Paliperidone - Canada

On May 05, 2020, Federal Court of Canada found dosage administration patent of INVEGA SUSTENNA valid & non-infringing with respect to certain claims.

In this litigation, Plaintiff (Janssen) sued Defendant (Teva) for filing Abbreviated New Drug Submission  (ANDS) with Health Canada to market generic version of INVEGA SUSTENNA.  Janssen is the owner of Canadian Patent No. 2,655,335 (US equivalent – US 9,439,906) which is titled, “Prolonged-Release Injectable Suspensions of Paliperidone Palmitate, and Dosage Forms and Delivery Systems Incorporating Same.” The invention relates to dosing regimens for long acting injectable paliperidone palmitate formulations for treatment of schizophrenia by administering two loading doses on day 1 (150 mg-eq) & day 8 (100 mg-eq) and then administering monthly maintenance dose (75 mg-eq) in deltoid or gluteal muscles with provided kit containing prefilled syringes.

CA’335 contains 63 claims, and Janssen alleges infringement of claims 1 to 48.

The Asserted Claims of the 335 Patent break down into three sets:

i. claims 1 to 16 relate to prefilled syringes adapted for administration according to the claimed dosing regimens;

ii. claims 17 to 32 relate to a use of a “dosage form” according to the claimed dosing regimens; and

iii. claims 33 to 48 relate to use of paliperidone as paliperidone palmitate in the manufacture/preparation of a “medicament” adapted for administration according to the claimed dosing regimen.

Obviousness:

Teva argued that inventive concept of the asserted claims is to provide  a dosing regimen for a depot formulation of paliperidone palmitate for the treatment of schizophrenia. Janssen on the other hand argued that the inventive concept is “standardized and optimized” dosing regimen of depot formulations of paliperidone for psychiatric patients in need of treatment for schizophrenia, which quickly and safely reaches and maintains potentially therapeutic plasma concentrations of paliperidone. But court said that “standardized and optimized” sets the bar for the inventive concept too high, and is not supported by the claim language or the disclosure. Court found that the inventive concept is a safe and effective dosing regimen using a depot formulation of paliperidone designed to quickly attain, and maintain, therapeutic plasma concentrations of paliperidone for treating patients with schizophrenia.

Teva primarily relied on the CA 2,309,629 Patent (discloses long acting formulation of paliperidone) and the Citrome article as relevant prior art for obviousness. Citrome summarizes information about ongoing and completed paliperidone clinical trials. Data in the paper was compiled from the clinicaltrials.gov website, and included information from 15 studies using an extended release oral formulation, and 7 studies using depot intramuscular formulations. Specifically, Citrome disclosed paliperidone depot injection with doses of 25, 50, 75, 100, and 150 mg-eq; fixed dosing (same dose administered on each dosing day) in the gluteal on days 1, 8, 36, 64 and One phase 3 trial was investigating monthly dosing. Thus, the difference with respect to asserted claims were: specific dose amounts as loading or maintenance dose at specific injection site; dosing windows of ± 2 days (second loading dose) and ± 7 days (maintenance doses); and an adjusted regimen for patients with renal impairment.

Teva argued that the prior art discloses dosing regimens for paliperidone palmitate depot formulations that include five dose amounts (25, 50, 75, 100, and 150 mg-eq), two injection sites (deltoid and gluteal), and two dosing schedules (monthly, or days 1, 8, and monthly thereafter). To get from here to the claimed dosing regimen, the POSITA would simply undertake routine testing to arrive at the claimed combinations of dose amount, dose schedule, and injection sites. Experts agreed that the POSITA would have needed to understand the pharmacokinetic profile of the paliperidone depot formulation in order to design a dosing regimen. As of the relevant date, the necessary pharmacokinetic data in humans was not disclosed in the prior art. Determining the rate of release of paliperidone from the depot formulation would at least require testing in animal models followed by testing in humans to confirm and adjust the dosing as necessary. Court said that even if the POSITA decided to pursue a loading dose regimen, they would have to run clinical trials to evaluate the safety and efficacy of a large number of variables including fixed doses, variable doses, and injection sites. Though the number of dosing regimen variables is finite, but based on the state of the art there were a not finite number of identified, predictable solutions. In fact, the only study disclosed in Citrome where a loading dose regimen was definitely being used had a fixed dosing regimen, that is, each loading and maintenance dose amounts were the same. Nothing in Citrome points the POSITA towards a variable dosing regimen such as that claimed in the 335 Patent. Court held that the POSITA would have had to carry out prolonged and arduous experimentation to the point that the trials would not be considered routine. Therefore, claimed dosing regimen elements is inventive, and the Asserted Claims of the 335 Patent are not obvious.

Infringement:

Janssen submitted that Teva will directly infringe claims 1 to 16 and 33 to 48 by selling its paliperidone palmitate product. Janssen’s position is that both of these claim sets are product claims and therefore no active use is required to support a finding of infringement. Teva submits that because it does not prescribe or administer medications, it cannot infringe these claims, as they all require administration in accordance with the claimed dosing regimens. Court agreed with Janssen.

With respect to other claims, parties agreed that Teva will not directly infringe “use” claims 17 to 32, and the Court need only consider inducing infringement in respect of these claims.

With respect to the dosing schedule, dose amounts, and injection sites, Janssen submits that the Teva’s label specifies the approved indications and dosage and administration instructions, which include administration according to the claimed dosing regimens of the 335 Patent. Janssen submitted that Teva will induce infringement of all three claim sets if it comes to market with its paliperidone palmitate product. Teva argued that Janssen has no evidence that there will be any actual infringement and speculation cannot establish infringement. Court said that IMS data and the expert evidence indicate that a large number of patients on INVEGA SUSTENNA receive 100 mg-eq or 150 mg-eq as their maintenance dose while very low patients receive maintenance dose of 75 mg-eq. Therefore, while acts of infringement may be few, at least some physicians will prescribe and administer paliperidone palmitate injections that fall within the scope of the claimed dosing regimens in the 335 Patent. Janssen argued that Teva’s label goes beyond mere encouragement, and contains clear and explicit instructions that the Teva product is approved to be used in an infringing manner. The 75 mg-eq maintenance dose is one of the “recommended” maintenance doses for non-renally impaired schizophrenia patients. However, Teva’s experts gave evidence that prescribing physicians do not look at generic labels once they are sufficiently familiar with label and subsequent use of the brand products. Teva’s label recommends that the prescribing physician select the maintenance dose for patients based on individual patient characteristics & not because of Teva’s label influence. The appropriate maintenance dose is determined individually for each patient, and in most cases the starting maintenance dose is 100 mg-eq. Court said that this evidence is also consistent with statements made by Janssen in a document submitted to Health Canada that “[g]ood clinical practice is to individualize treatment based upon clinical symptoms” and “[i]ndividualization of the dose of paliperidone palmitate can begin as early as day 36, the time corresponding to the third injection.” Therefore, label itself does not actually result in prescription and use of the 75 mg-eq maintenance dose of paliperidone palmitate.

Court thus held that Teva will not induce infringement of claims 17 to 32 of the 335 Patent if it comes to market with its paliperidone palmitate product. Teva must be aware that at least some infringement by third parties will occur, but this infringement is the result of prescribing physicians’ skill and judgment applied to specific patient characteristics, rather than influence exercised by Teva via its label.