In inventions relating to pharmaceutical products, methods of defining the claimed inventions widely vary. This is why it is beneficial to have a deeper understanding in what sort of method of defining the claimed inventions should work to get your pharmaceutical invention patented. How to define your pharmaceutical invention is one of the most important factors to interactively fulfill the requirements for description (the support requirement, the enablement requirement, etc.).

For example, in many inventions of antibody drugs, the claims are required to define the antibodies by the structures (by defining the CDR sequences or the sequences in wider regions such as variable regions containing the CDRs) while satisfying the requirements for description, for example, in the examination stages. In the meantime, some inventions have been patented by defining the antibodies by their functions without defining the structures.

This is evidenced by a recent court case (2019 (Ne) 10014) in which an invention of an antibody defined by its function was determined as satisfying the requirements for description. In the following sections of this newsletter, the court case will be introduced. Please see the detailed descriptions, and use this information as a reference in seeking patent protection for your antibody invention to find the most appropriate method of defining the antibody.

 

 

 

Herein below, overviews of the enablement requirement and the support requirement are given. Applications for many pharmaceutical inventions are rejected due to violation of those requirements.

 

(1) Enablement Requirement (Patent Act Article 36(4)(i))

Patent Act Article 36(4)(i) provides that the Detailed Description of the invention shall be stated clearly and sufficiently as to enable a person skilled in the art to carry out a claimed invention. The statement in the description does not satisfy the enablement requirement when a person skilled in the art cannot understand how to carry out the claimed invention based on the statements in the description and drawings as well as the common general knowledge at the time of filing. Furthermore, in a case when a person skilled in the art who intends to carry out the invention would have to make trials and errors and/or complicated and sophisticated experimentation beyond the reasonably expected extent, the statement in the description fails to comply with the enablement requirement.

 

(2) Support Requirement (Patent Act Patent Act Article 36(6)(i))

Patent Act Article 36(6)(i) provides that the claimed invention shall not exceed the extent of disclosure in the Detailed Description of the invention. Determination of the support requirement is made based on an examination on whether or not the claimed invention exceeds “the extent of disclosure in the description to which a person skilled in the art would recognize that a problem to be solved by the invention would be actually solved”. When it is determined that the claimed invention exceeds “the extent of disclosure in the description,” the statement in the claims does not satisfy the support requirement.

 

 

 

In the invention in question, the antibody is defined only by the function to “neutralize the binding of PCSK9 and LDLR protein and compete with a reference antibody”, but not by the structure (amino acid sequence). Please note that the reference antibody is a new antibody identified by the applicant of the invention. It is also to be noted that although the antibody, as itself, having a function to neutralize the binding of PCSK9 and LDLR protein is a new invention, there was a document suggesting the development of the antibody blocking the binding of PCSK9 and LDLR at the time of filing the application.

The specification discloses the mechanism of the antibody of the invention exerting an effect of the invention, and the method of screening through which the antibody of the invention is obtained.

With respect to the mechanism, there are descriptions inferring that the antibody that “neutralizes the binding of PCSK9 and LDLR protein and competes with the reference antibody” causes the decrease of serum cholesterols in a subject in the similar manner as the reference antibody does. Specifically, the specification provides the following disclosures: (1) an anti-PCSK9 monoclonal antibody that neutralizes (blocks) the binding of PCSK9 and LDLR was obtained; (2) the reference antibody excellently blocks the binding of PCSK9 and EGFa domain of LDLR (it is proven by the crystal structure analysis in an embodiment); (3) the anti-PCSK9 antibody blocks the binding of PCSK9 and EGFa domain of LDLR and increase the amount of LDLR, thereby resulting in a reduction in the　subject’s serum cholesterol level; (4) an antibody that competes with the reference antibody was obtained; and (5) the antibody that competes with the reference antibody binds to a small region on PCSK9 that interacts with EGFa domain of LDLR, thereby inhibiting the binding of PCSK9 and EGFa domain of LDLR.

With respect to the method of screening, there are descriptions of a series of the flow to finally obtain the antibody of the claimed invention including: the production of immunized mouse; the preparation of hybridomas by use of immunized mouse; the screening (such as Primary Screening, Large Scale Receptor Ligand Blocking Screening, etc.) to identify “an antibody that competes with the reference antibody and blocks the PCSK9 binding to LDLR” from the anti-PCSK9 antibody produced from hybridomas; the epitope binning assay; and the method of evaluating the effect of the antibody identified by the screening. These descriptions are provided at a feasible level (corresponding approximately to ”Materials and Methods” level in the structure of a research paper) for a person skilled in the art in compliance with the description of the specification. In the embodiment, the results of the crystal structure analysis are shown along with specific descriptions of where the binding domain to LDLR on PCSK9 is positioned, binding of the reference antibody to the binding domain, the reference antibody blocking the binding of PCSK9 and LDLR, etc. It is also described that a person skilled in the art who read these descriptions could have easily identified the binding domain on PCSK9 or another antigen-binding molecule that binds to the periphery, thereby identifying an antigen-binding molecule that can neutralize the binding of LDLR and PCSK9 in the similar manner as the reference antibody does.

 

 

 

The Intellectual Property High Court (hereinafter to be referred to as IP High Court) made a court decision that the invention in question satisfied the support requirement for the reasons described as below.

We can see from the description of the specification that a problem to be solved by the invention is to neutralize the binding of PCSK9 and LDLR and increase the amount of LDLR, thereby decreasing the amount of serum LDL in a subject, resulting in a reduction in the subject’s serum cholesterol level and this effect may treat or prevent or reduce the risk of the diseases associated with increased cholesterol level such as hypercholesteremia, and thus may be therapeutically beneficial.

