In its recent decision in Janssen Pharmaceuticals, Inc. v. Teva Pharmaceuticals USA, Inc. the Federal Circuit reminds us that most verities in patent law are not eternal and frequently subject to case-by-case interpretation, in this case the purported verity being that reciting the indefinite article ("a") in a patent claim is construed to mean "one or more." Besides showing that "it ain't necessary so" the case is beneficial for motivating a review of when and under what circumstances "a" means "one or more" and when it means "one," but it is also illustrates how this perhaps necessary flexibility in claim construction can also lead to what can appear to be outcome-oriented decisions producing more head scratching than enlightenment.

The issue arose in ANDA litigation over Janssen's Invega Sustenna drug, an "extended-release intramuscular injectable of paliperidone palmitate, which is indicated for the treatment of schizophrenia in adults," according to the opinion. Janssen asserted several claims of U.S. Patent No. 9,439,906; dependent claim 2 was considered representative by the Court:

2. 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 re-lease 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,
[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.

(where the italicized portion is the language of independent claim 1);

as was dependent claim 10:

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

(where the italicized portion is the language of independent claim 8).

Dependent claim 13 was also asserted, which limited the patient population to schizophrenics and included the limitation that the dose range was 25 mg-eq. to about 50 mg-eq. for the "maintenance dose"; and finally dependent claims 20 and 21 directed to the particle size of the dosage, the opinion setting forth claim 19, from which claims 20 and 21 depend as reciting the "most pertinent" particle size:

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 the 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
(e) water q.s. ad 100%.

(wherein here italics identify the relevant limitations):

The opinion recites that paliperidone itself is the "major active metabolite" of an earlier (1990's) antipsychotic drug, risperidone. Paliperidone esters such as the palmitate were known in the prior art to have the beneficial property of slow dissolution after intramuscular injection, and the opinion notes that the skilled worker could "easily determine the effective amount of paliperidone to administer." Although the drug has been on the market for some time in tablet form patient compliance has been an issue. There were earlier patents directed to methods for administering the drug by injection monthly (U.S. Patent Nos. 6,577,545 and 6,555,544). In addition to treatment regimens, the '906 patent discloses optimal particle sizes for the formulation, as well as injection in the deltoid muscle for rapid initial plasma concentrations and thereafter administering to the deltoid or gluteal muscles.

Teva stipulated to infringement but challenged the validity of the asserted claims on obviousness and indefiniteness grounds. The opinion notes that the "safety of paliperidone, its efficacy for treating schizophrenia, and its recommended dosing were all well established as of the '906 patent's priority date" and that "long acting injectables (LAIs)—administered intramuscularly—of other antipsychotics were [also] on the market" at that time. For its obviousness challenge under these prior art circumstances Teva asserted three references: "(1) clinical study protocol NCT00210548 ("the '548 protocol"); (2) the '544 patent; and (3) International Publication No. WO 2006/114384 ("WO'384")." The '548 protocol described a Phase III clinical trial intending to show that three fixed doses (50, 100, or 150 milligrams equivalent) of paliperidone administered to the buttocks were more efficacious than placebo in treating schizophrenia (both party's experts agreed that this protocol was expected to be safe and effective, although there were no results reported therein). Even though not available in the art at the '906 patent's earliest priority date, the opinion notes that the 50 mg dose was not more effective than placebo, while both the 100 and 150 mg doses had defects that precluded Janssen from using these results to support FDA approval.

The '544 patent (owned by Janssen) claimed "'[a] pharmaceutical composition [of paliperidone palmitate] suitable as a depot formulation for administration by intramuscular or subcutaneous injection, comprising,' among other things, a 'therapeutically effective amount' of paliperidone palmitate," as well as methods of using this pharmaceutical composition to treat schizophrenia. The specification of the '544 patent discloses ("emphasizes," according to the opinion) the ability to "space out" paliperidone palmitate administration by "three weeks to a month" while maintaining a blood plasma concentration of "above 10 ng/ml and below 100 ng/ml." "Most pertinent for our purposes on appeal," the opinion states, is disclosure of optimal particle size and "details related to applying 'mechanical means' to reduce the effective average particle size," specifically providing this table:

Finally, the PCT application (WO'384, also owned by Janssen) discloses both the Invega Sustenna formulation and particle sizes at drug concentrations of 25-150 mg-eq.

