Lead Compound Analysis Not Required Where the Prior Art References Expressly Suggest the Proposed Modification
When assessing obviousness of a chemical compound, Federal Circuit caselaw generally follows a two-part inquiry referred to as the “lead compound” analysis. However, in Cytiva BioProcess R&D AB v. JSR Corp.[1], the U.S. Court of Appeals for the Federal Circuit (“Federal Circuit” or “CAFC”) explained the flexibility in the use of lead compound analyses when determining patentability or validity of claimed chemical compounds under 35 U.S.C. § 103. While commonly used, the lead compound analysis is not, as a strict rule, always required. Rather, because the Supreme Court emphasized flexibility over rigid and formalistic rules in considering obviousness in KSR[2], such flexibility should also be applied to obviousness assessment of new chemical compounds.
The lead compound analysis typically involves a two-part inquiry, which includes: step 1) determining whether a chemist of ordinary skill would have selected the asserted prior art compounds as lead compounds, or starting points, for further development efforts; and step 2) determining whether the prior art would have supplied one of ordinary skill with a reason or motivation to modify the lead compound to make the claimed compound with a reasonable expectation of success.
In the present case, Cytiva appealed final written decisions from six inter partes reviews (“IPRs”), which determined that many claims of three challenged patents owned by Cytiva were unpatentable. Each of the challenged patents relate to affinity chromatography matrices that include a ligand made from Protein A (“SPA”) and processes for isolating target compounds with those chromatography matrices. The independent claims of the challenged patents include making the same amino acid modification (i.e., modifying a glycine residue to an alanine at position 29, or the “G29A” modification) in a Domain C of a protein that is used to produce an antibody targeting chromatography matrix. In their final written decisions in the IPRs, the Patent Trial and Appeals Board (“the Board”) determined that it would have been obvious to make the G29A mutation to Domain C based on express suggestions in the prior art.
On appeal to the Federal Circuit, Cytiva argued that (A) the Board erred by failing to conduct a lead compound analysis and (B) that the Board further erred by relying on KSR’s obvious-to-try rationale instead of the lead compound test. As part of its argument, Cytiva urged that a person of ordinary skill would not have been motivated to pick the Domain C region of the protein as the lead compound. However, the Federal Circuit disagreed on both points.
One of the key lessons from this CAFC decision is that a lead compound analysis is not always a strict requirement that must be performed when assessing obviousness of a claimed chemical compound under § 103. Instead, the lead compound analysis is merely an ordinary or generally applicable test that assists courts in assessing obviousness. Thus, the obviousness inquiry is a flexible one that does not follow rigid and formalistic rules; such analysis is not required where the prior art references themselves expressly suggest the claimed protein modification.
The Federal Circuit provided further clarity regarding an “express” suggestion noting that the Board correctly found two prior art references both expressly suggested that the glycine codon at position 29 can be mutated for an alanine codon in any one of the SPA highly homologous antibody binding domains of SPA (i.e., Domains E, D, A, B, or C). The court indicated that such a suggestion is an express disclosure of what is claimed in the challenged patents (i.e., the proposed G29A modification to Domain C). Requiring a separate justification for starting with Domain C in a lead compound analysis, as argued by Cytiva was necessary to invalidate the claims, would lead to the “erroneous ‘constricted analysis’ that KSR criticized.”[3]
Further, the Federal Circuit clarified that the “obvious-to-try” inquiry is similar to the lead compound inquiry as both effectively require a finite number of proposed starting points, and when there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill in the art has good reason to pursue the known options within his or her technical grasp. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103, as explained by the Supreme Court in KSR. Thus, it was determined that no lead compound analysis was required for the present case.
Even if a formal lead compound analysis was required, the CAFC explained that such an analysis supported the conclusion that any one of the five homologous domains of SPA, including Domain C, could serve as a lead compound in view of the prior art. Once Domain C is selected as the lead compound under step one, a person of ordinary skill in the art would have been motivated to make the claimed G29A modification in view of the express teaching in the prior art to mutate the G29A position to prevent degradation of the protein upon isolation and increase stability. That teaching supported the obviousness of incorporating the mutation into any of the five known antibody binding domains of the protein.
