In Tris Pharma, Inc. v. Actavis Labs. FL, Inc., 2020 WL 7028456, at *1 (D. Del. Nov. 30, 2020), the district court for the District of Delaware, on remand from the Federal Circuit, found that all the asserted claims of the patents-in-suits on remand are not invalid, and that Defendants (Actavis) infringed each of the asserted claims covering Quillivant XR®.
Early formulations of Methylphenidate (MPH) were immediate release (IR) forms that exhibited clinical benefits within 20 to 60 minutes after dosing, with the benefits lasting 2–4 hours. IR forms of MPH, however, had to be administered multiple times a day, making it challenging for patients to adhere to the dosing schedule. Sustained release (SR) formulations of MPH were thus developed for greater dosing convenience and patient compliance. But those SR formulations had their own shortcoming ─ a slow onset of action.
Tris Pharma, Inc. (Tris) holds the approved New Drug Application for Quillivant XR®. Quillivant XR® is an extended-release MPH formulation comprising both an IR component and a SR component, which achieves a relatively fast therapeutic onset (45-minute) and also a long lasting therapeutic effect (12 hours). When Actavis submitted an Abbreviated New Drug Application (ANDA) to the U.S. Food & Drug Administration (FDA) seeking approval to market generic versions of Quillivant XR®, Tris sued Actavis for infringement of U.S. Patent Nos. 8,465,765 ('765 patent), 8,563,033 ('033 patent), 8,778,390 ('390 patent), 8,956,649 ('649 patent), and 9,040,083 ('083 patent). Following a bench trial, the district court that originally presided over the case found all asserted claims of the patents-in-suit invalid under 35 U.S.C. § 103.
Federal Circuit Vacated and Remanded
Tris appealed the finding of invalidity for 7 of the previously asserted 21 claims, primarily raising three issues:
First, Tris argued that a skilled artisan would not have reasonably expected to successfully combine the claimed single peak PK profile with the claimed 45-minute onset of action and 12-hour duration of effect. (emphasis added).
Second, Tris contended that the district court failed to address why the combination of an early Tmax and a 12-hour duration of effect would have been obvious. (emphasis added).
Third, Tris claimed that the district court mistakenly disregarded Tris's evidence of unexpected results based on a belief that Tris's experts did not compare the claimed invention to the closest prior art. (emphasis added). See Tris Pharma, Inc. v. Actavis Labs. FL, Inc., 755 F. App'x 983, 988–89 (Fed. Cir. 2019).
Discussing each of the three issues, the Federal Circuit found that "the district court failed to make the necessary factual findings and provide sufficient analysis of the parties' arguments to permit effective appellate review." Id. at 989. Thus, the Federal Circuit vacated and remanded the case to the district court. Specifically, the Federal Circuit "invite[d] the district court to reconsider all the evidence of objective indicia in its overall determination of obviousness." Id. at 993.
District Court Decision on Remand
The original district court decision was by Judge Sleet. However, Judge Sleet retired, and the remand was handled by Judge Connolly. The parties submitted post-remand briefs on the fact-finding issues. Based on the records, the district court on remand made further fact-findings with respect to obviousness issues of the asserted claims.
A formulation claim containing all the key limitations, based on claim 10 in the '033 patent but presented in an independent claim form, is as below:
A methylphenidate aqueous extended release oral suspension comprising (1) an immediate release methylphenidate component, (2) a sustained release methylphenidate component, and (3) water, said suspension having a pH of about 4 to about 4.5,
wherein said suspension provides a single mean average plasma concentration peak and a therapeutically effective plasma profile for about 12 hours for methylphenidate, and
wherein the suspension has a pharmacokinetic profile in which the single mean plasma concentration peak for methylphenidate has an area under the curve (AUC)0→∞ of about 114 to about 180 ng-hr/mL, Cmax of about 11 to about 17 ng/mL, Tmax of about 4 to about 5.25 hours, and T1/2 of about 5 to about 7 hours following a single oral administration of said suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults.
wherein said suspension provides a therapeutically effective amount of methylphenidate within 45 minutes after administering of said suspension and a single average plasma concentration peak.
See Claim 10 of the '033 patent.
The district court found that the five claimed properties include: (a) a liquid formulation with (b) a single peak PK profile, (c) an extended duration of effect of about 12 hours, and one or both of (d) an onset of action within 45 minutes, and (e) a Tmax range of about 4 to 5.25 hours.
The following chart indicates whether the asserted claim possesses any of these five properties and shows that claim 10 possessed all five:
See Tris Pharma, 2020 WL 7028456, at *5.
Based on the claimed properties, the district court set forth three combinations relevant to the obviousness analysis:
- a liquid MPH formulation with a single peak, 12-hour duration, and 45-minute onset (four properties);
- a liquid MPH formulation with a single peak, 12-hour duration, and a the claimed Tmax range (four properties); and
- a liquid MPH formulation with a single peak, 12-hour duration, the claimed Tmax range, and 45-minute onset (five properties).
The district court on remand found that "each of the five properties in question was disclosed by at least one prior art reference." Id. at *9. In addition, "other than Scicinski and Focalin XR®, no prior art reference disclosed a combination of more than two of the properties. Scicinski and Focalin XR® each disclosed a combination of three of the properties." Id.
The following chart depicts how many of the five properties were disclosed in each of the seven prior art formulations:
After finding these facts, the district court analyzed each of the three relevant combinations recited above to determine "whether Actavis has demonstrated by clear and convincing evidence that an artisan of ordinary skill would have been motivated to achieve the combination in question and would have had a reasonable expectation of success in doing so." Id. at *5.
