Federal Circuit Affirms Validity of Janssen’s Invega Sustenna® Dosing Regimen Patent Against Obviousness Challenge

Introduction

The Federal Circuit’s July 2025 decision in Janssen Pharmaceuticals, Inc. v. Teva Pharmaceuticals USA, Inc. is an important decision for patents claiming dosing regimens. At the heart of the dispute was U.S. Patent No. 9,439,906 (“the ‘906 patent”), which protects the specific dosing strategies for Janssen’s Invega Sustenna® (paliperidone palmitate), a once-monthly injectable treatment for schizophrenia and related disorders. The case tested the boundaries of obviousness in the context of pharmaceutical regimens, scrutinizing whether the claimed sequence and combination of loading and maintenance doses were truly inventive or merely routine optimizations of known ranges. The Federal Circuit’s thorough analysis not only clarifies the limits of the “overlapping ranges” presumption in obviousness challenges but also underscores the importance of detailed factual findings regarding motivation to combine and reasonable expectation of success.

Patent at Issue

The litigation centered on the ’906 patent which claims specific dosing regimens for administering paliperidone palmitate—an ester form of the antipsychotic paliperidone. The patent is assigned to Janssen Pharmaceuticals, Inc. and Janssen Pharmaceutica NV (“Janssen”). The asserted claims cover various regimens for treating psychiatric disorders, including schizophrenia, with particular attention to both general and renally impaired patient populations.

What Is Technology?

The technology involves a long-acting injectable formulation of paliperidone palmitate (marketed as Invega Sustenna®), designed to treat schizophrenia and related disorders in adults. Specifically, the ‘906 patent addresses the problem of noncompliance and adverse effects through a proposed treatment regimen, which uses a long-acting injectable formulation of paliperidone palmitate, administered less frequently than the oral version of the medication.  The injectable formulation provides sustained plasma concentrations of paliperidone when administered once monthly, which greatly enhances compliance with dosing.  The patent claims regimens involving:

• Initial “loading” doses administered intramuscularly (specifically in the deltoid muscle) to rapidly achieve therapeutic drug levels;

• Followed by monthly maintenance doses administered either in the deltoid or gluteal muscle;

• With dosing adjustments for patients with renal impairment; and

• Specific formulation requirements (e.g., particle size, buffering agents, pH).

This regimen is intended to enhance compliance, maintain stable plasma drug concentrations, and improve patient outcomes.

Representative Claims

The parties agreed that claims 2, 10, 13, 20, and 21 of the ’906 patent are representative. Those claims and the claims on which they depend, are recited below.

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 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. 

2.  The dosing regimen of claim 1 wherein after administration of the first maintenance dose, subsequent maintenance doses of from about 25 mg-eq. to 150 mg-eq. are administered in the deltoid or gluteal muscle of the psychiatric patient in need of treatment at monthly (±7 days) intervals.

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

(a) administering intramuscularly in the deltoid of a renally impaired psychiatric patient in need of treatment a first loading dose of about 75 mg-eq. of paliperidone as paliperidone palmitate formulated in a sustained release formulation on the first day of treatment;

(b) administering intramuscularly in the deltoid muscle of the patient in need of treatment a  second loading dose of from about 75 mg-eq. of paliperidone as paliperidone palmitate formulated in a sustained release formulation on the 6th to about 10th day of treatment; and

(c) 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 75 mg-eq. of paliperidone as paliperidone palmitate in a sustained release formulation, a  month (±7 days) after the second loading dose. 

10.  The dosing regimen of claim 8 wherein the sustained release formulation is an aqueous nanoparticle suspension.

11.  A dosing regimen for administering paliperidone palmitate to a renally impaired psychiatric patient in need of treatment for psychotic disorder comprising:

(a) administering intramuscularly in the deltoid of a renally impaired psychiatric patient in need of treatment a first loading dose of about 75 mg-eq. of paliperidone as paliperidone palmitate formulated in a sustained release formulation on the first day of treatment;

(b) administering intramuscularly in the deltoid of the patient in need of treatment a  second loading dose of from about 75 mg-eq. of paliperidone as paliperidone palmitate formulated in a sustained release formulation on the eighth day of treatment; and

(c) 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 50 mg-eq. of paliperidone as paliperidone palmitate in a sustained release formulation, a  month (±7 days) after the second loading dose. 

13.  The dosing regimen of claim 11 wherein the psychiatric patient is in need of treatment for of a psychotic disorder wherein the psychotic disorder is schizophrenia.

