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PTAB Invalidates United Therapeutics Patent Relating To The Hypertension Drug – Tyvaso® – Patent



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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. 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.

Footnotes

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).

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.



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