The U.S. Patent and Trademark Office (USPTO) recently instituted two of Mylan’s petitions seeking Inter Partes Review of Regeneron’s U.S. Patent No. 9,669,069 B2 (the “’069 Patent,” subject of IPR2021-00880) and U.S. 9,254,338 B2 (the “’338 Patent,” subject of IPR2021-00881), finding that Mylan (now part of Viatris) established a reasonable likelihood in prevailing in showing unpatentability of at least one claim in each patent.  Regeneron markets Eylea® (aflibercept), a recombinant VEGF-binding fusion protein, for treatment of retinal diseases.  This is the latest development in a series of battles over Eylea®, which has been marketed in the United States since 2011, has enjoyed $8.36 billion in revenues in 2020, and is the third highest grossing biologic product in the world as reported here. We recently reported on Regeneron’s battle with Novartis over a pre-filled glass syringe for injecting a VEGF-antagonist such as aflibercept into the eye.

Both of Regeneron’s patents claim treating an angiogenic eye by “sequentially administering to the patient a single initial dose of a VEGF antagonist, followed by one or more secondary doses of the VEGF antagonist, followed by one or more tertiary doses of the VEGF antagonist” and further recite “wherein each secondary dose is administered 2 to 4 weeks after the immediately preceding dose.” The ’069 patent specifies that “each tertiary dose is administered on an as-needed/pro re nata (PRN) basis,” while the ’338 Patent specifies that “each tertiary dose is administered at least 8 weeks after the immediately preceding dose.”

The Patent Trial and Appeal Board (the “Board”) instituted both petitions on all grounds asserted by Mylan.  Mylan cited several references in each of its petitions as being anticipatory references, but the respective parties’ arguments and the Board’s focus centered substantially on the Dixon reference. Dixon was relied upon both as an anticipatory reference and as a primary reference for the obviousness grounds in each petition in combination with (IPR2021-00881), or optionally in combination with (IPR2021-00880), Regeneron’s earlier publications (“Papadopolous” and “Dix” references).

Regeneron urged the Board to apply its discretion to deny institution as Dixon or other references that “were before the Examiner and considered during prosecution” constitute “substantially the same art that was already considered by the Examiner.” See IPR2021-00881 at pp. 9-11; see also IPR2021-00880 at pp. 10-13. However, reviewing the prosecution of the ’069 patent (IPR2021-00880), the Board found that only a single page of the Dixon reference was filed in an information disclosure statement (IDS). The Board found that based on the single page of Dixon, “[i]t would consequently have been impossible for the Examiner to analyze the limitations of the challenged claims.” IPR2021-00880 at pp. 12-13.  While Regeneron also argued that a 2008 press release provided to the Examiner in an IDS in connection with ’338 Patent disclosed the same teachings of the cited prior art in the petition, the Board disagreed.  See IPR IPR2021-00881 at pp. 9-14.  In particular, the Board found that the disclosed press release failed to provide the additional disclosures relied upon by Mylan, including that “VEGF Trap-Eye and aflibercept (the oncology product) have the same molecular structure,” and therefore the same sequence. Id. at p. 14.

Interestingly, while the Board agreed with Regeneron that the claim preamble “method for treating an angiogenic eye disorder in a patient” was limiting, the Board was not persuaded by Regeneron’s arguments that the claims require a certain level of efficacy because the specification merely stated that “[t]he amount of VEGF antagonist administered to the patient in each dose is, in most cases, a therapeutically effective amount” and a therapeutically effective amount means “detectable improvement in one or more symptoms or indicia of an angiogenic eye disorder, or a dose of VEDF [sic] antagonist that inhibits, prevents, lessens, or delays the progression of an angiogenic eye disorder.” See IPR2021-00881 at p. 20 (emphasis in original) (citing ’338 Patent at 6:48–50 and 6:50–55).

The Board was also unpersuaded by Regeneron’s arguments that the claimed “tertiary dose” requires maintaining efficacy gained by the claimed “initial” and “secondary doses,” even in light of Regeneron’s alleged showing during prosecution that “less frequent, tertiary dosing ‘once every 8 weeks’ was surprisingly efficacious.” See IPR2021-00881 at p. 22.  Instead, the Board found that the specification clearly indicated that the terms “initial dose,” “secondary doses,” and “tertiary doses,” merely refer to the temporal sequence of administration of the VEGF antagonist.  See id. (citing ‘338 Patent at 3:31–38).