(1) Four properties: a liquid MPH formulation with a single peak, 12-hour duration, and 45-minute onset (combination (1))
The court clarified that "the question is whether an artisan of ordinary skill would have been motivated to combine a single peak profile with the formulation covered by the stipulation—i.e., a liquid MPH formulation with a 12-hour duration and 45-minute onset." Id. at *9.
While Actavis's expert, Dr. Staller, opined that an ordinary skilled artisan would have been motivated to develop a product with a plasma-release profile that avoids "peaks and valleys" in order to allow "smooth performance," the record did not fully support that position. Id. Dr. Staller, in fact, previously provided contradictory testimony during cross examination. Id. at *10.
In addition, the court pointed out that Dr. Staller established at trial "that [an artisan of ordinary skill] would not have been concerned about the specific shape of the PK curve—[because] clinical effects [i.e., PD characteristics as opposed to PK characteristics] are what matter." Id. at *10 (emphasis in the original). As such, the district court found, with respect to the claimed single peak, that "[Actavis's] arguments are confusing and conflicting." Id. at *9.
Reasonable Expectation of Success
Additionally, the district court found that the prior art "taught away" from use of a single peak to achieve the combination of clinical effect because "the prior art taught that multiple peaks, achieved by multiple pulses of medication, were required to achieve both a 12-hour duration and 45-minute onset." Id. at *12.
These findings for Tris were further supported by objective evidence of unexpected results and long-felt, unmet need. Id.
Therefore, the district court concluded that Actavis failed to meet its burden of proving by clear and convincing evidence that an ordinary skilled artisan would have been motivated to develop with a reasonable expectation of success the combination (1). Id. at *9.
(2) Four properties: a liquid MPH formulation with a single peak, 12-hour duration, and the claimed Tmax range (combination (2))
The district court found that Actavis did not offer any argument in its post-trial or post-remand briefing on whether an ordinary skilled artisan would have been motivated to combine a liquid MPH formulation with the properties of 12-hour duration, single peak, and the claimed Tmax range. Id. at *13. Accordingly, Actavis failed to establish this issue by clear and convincing evidence. Id.
Reasonable Expectation of Success
Arguing that Scicinski "already disclosed such a formulation," Actavis contended that an ordinary skilled artisan reasonably would have expected to achieve a liquid MPH formula that combined a single peak with 12-hour duration and the claimed Tmax range. Id.
The district court, however, disagreed for the three reasons: first, Actavis did not prove Scicinski discloses a "liquid" formulation; second, Scicinski's formulation was never administered to humans and it was "not a real product"; and third, Scicinski did not offer any explanations about why he thought his formulation could achieve a single peak combined with 12 hour duration and a Tmax of 4 to 5.25 hours. Id.
Thus, the district court concluded that Scicinski would not have provided an ordinary skilled artisan with a reasonable expectation of successfully developing the combination (2). Id.
To prove unexpected results, Tris "relie[d] exclusively on the fact that the commercially available second-generation products do not include a single peak formulation with a 12-hour duration and the claimed Tmax range." Id. at *14. Because of lack of other evidence, the court concluded that "Tris did not prove [to the district court's] satisfaction that the claimed combination was an unexpected result[.]" Id. "Had Tris adduced expert testimony that explained why the achievement of this combination was unexpected . . . [the court] might have reached a different conclusion." Id.
Tris's failure to prove an unexpected result, however, did not change the court's conclusion that Actavis failed to meet its burden for combination (2). Id.
(3) Five properties: a liquid MPH formulation with a single peak, 12-hour duration, the claimed Tmax range, and 45-minute onset (combination (3))
Based on the district court findings on combinations (1) and (2), it necessarily followed that the district court concluded that "Actavis ha[d] not established by clear and convincing evidence that an artisan of ordinary skill would have been motivated to combine with a reasonable expectation of success a liquid MPH formulation [of combination (3)]." Id. at *14.
Based on the findings, the district court concluded as a matter of law that Actavis failed to establish the asserted claims would have been invalid as obvious under §103. Id. at *14-*15.
Following the validity conclusion, the district court briefly discussed the infringement issue. Due to Actavis' stipulations, "the only dispute regarding infringement is whether Actavis' s ANDA products satisfy the single peak limitation." Id. at *15. It was undisputed that Actavis' generic formulation had the same plasma profile as Quillivant®, and experts from both parties testified that the profile shows a single peak. Id. at *16. Accordingly, the court concluded that Actavis is liable for direct, induced, and contributory infringement of the asserted claims as a matter of law under 35 U.S.C. 271 (e)(2)(A). Id. at *16-*17.
This decision is a reminder of the importance of making consistent arguments supported by coherent, credible expert testimony in attacking patent claims in district court litigation or before PTAB. In this case, Actavis's expert made contradictory statements, which harmed credibility. The same reminder would apply to consistent argumentation to establish ex parte patentability, particularly if accompanied by expert evidence.
This case is also a cautionary tale to argue all relevant issues raised by a patent examiner in ex parte proceedings or by an opponent before PTAB or in district courts. The party with the burden of proof could lose an issue when no arguments and/or evidence are offered on the issue.
Following the district court's decision on remand, Actavis filed a Notice of Appeal on December 31, 2020. This case is now back at the Federal Circuit. Stay tuned for further development of this case.
The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.