May a court rely on post-priority-date evidence offered to show that a patent lacks written description support even though written description is judged based on the state of the art as of the priority date? Yes, at least when the evidence relates to whether or not a claimed genus discloses a representative number of species. Amgen v. Sanofi, No. 2017-1480 slip op. Fed. Cir. Oct. 5, 2017 (“Amgen”). Such evidence, the Federal Circuit observed, is likely to postdate the priority date, because were it to predate, it might be anticipatory. To consider such evidence is therefore a matter of “common-sense,” the Court added.
The facts of Amgen were described in a previous post and are reproduced here only in brief. Amgen markets the low-density lipoprotein (LDL) lowering drug Repatha™, the active ingredient of which is a monoclonal antibody called evolocumab. The antibody binds the protein PCSK9 and prevents it from causing destruction of another protein, LDL receptor (LDL-R), which helps extract LDL from the blood stream. Amgen’s patents US 8,829,165 (“’165 patent”) and US 8,859,741 (“’741 patent”) claim the entire genus of antibodies that bind to PCSK9 and block it from binding to LDL-R. Claim 1 of the ’165 patent is representative and reads:
An isolated monoclonal antibody, wherein, when bound to PCSK9, the monoclonal antibody binds to at least one of the following residues: S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, or S381 of SEQ ID NO:3, and wherein the monoclonal antibody blocks binding of PCSK9 to LDL-R.
The patents do not specifically claim any antibody by its amino acid sequence. The specifications identify 85 antibodies as having the ability to block interaction between PCSK9 and LDL-R at greater than 90%. They also disclose two three-dimensional structures of a complex of an antibody (evolocumab or 31H4) bound to PCSK9, the structures showing residues recited in the claim as being involved in the binding. Further, they disclose the amino acid sequences of twenty two other antibodies that compete with evolocumab or 31H4 for binding to PCSK9. Id. at 5, 6.
Sanofi, Aventisub LLC, Regeneron Pharmaceuticals Inc., and Sanofi-Aventis U.S., LLC (collectively, “Sanofi”) developed the competing drug Praluent, which, similar to Repatha™, has as its active ingredient a monoclonal antibody that binds PCSK9, preventing it from binding to and causing destruction of LDL-R. Praluent was developed after the priority date of Amgen’s patents. It received FDA approval. Subsequently, Amgen sued Sanofi for infringement of the patents. Sanofi stipulated to infringement but challenged the patents’ validity on grounds of written description, enablement, and obviousness. Id.
As evidence of lack of written description, Sanofi presented its antibodies, including the infringing Praluent. This evidence was excluded by the district court on the ground that it did not illuminate the state of the art at the time of filing, and hence was not relevant to determine if there was sufficient disclosure of the claimed invention. Id. at 7. On appeal, the Federal Circuit found the exclusion of evidence to be based on a misapplication of the law. Id. The Court’s reasoning and the parties’ position are described below.
Sanofi argued that since the requirement for written description protects against attempts to preempt the future before it has arrived, preventing future innovators from introducing evidence of their own innovations in written description challenges is unreasonable. Id. at 8. Amgen’s argument was that since written description and enablement are judged at the time of filing, post-priority-date evidence might be relevant only if it illuminated the state of the art at the filing date (citing In re Koller, 613 F.2d 819, 825 (CCPA 1980); and In re Hogan, 559 F.2d 595, 605(CCPA 1977)). Id. And, given that Praluent did not exist until after the priority date, it was not part of the state of the art and therefore could not illuminate it. Id.
Satisfying written description requires a patent disclosure to convey that the patentee had possession of the invention as of the filing date. For a claim to a genus, possession requires disclosing (i) a representative number of species falling within the scope of the genus, or (ii) structural features common to the members of the genus, so that one of skill in the art can visualize or recognize the members of the genus. Id.at 7-8. The Federal Circuit found that “as a logical matter” evidence introduced not to illuminate the state of the art on the priority date but to show that the patent purportedly did not disclose a representative number of species was relevant to the representative question. Id. at 9. Such evidence, it observed, might include species that fell within the claimed genus, and was likely to postdate the priority date, as otherwise it might anticipate the genus. This “common-sense logic of admissibility”, the Court pointed out, was supported by its opinion in AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 759 F.3d 1285 (Fed. Cir. 2014) (“AbbVie Deutschland”). Id.
