Paliperidone palmitate – USA

Paliperidone palmitate – USA

On Nov. 16, 2021, New Jersey district court found Invega Sustenna® method-of-use patent valid.

 

Plaintiffs, Janssen Pharmaceuticals holds NDA for Invega Sustenna®, which was approved by USFDA in Jul. 2009 for the treatment of Schizophrenia and Schizoaffective disorders. Teva filed ANDA with P-IV certification to US 9,439,906 (expires on Jan. 26, 2031) patent. US’906 patent covers covers “a dosing regimen for administering paliperidone palmitate to a psychiatric patient in need of treatment for schizophrenia, schizoaffective disorder, schizophreniform disorder, or other psychotic disorders.” Janssen sued Teva for infringement of US’906 patent.

 

Claim 1 of US’906 patent recites:

1. A dosing regimen for administering paliperidone palmitate to a psychiatric patient in need of treatment for schizophrenia, schizoaffective disorder, or schizophreniform disorder comprising:

(1) administering intramuscularly in the deltoid of a patient in need of treatment a first loading dose of about 150 mg-eq. of paliperidone as paliperidone palmitate formulated in a sustained release formulation on the first day of treatment;

(2) administering intramuscularly in the deltoid muscle of the patient in need of treatment a second loading dose of about 100 mg-eq. of paliperidone as paliperidone palmitate formulated in a sustained release formulation on the 6th to about 10th day of treatment; and

(3) administering intramuscularly in the deltoid or gluteal muscle of the patient in need of treatment a first maintenance dose of about 25 mg-eq. to about 150 mg-eq. of paliperidone as paliperidone palmitate in a sustained release formulation a month (+/-7 days) after the second loading dose.

 

Obviousness:

To establish obviousness, Teva primarily relied on three prior art references at trial:
(1) a summary protocol for Janssen’s PSY-3003 clinical study titled “A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Dose-Response Study to Evaluate the Efficacy and Safety of 3 Fixed Doses (50 Mg eq., 100 Mg eq., and 150 Mg eq.) of Paliperidone Palmitate in Subjects With Schizophrenia” (the “’548 Protocol”);

(2) U.S. Patent No. 6,555,544 (the “’544 Patent”), titled “Aqueous Suspensions of Submicron 9-Hydroxyrisperidone Fatty Acid Esters”; and

(3) WO 2006/114384 (the “WO’384 Publication”), by Janssen Pharmaceutica, N.V. disclosing formulation of paliperidone.

 

The main prior art references focused on by the parties relate to the initiation of treatment with loading doses (the ’548 Protocol), a specific formulation of paliperidone palmitate (the WO’384 Publication), and monthly administration of aqueous nanoparticle suspensions of paliperidone palmitate formulations to treat schizophrenia (the ’544 Patent). Defendant asserted that, when considering these references and the other prior art in the record individually and in combination, a POSA would have been motivated to arrive at the claimed dosing regimens with a reasonable expectation of success.

 

But, Court said that Teva has failed to show that a POSA would have been motivated to arrive at the claimed dosing regimens with a reasonable expectation of success. Court said that the ’548 Protocol is summary protocol of Janssen’s unsuccessful PSY-3003 clinical trial aimed at measuring the safety and efficacy of administering “fixed doses” of either 50, 100, or 150 mg-eq. of paliperidone palmitate “in the gluteal muscle” for “treating subjects with schizophrenia.” In the study, equal doses were to be administered on “Days 1, 8, 36, and 64.  The ’548 Protocol and the ’906 Patent differ in several material respects. The ’548 Protocol discloses equal doses of paliperidone palmitate administered in the gluteal muscle on fixed treatment days, while the ’906 Patent contains regimens comprised of unequal doses, two of which must be administered in the deltoid muscle, and a broader dosing window for the second and monthly maintenance doses. Court further said that Defendant failed to adequately explain why a POSA would modify the ’548 Protocol’s teachings in the precise ways required to achieve the dosing regimens claimed in the ’906 Patent, and the mere fact that the ’548 Protocol and the ’906 Patent contain some similar features is not enough to show obviousness. Moreover, the ’548 Protocol does not contain clinical results or safety data, without such safety and efficacy information, a POSA would have had no reason to alter the regimen disclosed in the reference. In fact, the only way to know how to modify the ’548 Protocol to match the ’906 Patent would be to look back at the protocol later with its results in hand, but that type of hindsight analysis is impermissible here. Defendant’s next argument that the WO’384 Publication, in combination with the ’544 Patent, would motivate a POSA to arrive at claimed invention is also unavailing.

