The Federal Circuit’s recent decision in Daiichi Sankyo Co., Ltd. v. Matrix Labs., Ltd. is a nice example of a thorough analysis of the patentability of a new chemical entity by the "lead compound" approach to obviousness. The case emphasizes the perspective of the "medicinal chemist of ordinary skill" and illustrates how evidence on multiple aspects of non-obviousness can insulate a patent from obviousness challenges.
The Claimed Compound
The patent at issue (U.S. Patent 5,616,599) was directed to new chemical entities useful as angiotensin receptor blockers (ARBs). The specific compound at issue was olmesartan medoxomil, marketed as Benicar®.
The ‘599 patent was filed in 1995, and built on research dating back to the 1970s. The Federal Circuit traces some of this history, starting with ARBs developed by Takeda Pharmaceutical Co. Ltd. in the late 1970s and early 1980s, moving to ARBs developed by E.I. du Pont de Nemours and Company in the late 1980s, and other "second-generation" ARBs developed by DuPont, Merck & Co., and Ciba-Geigy Corp.
The Obviousness Challenge
The Federal Circuit appeal stems from Abbreviated New Drug Application (ANDA) litigation that resulted from Mylan’s ANDA filings seeking FDA approval to market a generic version of olmesartan medoxomil, and alleging that the ‘599 patent is invalid.
Mylan’s obviousness challenge was based on:
- The selection of second generation ARBs disclosed in DuPont’s U.S. Patent 5,137,902 as lead compounds.
- Example 188 of DuPont’s U.S. Patent 5,138,069 providing motivation to replace a lipophilic group of the ‘902 compounds with the hydrophilic hydroxyalkyl group of the claimed compound.
- The well-known use of medoxomil as a prodrug.
The District Court Decision
According to the Federal Circuit,
the district court held in a comprehensive and well-reasoned opinion, that claim 13 of the ‘599 patent was not invalid as obvious.
(If you missed the "we affirm" statement at page 2 of the slip opinion, this favorable characterization of the district court opinion gives a strong hint as to the result!)
The district court rejected every step of Mylan’s obviousness argument, and also found that the claimed compound achieved unexpected results in terms of "enhanced potency and other favorable biological properties," and was associated with commercial success.
The Federal Circuit Decision
The Federal Circuit commenced its analysis by noting that "[w]hen a patent claims a chemical compound, a prima facie case of obviousness . . . frequently turns on the structural similarities and differences between the compounds claimed and those in the prior art." The court framed the issue:
Proof of obviousness based on structural similarity requires clear and convincing evidence that a medicinal chemist of ordinary skill would have been motivated to select and then to modify a prior art compound (e.g., a lead compound) to arrive at the claimed compound with a reasonable expectation that the new compound would have similar or improved properties compared with the old.
The Federal Circuit addressed in turn Mylan’s arguments that (1) someone of ordinary skill in the art would have selected the ‘902 patent compounds as lead compounds and (2) someone of ordinary skill in the art would have been motivated to modify those compounds to arrive at the claimed compound, olmesartan medoxomil.
(1) Selection of the ‘902 Patent Compounds as Lead Compounds
The district court had found that "a medicinal chemist of ordinary skill would not have been motivated to select the ‘902 [patent] compounds" because other, later-developed ARBs had "demonstrated greater potency" and had "been more thoroughly studied." The Federal Circuit found "no clear error" in those findings.
Mylan argued that because the ‘902 patent compounds "are undisputedly the closest prior art," that determination "should have been dispositive of the lead compound issue."
The Federal Circuit disagreed, warning against the use of "hindsight bias." The court noted that selecting a lead compound involves consideration of not only "structural similarity, but also knowledge in the art of the functional properties and limitations of the prior art compounds." When identifying a lead compound, "[p]otent and promising activity in the prior art trumps mere structural relationships."
(2) Modifying the ‘902 Patent Compounds to Make Olmesartan Medoxomil
The district court had found that the prior art taught away from replacing the lipophilic group of the ‘902 patent compounds with a hydrophilic group, as would be required to arrive at olmesartan medoxomil. The court cited structure-activity relationship (SAR) data presented in the ‘069 patent, and the presence of lipophilic groups in second-generation ARBs.
Mylan argued that the presence of a lipophilic group in Example 118 of the ‘902 patent provided the required motivation, but the Federal Circuit disagreed.
The court noted that the single example did not outweigh the numerous other examples with hydrophobic groups at the position at issue, which together "demonstrate a clear preference for lipophilic groups over hydrophobic ones." The court also noted that Mylan’s argument would have required the skilled artisan to first select the ‘902 patent compounds, which improved on previous compounds by using an even more lipophilic group, and then eliminating "that very feature" to arrive at the claimed compound.
Interestingly, the Federal Circuit noted that even if the prior art ‘902 patent "does not teach away from a hydrophilic group at the 4-position, [it] simply does not provide a reason to make such a modification."
Having agreed with the district court on each of these issues, the Federal Circuit found no reason to address the other holdings on obviousness or the secondary considerations of unexpected results and commercial success.
The Perspective of the Medicinal Chemist
The court’s reference to "a medicinal chemist of ordinary skill" caught my eye, particularly having just read the USPTO’s new Obviousness Examination Guidelines that indicate in the discussion of Eisai Co. Ltd. v. Dr. Reddy’s Labs., Ltd., 533 F.3d 1353 (Fed. Cir. 2008), that a different perspective might apply. (I urge the USPTO revises the Guidelines in view of this decision.) Indeed, the whole analysis presented in the Daiichi opinion is impressive for its consideration of how the skilled artisan would have viewed the teachings of the prior art as a whole, rather than focusing on one teaching that, in a vacuum, might have supported obviousness.
Telling a Story of Non-Obviousness
The Daiichi opinion also is interesting for its recitation of the history of the development of the claimed compound. As noted above, the court walks through the development of ARBs and the different chemical modifications that were attempted at different stages, and why. The court also digs into the SAR data presented in the ‘902 patent, and what that data may or may not have meant to the skilled artisan. None of this would be in the opinion if Daiichi had not developed a factual record that told a good story of non-obviousness. The Federal Circuit begins telling us this story at page 2 of its opinion, again foreshadowing its determination that the "years of research" did not lead to a compound that was merely obvious.
This case would be a useful training case for both practitioners and examiners, illustrating to the former how to develop a record that supports non-obviousness, and to the latter how to consider the evidence without letting hindsight bias the conclusion towards obviousness.