19.  The dosing regimen of claims 1, 4, 8 or 11 wherein the sustained release depot formulation is an aqueous nanoparticle suspension consists essentially of:

(a) 156 mg/ml of paliperidone palmitate having an average particle size (d50) of from about 1600 nm to about 900 nm;

(b) 12 mg/ml of polysorbate 20;

(c) one or more buffering agents sufficient to render the composition neutral to very slightly basic (pH 8.5);

(d) 30 mg/ml of a suspending agent wherein the suspending agent is polyethylene glycol 4000; and

(f) water q.s. ad 100%.

20.  The dosage regimen of claim 19 wherein in the buffering agents contained in the aqueous nanoparticle suspension are citric acid monohydrate, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate monohydrate, sodium hydroxide.

21.  The dosage regimen of claim 19 wherein in the pH of the aqueous nanoparticle suspension is the range of pH 7 to 7.5.

Procedural History

In December 2017, Teva Pharmaceuticals USA, Inc. (Teva) filed an Abbreviated New Drug Application seeking approval from the U.S. Food and Drug Administration for the manufacture and sale of a generic version of Janssen’s Invega Sustenna®.  In January 2018, Janssen sued Teva, alleging infringement of the ‘906 patent under the Hatch-Waxman Act.  Teva stipulated infringement but challenged the patent’s validity on several grounds, including that all claims (1-21) were invalid for obviousness, and claims 19-21 were also invalid for indefiniteness and lack of written description. 

In its obviousness challenge, Teva relied primarily, although not exclusively, on three prior-art references involving Janssen’s work:

1.      NCT00210548 – A Study to Evaluate the and Safety Effectiveness of 3 Doses of Paliperidone Palmitate in Treating Subjects with Schizophrenia (“the ‘548 protocol”):  Details a Janssen Phase III clinical trial for testing the hypothesis that a regimen of three equal-amount doses of paliperidone palmitate would be more effective than a placebo.  The testing protocol describes administering at least three equal doses of 50, 100, or 150 mg-eq. of paliperidone palmitate at specified time intervals.  The ‘548 protocol did not contain any clinical results or safety data.

2.      U.S. Patent No. 6,555,544 (“the ‘544 patent”) owned by Janssen:  Discloses a “pharmaceutical composition suitable as a depot formulation for administering by intramuscular or subcutaneous injection, comprising,” among other materials, a “therapeutically effective amount” of paliperidone palmitate.

3.      WO 2006/114384 (“WO ‘384”) owned by Janssen:  Discloses a process for preparing aseptic crystalline paliperidone palmitate.  The WO ‘384 reference states that the formulation was “filled aspectically into sterile syringes” in dose volumes “between 0.25 ml and 1.50 ml depending on the dose needed, which corresponds to 25 to 150 mg-eq. of paliperidone”. 

Other references relied upon by Teva included: 

1.      Larry Ereshefsky et al., Kinetic and Clinical Evaluation of Haloperidol Decanoate Loading Dose Regimen, 26 Psychopharmacology Bull. 108 (1990).  J.A. 14113-20 (“Ereshefsky 1990”);

2.      Larry Ereshefsky et al., A Loading-Dose Strategy for converting from Oral to Depot Haloperidol, 44 Hosp. & Cmty. Psychiatry 1155 (1993).  J.A. 14121-29.  (“Ereshefsky 1993”);

3.      James L. Karagianis et al., Rapid Tranquilization with Olanzapine in Acute Psychosis:  A Case Series, 62 J. Clinical Psychiatry 12 (2001).  J.A. 1619-16203.  (“Karagianis”); and

4.      HALDOL®Decanoate 50 (halperidol) HALDOL® Decanoate 100 (haloperidol) For IM Injection Only (last modified May 2007).  J.A. 16640-53.  (“Haldol”)

The district court, after a bench trial, held that the challenged claims were not invalid for obviousnesss, lack of written description, or indefiniteness.  Janssen Pharmaceuticals, Inc. v. Teva Pharmaceuticals USA, Inc., 571 F. Supp. 3d 281, 291 (D.N.J. 2021).  In 2024, on Teva’s appeal, the Federal Circuit affirmed the district court’s rejection of Teva’s indefiniteness challenge but vacated the rejection of Teva’s obviousness challenge and remanded for further proceedings on that issue. Janssen Pharmaceuticals, Inc. v. Teva Pharmaceuticals USA, Inc., 97 F.4th 915, 918 (Fed. Cir. 2024).

On remand, the district court reconsidered obviousness based on the existing trial record and the parties’ new submissions based on the Federal Circuit's 2024 opinion.  The district court held Teva had not proved any of the asserted claims of the ‘906 patent invalid for obviousness.   Teva appealed.

