Treprostinil – USA

Treprostinil – USA

On Aug. 31, 2022, Delaware court found one patent invalid and other valid and infringed in Tyvaso® litigation.

 

United Therapeutics Corporation (“UTC”) sued Liquidia Technologies, Inc. for infringement of US 9,593,066; and US 10,716,793 because Liquidia filed NDA (LIQ861 / Yutrepia™) for treprostinil with P-IV certification. Tyvaso®, is an inhaled solution formulation of treprostinil approved for the treatment of pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease. And LIQ861 is a dry powder formulation of treprostinil sodium.

 

US’066 patent:

Infringement

Liquidia only disputes infringement of the impurities limitations in claims 1, 2, and 3. Claim 1 recites “providing a starting batch of treprostinil having one or more impurities resulting from prior alkylation and hydrolysis steps . . . wherein said alkylation is alkylation of benzindene triol.” As a preliminary issue, the parties dispute the proper construction of “impurities resulting from prior alkylation and hydrolysis steps.” Liquidia argues that the claimed
impurities must result from alkylation and hydrolysis of “BTO,” not the alkylation and hydrolysis of any compound that may be present in the reaction vessel. UTC argues that the claimed impurities encompass any impurities generated during the process steps of alkylating and hydrolyzing a batch of BTO (including from side reactions, impurities in reagents, solvents, or starting materials). Court agreed with UTC and said that the POSA would understand that any impurities generated during the alkylation and hydrolysis steps (including from side reactions) are within the scope of the claim. Based on studies conducted by UTC expert, court concluded that UTC has
proven that Liquidia will meet the impurities limitations of claim 1. Court however found non-infringement with respect to claims 6, 8 and 9 (storage of treprostinil salt at ambient temperature) because Liquidia’s product was not stored at ambient temperature.

Invalidity

Claims 1, 2, 3, 6, and 9 are product-by-process claims, which claim a “pharmaceutical composition(/product] comprising treprostinil or a pharmaceutically acceptable salt thereof.” Liquidia argues that these claims are invalid because the claimed product is the same product previously disclosed in the prior art by the ‘2004 Moriarty’ publication. The 2004 article published in the Journal of Organic Chemistry by Robert M. Moriarty et al. , entitled, in relevant part, “Synthesis of UT-15 (Treprostinil)” (“Moriarty”), teaches the synthesis of treprostinil free acid by alkylation and hydrolysis of BTO. UTC argues that Moriarty cannot invalidate the product-by-process claims because it only discloses treprostinil, not a “pharmaceutical composition[/product] comprising treprostinil.” Court, however said that the ‘ 066 patent, however, makes no distinction between treprostinil and a pharmaceutical composition/product comprising treprostinil. The specification only describes the steps for synthesizing treprostinil or treprostinil salt. Moreover, No UTC expert or fact witness rebutted Dr. Winkler’ s opinions or provided testimony
identifying any structural or functional difference between the Moriarty treprostinil free acid and the claimed treprostinil free acid product/composition. Liquidia has shown by clear and convincing evidence that the claimed treprostinil product is functionally and structurally the same as the UT-15 treprostinil disclosed in Moriarty. Thus, claims 1, 2, 3, 6, and 9 of the ‘ 066 patent are invalid as anticipated.

 

US’793 patent:

Infringement

Claim 1 of US’793 patent relates to method of treating pulmonary hypertension by administering a therapeutically effective single event dose of a formulation comprising treprostinil. Liquidia argued that UTC has failed to prove that LIQ861 is administered in “a therapeutically effective single event dose,” as required by claim 1. Liquidia argues that claim 1 is limited to one single event dose per day rather than multiple doses per day. Court disagreed and said that Liquidia’ s argument lacks merit. The term “single” modifies “event,” not “dose.” The experts agree that “single event dose” refers to a dose that is delivered in a single treatment session (i.e., a “single event”), including a session that involves multiple breaths. The claim language does not limit the number of single event doses per day. The proposed LIQ861 label states that LIQ861 “should be administered 3 to 5 times per day.” Each administration is a single event dose. Therefore, LIQ861 will infringe claims 1, 4, 6, 7, and 8 of the ‘793 patent.

Invalidity

Liquidia argued that the asserted claims are invalid under lack of written description support and enablement. Liquidia asserted that the phrase “treating pulmonary hypertension” encompasses treating all five WHO groups of pulmonary hypertension (“PH”) and specification discloses only subpart of it. UTC argued that a POSA would understand claim 1 to be limited to “treating varieties of PH where using a vasodilator addresses the cause of the disease.” Court said that the specification expressly includes all five Groups when describing “pulmonary hypertension.” The ‘793 patent describes how administering inhaled treprostinil targets the lungs, dilates
the blood vessels, and reduces blood pressure. Accordingly, these disclosures “reasonably convey to those skilled in the art that the inventor had possession” of the full scope of claims and also there is no undue experimentation required. Therefore, Liquidia has failed to prove by clear and convincing evidence that claims 1, 4, 6, 7, and 8 of the ‘ 793 patent are invalid.

 

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