Purity patents might be the most overlooked patent in the arsenal of innovative drug companies. All drug companies – even generic drug companies – must meet the same FDA purity standards, and considerable work is often needed to purify an NCE (new chemical entity) to these standards. Moreover, because the original synthesis of the NCE, as reported in the NCE patent, often results in a purity well below FDA’s purity standards, subsequent work to purify the compound can give rise to a novel and patentable invention based on the purity of the compound.
Section 2144.VII of the USPTO’s Manual of Patent Examining Procedure addresses purity patents as follows:
Factors to be considered in determining whether a purified form of an old product is obvious over the prior art include whether the claimed chemical compound or composition has the same utility as closely related materials in the prior art, and whether the prior art suggests the particular form or structure of the claimed material or suitable methods of obtaining that form or structure. In re Cofer, 354 F.2d 664, 148 USPQ 268 (CCPA 1966) (Claims to the free-flowing crystalline form of a compound were held unobvious over references disclosing the viscous liquid form of the same compound because the prior art of record did not suggest the claimed compound in crystalline form or how to obtain such crystals.).
While the Patent Office is certainly willing to grant purity patents, the courts are not always very willing to enforce them. In 2007, for example, the Federal Circuit struck down King Pharmaceutical’s enantiomeric purity patent for Altace® (Ramipril) in Aventis Pharma Deutschland GmbH v. Lupin, Ltd., 499 F.3d 1293 (Fed. Cir. 2007). More recently, the Federal Circuit affirmed a New York trial court’s decision to strike down Purdue Pharma’s patent covering a low-ABUK impurity version of oxycodone, the active ingredient in Oxycontin®. Purdue Pharma L.P. v. Teva Pharms., USA, Inc., 994 F. Supp. 2d 367 (S.D.N.Y. Jan. 14, 2014).
Given this checkered history for purity patents, it was refreshing to see a Federal Circuit decision earlier this month that affirmed the validity of Mylan’s purity patent in Mylan Institutional Llc v. Aurobindo Pharma, 2017 U.S. App. LEXIS 8792 (“Mylan”). Mylan involved U.S. Patent 9,353,050 (“the ‘050 patent”), which claimed a highly pure form of isosulfan blue, a compound used to map lymph nodes by oncologists when attempting to learn whether a cancer has metastasized.
Covidien Ltd., the original distributor of isosulfan blue, had difficulties with the drug’s purity from the moment FDA first approved the drug in 1981. Covidien changed manufacturers several times, was unable at times to supply its customers, and even approached FDA for advice on handling the issue. The inventors of the ‘050 patent recognized the difficulties Covidien was having and in 2003 formed Apicore to develop a better method of synthesis and purer form of isosulfan blue. They eventually succeeded, entered into a distribution agreement with Mylan International (“Mylan”) and, based on the method of synthesis they developed, secured patents that covered both the method of synthesis and purity of the drug. Claim 1 of the ‘050 patent recites:
1. A compound [isosulfan blue] sodium salt having a purity of at least 99.0% by HPLC.
Mylan secured FDA approval for the drug in 2012 and achieved instant commercial success because of the supply disruptions Covidien was suffering. Mylan, however, had a big problem. Because Mylan’s product was approved as a generic version of Covidien’s isosulfan blue under Section 505(j) of the FD&C Act, Mylan could not list Apicore’s patents in the Orange Book. As a consequence, Aurobindo did not send Mylan the paragraph IV patent certification notice normally sent under Hatch Waxman and, by the time Mylan learned of Aurobindo’s approval in March 2016, Aurobindo was already making huge inroads in the marketplace.
Mylan did eventually stop Aurobindo, but not until February 2017, when a federal judge in the Eastern District of Texas entered a preliminary injunction against Aurobindo’s continued distribution of the drug. The Federal Circuit affirmed the preliminary injunction on May 19, 2017
The validity of the '050 purity patent was one of the central issues in the case, and this issue turned on two critical pieces of evidence. The first was a certificate of analysis produced by Sigma Aldrich, which allegedly showed that Sigma Aldrich had manufactured and sold a 100% pure version of the compound as a USP reference standard. The Court rejected this evidence, however, because the certificate of analysis contradicted other documents produced by Sigma Aldrich which showed that the lot in question had a purity of from 83% to 95%.
The second piece of evidence was a more general HPLC reference teaching that triarylamine dyes, a class of compounds that includes isosulfan blue, could be purified via HPLC to purities ranging from 96% to 98%. According to Aurobindo, it would have been obvious to adapt these prior art HPLC methods to isosulfan blue to obtain a purity exceeding 99%.
This is the point where Mylan’s case came together. Mylan cited its own method of synthesis patent and pointed out to the Court that before its process was invented, isosulfan blue was produced in crude batches that contained large amounts of compounds closely related to isosulfan blue. Mylan argued that these closely related compounds could not easily have been removed by HPLC, and certainly could not have been removed without a substantial loss of yield. It took Apicore to develop a patentable synthetic process that did not generate these closely related compounds before HPLC purification could even be considered to purify the compound at levels approaching 99%. In the words of MPEP 2144.VII, the prior art did not suggest “the particular form or structure of the claimed material or suitable methods of obtaining that form or structure.”
Which brings us back to the NCE company. An NCE’s purification hurdles will certainly not be as well publicized as those surrounding isosulfan blue, but every company confronts some challenges before it attains the purity necessary for FDA approval. Did the company need to develop a new route of synthesis to avoid producing closely related compounds, like Apicore did? Did the company need to develop a novel crystallization technique? Can the company secure a patent for its improved method of synthesis? These are all questions a patent attorney must be vigilant to ask when evaluating the possibility of a purity patent.
Congratulations, by the way, to David Steuer and his team at Wilson Sonsini, who did an excellent job presenting Mylan’s case and pushing it through so quickly to a preliminary injunction. It’s nice to see such expertise coming out of the west coast!
