Background

It is widely known that the biotechnology industry heavily relies on patent protection, and use of biological sequences (such as nucleotide or amino acid sequences) to define the scope of patent claims is a conspicuous feature in this field. However, whether such claims are supported by the description has been a prominent issue in examination and litigation, with China's standards generally being more stringent compared to other countries and regions like the United States, Japan, and Europe.

Article 26.4 of the Chinese Patent Law states that "the claims shall be supported by the description and shall define the extent of the patent protection sought for in a clear and concise manner".

In the examination and judicial practice of China, there is strict scrutiny regarding the support issue of patent applications related to biological sequences. It is commonly believed that for inventions in the field of biotechnology, the predictability of technical effects is low without experimental data. Particularly for biological sequences, even slight changes in biological molecules can result in changes of spatial structure, which may result in functional changes. Therefore, without specific examples of implementation, those skilled in the art cannot predict whether variants of the specific sequence would possess the same functional activity.

This viewpoint makes it difficult for applicants to generalize the technical solution of their invention. The results of examination practice may discourage the enthusiasm for applying for patents related to biological sequences because even if granted, competitors can easily circumvent the patented invention by making minor changes.

For example, a Chinese patent application involves an improved HPV vaccine. Claim 1 requests protection for "An HPV antigen, comprising an amino acid sequence selected from SEQ ID NO:1, a sequence having at least 90% homology with SEQ ID NO:1, or a fragment of SEQ ID NO:1".

For this application, Chinese examiner issues a decision of rejection, and the opinions could be summarized as below:

Claim 1 defines amino acid sequence by means of the open-ended manner of “comprising”, which means that any type of and any number of amino acid residues may be added at both ends of the amino acid sequence.  An amino acid sequence is a primary structure of a polypeptide, determines the spatial structure of the polypeptide and thereby determines the function of the polypeptide, a slight change in the amino acid sequence may result in a change in the spatial conformation of a polypeptide, thereby leading to a changes or even missing in the function thereof.  The description of the application merely verifies the functions of the specific amino acid sequence.  The function of a polypeptide obtained by adding any number and any type of amino acid residues at both ends of the amino acid sequence cannot be determined.  In the case, experimental evidences are required for verification.  Therefore, the above generalization has gone beyond the scope of the disclosure contained in the description, lacks support from the description. 

In addition, claim 1 covers a great number of amino acid sequences by means of the expressions “fragment” and a certain percent “homology”.  The description merely verifies the functions of specific amino acid sequence.  As is well-known, the change of a few or even one amino acid residue may affect the structure and function of a polypeptide, and the effect of a change in sequence on polypeptide function is unpredictable.  A person skilled in the pertinent art would not be able to determine which sequences other than the specific sequences of which the functions have been verified in the description also have the same or similar functions.  It can be seen that the expressions “fragment” and a certain percent “homology” generalize a great number of function-unknown amino acid sequences, which has gone beyond the scope of the disclosure contained in the description and lacks support from the description, which does not comply with Article 26.4 of the Patent Law.

From the above example case, we could see that for the amino acid sequence of antigen protein or the encoding nucleotide sequence thereof, it is usually only allowed to limit the claims to the specific sequences demonstrated in the description by experimental examples, and a generalization by "comprising", "fragment", or "homology" may be generally not accepted for antigen protein.

However, this does not mean that all claims involving biological sequences should exclude the features of "comprising", "fragment", and "homology". This article will discuss the support issue of claims involving biological sequences from an invalidation case.

Basic Information of the Invalidation Case

Patent Title: "Hepatitis B virus (HBV) iRNA compositions and methods of use thereof".

Patent Number: ZL201580072874.0

Patentee: ALNILAM PHARMACEUTICALS INC

Decision Date: September 15, 2022

Conclusion: Validity upheld on basis of amended claims

The AMENDED claim 1 in invalidation process

A double stranded RNAi agent for inhibiting expression of hepatitis B virus (HBV) in a cell, wherein said double stranded RNAi agent comprises a sense strand and an antisense strand forming a double-stranded region,
wherein said sense strand comprises 5'-GUGUGCACUUCGCUUCACA-3' (SEQ IDNO:39) and said sense strand is no more than 21 nucleotides in length, and said antisense strand comprises 5'-UGUGAAGCGAAGUGCACACUU-3' (SEQ ID NO:40) and said antisense strand is no more than 23 nucleotides in length,
wherein all of the nucleotides of said sense strand and all of the nucleotides of said antisense strand comprise a modification,
wherein said sense strand is conjugated to a ligand attached at the 3'-terminus, and
wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker.

Opinions of petitioner for invalidation

Claim 1 defining the sequences of the sense and antisense strands by means of the term "comprise" covers a too large scope, which is not supported by the description, because a person skilled in the art could not determine which nucleotide sequences can retain RNA interference activity similar to the specific sequence validated in the description.

Decision of Invalidation

The panel started with a detailed analysis based on the technical principle, explaining that the complementarity between the core sequence of double-stranded RNAi and the target RNA is the key to achieving mRNA degradation and thereby inhibiting hepatitis B virus expression. Therefore, when understanding the term "comprise" in the claims, it should be assumed that it does not compromise the complementarity between the core sequence of double-stranded RNAi and the target RNA. Building on this understanding, combined with the explanation of terms in the description and the rules for nucleotide addition, those skilled in the art have the ability through conventional technical means to make selection and verification, so as to add one to two nucleotides at each end of the core sequence to form protruding ends or similar structures, while maintaining the corresponding basic functional activity.  The panel thus believes that the amended claim 1 is sufficiently supported from the description. 

Discussion

From the invalidation case, we could see that, the specific technical field, the format of the claims, the technical problems to be solved, and the level of disclosure in the patent application involving biological sequences are diverse and complex, making it difficult to have a "one-size-fits-all" standard for judgment. Therefore, in the examination practice, specific analysis should be conducted based on the specific circumstances of each case to substantively grasp the issues of support. For example, the presence of terms such as "comprising" or "homology" in the claims should not automatically lead to the conclusion that they are not supported by the description, thus avoiding a formalized and mechanized approach to determining support issue.

The invalidation case demonstrates the potential for obtaining reasonable protection of rights for biological sequence claims in China.  Applicants could pay more attention to the preparation of patent applications for such inventions, providing a detailed description for the relationship between the biological sequence and its function. It may be preferable to provide multiple examples of implementation, along with an explanation of the effects of variations. Furthermore, the claims could be drafted in multiple ways to describe the technical solution from different levels and perspectives (such as function, length, mutation site and so on), in order to seek a broader scope of protection.