Can Regeneron defeat the PGR challenging its formulation patent for Eylea HD?
Zachary Silbersher
Regeneron perpetuated Eylea as a blockbuster by using its patents to block entry of lower-cost generics. When those patents neared expiration, Regeneron launched a new formulation covered by at least one patent, namely, Eylea HD. One of those patent only recently issued, but has already been challenged by at least one prospective generic in a Post-Grant Review (PGR) proceeding before the Patent Trial and Appeal Board of the Patent Office (PTAB). Will that challenge succeed?
Eylea® (aflibercept) is a vascular endothelial growth factor (VEGF) inhibitor indicated for treatment of certain angiogenic eye disorders. The drug is administered through an intravitreal injection. Eye injections are problematic because they are uncomfortable for patients and carry the risk of serious side effects dure to injection site reactions.
Eylea’s original formulation was covered by numerous patents. With those patents expiring, Regeneron launched in 2023 a new formulation for Eylea, namely, Eylea HD, that included a higher concentration of aflibercept. Whereas Eylea’s original formulation included 2mg of administered dose of aflibercept, Eylea HD included 8mg of aflibercept. In 2021, before launching Eylea HD, Regeneron filed for a patent directed to a higher concentration of aflibercept. The upside of a higher concentration dose would be that patients would be required to endure fewer eye injections.
The Patent Office issued the patent, U.S. Patent No. 12,168,036, in December 2024. The patent is generally directed to a method of treating an angiogenic eye disorder by administering at least 8mg of a VEGF receptor fusion protein such as aflibercept.
In September 2025, Alvotech filed a PGR proceeding seeking to the invalidate the ‘036 patent. A PGR proceeding is similar to an inter partes review (IPR) proceeding, but with a few important differences. Both proceedings are filed before the PTAB and challenge the validity of an issued patent. However, whereas IPR proceedings may be filed at any time during the life of a patent, PGR proceedings may only be filed within nine months after a patent issues. In addition, whereas IPR proceedings are generally limited to making obviousness arguments based upon prior art, PGR proceedings permit additional invalidity arguments based upon, for example, lack of written description or enablement. In short, PGR proceedings can only be filed shortly after a patent issues, but they afford a wider breath of arguments to invalidate the patent.
Alvotech’s PGR is fairly straightforward. It argues that increasing the dose concentration for aflibercept from 2mg to 8mg was obvious. Intravitreal injections (eye injections) are uncomfortable, inconvenient and carry great risks for patients, including injection site reactions or potential blindness. Given that, a formulation that can reduce the frequency of eye injections was nothing inventive. Indeed, Alvotech claims that Regeneron itself published literature disclosing upwards of 10mg. Alvotech also argues that, even though Regeneron claims that the higher dose formulation includes a higher concentration component that purportedly solved a viscosity problem, the patent claims themselves do not recite or require this alleged solution.
In response, Regeneron argues that formulating a higher concentration dosage for aflibercept was not obvious at all. Indeed, increasing the concentration of liquid formulated antibodies face challenges of increased protein aggregation and viscosity. Because Eylea must be administered through a narrow-bore needle that creates shear stress, higher concentration doses could lead to protein aggregation and come out of solution. That in turn can negatively impact protein potency as well as storage stability. Regeneron claims that the ‘036 patent embodies its inventive formulation for overcoming these challenges to develop a stable, high-concentration, low-viscosity aflibercept formulation.
Regeneron claims that it specifically achieved its higher-concentration formulation from at least three constraints on the 8mg dosage of aflibercept: (i) the dosage is administered in a volume not greater than 100 microliters; (ii) at a concentration of at least 100 mg/ml; and (iii) with a viscosity of about 5-15 centiPoise (cP) at 20° C.
Alvotech wages five separate “Grounds” to challenge the claims of the ‘036 patent. The patent has 38 claims. (The “claims” are the numbered paragraphs at the end of the patent that, quite literally, are the purported “inventions” that are covered, or “claimed,” by the patent.) In Grounds 1 and 2, Alvotech relies upon prior art to challenge claims 1 and 4-38. In Ground 3, Alvotech argues that all 38 claims are invalid for a lack of written description. Grounds 4 and 5 specifically challenge claims 2 and 3 based upon prior art.