The District Court held that Teva had not established that any of the claims of the '906 patent were invalid for obviousness or indefiniteness, and this appeal followed.

The Federal Circuit affirmed the trial court's finding regarding indefiniteness of claims 19-21 but vacated and remanded its non-obviousness determination as to all claims, in an opinion by Judge Prost joined by Judges Dyk and Hughes. The Court agreed with Teva that the District Court erred in requiring Teva to show that:

[I]t would have been obvious to use the recited dosing regimens for the general population of patients—i.e., a generalized dosing regimen. The court found that the prior art did not demonstrate population-wide safety and efficacy and thus did not teach a generalized dosing regimen. Teva contends that the claims were not directed to a generalized dosing regimen and therefore the district court asked for a showing of obviousness that went beyond what was claimed.

The opinion specifically asserts that the claims were directed to "a psychiatric patient in need of treatment for schizophrenia" using certain dosage amounts and administration times (emphasis in opinion). In the Court's opinion:

Nothing in the claims requires that the regimen be used for—let alone be ideal for—the patient population generally or a certain percentage of the patient population. On their face, the claims only recite a dosing regimen for a psychiatric patient. Because "[w]hat matters is the objective reach of the claim," KSR[ v. Teleflex], 550 U.S. at 419, the district court erred to the extent it effectively defined its obviousness inquiry as one concerning the "generalized" suitability of the dosing regimens [emphasis in opinion].

This sentiment raises at least two questions: first, the proper scope of claims reciting "a" member of a patient population (and how it Is to be determined) and second whether disclosure of clinical trial results can be interpreted as being insufficient to satisfy patentability standards for patient populations for such claims. The jurisprudential history of construction of the indefinite article "a" is not completely straightforward; although treatises somewhat blithely assert that using "a" indicates the proper construction to be "one or more" (see Robert C. Faber, Landis on Mechanics of Patent Claim Drafting 531 (3d ed. 1990)), in fact the case law is more nuanced. The Federal Circuit in KCJ Corp. v. Kinetic Concepts, Inc. 223 F.3d 1351 (Fed. Cir. 2000), opined that "[t]his court has repeatedly emphasized that an indefinite article 'a' or 'an' in patent parlance carries the meaning of 'one or more' in open-ended claims containing the transitional phrase 'comprising,'" citing Elkay Mfg. Co. v. Ebco Mfg. Co., 192 F.3d 973, 977, 52 USPQ2d 1109, 1112 (Fed. Cir. 1999); AbTox, Inc. v. Exitron Corp., 122 F.3d 1019, 1023, 43 USPQ2d 1545, 1548 (Fed. Cir. 1997); and North Am. Vaccine, Inc. v. American Cyanamid Co., 7 F.3d 1571, 1575-76, 28 USPQ2d 1333, 1336 (Fed. Cir. 1993). And "[m]oreover, standing alone, a disclosure of a preferred or exemplary embodiment encompassing a singular element does not disclaim a plural embodiment." The opinion also states that "although the specifications may well indicate that certain embodiments are preferred, particular embodiments appearing in a specification will not be read into the claims when the claim language is broader than such embodiments," citing Electro Med. Sys., S.A. v. Cooper Life Sciences, Inc., 34 F.3d 1048, 1054, 32 USPQ2d 1017, 1021 (Fed. Cir. 1994).

But some of this cited case law embodies the exceptions to this general rule (to the extent it is general); for example, Abtox, wherein "a" gas chamber was construed as limiting the claims to a single gas-containing chamber based on intrinsic evidence, including the specification (and drawings) as well as the prosecution history that were consistent with construing the claim language to be limited to a single chamber and North Am. Vaccine, Inc. where in the absence of use of "a" in the specification to mean "one or more" (by example) construing the claim to encompass more than one would create a written description deficiency, the Court stating that "[a] patent applicant cannot disclose and claim an invention narrowly and then, in the course of an infringement suit, argue effectively that the claims should be construed to cover that which is neither described nor enabled in the patent." It is fair to say that "construction of the indefinite article does not conform to uniform treatment or 'black letter law' but rather is interpreted based on how it is used in the intrinsic evidence (claims, specification, and prosecution history)," Insituform Technologies v. Cat Contracting, 99 F.3d 1098 (Fed Cir 1996).

