How Much Homology is Enough Under § 112?
How much homology is required to claim a variant of a known nucleic acid sequence when the function of the nucleic acid is recited in the claims? The Patent Trial and Appeal Board (PTAB) provides some insight on this question in Ex parte Livshits (Appeal 2013-001807; US Patent Application 11/106,455).
Applicants claimed a method for producing certain L-amino acids (L-homoserine and L-threonine) by a method of over-expressing a DNA that encodes an efflux protein in E. coli. The relevant claims (see for example, claim 4) defined the DNA as having a sequence: i) of nucleotides 187-804 in SEQ ID NO:3; or ii) which hybridizes under stringent conditions (a defined term in the specification) under which said DNA is 70% or more homologous to the recited sequences in SEQ ID NO:3 and wherein the DNA encodes a protein that, when over-expressed, results in a larger amount of L-amino acid in the culture medium as compared to a non-modified E. coli. This claim defined the variant sequence in terms of both homology and function. Claim 4 was rejected under 35 USC § 112, first paragraph, as failing to comply with written description requirements.
PTAB’s Question and Resolution
The PTAB asked whether the specification provides sufficient descriptive support of a nucleic acid that is “70% or more homologous to the recited sequence that when over-expressed in E. coli results in increased amounts of L-amino acid in the culture medium than a non-modified E. coli.”
The answer in this case was no. The PTAB agreed with the Examiner that a PHOSITA could envision sequences that met the 70% homology requirement and hybridized under the recited conditions to SEQ ID NO:3. Further, the Examiner admitted that by using conservative substitutions, a PHOSITA could likely envision a DNA sequence that encoded a polypeptide having the same tertiary structure as the polypeptide encoded by SEQ ID NO:3. However, the PTAB found there was no teaching that the conservation of structure (whether in the DNA or encoded polypeptide) would be a surrogate for conservation of the function claimed (over-expression of L-amino acids in the culture medium).
In other words, PTAB wanted some teaching as to which of the 30 percent of the nucleotides in the recited DNA could be altered while still conserving the function of the encoded polypeptide. The specification demonstrated the recited function for the polypeptide encoded by SEQ ID NO:3, but offered no teaching as to what regions of the recited DNA or protein were critical for conservation of the recited function and which regions could be modified. The PTAB stated that the specification “leaves it to others to discover the nature and scope of substitutions, deletions, and insertions that can be made to arrive at a 70% homologous sequence that additionally allows for increased amino acid accumulation in the culture medium.” The applicants attempted to use BLAST homology data to argue that a PHOSITA would be able to address the issue, but the evidence was accorded little weight and characterized as an “invitation to experiment” by the PTAB.
The PTAB also noted that even though the DNA/polypeptides that could be envisioned by the PHOSTIA could be easily tested as set forth in the specification for conservation of the recited function, this was not enough to describe the structure so that a PHOSITA could determine “beforehand whether or not a particular structure meets the functional requirements.” As such, the PTAB held that for a nucleic acid variant which is claimed by homology and function of the expressed protein, the PHOSITA must be able to determine if the nucleic acids claimed produce a protein that accomplished the recited function from the specification itself in order to meet the written description requirement.
Implications for Claim Drafting
Given the PTAB’s decision, one wonders why the functional requirement was joined as a limitation to the sequence homology claims. In this case, a published protein sequence was a 100% match for the polypeptide encoded by SEQ ID NO:3. However, no corresponding nucleic acid was disclosed. Could the homology claims have stood on their own in a separate independent claim? Probably not given the Federal Circuits decision in In re Kubin. Note, the PTAB reversed the Examiner’s obviousness rejection of claim 4 based on this reference (as well as several others), reasoning that while the function of the polypeptide was known as a threonine export protein prior to the effective date, there was no evidence to show that when a DNA encoding the protein was over-expressed it would result in accumulation of L-amino acids in the culture medium as claimed.
An alternative approach could be comparing the sequence of the identified DNA to other transport proteins for amino acids to identify conserved regions and limit the substitutions allowed in the variants claimed to those regions outside the conserved regions. In this case, the specification did not contain this information, and the applicant’s attempt to recreate this after the fact was rejected.
Whatever approach is taken, when nucleic acids are claimed by homology and function is implicated, a patent applicant should provide as much information as possible regarding the structure/function relationship and specifically identify areas that may be subject to alteration while maintaining function.