Pharmacyclics LLC v. Alvogen, Inc.

Case Name: Pharmacyclics LLC v. Alvogen, Inc., No. 2021-2270, 2022 WL 16943006 (Fed. Cir. Nov. 15, 2022) (Circuit Judges Chen, Bryson, and Hughes presiding; Opinion by Bryson, J.) (Appeal from D. Del., Connolly, J.) 

Drug Product and Patent(s)-in-Suit: Imbruvica® (ibrutinib); U.S. Patents Nos. 8,008,309 (“the ’309 patent”), 8,754,090 (“the ’090 patent”), 9,725,455 (“the ’455 patent”), 9,655,857 (“the ’857 patent”)

Nature of the Case and Issue(s) Presented: In November 2018, Alvogen filed its ANDA to market a generic version of Imbruvica, a BTK inhibitor used to treat relapsed/refractory mantle cell lymphoma (R/R MCL). Pharmacyclics filed suit, asserting 17 patents. Pharmacyclics later narrowed its case to five asserted claims from four asserted patents, directed to the ibrutinib compound, a method of treating R/R MCL using ibrutinib, a crystalline form of ibrutinib, and tablet formulations of ibrutinib. After presiding over a bench trial, the district court determined that all asserted claims were infringed and not invalid. Alvogen stipulated to infringement of three of the four patents, and the district court determined that Alvogen infringed the asserted claim of the ’857 patent, in addition to rejecting its invalidity defenses.

Alvogen appealed several issues: (i) its written description, enablement, and obviousness challenges to the ’090 patent (method of treatment); (ii) its anticipation and obviousness challenges to the ’455 patent (crystalline form); (iii) its written description challenge to the ’857 patent (tablet formulations); and (iv) its anticipation challenge to the ’309 patent (compound). The Federal Circuit rejected Alvogen’s arguments and affirmed.

Why Pharmacyclics Prevailed: The ’090 patent: Alvogen argued that the district court erred in rejecting its arguments that the method-of-treatment claim lacked written description support and was not enabled, and that it was obvious in view of a combination of four prior art references. Regarding written description, the Federal Circuit determined that the ’090 patent disclosed two clinical trial protocols related to treating R/R MCL with a BTK inhibitor. No example identified ibrutinib specifically, but the summary of the invention described treating R/R MCL with ibrutinib. The Federal Circuit rejected Alvogen’s suggestion that the district court had “cherrypicked” that aspect of the specification to reject the written description challenge. The patent identified only one BTK inhibitor by name (ibrutinib), and that provided sufficient “blaze marks” identifying ibrutinib as “the inventor’s preferred BTK inhibitor.” Further, the claimed dosage of “about 560 mg/day” was expressly recited by itself (rather than as part of a range) in the specification, and an Example used a dosage of 560 mg/day. Alvogen’s enablement defense, related to the “about 560 mg/day” limitation, failed for the same reason.

The Federal Circuit also found no error in the district court’s obviousness analysis, which depended on several findings, including (i) treating MCL (as opposed to R/R MCL) with ibrutinib did not render obvious the claimed method of treating R/R MCL; and (ii) Alvogen’s combination did not teach reaching the claimed dosage of about 560 mg, which would have required conducting a study using pharmacodynamic endpoints.

The ’455 patent: Alvogen argued that a clinical study (the “Pollyea” article) and another reference (“Fowler”) inherently anticipated the asserted crystalline form claim. The Federal Circuit affirmed the district court’s finding that Pollyea and Fowler did not anticipate because Alvogen did not show that the studies necessarily used the claimed crystalline form. Alvogen also argued that a combination of four references rendered the claim obvious. The parties agreed that a skilled artisan would have been motivated to develop a crystalline form of ibrutinib. But the district court found that discovering new crystalline forms is challenging and unpredictable, and the Federal Circuit determined that the finding was not clearly erroneous.

The ’857 patent: Alvogen argued that the asserted tablet formulation claims lacked written description support, in particular, because the specification disclosed one species of the claimed genus (the claims recited ranges). But the specification described formulations within the claimed ranges. Because the specification described experiments conducted using two different doses of ibrutinib, both within the claimed ranges, the district court’s finding that the claims had written description support was not clearly erroneous.

The ’309 patent: Alvogen argued that an article (“Pan”) anticipated the ’309 patent, claiming the ibrutinib compound. Pharmacyclics did not dispute that the article described ibrutinib, but it was able to claim priority to a provisional application predating the article. On appeal, Alvogen argued improper incorporation by reference with respect to the provisional application. But the district court determined that a skilled artisan could have synthesized ibrutinib without reference to the incorporated material, and the court affirmed that finding.