Issues on Appeal

The primary issues before the Federal Circuit were:

• Whether the district court erred by not applying a presumption of obviousness to the claimed dosing regimen in claim 2 due to overlapping dose ranges in the prior art. Specifically, Teva argued that because the ‘548 protocol disclosed equal loading doses of 150 mg-eq. or 100 mg-eq., and WO' ‘384 disclosed a range that contains both these values, the prior art rendered claim 2’s loading doses prima facie obvious.

• Even if a presumption of obviousness did not apply, the district court erred in determining that claim 2 was not invalid for obviousness.  Teva argued: (1)  the “only patentable difference the district court identified between the claim and the prior art was the ‘unequal, decreasing loading doses’”; and (2) the district court placed too much emphasis on the “unequal” and “decreasing” characteristics of the claimed dosing regimen and “erred by requiring ‘motivation … to reach the specific dosing regimen of Claim 2.’”

Decision of the Federal Circuit

The Federal Circuit affirmed the district court’s judgment that Teva had not proven the asserted claims invalid for obviousness. Key aspects of the decision include:

No Presumption of Obviousness: The Court held that the “overlapping ranges” presumption did not apply because the claimed regimen was not simply a matter of selecting a value within a known range, but rather involved a specific sequence and combination of doses not disclosed or suggested in the prior art.  Specifically, the Court stated:

“The treatment regimen at issue is a combination of dosages and times of injection – with decreasing loading doses-where the evidence reasonably characterizes the combination as an integrated unit of steps taken over time for achieving desired medicinal effects (on the brain) in a patient over time.  The crucial choice made by Janssen, as the district court properly framed the matter, was the choice to start with a particular high first loading dose and then follow it with a second, lower loading dose.  That choice for the combination of loading doses is addressed to the relation between two dosage figures in a way that does not clearly fit within the presumption’s focus on simply selecting a number or range overlapping a prior-art range of a variable or, even, a plurality of variables that overlap with prior-art ranges where the variables are properly considered separately from each other.”

The Court emphasized that the presumption’s applicability is context-dependent and is not triggered merely because multiple variables overlap numerically.  Thus, a normal full obviousness analysis was to be applied.

Lack of Motivation: Teva challenged the following findings by the district court regarding a lack of motivation:

1.      A person of ordinary skill in the art (POSITA) would not have been motivated to administer “sufficiently high long-acting injectable loading doses to treat acutely ill patients”, since such treatment would not work fast enough to treat acute conditions. 

2.      Teva’s expert testimony undermined Teva’s Karagianis-based proposed motivation for a high first loading dose. 

3.      A POSITA would have been motivated to modify the particle sizes of the dose to achieve therapeutic effects more rapidly, rather than the dose amount.

4.      The district court’s understanding that Ereshefsky 1993 taught the reduction of maintenance doses, not loading doses, was too narrow and ignored the application of Ereshefsky’s teachings to loading doses. 

5.      The district court was required to find that the Haldol label, which provides guidance on the injectable administration of haloperidol decanoate, another antipsychotic medication, would have motivated a POSITA to reach the claimed dosage regimen.  Teva argued that this reference taught (1) “that an injectable dose should be approximately 10 to 20 times the daily oral dose”; and (2) that because a dose of Haldol should not exceed a certain amount (100 mg), if a patient required a larger dose, the dose should be administered in two injections:  an initial dose of the maximum amount and the remaining (smaller balance) in a second dose.  Teva argued that the district court erred in reading the label’s teachings as being limited to the particular drug and specific numbers recited in the label.

The Federal Circuit found no clear error in the district court’s factual findings that a POSITA would not have been motivated to arrive at the claimed regimen.   Specifically, the Court stated:

1.    The district court had an adequate basis for rejecting Teva’s argument that a POSITA would have wanted to use the maximum safe dose as a first loading dose.  With support from the Ereshefsky references and testimony from Janssen’s expert, the district court reasonably found that the Ereshefsky references addressed studies of patients who were already stabilized on oral haloperidol, a known and established medication, before starting experimental regimens with long-acting injectables.  Thus, these references would not have taught a POSITA to use long-acting injectables to “load” patients. 

2.     The district court had an adequate basis for rejecting Teva’s argument about the teachings of Karagianis.  One of Teva’s experts testified that Karagianis taught using a high first loading dose to treat acutely ill patients.  A second Teva expert explained that a POSITA would not use long-acting injectables to treat acutely agitated patients.  The court credited the testimony of Janssen’s expert that administering a larger dose would not help a patient reach the therapeutic threshold more quickly and found insufficient evidence supporting adjusting the dose amount.