AbbVie Deutschland involved alleged infringement by Centocor of AbbVie’s functional claim to a genus of anti-human IL-12 antibodies. The claim read: A neutralizing isolated human antibody, or antigen-binding portion thereof that binds to human IL-12 and disassociates from human IL-12 with a koff rate constant of or less, as determined by surface plasmon resonance. AbbVie Deutschland at 1292. Centocor stipulated to infringement, but challenged validity based on lack of written description, arguing that the antibodies disclosed in AbbVie’s patent were not representative of the entire genus. Id. at 1298. To support unrepresentativeness, Centocor relied on its own accused antibody as evidence, contending that it differed considerably from the antibodies described in the asserted patent. Id.at 1300. AbbVie’s patent described about 300 human antibodies, all having VH3-class heavy chains and lambda-class light chains and sharing 90 percent or more amino acid sequence similarity in the variable regions. Id. at 1291. On the other hand, the Centocor antibody was made of VH5-class heavy chain and kappa-class light chain and shared about 50 percent sequence similarity in the variable regions to the antibodies described in AbbVie’s patent. Id. at 1291. The jury found the patent invalid for lacking adequate written description and the Federal Circuit upheld the verdict. Id. at 1301. At the time of the trial, owing to an ongoing interference, it was unclear whether the Centocor antibody pre- or post-dated the Abbvie antibodies. Amgen at 10. Regardless it served as a basis for the unrepresentativeness ruling. Id.
Turning back to Amgen, one key question was whether In re Hogan bars the use of post-priority-date evidence offered to show that a patent fails to disclose a representative number of species. Amgen argued, as noted above, that it does, and the district court agreed. Id. at 1301.
In re Hogan prevents use of a later-developed improvement to show lack of enablement in an earlier-filed application. In re Hogan at 606. In Amgen, the Court observed that while In re Hogan prohibited the use of post-priority-date evidence offered to illuminate the post-priority-date state of the art, it was silent with respect to the use of such evidence when offered to show that a patent fails to disclose a representative number of species. Amgen at 10. To understand the relevance of In re Hogan to Amgen some familiarity with the former is essential.
In In re Hogan the claim at issue was directed to “[a] normally solid homopolymer of 4-methyl-1-pentene.” The patent disclosure described a method of making the crystalline form of the claimed homopolymer, which was the only way of making the homopolymer known at that time of filing. The claim was rejected by the PTO for not disclosing how to make a second “amorphous form” which, however, was not developed until many years later. The CCPA reversed, stating “[t]o now say that appellants should have disclosed in 1953 the amorphous form which on this record did not exist until 1962, would be to impose an impossible burden on inventors and thus on the patent system.” In re Hogan at 606. The Court did not decide what scope of protection applicant’s contribution to the art was entitled, but pointed out that PTO’s concern that allowance of the claim might lead to enforcement efforts against the later developers was unwarranted. Id. at 606, 607. According to the Court, the requirement that claims be interpreted in light of the specification provided assurance that improper enforcement against later developers would not occur. Id. at 610.
Consistent with the above pronouncements of the CCPA, one framework for understanding the relevance of In re Hogan to the question of post-priority-date evidence offered to show lack of written description can be found in the article, “AbbVie Deutschland and Unknown Embodiments: Has the Written Description Requirement for Antibodies Gone Too Far? 2015, Bloomberg BNA Life Sciences Law and Industry ReportTM, authored by Jorge Goldstein (“LSLR 2015”). The article points out that under Hogan, courts generally invalidated generic claims for not enabling later-developed species only if a skilled artisan, at the time of filing, could have reasonably foreseen those species but did not know how to enable them. LSLR 2015 at 3, left col. If the species could not have been foreseen, the claim was not found invalid; instead it was construed narrowly to only cover the species described at the time of filing such that the claim survived and was not infringed. LSLR 2015 at 2, right col. It argues that the patentee in AbbVie Deutschland could not have reasonably foreseen that anti-IL-12 antibodies with VH chains other than VH3, and VL chains other than lambda, could be made with a koff rate satisfying the claimed limits. LSLR 2015 at 4, left col. As such, under In re Hogan the Abbvie genus claim need not have been invalidated. The Court could have construed the claim narrowly to only cover anti-human IL-12 antibodies having VH3-class heavy chains and lambda-class light chains and a koff of or less. The article makes the additional point that unlike small molecules, where minor structural differences can cause dramatic changes in behavior, antibodies of all class combinations have the same well-known general structure and as such, representativeness should not require exemplification of all class combinations. LSLR 2015 at 5, left col.
Turning back to Amgen, how would the genus claim in this case fare if the district court were to be presented with arguments under the above framework? The case is currently on remand for a new trial on the question of written description and enablement, and in accordance with Federal Circuit opinion, post-priority-date evidence of Praulent will be considered at the trial.
If Praulent is found to indeed be represented by the patent disclosures, the claim will survive invalidation for lacking written description. Here it bears remembering that at trial, the jury had concluded that Amgen’s asserted claims were not invalid for lack of written description. However, note also that on appeal the Federal Circuit found that one part of the jury instructions on written description was in error, and in all likelihood the instructions at the new trial would be more restrictive.
If, on the other hand, the district court finds that Praulent is not represented, the above framework would require asking if the development of Praulent could have been reasonably foreseen. This question may not be easily answered since, as with the basic issue of representativeness, it also would require addressing the state of the art of structure-function correlation of antibody-antigen interactions in all its complexities.