PTAB Invalidates United Therapeutics Patent Relating to the Hypertension Drug - Tyvaso®

Holding:

In Liquidia Techs., Inc. v. United Therapeutics Corp.,[1] the Patent Trial and Appeal Board (“the PTAB”) held all challenged claims of U.S. Patent No. 10,716,793 (“the ’793 patent”) unpatentable under 35 U.S.C. § 103.

Background:

Liqudia challenged claims 1-8 of the ’793 patent. The ’793 patent relates to therapeutic methods involving administering high doses of treprostinil using a metered dose inhaler over a short period of time. Treprostinil is a prostacyclin analog used to treat pulmonary hypertension. The ’793 patent covered United Therapeutic’s pulmonary hypertension treatment, Tyvaso®.

Representative Claim 1

1. 1. A method of treating pulmonary hypertension comprising administering by inhalation to a human suffering from pulmonary hypertension a therapeutically effective single event dose of a formulation comprising Treprostinil or a pharmaceutically acceptable salt thereof with an inhalation device, wherein the therapeutically effective single event dose comprises from 15 micrograms to 90 micrograms of Treprostinil or a pharmaceutically acceptable salt thereof delivered in 1 to 3 breaths.

Obviousness

Liquidia asserted that claims 1-8 of the ’793 patent were unpatentable as obvious. To support this assertion, Liquidia put forth numerous prior art references. The PTAB relied on three: (1) U.S. Patent No. 6,521,212 (“the ’212 patent”), (2) Voswinckel JESC, and (3) Voswinckel JAHA.[2]

The ’212 patent teaches the use of a benzidine prostaglandin, UT-15, to treat mammals with pulmonary hypertension. Liquidia, at *6. The specification teaches superior results when the drug was administered by inhalation compared to parentally administered UT-15. UT-15 is also known as “Remodulin” or “Treprostinil salt.” Id. Voswinckel JESC is a study that investigates “the acute hemodynamic response to inhaled treprostinil.” Id. at *7. The study concluded that 16 µg/mL was the maximum concentration of the drug that could be delivered without adverse effects. Id. at *7-8. Voswinckel JAHA discusses a study of treating 17 patients with severe pulmonary hypertension with Treprostinil inhalations. Id. at *8. Each inhalation involved 3 single breaths using a nebulizer and a 600 µg/ml Treprostinil solution. Id.

United argued that the combination of references failed to teach or suggest delivering a dose of treprostinil within the claimed 15-90 micrograms of treprostinil in a single dosing event of one to three breaths. Id. at *12. United did not dispute that the cited prior art taught the remaining features of claim 1.

Liquidia argued that although the cited prior art did not disclose the exact dose of treprostinil used, the dosage could be calculated based on the information disclosed within the prior art references. Liquidia did this in three separate ways: (1) relying on Voswinckel JESC’s solution concentrations and solution volumes taught by specific examples, (2) relying on Voswinckel JESC’s solution concentrations and solution volumes normally delivered according to the testimony of the petitioner’s declarants, and (3) relying on the ’212 patent’s conversion from an intravascular treprostinil dose to an equivalent inhaled dose. Id. at *14. According to Liquidia, all three calculation methods resulted in a single event dose within the claimed 15-90 micrograms of treprostinil. Id. at *14-15.

Without providing much explanation, the PTAB did not agree with Liquidia’s first and third calculation methods and stated that they did not demonstrate that the prior art taught the claimed dosage range. Id. at *15. However, the Board stated that the second calculation method did demonstrate that the art taught the claimed dosage range. Id. Voswinckel JESC disclosed treating patients with inhaled treprostinil for 6 minutes in concentrations of 16, 32, 48, and 64 µg/ml. Id. The study did not disclose the amount of solution administered, which is necessary to calculate the dose. Liquidia relied on the testimonies of two experts to provide this amount. Id. The experts testified that the nebulizers used in the study typically used between 1 and 5 mL of solution. Id. Liquidia then multiplied each of the concentrations of treprostinil disclosed in the study by 1 to 5 mL of solution based on expert testimony and found that each calculated dose fell within the claimed range. Id. at *15-16.  

United countered that the volumes of solutions disclosed by the expert testimony did not account for a range of factors that prevents the entire solution from being nebulized and then inhaled by the patient. Id. at *16. The PTAB dismissed this counterargument by pointing to portions of the expert testimony that explained how at least 1 mL of solution would nebulize and that it was rare to administer a dose with a solution as low as 1 mL. Id. at *17. Accordingly, one skilled in the art would have understood the volume of solution nebulized to be at least 1 mL. Id.