In the specification, descriptions are given of the method of preparing hybridomas that produces antigen binding protein against PCSK9, and the method of screening and epitope binning to identify an “antibody that competes with the reference antibody and neutralizes the binding of PCSK9 and LDLR” from the antibody obtained from the hybridomas. It is recognized that these descriptions enable a person skilled in the art to obtain a neutralizing antibody competing with the reference antibody in addition to the neutralizing antibodies competing with the reference antibody specifically described in the specifications by repeatedly carrying out a series of procedures described.

From the above, it is determined that a person skilled in the art could obtain, based on the descriptions of the specification, an “isolated monoclonal antibody that neutralizes the binding of PCSK9 and LDLR protein and competes with a reference antibody”, and he/she would have recognized that a problem to be solved by the invention, namely, to treat or prevent or reduce the risk of the diseases associated with increased cholesterol level by use of the antibody would be actually solved, and thus the invention in question conforms to the support requirement.

 

As to the appellant’s allegation that the invention does not define the antibody structure (amino acid sequence), the IP High Court judges that it is a matter of common general knowledge that amino acid sequence is identified in a process of identifying an antibody having specific binding properties, and thus it is not recognized as essential to define the structure of the antibody (amino acid sequence) in advance for obtaining an antibody having specific binding properties.

 

 

The IP High Court made a court decision that the invention satisfies the enablement requirement for the reasons described as below.

As aforementioned in determining the conformance to the support requirement, it can be said that the descriptions of Detailed Description of the specification definitely and sufficiently describes to the extent that allows a person ordinarily skilled in the art to implement each of the inventions because it is determined that the antibody of the invention can be prepared and used based on the description of the specification. Accordingly, the invention in question satisfies the enablement requirement.

 

As to the appellant’s allegation that the invention does not define the antibody structure, but defines only functionally, and includes an extremely broad range of antibodies, whereas it takes enormous time and effort as well as many trials and errors for a person ordinarily skilled in the art to obtain an antibody included in the whole range of the invention that does not define the structure, and thus each of the Inventions fails to satisfy the enablement requirement, the IP High Court made a judgement described as follows. If the descriptions of the Detailed Description should have such a description that allows us to make an antibody which embodies a technical idea of an isolated monoclonal antibody that can neutralize the binding of PCSK9 and LDLR protein and competes with the reference antibody for binding with PCSK9, it must be said that a person ordinarily skilled in the art could implement the technical idea. It is not necessary to describe to the extent that every antibody having every amino acid sequence which can fall within a technical scope of the patent invention may be obtained. A person ordinarily skilled in the art can obtain a neutralizing antibody that competes with the reference antibody included in the scope of the claim in addition to the neutralizing antibodies that compete with a reference antibody described in the specification in compliance with the description the specification. Thus, it cannot be said that it would take many trials and errors that go beyond the level that can be expected for a person ordinarily skilled in the art to obtain an antibody encompassed into the technical scope of the invention.

 

 

 

As the judgment on this case proves, there is a possibility in Japan that even an invention that does not define the antibody structure but defines only functionally can be patented if it is determined that the requirements for description are fulfilled depending on how the specification is described, provided that the other requirements are satisfied.

Indeed, the properness of the court decision was a cause of controversy.　However, in the specification, there are detailed descriptions of a possible mechanism in which an antibody having a function of “neutralizing the binding of PCSK9 and LDLR protein and competing with a reference antibody for binding with PCSK9” causes the decrease of serum cholesterols in a subject, regardless of amino acid sequence, along with the experimental results. In this regard, these descriptions are apparently provided so as to disclose a technical idea that a problem to be solved by the invention can be actually solved by the antibody having such a function to a person skilled in the art. Furthermore, in the specification, the method of screening to obtain the antibody having the function, etc. are described in such a manner that enables a person skilled in the art to carry out the method, the method being able to be carried out regardless of whether or not amino acid sequence is disclosed. What is learned from the judgment is that, in an invention that defines the antibody by its function, at least the specification should include descriptions provided in such a manner that a person skilled in the art can recognize that a problem to be solved by the invention can be actually solved by the antibody defined by its function (not only some examples but all antibodies having the function), regardless of amino acid sequence, as well as descriptions of the method of obtaining the antibody having the function with high reproducibility regardless of whether or not amino acid sequence is disclosed.

If you have an antibody invention in which the specific structure is not yet identified, or if you do not wish to define your invention by its structure, it is recommended that you consider filing an application for the invention defining the antibody by its function. It should be noted, however, that the specification must be described fully enough to fulfill the requirements for description (descriptions of, such as a mechanism of exerting the effect and a method of screening should be included) in an invention defining the antibody by its function. If amino acid sequence is already identified, it would be preferable to include the amino acid sequence in the specification so that an amendment can be made when it is determined as failing to fulfill the requirements for description.

If you are considering filing an antibody invention that falls under these cases, please contact our firm and we will be pleased to give you our professional advises on your specific case.

Determinations vary among the U.S., Europe and Japan on to what extent a sequence limitation is required in an antibody invention. According to the recent researches conducted in Japan, there was a trend that antibody drug inventions with no sequence limitations were more registered in Japan and Europe than in the U.S. (“Recent Trends in the Examination of Antibody Drug and Food Use Inventions and Their International Comparison”, Patent 2020, Vol. 73, No. 6). Let’s say an antibody drug invention was required to define by the antibody structure (amino acid sequence) in the U.S.: the invention may be registered in Japan by not defining the antibody by its structure, but by functionally defining. Defining an antibody this way could be another possible measure.

We will be keeping our eyes on the future trend of how antibodies inventions are defined.