 

A POSA would not have a reasonable expectation of success in arriving at the claimed dosing regimens. Court further said that the unpredictability of developing treatment initiation regimens using Long Acting Injectables (LAIs) supports a finding of nonobviousness. Here, the record establishes that developing a generalized multi-dose regimen using an LAI to initiate therapy was an unpredictable process. As Dr. Wermeling acknowledged, there were “a large number of possibilities for combining” the dose amounts disclosed in the ’548 Protocol with “different injection sites.” He further testified that different injection sites, dosing intervals, and dose amounts can affect therapeutic blood levels. The record further indicates that, in contrast to single doses, multi-dose regimens must
account for effects like “accumulation” and “fluctuations [in a patient’s blood levels] between administrations. ”Therefore, to successfully arrive at a multi-dose regimen based on the prior art, a POSA would need safety, efficacy, and pharmacokinetic data in order to evaluate how a generalized dosing regimen would perform in patients. The prior art, however, contained no such data.

 

Objective Indicia of Nonobviousness (secondary considerations) also supports nonobviousness.

Unexpected results: Court said that prior to the invention of Invega Sustenna, the conventional wisdom for both first-generation and second generation antipsychotics was to “start low and go slow.” The claimed dosing regimens run contrary to the prior art teachings because they use depot injections of high, rather than low, loading doses to initiate treatment. The evidence at trial showed that Invega Sustenna improved patient treatment adherence through its use of high initial loading doses that rapidly achieved therapeutic concentrations of paliperidone palmitate and monthly loading doses which maintained these concentrations.

Skepticism: Court said that the trial record indicates that on February 28, 2007, in response to Janssen scientists’ proposal of the dosing regimen of 150 mg-eq. on the first day of treatment and 100 or 50 mg-eq. on the eighth day, a panel of external advisors “expressed their opinion” that a lower dosing regimen with “lesser risk” should be considered. Indeed, after Janssen initially applied for regulatory approval of a dosing regimen of “100/100 mg-eq., day 1/8, deltoid dosing regimen” in October 2007, the FDA suggested that Janssen use even lower initiation doses starting at 75 mg-eq. up to 100 mg-eq. on the first and eighth days of treatment. This evidenced skepticism toward the high loading dose strategy later claimed in the ’906 Patent.

Praise: Plaintiffs identify several sources of industry praise in support of their position, including Dr. Kohler’s testimony that Invega Sustenna is his “first choice” LAI, trade publication articles, an FDA employee’s remarks at a 2013 industry conference, and Invega Sustenna’s nomination for the Prix Galien award. The Court found that certain of the cited trade publications are the most probative evidence of praise.

Long-Felt Need and Failure of Others: The ti·ial evidence showed that the claimed invention satisfied the long-felt need for an LAI that could successfully initiate and maintain ti·eatment without oral supplementation. Prior to the
invention of Invega Sustenna, all antipsychotics on the market had significant limitations. For example, first-generation antipsychotics had unfavorable side effect profiles and required oral pretreatment and individualized dosing. The ’906 Patent fulfilled this long-felt need.

Commercial Success: Plaintiffs demonstrated that the claimed dosing regimens contributed to Invega Sustenna’s commercial success. The record indicates that, when adjusted for rebates and discounts, Invega Sustenna’s net sales in the United States have grown annually since its launch in 2009 and have exceeded $1 billion from 2015 through 2019. Furthermore, Invega Sustenna has accounted for over 50 percent of all revenue generated by sales of LAI antipsychotics in the United States annually from 2013 through 2019.

Thus, Teva has failed to meet its burden of showing that the ’906 Patent is invalid as obvious.

 

Teva also argued that the patent is invalid under lack of written description support and indefiniteness. But, Court also rejected these arguments and found patent not invalid.

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