On the Support for Sequence Homology in Patent Specification
Fangyuan ZHENG
Chinese Patent Attorney
Biotech patent applications constantly face the challenge of the description providing adequate support for claims involving protein or nucleic acid sequences. In particular, when a claim is defined by “homology + function,” the examiner tends to question whether the description fully supports the drafting of the claim.
During patent examination, biotech patent applications frequently face rejections on the following grounds: (1) the low predictability of function when sequence structures are altered; (2) insufficient test data supporting the function of not only the specific gene or protein but also the claimed derivative sequences. Drawing on a real application and a precedent court ruling, this article proposes drafting and response strategies to address these rejections by strengthening the specification’s support for sequence homology and functional definitions.
<Case Introduction>
Claim 1 is directed to a modified enzyme, which, as compared to the wild-type, has improved tolerance to amide compounds under high-temperature conditions, wherein the enzyme derives from a specific genus, the wild-type thereof contains an α-subunit and a β-subunit, the α-subunit comprises a fixed sequence and a specific amino acid substitution at a specific site, the α-subunit consists of an amino acid sequence as shown in SEQ ID NO: 4 or an amino acid sequence having 98% or more homology with an amino acid sequence as shown in SEQ ID NO: 4, the β-subunit consists of an amino acid sequence as shown in SEQ ID NO: 2 or an amino acid sequence having 95% or more homology with an amino acid sequence as shown in SEQ ID NO: 2.
During the prosecution, the examiner doubted that definition by homology could not be substantively supported by the specification. Specifically the examiner stated that “Claim 1 merely defines an α-subunit comprising a fixed sequence in a specific segment. The sequence of SEQ ID NO: 4 has 203 amino acids. The 98% homology means that at least 4 amino acids are altered. The sequence of SEQ ID NO: 2 has 229 amino acids. The 95% homology means that at least 10 amino acids are altered. As the sites and the types of the altered amino acids are not limited, the number of derivative sequences is huge, far exceeding the mutant sequences tested in the examples of the description.” Hence, claim 1 was determined to lack support in the description and therefore does not comply with Article 26.4 of the Patent Law.
The applicant formulated the following response strategy and convinced the examiner that claim 1 could be supported by the description.
First, the applicant emphasized that the improved function of the enzyme relied on the specific substitution at specific sites of the α-subunit, rather than the change in the entire sequence. The description has described in detail how the substitution improved the resistance to amide compounds and has verified the claimed effect in the examples.
Second, the fixed sequence defined in the claim is the active center of the enzyme. That is, the modified enzyme does not involve alteration to the amino acid sequence of the active center. As the mutation does not occur in the active center, the catalytic activity of the modified enzyme of the application can be reasonably predicted.
Furthermore, the applicant submitted comparative data from multiple strains within the genus, demonstrating that they had 95% or more identity in the α- and β-subunits with the sequences described in the examples and were highly conserved in particular in the critical functional domains. To further strengthen the argument, the applicant cited data from KEGG and other databases to establish that the homologous proteins shared the same function of improved tolerance to amide compounds, which was consistent with the objective of the application. Hence, even without enumerating the sequences exhaustively, the applicant made a convincing argument that the functional consistency verified in the examples of the description has provided support for the homology defined in the claim.
<Inspiration from the case>
● In drafting an application involving sequence homology, it is advisable to:
1. Include more detailed description. This may include more examples of specific percentage values for sequence homology or identity, accompanied by functional description explaining that the homology is defined for a non-critical domain while the critical domain must be conservative, without mutations;
2. Avoid restriction solely by percentage. It would be helpful to describe the principle such as “as long as this domain remains intact, conservative substitution in the other domains generally does not significantly impair activity.” In addition, a functional description of the critical sites, the functional domain, or the binding affinity should be included;
3. Provide functional data of the original sequence and specific mutants which are directly verified in the examples. Data of homologous sequences from different species or modified to various degrees, even in a limited number, can convincingly demonstrate that the claimed function is insensitive to alterations of the sequence and thereby greatly strengthen the argument for the predictability of the effect.
● In making a response to an office action, it is advisable to:
a. Leverage comparative data. Data provided in the examples can be cited to explain that introducing the same mutation into homologous sequences would predictably yield the same technical effect;
b. Submit a multi-sequence sequence alignment chart. This can visually demonstrate that homologous sequences are highly conserved in critical functional domains, thereby highlighting the natural existence of sequences mutated in a domain other than the critical functional domains to thereby prove the functional consistency;
c. Introduce experimental data or structural prediction tool. This can form supplementary evidence to support the mutated sequences.
Notably there has been a ruling of the Supreme People’s Court on this issue. In 2016, the Supreme People’s Court reviewed a case of administrative dispute over invalidation declaration of a patent entitled “Thermally Stable Glucoamylase.” One major dispute in this case was whether nor not the expression “having at least 99% identity to a sequence as shown in SEQ ID NO: 7” in the amended claims was supported in the description.
“6. An isolated enzyme having glucoamylase activity, having at least 99% homology to a full-length sequence as shown in SEQ ID NO: 7, and having an isoelectric point lower than 3.5 as determined by isoelectric focusing.
10. The isolated enzyme according to any one of claims 6 to 9, wherein the enzyme is derived from a filamentous fungus of the genus Talaromyces, wherein the filamentous fungus is a T.emersonii strain.
11. The enzyme according to claim 10, wherein the filamentous fungus is T.emersonii CBS 793.97.”
The patentee submitted counterevidence in the second instance to prove the capability of a person skilled in the art, similarities of the claimed strains in the survival environment and the biological characteristics, and the conserved evolution of the enzyme in fungi. Ultimately the court ruled that “the 99% or more homology and the source species or strains have already restricted the scope of protection to limited enzymes. As the examples described in the description have proven that the protein of the original sequence has specific enzymatic activity, the protein limited by the 99% or more homology is also supported by the description.”
The above ruling of the Supreme People’s Court specifies the principle that a biological sequence claim defined by “homology+source+function” is supported by the description. It also sets forth the standards for granting a patent to an invention relating to biological sequences. Hence, this ruling provides guidance for the drafting and examination of patent applications relating to proteins and genes.
Although judicial precedents are not binding in China, applicants can cite the above ruling in the response to an office action to persuade the examiner.
<Suggestions for drafting a PCT application>
The drafting strategy should account for the examination standard applied to claims defined by sequence homology in the target jurisdiction. The acceptable homology thresholds vary across countries and regions. For example, Japan and the U.S. generally accept a homology of 90% or more while a homology of 85% or 90% or more may be accepted in Europe. The variance can also be observed in the case introduced above, in which the JP, US, and EP counterpart applications were granted despite containing a sequence formula with variable positions denoted by “X”. This suggests that CNIPA applies a stricter examination standard when it comes to the claims defined by homology+function.
Further to the above, for a PCT application with “homology+function” definitions, a recommended strategic approach is to draft the specification for the international phase to include technical solutions adapted to the examination practices varying across different countries, thereby allowing for strategic adjustment to the claims during the national phase to satisfy specific requirements of the target member country. Here, it is crucial to ensure the verifiability of the functional definitions. That is, the description must be drafted to support the claimed functions, for instance, by including experimental data or structural predictions.