Here, the claim recites "a" dosing regimen for treating "a" psychiatric patient (this of course is done individually to a population of individuals not to a population per se) comprising the details of the regimen. The Court held that the District Court used evidence adduced by Janssen of clinical trial results improperly to read a limitation regarding patient populations into the claim that recited the dosing regimen for treating "a" psychiatric patient. (In a footnote the panel states "it is unclear whether that [dosing] requirement would indicate that physicians typically (or always) dose that way or that some (or all) patients achieve a certain level of a particular unnamed result"). This principle brings to mind recent precedent on enablement, and whether claims to therapeutic treatments and regimens for administering them will be subject to similar requirements for a showing of how many psychiatric patients would be enough for these claims to be non-obvious under similar circumstances as in this case (contrary, for example, to distinctions by the Court between patentability requirements and regulatory requirements; see, In re Brana, 51 F.3d 1560 (Fed. Cir. 1995)).

The District Court's "misunderstanding" the Court apprehends based on these distinctions made it clear to the panel that they "impacted the district court's overall obviousness analysis," citing statements in the district court decision related to injection site (deltoid, thigh, or gluteal) and dosing amounts. The opinion asserts that the District Court erred for not considering evidence that the prior art taught making these choices on an individualized rather than patient population basis, based on the Court's construction that such individualized evidence was indicated if not mandated by claim limitations to "a" psychiatric patient being treated by "a" dosage regimen. And with regard to the District Court's assessment of there not having been a reasonable expectation of success in combining the asserted prior art the panel states that "there too [the District Court] seemed to require an expectation of success not for administering paliperidone palmitate to a patient according to the dosing regimen claimed, but rather success in achieving the goals a POSA would have across an (undefined) average population of patients, such that a POSA would expect to use the regimen as a 'generalized multi-dose regimen.'" This error, according to the opinion was the result of "conflat[ing] the invention of the claims with Janssen's approval process when it referred to the difficulties Janssen encountered with the . . . clinical trial as an indication of unpredictability in the 'invention process.'" "In sum," according to the opinion, " . . . the court's framing led it to ask the wrong questions about important aspects of the obviousness inquiry. This error requires a remand as to all claims because as it currently stands, the record does not contain underlying obviousness factfindings that are cued to the 'a psychiatric patient' claims at issue here."

The opinion also faults the District Court for assessing obviousness of claims regarding administration to patients having renal impairment to those patients wherein the impairment was "mild," there being no such limitation recited in the claims.

