PTAB

IPR2016-00006

SteadyMed Ltd v. United Therapeutics Corp

Key Events

Petition

Title: Process to Prepare Treprostinil, The Active Ingredient in Remodulin
Brief Description: The ’393 patent discloses product-by-process claims for preparing prostacyclin derivatives, specifically treprostinil. The process involves alkylating a precursor, hydrolyzing the result to form treprostinil acid, and then contacting the acid with a base to form a carboxylate salt for purification.

Prior Art Relied Upon: Phares (International Publication No. WO 2005/007081).
Core Argument for this Ground:
- Prior Art Mapping: Petitioner argued that Phares discloses every element of the claimed product and the process for making it. Phares teaches the synthesis of treprostinil through the same alkylating (step a) and hydrolyzing (step b) steps claimed in the ’393 patent. Crucially, Phares also explicitly discloses contacting the resulting treprostinil acid with the base diethanolamine to form the identical treprostinil diethanolamine salt (step c). Petitioner asserted that Phares discloses making the same stable crystal form ("Form B") of the salt, which has a higher melting point (and thus higher purity) than the product disclosed in the ’393 patent.
- Key Aspects: Because the ’393 patent claims are product-by-process claims, Petitioner contended they are anticipated because Phares discloses the identical product. The process limitations do not confer patentability because they do not result in a product that is materially distinct from the prior art product.

Prior Art Relied Upon: Moriarty (J. Org. Chem. 2004, 1890-1902), in view of either Phares (WO 2005/007081) or Kawakami (Japanese Patent App. No. 56-122328A).
Core Argument for this Ground:
- Prior Art Mapping: Petitioner contended that Moriarty taught the synthesis of treprostinil acid, explicitly disclosing the alkylating (step a) and hydrolyzing (step b) steps of the claimed process. While Moriarty did not disclose the salt formation purification step (step c), this step was well-known. Phares taught purifying treprostinil by forming a diethanolamine salt, and Kawakami taught a general method for purifying other prostacyclin derivatives by forming a crystalline amine salt.
- Motivation to Combine: A person of ordinary skill in the art (POSITA), starting with the synthesis of treprostinil acid taught by Moriarty, would have been motivated to employ a known purification technique to improve the final product's purity and crystallinity. Phares and Kawakami provided clear teachings of using salt formation for exactly this purpose with the same or analogous compounds. A POSITA would combine these teachings to obtain a purer product, which was a predictable outcome.
- Expectation of Success: A POSITA would have had a high expectation of success because combining a known synthesis with a standard purification technique like salt formation is a routine and predictable practice in organic chemistry.

Prior Art Relied Upon: Moriarty (J. Org. Chem. 2004, 1890-1902), Phares (WO 2005/007081) or Kawakami (Japanese Patent App. No. 56-122328A), and Ege (Organic Chemistry Second Edition, 1989).
Core Argument for this Ground:
- Prior Art Mapping: This ground builds upon Ground 2 to address claims reciting the optional step (d): reacting the carboxylate salt with an acid (e.g., HCl) to regenerate the purified free carboxylic acid. Moriarty and Phares/Kawakami established the obviousness of steps (a) through (c). Petitioner argued that Ege, a standard organic chemistry textbook, taught that converting a carboxylate salt back to its corresponding carboxylic acid by treatment with a strong acid is a fundamental and conventional purification technique.
- Motivation to Combine: The motivation for adding step (d) was to isolate the final product in its free acid form after purification via the intermediate salt. This is a common objective in chemical synthesis. Kawakami expressly taught that the purified salt can be easily reverted to the free acid by conventional methods, and Ege provided the textbook example of how to do so.
- Expectation of Success: The expectation of success was exceptionally high, as regenerating a free acid from its salt is a basic, universally known reaction described in introductory chemistry textbooks.

"Product": Petitioner proposed that "product" should be construed as "chemical composition." This construction was argued to be critical because for product-by-process claims, the analysis focuses on the patentability of the final product itself, not the method of making it, unless the process imparts novel structural or functional properties.
"A process comprising": Petitioner proposed this term means "a process that includes, but is not limited to, the recited process steps, and may include, without limitation, any other non-recited steps." This construction, based on the patent's own definition of "comprising," was used to argue that the process was not limited to the exact steps performed by the patent owner, reinforcing that the final product's characteristics are paramount.

Product is Not Materially Distinct from Prior Art: A central theme of the petition was that the product claimed in the ’393 patent is not materially distinct from the treprostinil produced by prior art methods. During prosecution, the Patent Owner overcame a rejection by arguing its process yielded a higher purity product (e.g., 99.8%) than Moriarty (reported as 99.7%, but alleged by Patent Owner to be 99.4%). Petitioner countered that such small differences in purity are insufficient to confer patentability, arguing they are differences in degree, not kind, and fall within the expected experimental error of HPLC measurement techniques. Petitioner further noted that the ’393 patent itself discloses a product with 100.4% purity, indicating an instrumental deviation of at least ±0.4%.

Petitioner requested institution of an inter partes review and cancellation of claims 1-22 of the ’393 patent as unpatentable.