In the Patent Owner’s Preliminary Response to each petition, Regeneron argued that Dixon fails to disclose the amino acid sequences required by the challenged claims. Regeneron argued that Dixon fails to disclose the amino acid sequence of the VEGF antagonist described by the reference and the evidence of record failed to show that the amino acid sequence of VEGF Trap-Eye taught in Dixon was known to be the same as the amino acid sequence of aflibercept. See IPR2021-00880 at pp. 28-29 and IPR2021-00881 at p. 30. Regeneron also argued that the prior art used varying nomenclature referring to different VEGF-trap proteins and also reported VEGF-Trap Eye with varying molecular weights. See id.  The Board disagreed and found that the evidence of record stated sufficient facts to support institution. The Board noted that Dixon expressly teaches that VEGF Trap-Eye and aflibercept (the oncology product) have the same molecular structure, but there are substantial differences between the preparation of the purified drug product and their formulations. See IPR2021-00880 at p. 36. The Board also found that that VEGF-Trap Eye was taught in prior art references, including a 2002 publication (“Holash”) disclosing that VEGF-TrapR1R2 was created by fusing the second Ig domain of VEGFR1 with the third Ig domain of VEGFR2, and an earlier and now expired Regeneron patent (“Papadopoulos”), which expressly disclosed “VEGFR1R2-FcΔC1(a) encoded by the nucleic acid sequence of SEQ ID NO: 1,” as recited in dependent claim 12” and this fact was not disputed by Regeneron. See pp. 36-37. The Board did, however, acknowledge an apparent discrepancy concerning the molecular weight of aflibercept and VEGF Trap-Eye in the prior art, but did not find this discrepancy to be sufficient to deny institution given the identical structures.  The Board credited expert testimony that the sequence of the VEGF antagonist which is marketed as aflibercept “was disclosed well before January 2011” and that numerous references demonstrated that “aflibercept, VEGF Trap (R1R2), and VEGF Trap-Eye, among other terms, were understood by a person of ordinary skill in the art to refer, interchangeably, to the same drug.”  IPR2021-00880 at p. 38 (quoting Mylan’s Declarant’s expert testimony).

Regeneron also argued in connection with the ’069 Patent that  Dixon and another cited prior art reference, Heier 2009, failed to disclose the claim feature reciting “wherein each tertiary dose is administered on an as needed/ pro re nata (PRN) basis, based on visual and/or anatomical outcomes as assessed by a physician or other qualified medical professional.” However, the Board disagreed.  The Board found first that Dixon expressly discloses that patients were treated on a “p.r.n. basis.” Secondly, the Board concluded that, while a physician doing an assessment is not expressly mentioned in the cited references, a person or ordinary skill in the art would recognize that the prescription of the appropriate medication would necessarily need to be performed by a physician or other qualified medical professional licensed by the state. See IPR2021-00880 at p. 31. (citing, inter alia, Continental Can Co. USA v. Monsanto Co., 948 F.2d 1264, 1269 (Fed. Cir. 1991) (holding that anticipation requirement that every element of a claim appears in a single reference accommodates situations where the common knowledge of “technologists” is not recorded in a reference, i.e., where technical facts are known to those in the field of the invention).

Thus, the Board found that Mylan had established a reasonable likelihood in prevailing in showing unpatentability of at least one claim in each of the challenged patents.

This is the latest development in a series of challenges to Regeneron’s thicket of patents covering Eylea® including IPR2021-00402 (challenging U.S. Pat. No. 10,464,992, terminated due to settlement), PGR2021-00035 (challenging U.S. Pat. No. 10,828,345, terminated due to settlement), PGR2021-00117 (challenging U.S. Pat No. 10,857,231), IPR2022-00298 (challenging U.S. Pat. No. 9,254,338), IPR2022-00257  (challenging U.S. Pat. No. 9,669,069); IPR2022-00258 (challenging U.S. Pat. No. 9,254,338); Reexamination 90/014,448 (challenging U.S. Pat. No. 10,464,992), and Reexamination 90/014,449 (challenging U.S. Pat. No. 10,406,226).

Regeneron’s Patent Owner’s Response in each case is due by February 2, 2022.  We will keep monitoring these cases and report on future developments.