Alvotech’s prior art challenges potentially rest upon shaky ground. One of Alvotech’s goals is to prove that it was obvious to administer a higher dosage (8mg) of aflibercept. To do so, Alvotech must identify prior art, such as prior scientific literature, that teaches it would be generally safe and effective to administer the drug at a higher 8mg dose. Alvotech’s expert relies upon an Australian label for Eylea, but the label does not explicitly say that administering the drug at 8mg doses would be safe and effective. Instead, Alvotech relies upon the label’s Overdosage section that includes warnings about administering the drug at this high dosage.
Another one of Alvotech’s goals is to prove that it was obvious to administer aflibercept at higher concentrations as recited in the patent, namely proving a stable intravitreal aflibercept formulation of roughly 103-126 mg/ml. To do so, Alvotech relies upon prior art that appears to teach stable formulations at concentrations of only 40 to 50 mg/ml. That, however, is arguably far from identifying prior art that teaches concentrations over 100 mg/ml as required by the patent.
Together, these two deficiencies in the prior art relied upon by Alvotech could undermine its entire arguments in Grounds 1 and 2 of its PGR petition. Worse, however, is that Alvotech’s experts did not appear to fare too well under deposition. Regeneron identifies numerous instances where it appears to have solicited fairly damaging admissions from Alvotech’s experts that the prior art did not cleanly teach that 8mg was safe or that concentrations over 100 mg/ml could be stable. PGR and IPR decisions can often turn on how well experts fare at deposition, especially given that it is very unlikely they will testify again in the case, such as at trial.
Alvotech also argues that the claims are invalid for lacking written description. That is another way of arguing that Regeneron claimed as an invention something it did not really invent. The way written description is assessed is typically by comparing the patent “claims” (the numbered paragraphs at the end of a patent) with the examples, data and other teachings disclosed in the “specification” (mostly everything written in the patent before the “claims”). Alvotech primarily argues that there are no example embodiments disclosed in the specification that match the embodiments “claimed” in the patent.
Alvotech’s written description is not without merit, but written description can nevertheless be satisfied even without example embodiments that mirror the claimed embodiments. This can be a highly factual question that incorporates the general understanding of persons of skill in the art, even if that knowledge is not spelled out in a patent. The bigger problem for Alvotech is that its experts, once again, did not appear to fare too well during the deposition, and Regeneron claims to have solicited damaging admissions that certain patent claims do indeed have adequate written description. If the PTAB credits those admissions, that will significantly hobble Alvotech’s written description arguments because, without viable expert testimony, petitioners cannot typically maintain a written description challenge based upon attorney argument alone.
Finally, Grounds 4 and 5 challenge claims 2 and 3 from the patent. These claims include the additional requirement that the patient taking Eylea HD does not experience “a significant increase in blood pressure.” Alvotech relies upon prior clinical trials for Eylea that purportedly disclose that aflibercept was not observed to increase diastolic or systolic blood pressure. Regeneron, in response, argues that these clinical trials are not related to the 8mg formulation for Eylea HD covered by the ‘036 patent. Regeneron may be correct about that, but even if claims 2 and 3 from the ‘036 patent survive, that may not provide much comfort to Regeneron. The Eylea HD label does not appear to include a disclosure regarding the absence a significant increase in blood pressure. Indeed, the label expressly warns of potential increases in intraocular pressure. In short, even if claims 2 and 3 survive, they may not be infringed by prospective generic formulations for Eylea HD, and thus, may not assist Regeneron from protecting monopoly pricing for its drug.
Alvotech is scheduled to file a reply brief on August 18, 2026. In that brief, Alvotech is likely to respond to Regeneron’s attacks on Alvotech’s petition as well as defend the purported damaging admissions by Alvotech’s experts in deposition. Alvotech’s reply brief is likely to provide more transparency into handicapping the outcome of this PGR proceeding, and whether Regeneron will be able to enjoy several more years of monopoly pricing free from generic competition.