairment (CrCl 10 to 29 mL/min),
`corresponding to an average increase in AUC of 1.5-, 2.6-, and 4.8-fold,
`respectively. The mean terminal elimination half-life was 24, 40, and 51
`hours in patients with mild, moderate, and severe renal function
`impairment, respectively, compared with 23 hours in subjects with
`healthy renal function (CrCl 80 mL/min or greater).
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`Paliperidone Formulary at 638.
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`4.
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`Claims 1-7, 15, and 17-21 would have been obvious over the combination of
`NCT 548, Cleton 75, and/or the ’544 patent, as well as the general knowledge
`of a POSA
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`a) Claims 1 and 4
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` Preamble: A dosing regimen for administering paliperidone palmitate to a
`psychiatric patient in need of treatment for schizophrenia, schizoaffective
`disorder, or schizophreniform disorder (claim 1) or psychotic disorder (claim
`4) comprising
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`NCT 548 discloses administering three doses of 50 mg eq., 100 mg eq., and 150 mg eq.
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`paliperidone as paliperidone palmitate to schizophrenia patients in the gluteal muscle on days 1,
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`8, 36, and 64 of a treatment regimen.
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`5.
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`Claims 8-14, and 16 Would Have Been Obvious Over NCT 548, Cleton 75,
`the Paliperidone Formulary and/or the ’544 patent, as well as the general
`knowledge of a POSA
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`a) Claims 8 and 11
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` Preamble: A dosing regimen for administering paliperidone palmitate to a
`renally impaired psychiatric patient in need of treatment for schizophrenia,
`schizoaffective disorder, or schizophreniform disorder (claim 8) or psychotic
`disorder (claim 11) comprising
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`NCT 548 discloses administering three doses of 50 mg eq., 100 mg eq., and 150 mg eq.
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`paliperidone as paliperidone palmitate to schizophrenia patients in the gluteal muscle on days 1,
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`8, 36, and 64 of a treatment regimen. The Formulary for Paliperidone discloses that paliperidone
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`may be administered to patients with renal function impairment. Paliperidone Formulary at 638.
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` Element (a): administering intramuscularly in the deltoid of a renally
`impaired psychiatric patient in need of treatment a first loading dose of from
`about 75 mg-eq. of paliperidone as paliperidone palmitate formulated in a
`sustained release formulation on the first day of treatment
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`NCT 548 discloses administering three doses of 50 mg eq., 100 mg eq., and 150 mg eq.
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`paliperidone as paliperidone palmitate to schizophrenia patients in the gluteal muscle on days 1,
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`8, 36, and 64 of a treatment regimen.8 Thus, NCT 548 discloses administering intramuscularly a
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`first loading dose of 50 mg-eq. to 150 mg-eq. of paliperidone as paliperidone palmitate on the first
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`day of treatment. Because overlapping ranges in the prior art establish a prima facie case of
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`obviousness, In re Peterson, 315 F.3d at 1329-30, administering a first dose of “from about 75
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`mg-eq. of paliperidone as paliperidone palmitate” would have been obvious.
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`8 The POSA would have understood that these formulations were depot, sustained-release
`formulations. See, e.g., Citrome at Table 1 (“PD, palmitate depot”).
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`Date: December 20, 2019
`
`/s/ Guylaine Hache
`
`Arnold B. Calmann (abc@saiber.com)
`Jeffrey Soos (jsoos@saiber.com)
`Katherine A. Escanlar (kae@saiber.com)
`SAIBER LLC
`One Gateway Center, 10th Floor
`Newark, NJ 07102-5311
`Telephone: (973) 622-3333
`Facsimile: (973)-286-2465
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`Deepro R. Mukerjee
`Lance A. Soderstrom
`KATTEN MUCHIN ROSENMAN LLP
`575 Madison Avenue
`New York, NY 10022-2585
`Telephone: (212) 940-6330
`Facsimile: (212) 940-8776
`deepro.mukerjee@katten.com
`lance.soderstrom@katten.com
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`Jitendra (“Jitty”) Malik Ph.D.
`Alissa Pacchioli
`KATTEN MUCHIN ROSENMAN LLP
`550 S. Tryon Street, Suite 2900
`Charlotte, NC 28202-4213
`Telephone: (704) 444-2000
`jitty.malik@katten.com
`alissa.pacchioli@katten.com
`
`Guylaine Haché, Ph.D.
`KATTEN MUCHIN ROSENMAN LLP
`525 West Monroe Street
`Chicago, IL 60661-3693
`Telephone: (312) 902-5200
`guylaine.hache@katten.com
`
`Attorneys for Defendant
`Mylan Laboratories Limited
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`CERTIFICATE OF SERVICE
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`I hereby certify that on December 20, 2019, I served via electronic mail on counsel of
`record a true and correct copy of the foregoing Defendant’s Invalidity Contentions.
`
`By: /s/ Guylaine Hache
`Guylaine Hache
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