477 F.Supp.3d 306
D. Del.2020Background
- Plaintiffs Bristol-Myers Squibb and Pfizer own U.S. Pat. Nos. 6,967,208 (the '208 patent) and 9,326,945 (the '945 patent), listed in the FDA Orange Book for Eliquis (apixaban). Plaintiffs sued ANDA filers Sigmapharm, Sunshine Lake, and Unichem under the Hatch‑Waxman framework. A nine‑day bench trial was held.
- The '208 patent claims apixaban (claim 13) and crystalline apixaban (claim 104); the '945 patent claims specific immediate‑release tablet compositions containing crystalline apixaban particles with D90 ≤ about 89 µm and a dissolution rate ≥ 77% in 30 minutes.
- Sigmapharm, Sunshine Lake, and Unichem each submitted ANDAs for 2.5 mg and 5 mg apixaban tablets; defendants challenged infringement and asserted invalidity defenses (improper dependency, lack of enablement and written description, and obviousness).
- Plaintiffs’ experts (XRPD, solid‑state NMR, SEM‑EDS, process analysis) found crystalline apixaban in Sigmapharm and Sunshine Lake products and very small apixaban particles (≈1 µm) in Unichem product; defendants’ experts disputed sensitivity, LOD, and interpretation of data.
- The court credited Plaintiffs’ testing and process‑based analyses, found: Sigmapharm’s product infringes the '208 claims (13 and 104); Sigmapharm, Sunshine Lake, and Unichem infringe the asserted '945 claims; and the asserted claims of both patents are not invalid.
Issues
| Issue | Plaintiff's Argument | Defendant's Argument | Held |
|---|---|---|---|
| Whether claim 1 of the '208 patent covers apixaban (impacting dependent claims 13, 104) | Claim language means rings may be "substituted with 0–2 R" (i.e., zero replacements allowed), so apixaban falls within claim 1 and thus claims 13 and 104 cover apixaban | Defendants argued "substituted" requires counting hydrogen as substituents so apixaban exceeds allowed substitutions and is excluded | Court adopted Plaintiffs’ plain‑meaning construction ("substituted with 0" can mean no change); claim 1 covers apixaban; dependent claims validly encompass apixaban |
| Infringement of '208 claim 104 (crystalline apixaban) by Sigmapharm | Plaintiffs: XRPD and SSNMR detected characteristic crystalline apixaban peaks; Sigmapharm also starts with crystalline apixaban in its U.S. process | Sigmapharm: Tests lack sensitivity/LOD, observed signals are noise, experiments show amorphous dispersion so no crystalline API in final tablets; ANDA safe‑harbor protects some activities | Court found Dr. Atwood (XRPD) and Dr. Munson (SSNMR) persuasive; Sigmapharm's lower‑sensitivity tests (short count times) were unpersuasive; held Sigmapharm product contains crystalline apixaban → infringes claim 104 |
| Whether accused products meet '945 particle‑size limitation (D90 ≤ ~89 µm) | Plaintiffs: process evidence + crystallization theory show API particles cannot grow to ≥89 µm in these formulations; for Unichem, SEM‑EDS directly showed ~1 µm particles | Defendants: Plaintiffs failed to measure D90 post‑tableting; opposing tests (with different methods) show larger sizes or lack of crystalline signal; SEM‑EDS not accepted to determine D90 | Court held circumstantial proof (process and crystallization principles) and direct SEM‑EDS (Unichem) were probative; found D90 limitation met for all three accused products → infringement of '945 claims |
| Validity — enablement, written description, obviousness of '208 and '945 | Plaintiffs: specification and examples, and experiments (Dr. Jacobsen made apixaban salts) enable and describe claimed subject matter; prior art showed apixaban had good BCS‑relevant solubility so asserted '945 claims were not obvious | Defendants: asserted claims are overbroad (improper dependency), salts not enabled or pharmaceutically acceptable, D90 measurement/teaching absent, and claimed particle/dissolution limits obvious from prior art | Court rejected defendants' challenges: '208 describes salts and Dr. Jacobsen created salts; written description is adequate; Wands factors do not show undue experimentation; '945 enabled and described (particle‑size measurement for bulk disclosed; formulation not expected to increase particle size); obviousness not shown given the prior art and BCS context |
Key Cases Cited
- Markman v. Westview Instruments, Inc., 52 F.3d 967 (Fed. Cir.) (claim construction two‑step framework)
- Southwall Techs., Inc. v. Cardinal IG Co., 54 F.3d 1570 (Fed. Cir.) (literal infringement requires every claim limitation)
- SmithKline Diagnostics, Inc. v. Helena Lab. Corp., 859 F.2d 878 (Fed. Cir.) (patent owner bears burden to prove infringement)
- Acorda Therapeutics Inc. v. Mylan Pharm. Inc., 817 F.3d 755 (Fed. Cir.) (ANDA context: infringement judged on whether marketed drug would infringe)
- Enzo Life Scis., Inc. v. Roche Molecular Sys., Inc., 928 F.3d 1340 (Fed. Cir.) (enablement requires teaching to make and use full scope without undue experimentation)
- MagSil Corp. v. Hitachi Global Storage Techs., Inc., 687 F.3d 1377 (Fed. Cir.) (enablement standards)
- In re Wands, 858 F.2d 731 (Fed. Cir.) (factors for undue experimentation)
- Genentech, Inc. v. Novo Nordisk A/S, 108 F.3d 1361 (Fed. Cir.) (specification must disclose more than a germ of an idea)
- Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir.) (written description requires disclosure showing possession)
- Graham v. John Deere Co., 383 U.S. 1 (U.S.) (obviousness framework and Graham factors)
- KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (U.S.) (flexible obviousness analysis; guard against hindsight)
- Procter & Gamble Co. v. Teva Pharm. USA, Inc., 566 F.3d 989 (Fed. Cir.) (clear‑and‑convincing burden to invalidate an issued patent)
- Hewlett‑Packard Co. v. Bausch & Lomb Inc., 909 F.2d 1464 (Fed. Cir.) (difficulty of invalidating claims when relied upon by PTO)