The PTAB rejected United’s arguments that adverse side effects would have discouraged one of ordinary skill in the art from modifying the asserted references. “[C]onsiderable evidence,” in the form of expert testimony supported the position that “a person of ordinary skill in the art would not have avoided increasing Voswinckel JESC’s dose due to the side effects reported in Voswinckel JESC.” Id. at *20.

The PTAB then turned to United’s arguments relating to objective evidence of unexpected results, copying, and long-felt unmet need. The PTAB rejected all three arguments.

The PTAB held that the evidence on record failed to establish unexpected results. United argued that the challenged claims unexpectedly achieved a therapeutically effective dose that was well tolerated even though such high doses were known to produce dose-limiting side effects. The PTAB stated that known dose-limiting side effects referenced in United’s argument were from treatments using different drugs or intravenous treprostinil, not inhaled treprostinil. Furthermore, United failed to allege that the results were unexpected over the ’212 patent, Voswinckel JESC, or Voswinckel JAHA. Id. at *23. Accordingly, the PTAB held the evidence failed to establish unexpected results over the closest prior art. Id.

The PTAB next held that United failed to show that Liquidia copied the challenged claims. Proof of copying requires “actual evidence of copying efforts as opposed to mere allegations regarding similarities between the accused product and patent.”[3] Fox Factory, Inc. v. SRAM, LLC, 944 F.3d 1366, 1373 (Fed. Cir. 2019) requires both a showing that the product in question embodies the claims and a showing that the product in question is coextensive with the [c]laims.” Id. at *24. United argued that Liquidia copied United’s product that embodies the claims (Tyvaso®), when Liquidia developed LIQ861. But the evidence on record did not show Liqudia copied anything that wasn’t already in the prior art. Id. at *27. Having similar properties that were not even recited as claim limitations does not show sufficient nexus to the claimed invention and “is, at most, very weak evidence of copying as to the claims at issue here.” Id.

Lastly, the PTAB rejected the argument that the challenged claims satisfied a long-felt unmet need in the treatment of pulmonary hypertension. United’s argument highlighted the approval of inhaled treprostinil as the first treatment for pulmonary hypertension associated with interstitial lung disease. Id. at *28. The PTAB rejected this argument because the challenged claims did not cover treating pulmonary hypertension associated with interstitial lung disease. Id. at *29. The PTAB also rejected United’s argument that the challenged claims avoided the dosing problems and side effects associated with a similar drug, Ventavis®, because United raised this argument for the first time in their sur-reply. Id. at *28.

In conclusion, the PTAB held that Liquidia showed by a preponderance of the evidence that the combination of the ’212 patent, Vosweinckel JESC, and Voswinckel JAHA teaches or suggests the subject matter of claims 1-8, and one of ordinary skill in the art would have had a reason to combine the teachings of the ’212 patent, Voswinckel JESC, and Voswinckel JAHA with a reasonable expectation of success in doing so in order to arrive at the invention of the challenged claims. Id. at *35. Evidence of objective indicia of nonobviousness, copying, and a long-felt but unmet need was insufficient to overcome the prima facie case of obviousness. Accordingly, the PTAB struck down claims 1-8 of the ’793 patent as obvious under 35 U.S.C. § 103.

Takeaways

Liquidia v United serves as a reminder that patent challengers can use the implicit teaching of a prior art reference to cover certain claimed features. In this case, none of the cited prior art references explicitly disclosed the claimed dosage range nor provided the amount of solution used with the recited concentration of treprostinil needed to calculate the dosage. The PTAB allowed Liquidia to rely on solution values disclosed by experts to calculate the dosage range and eventually successfully knock out the claims.

Objective evidence may be very valuable, but in order to rebut a prima facie case of obviousness, the patent owner must show a nexus between the evidence and the merits of the claimed invention. Take the time to fully develop the nexus between objective evidence and the claimed invention to get the most from such evidence. 

Furthermore, this IPR should serve as a cautionary reminder to avoid introducing new arguments in a sur-reply that are not responsive to arguments made in a corresponding reply. Here, the PTAB rejected one of United’s arguments relating to a long-felt unmet need because United presented this argument for the first time in its sur-reply and not in response to any arguments Liquidia made in its corresponding reply.

[1] IPR2021-00406, Paper 78 (P.T.A.B. July 19, 2022).

[2] United Therapeutics disputed the “public accessibility” of Voswinckel JESC and Voswinckel JAHA, but the PTAB agreed with Liquidia that the references qualified as printed publications.

[3] Liquid, Inc. v. L’Oreal USA, Inc., 941 F.3d 1133, 1137-38 (Fed. Cir. 2019).