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Two Asserted Lantus Patents Cancelled—Commercial Success Evidence Insufficient Because of Blocking Patents

On December 12, 2018, the U.S. Patent and Trademark Appeal Board (PTAB) ruled in favor of Mylan in its inter partes review (IPR) proceedings. It found all claims of Sanofi’s Lantus formulation patents (U.S. Patent Nos. 7,476,652 and 7,713,930) unpatentable as obvious on numerous grounds, and held that despite over $2 billion in annual sales, commercial success evidence was insufficient and weak in light of Sanofi’s blocking patents.

Lantus (insulin glargine 100 Units/mL) is a long-acting insulin used to treat adults with type 2 diabetes and adults and pediatric patients with type 1 diabetes for the control of high blood sugar. Sanofi sells the product in vials (Lantus) and as a disposable injection pen (Lantus SoloSTAR®).

Mylan filed a 505(b)(2) New Drug Application (NDA) for generic versions of Lantus and Lantus SoloSTAR, co-developed with Biocon, and it is under active review by the U.S. Food and Drug Administration.  In October 2017, Sanofi initiated patent infringement litigation against Mylan’s NDA in the United States District Court for the District of New Jersey that includes these two formulation patents listed as covering Lantus, as well as other patents listed as covering the Lantus SoloSTAR injection pen. On June 9, 2017, Mylan filed two IPR petitions challenging Sanofi-Aventis’s U.S. Patent No. 7,476,652 (IPR2017-01528) and U.S. Patent No. 7,713,930 (IPR2017-01526), related to Sanofi’s Lantus® (insulin glargine injection).  Both petitions were instituted on December 13, 2017.  On September 10, 2018, Mylan filed ten additional IPR petitions challenging five additional Sanofi patents related to pen-type injectors, U.S. Patent No. 8,603,044 (IPR2018-01675 and IPR2018-01676); U.S. Patent No. 8,679,069 (IPR2018-01670); U.S. Patent No. 8,992,486 (IPR2018-01677[1], IPR2018-01678, IPR2018-01696, IPR2019-00122); U.S. Patent No. 9,526,844 (IPR2018-01680, IPR2018-01682 and IPR2018-01696); and U.S. Patent No. 9,604,008 (IPR2018-01684).  None of these additional petitions has been instituted to date.

With regard to U.S. Patent No. 7,476,652 (“the ’652 patent”), the PTAB found all claims to be unpatentable based on six grounds of invalidity.  The claims of the ’652 patent are principally directed to the combination of insulin glargine with at least one surfactant selected from polysorbates and poloxamers in an acidic formulation.  With regard to U.S. Patent No. 7,713,930 (“the ’930 patent”), the PTAB found all claims to be unpatentable based on eight grounds of invalidity.  The claims of the ’930 patent are principally directed to the combination of insulin glargine with at least one surfactant selected from esters and ethers of polyhydric alcohols in an acidic formulation.  The patents’ specification asserted that the applicants had surprisingly found that adding surfactants to the insulin solution or formulation increases the stability of acidic insulin preparations that resist aggregation for several months under temperature stress.

Given that it was undisputed that insulin glargine was known in the prior art, e.g., as evidenced by the label of the earlier marketed Lantus product, and Mylan submitted evidence that multiple prior art publications suggested adding the claimed surfactants to insulin glargine, the PTAB found that, by a preponderance of evidence, the various combinations of prior art references taught all of the elements of the ’652 patent claims.  The PTAB found that because the ’652 and ’930 patent specifications explained that insulins had a known tendency to aggregate in the presence of hydrophobic surfaces that come into contact with insulin formulations, and because the prior art taught many examples of successful stabilization of insulins and other peptides against aggregation by adding nonionic surfactants, a person of ordinary skill in the art would have had a reasonable expectation of success.  The PTAB dismissed Patent Owner’s arguments regarding the unpredictability of protein formulations and potential negative consequences in view of the many successful examples of nonionic surfactants helping stabilize other insulins and proteins.

With regard to Sanofi’s proffered evidence of U.S. sales growing from $1.1 billion at its introduction to approximately $2.6 billion in 2017, which accounted for approximately 33% of all sales of long-acting injectable insulin and/or insulin analog therapies, the PTAB noted that Sanofi failed to account for the blocking patents covering the insulin glargine compound, which would have blocked competitors from commercializing a product that embodied “the same technologies” and “provided strong disincentives for others to develop and commercialize” the technology described in the ‘652 patent.  The PTAB noted that Sanofi’s commercial success expert did not investigate whether there was a blocking patent, much less account for it in his analysis.  Following the Federal Circuit’s line of pharmaceutical cases finding that commercial success of FDA-approved products was of minimal probative value and insufficient to justify a conclusion of non-obviousness when blocking patents blocked competition, most recently articulated in Acorda Therapeutics, Inc. v. Roxane Labs., Inc., 903 F.3d 1310, 1339 (Fed. Cir. 2018)[2], the PTAB held that the evidence of commercial success was weak in light of Sanofi’s blocking patents precluding others from market entry prior to the patents covering insulin glargine expiring.

Accordingly, the PTAB concluded that Mylan had satisfied its burden of demonstrating, by a preponderance of the evidence, that each claim of the ’652 and ’930 patents would have been obvious over the various combinations of prior art references.  Given the PTAB’s recognition that Sanofi presented evidence of commercial success while ignoring the existence of its blocking patents, it will be interesting to see if Sanofi applies a different strategy in presenting objective indicia of non-obviousness in defending against the ten additional IPR petitions.

[1] Dismissed in favor of filing new petition number IPR2019-00122 to correct a clerical error.

[2] See also Merck & Co. v. Teva Pharmaceuticals USA, Inc., 395 F.3d 1364, 1377 (Fed. Cir. 2005)(patent barring entry supported a finding commercial success evidence was weak); Galderma Labs, LP v. Tolmar, Inc., 737 F.3d 731, 740–41 (Fed. Cir. 2013) (finding “[w]here ‘market entry by others was precluded due to blocking patents, the inference of non-obviousness of the asserted claims, from evidence of commercial success, is weak”).