3.     There was no clear error in the district court’s determination that a POSITA would seek to speed up a patient’s absorption of the medication by reducing the particle size and not by increasing the dose.  The district court recognized that a POSITA “can be motivated to do more than one thing” and found that a person skilled in the art would have been motivated to modify the particle size to achieve therapeutic effects more rapidly.  There was insufficient evidence to support that a POSITA would have been motivated to modify the loading dose size to achieve the same.

4.     The district court had an adequate evidentiary basis for rejecting Teva’s theory that Ereshefsky 1993 taught reducing second loading doses, including testimony from Teva’s expert that “loading doses and maintenance doses are distinct concepts,” so a POSITA “would not infer that Ereshefsky’s teachings on maintenance doses would apply equally to loading doses”. 

5.     The district court reasonably found that Teva had not met its evidentiary burden of showing that a POSITA would “reasonably infer from the reduction of a maintenance dose a motivation to reduce a second loading dose”.

6.         The district court’s determination that the Haldol label would not have taught a POSITA an unequal, decreasing dosing regimen was not clearly erroneous.   In fact, the district court stated that the label instructs a practitioner to begin with lower initial doses and adjust the dose upward as needed.  The Federal Circuit stated that the district court reasonably found that the specific instructions of the Haldol label taught an increasing rather than decreasing dosing regimen.  Moreover, both parties agreed that haloperidol decanoate and paliperidone palmitate behaved differently in the human body.

No Reasonable Expectation of Success: Teva challenged the district court’s finding that a POSITA would not have a reasonable expectation of success in achieving the claimed invention’s therapeutic benefits based on the prior art.  Specifically, Teva presented two specific arguments that the district court:

1.      Erroneously considered factors not in the claims, like safety, efficacy, or regulatory approval; and

2.      Erred in finding that the multi-dose nature of the claimed regimens added complexity that would have precluded a POSITA from expecting success.

Regarding Teva’s first argument, the Federal Circuit stated that it was not a legal error or clear error for the district court to have considered unclaimed factors in its analysis if a POSITA would have reasonably considered those unclaimed factors in the process of creating a useful claimed invention.  The district court, relying on testimony from Teva’s expert, properly found that a POSITA would have been motivated to use a dosing regimen that was safe and effective.  Therefore, the Federal Circuit found no reversible error in the consideration of those factors.

Regarding Teva’s second argument, the district court found that a POSITA would not have reasonably expected the claimed dosing regimen to be a safe and effective treatment.  This finding was supported by the testimony from Janssen’s expert that multi-dose regimens introduce additional complexities (e.g., excess accumulation of the drug in a patient’s body and fluctuation of drug levels between administrations), beyond those of single-dose regimens, and may lead to adverse effects.  While the ‘548 protocol disclosed multi-dose regimens, it included no safety or efficacy results, which further bolstered the district court’s findings that a POSITA would have found multi-dose regimens more unpredictable.  Thereupon, based on the evidentiary record, the Federal Circuit found no clear error in the district court’s determinations that a POSITA would not have had a reasonable expectation of success.

Other claims: Teva also challenged the district court’s decision to uphold two groups of other representative claims, claims 10 and 13 (representative renal-impairment claims) and claims 20 and 21 (which depend on claim 19, which in turn depends on claims 1, 4, 8, or 11).  Regarding claims 10 and 13, like the above analysis, the Federal Circuit found no clear error in the district court’s weighing of experts’ testimony in determining that the record did not support Teva’s theory of motivation.  Regarding claims 20 and 21, the Federal Circuit stated that because it was affirming the district court’s determinations that claims 2 (representative of claims 1 and 4), 10 (representative of claim 8), and 13 (representative of claim 11) had not been proven invalid for obviousness, claims 20 and 21 had likewise not been proven invalid for obviousness.

Key Takeaways

• Overlapping Ranges Presumption Is Not Automatic: The Federal Circuit reaffirmed that the presumption of obviousness for overlapping numerical ranges does not apply when the claimed invention involves a unique combination or sequence—such as a specific regimen of loading and maintenance doses—rather than a simple selection within a known range.

• Detailed Fact-Finding Is Decisive: The outcome turned on the district court’s granular factual findings about what the prior art taught, the motivations of a POSITA, and the reasonable expectations of success. Appellate review will defer to these findings absent clear error.

• Motivation and Expectation of Success Must Be Supported: The court found no clear error in the district court’s conclusion that the prior art did not motivate a POSITA to adopt Janssen’s specific decreasing loading dose regimen, nor provide a reasonable expectation of success for achieving the claimed therapeutic benefits.

• Practical Impact: This decision reinforces the strength of thoughtfully drafted dosing regimen patents and clarifies the limits of obviousness attacks based on overlapping ranges, providing valuable strategic insights for both prosecution and litigation in the pharmaceutical space.

This post was written by Lisa Mueller.