Patent based on dose of diabetes drug ruled invalid.

Last month the Federal Circuit affirmed the New Jersey District Court’s decision to invalidate two key Boehringer Ingelheim patents for Tradjenta® (linagliptin), a drug used to reduce glucose levels in Type II Diabetes. Boehringer Ingelheim Pharm. v. HEC Pharm. Co., No. 15-cv-5982 (PGS)(TJB), 2017 U.S. Dist. LEXIS 2543 (D.N.J. Jan. 4, 2017).  The patents at issue – U.S. Patent Nos. 8,673,927 (the ‘927 patent) and 9,173,859 (the ‘859 patent) – were based on the 5 mg dose of Tradjenta® approved by the U.S. FDA.

Claim 14 of the ‘859 patent is illustrative:

14. An oral tablet formulation comprising 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine in an amount of 2.5 mg or 5 mg optionally in combination with metformin, and a pharmaceutically acceptable carrier or diluent.

The prior art essentially consisted of Boehringer Ingelheim’s earlier compound patent for linagliptin.  The District Court held, and the Federal Circuit affirmed, that the asserted claims of Boehringer Ingelheim’s ‘927 and ‘859 patents were invalid based on obviousness-type double patenting over U.S. Patent No. 8,178,541 (the ‘541 patent) and obviousness over the U.S. Patent Application Publication No. 2004/0097510 (the ‘510 publication) (the priority application with the same specification as the ‘541 patent).  Both of these patent documents disclosed linagliptin and its use along with many other compounds to treat type-II diabetes in doses ranging from 1 to 100 mg.

The District Court held that the asserted patents were invalid because the 2.5 and 5 mg doses claimed in the '927 and '859 patents would have been arrived at by routine experimentation with a reasonable expectation of success based on the teachings of Boehringer Ingelheim's earlier ‘541 patent and the ‘510 publication.  As support for its finding of routine experimentation, the District Court cited evidence of the normal pathway companies use when developing drugs for FDA approval, and FDA policies governing that approval.  In particular, the District Court cited evidence that:

  • Dose ranging studies are “conducted starting with a low dose, and sequentially moving through increasing doses.”
  • “[A] person of ordinary skill in the art would understand the general guidelines that were issued by the FDA would include . . . dose-ranging studies.”
  • Linagliptin is one of many compounds disclosed in the ‘541 patent, but it also has one of the lowest IC50 values; a drug developer would be guided by that information to look at the lower end of the 1-100 mg dose range.
  • “Regulators expect you to define the lowest maximum therapeutic dose.”

One wonders if these patents would have survived if Boehringer had not disclosed such a narrow range of doses, or the IC50 of linagliptin, in its earlier compound patent.

The decision imposes a terrible dilemma on drug developers and how much information they should include in their compound patent.  The question naturally arises: Are patent attorneys, in their zeal to strengthen their clients’ compound patents by including this level of detail, unnecessarily compromising their ability to file new patent applications for new discoveries as drug development proceeds?  If any of our readers has developed a set of best practices for resolving this dilemma we would be glad to share it with our readers.