On January 3, 2018, Momenta and Mylan announced their development plan for a proposed biosimilar to Regeneron’s Eylea® whose active ingredient is aflibercept, a recombinant fusion protein. Eylea® was first approved as an intravitreal injection indicted for the treatment of patients with neovascular (wet) age-related macular degeneration. Eylea® is now also indicated for macular edema following retinal vein occlusion, diabetic macular edema, and diabetic retinopathy in patients with diabetic macular edema.
Momenta and Mylan’s announcement indicated that a pivotal clinical trial — a comparative study of the biosimilar and Eylea for diabetic macular edema — is planned to begin in the first half of 2018. While at least one other company, Formycon, has indicated that it is in the process of developing an Eylea® biosimilar, that product appears to still be in a preclinical phase. As such, Momenta and Mylan’s pivotal trial indicates that their development is much further along, and as such, their product is likely to be the spearhead in any attacks on Regeneron’s patent protections.
As of the writing of this article, there have not yet been any challenges, either through litigation or through the PTAB, to Regeneron’s patents that may cover aflibercept. Assuming that Momenta and Mylan’s clinical trial goes smoothly, this may not be the case for long.
Regeneron holds several active patents that could prevent the entry of a biosimilar to Eylea® through 2023. For example, U.S. Patent No. 7,070,959, “Modified Chimeric Polypeptides with Improved Pharmacokinetic Properties,” contains claims covering nucleic acid molecules encoding fusion proteins for binding vascular endothelial growth factor (VEGF) which may read on aflibercept. This patent was filed May 23, 2000, and has received 1,119 days of extension time under 35 USC § 156, pushing the expiration date into June 2023.
Several other patents, including U.S. Patent Nos. 7,303,746; 7,303,747; and 7,306,799 expire slightly earlier due to not being extended under § 156. These specifically named patents cover methods of treating eye disorders by administering VEGF-binding fusion polypeptides, which may read on aflibercept, but other patents with similar early 2020s expiration dates cover the actual fusion protein and methods of inhibiting tumor growth by administering the protein.
Beyond the above patents, which may require attempts at invalidation in order for a biosimilar to Eylea® to come to the market prior to 2023, Regeneron holds more specific patents which read on the currently approved Eylea® formulation. For example, claim 1 of U.S. Patent No. 7,608,261 covers formulations of a certain concentration of VEGF antagonist with certain concentrations of compounds including polysorbate, sodium phosphate, and sodium or potassium chloride. All of the compounds and ranges required in the claim are found in the approved product. Further claims require sucrose or pH, also at levels in the approved product. U.S. Patent No. 8,092,803 similarly claims the ingredients of the Eylea® product, further claiming a stability requirement. These claims, compared to the method of treatment claims or those claiming the protein or its method of production, potentially present more opportunity for pharmaceutical companies to design around them.
Ultimately, without invalidating or designing around claims, a biosimilar to Eylea® is likely still more than 5 years away. The patent landscape covering the product will require careful consideration for any potential biosimilar, and with Mylan and Momenta soon to initiate a pivotal clinical trial, they have almost certainly already been thoroughly reviewed. With U.S. net sales of Eylea® of more than $3 billion in 2016 and reported increases in quarterly figures in 2017, Regeneron is sure to vigorously defend its patent portfolio covering the product.