More generally, the Court gave credence to Teva's argument that the District Court had contravened the dictates in KSR regarding "impermissibly rigid" assessment of obviousness, based on the District Court not giving the proper weight to the ability of the skilled worker to deduce what the references "fairly suggest[ed]" or employing "ordinary creativity," inter alia by purportedly applying these references to the claims in a "one-by-one" manner (a criticism countless patent prosecutors have heard from PTO examiners), calling it a "seemingly siloed and inflexible approach." Consequently, the panel believed that the District Court did not consider "how background knowledge in the art would have impacted a POSA's understanding of, or motivation to modify, the primary references at issue, thereby inflating the significance of minor variations between the prior art and the claims." The opinion also criticizes how the District Court relied on the '548 protocol with regard to the skilled worker's motivation to combine, insofar as the District Court "concluded that in the pharmaceutical context, if a prior art reference does not contain safety and efficacy data, there is no reason to combine it with other prior art references." The Federal Circuit rejected this approach, stating that the lack of safety and efficacy data in a prior art reference to a clinical trial did not justify the lower court "discarding" that prior art (echoing recent Federal Circuit precedent that claims directed to pharmaceutical compositions and methods of treatment require affirmative recitation of safety and efficacy requirements; see United Therapeutics Corp. v. Liquidia Technologies, Inc., cited in the opinion). The opinion faults the District Court for not considering what the results of the '548 protocol would have suggested to the skilled worker, or the relevance of the Phase III status of the clinical trial, or that "paliperidone was already on the market and prescribed to patients in need of treatment for schizophrenia" (which might be an important motivation for the Court's opinion). According to the opinion, what was "more important" was that the '906 claims "do not recite any particular result or outcome, nor do they recite a need for population-wide statistically significant data" (ignoring the implicit meaning of claims to a therapeutic treatment regimen as being safe and effective, or the formalistic futility of requiring such claims (or all such claims) to affirmatively make such representations, with the opinion once again making a distinction between "a psychiatric patient" and a population of such patients). The status of the clinical trial as having failed was not public knowledge and thus, the panel reasonably contends the skilled worker might have had a different motivation towards combining this reference with other prior art in the absence of such knowledge. Finally, the Court found error in the District Court's analysis of modifications of unequal loading doses and injections sites, based on its erroneous consideration of the '548 protocol, as well as asserting particular error regarding claims to treatment of renally impaired psychiatric patients (such as not giving sufficient weight to prior art dosage information from orally administered paliperidone palmitate for claims to the drug administered by injection).

Turning to the District Court's nonobviousness determination for claims directed to particle size, the panel found error over the standard applied for teaching away from the '544 patent, based on lack of specific disclosure regarding this parameter ("[S]ilence does not imply teaching away," Allergan, Inc. v. Apotex Inc., 754 F.3d 952, 964 (Fed. Cir. 2014)).

The opinion also provides a thorough discussion of the remedial requirements on remand for the District Court regarding secondary considerations (objective indicia) of non-obviousness, including unexpected results (involving comparisons to psychiatric drugs other than paliperidone palmitate and reliance on the unknown bases for clinical failure in the '548 protocol). The opinion criticizes the District Court's lack of proper nexus evidence regarding industry praise, and disregard for the effect of blocking patents to the long-felt need and commercial success considerations, citing Acorda Therapeutics, Inc. v. Roxane Labs., Inc., 903 F.3d 1310, 1339 (Fed. Cir. 2018).

Regarding the indefiniteness decision for claims 19-21 directed to particular particle sizes, the Court affirmed the District Court based on that decision being supported by "factual findings that Teva has not shown to be clearly erroneous." Teva argued that various means for determining particle sizes could lead to "meaningfully different results, creating a situation where the same physical samples of paliperidone palmitate would simultaneously fall inside and outside the claim depending only on how its particle-size measurement is taken," and in particular on particle size deviations that the District Court found were "an outlier measurement taken with a defective device." The Federal Circuit held that Teva had not established that this District Court determination was clearly erroneous, citing Takeda Pharm. Co. v. Zydus Pharms. USA, 743 F.3d 1359, 1366–67 (Fed. Cir. 2014), for the principle that "the 'mere possibility of different results' is insufficient for indefiniteness."

The panel opinion is sufficiently thorough that the District Court should have ample direction regarding how it should fashion its considerations of the facts, claims, and prior art references to satisfy the Federal Circuit's criticisms of its non-obviousness determinations. More concerning is the extent to which a court created to harmonize U.S. patent law has apparently endeavored to decide the specific case before it without due considerations on how "black letter" law will be properly applied to the next case it reviews, with regard to claims reciting "a" limitations and the inherent limitations of safety and efficacy for therapeutic treatments and methods of use thereof otherwise not challenged on written description or enablement grounds. The decision (and United Therapeutics before it) suggests that it would be prudent in future to include affirmative disclosure regarding these inherencies in specifications supporting claims to therapeutic treatments and administration regimens therefor.

Janssen Pharmaceuticals, Inc. v. Teva Pharmaceuticals USA, Inc. (Fed. Cir. 2024)
Panel: Circuit Judges Dyk, Prost, and Hughes
Opinion by Circuit Judge Prost

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