June, 2019｜News Letter

1. What Extent of Disclosure should be Made in Specification to Satisfy Enablement Requirement for Antibody-Related Invention?

Alexion Pharmaceuticals Inc. v. Chugai Pharmaceutical Co., Ltd., Case No. 2018 (Gyo-Ke) 10045 (Decision rendered on June 26, 2019)

The Patentee, Chugai, obtained a patent relating to a pharmaceutical composition comprising an antibody in 2015. Against the Chugai’s patent, Alexion filed an invalidation trial with the JPO in 2016. The JPO dismissed the Alexion’s demand in 2017. Alexion filed an appeal against the JPO's decision to the IPHC in 2018.

The granted claim 1 of the Chugai’s patent at issue claims as follows:
A pharmaceutical composition comprising an antibody having a KD(pH5.8)/KD(pH7.4) value … and an increased ability to eliminate an antigen in plasma,
wherein at least one amino acid of a variable region is substituted with histidine, or one histidine is inserted into at least a variable region.

One of the main issues in this case related to what extent of the disclosure should be made in the specification of the patent at issue to satisfy the enablement requirement for an antibody-related invention. The IPHC answered to the issue as follows:

To begin with, in the JPO’s decision, having reviewed the description of the specification of the patent at issue, including the working examples, the JPO found (i) that those skilled in the art could have rationally inferred on the basis of the description that antibody H3pI/L73 was an antibody obtained by introducing histidine mutations to the variable regions of the antibody H53/PF1L to impart the property of an increased ability to eliminate an antigen in plasma, (ii) that the description showed that, taking anti-human IL-6 antibody and anti-mouse IL-31 receptor antibody as examples, it was possible to provide an antibody with a remarkable pH-dependent binding property by introducing histidine mutation(s) to the variable region(s), and (iii) that the description clarified that histidine scanning, three-dimensional modeling, screening from antibody libraries and the like, were cited as specific methods for preparing such antibodies.
On the basis of the above findings, the JPO decided (i) that those skilled in the art could have understood the mechanism that a predetermined pH-dependent binding property was able to be obtained by introducing histidine mutation(s) to the variable region(s) of an antibody, by which an increased ability to eliminate an antigen in plasma was imparted, (ii) that the disclosure of the description was sufficient for those skilled in the art to understand that there were methods for obtaining such antibodies, such as histidine scanning, three-dimensional modeling, and screening from antibody libraries, and (iii) that the working examples sufficiently supported that such antibodies were actually able to be obtained; and therefore that the description was clearly and sufficiently disclosed so that those skilled in the art could have carried out the invention claimed in the patent at issue.
Further, the JPO added that, even though there might be some exceptions where it was difficult to obtain antibodies having a predetermined pH-dependent binding property and an ability to eliminate an antigen in plasma by introducing histidine mutation(s), it was inappropriate to conclude that the enablement requirement was not satisfied as far as it could be rationally inferred that the increased ability to eliminate an antigen in plasma by introducing histidine mutation(s) could be widely recognized in various antibodies.

However, the IPHC overturned the above JPO’s decision as follows:

(1) Claim 1 of the patent at issue fails to restrict the original antibody and the positions and the number of histidine substitutions or insertions, and thus, it can also be understood that an original antibody or positions and the number of histidine substitutions or insertions are not restricted for an antibody included in a pharmaceutical composition of Claim 1 of the patent at issue. Therefore, the technical scope of Claim 1 of the patent at issue includes pharmaceutical compositions comprising every antibody having one or a plurality of histidine substitutions and/or insertions, and a predetermined pH-dependent binding property, with a lengthened half-life in plasma.
As such, in order for Claim 1 of the patent at issue to conform to the enablement requirement, it is considered that the description of the specification of the patent at issue is required to describe the invention to the extent that allows those skilled in the art to implement the entire range of pharmaceutical compositions included in Claim 1 of the patent at issue.

(2) The CDR sequence described in [Best Mode for Carrying out the Invention] of the specification of the patent at issue as a position to be substituted with histidine is at most an example, and a desired antibody may possibly be obtained by modification of another position. Therefore, the CDR sequence does not apply to the entire range of pharmaceutical compositions included in Claim 1 of the patent at issue.

(3) Example 2 in the specification of the patent at issue describes a method using homology modeling and a three-dimensional model. However, the homology modeling is a method that predicts a three-dimensional structure of a protein with an unknown structure with a computer on the basis of a three-dimensional structure of a protein with a known structure having homology with an amino acid sequence.
As such, the method using homology modeling described in Example 2 cannot be necessarily used in all cases when studying histidine substitution positions in an antibody with an unknown structure in general.
Example 3 in the specification of the patent at issue describes a method of selecting in advance positions where substitution of the CDR residue with histidine did not significantly alter the binding ability by a method of histidine scanning, and preparing an antibody where one position among the positions is substituted with histidine. This method, unlike the method described in above Example 2, can be said to be applicable to an antibody with an unknown structure.
However, from the descriptions of the specification of the patent at issue, it is unclear that a position substituted with histidine in an antibody of Claim 1 of the patent at issue necessarily is contained in the “positions where substitution of the CDR residue with histidine did not significantly alter the binding ability” in Example 3. Moreover, there is no evidence to acknowledge common technical knowledge that a position substituted with histidine in an antibody of Claim 1 of the patent at issue necessarily is contained in the “positions where substitution of the CDR residue with histidine did not significantly alter the binding ability”.
Therefore, the methods described in Example 2 and Example 3 cannot be applied to the entire range of pharmaceutical compositions included in Claim 1 of the patent at issue.

Conclusively, the IPHC upheld the Alexion’s appeal and cancelled the JPO’s decision.

An appeal to the Supreme Court was filed against this decision, and thus the decision is NOT made final and binding.

K&P’s Comments As shown above, the JPO moderately made a decision on the enablement requirement by recognizing that there can be exceptions which actually do not work even by introducing histidine mutation(s), whereas the IPHC made a decision on a very rigorous basis. We believe that the IPHC decision is based on overly stringent criteria, and hope that this case would be reconsidered before the Supreme Court.

(by Katsumasa OSAKI, Patent Attorney)

In June, 2019, the IPHC handed down 13 decisions including the above case on patent, and overturned the previous decisions in 4 cases.

In June, 2019, the IPHC handed down 1 decision on trademark, and maintained the previous decision.

In June, 2019, the IPHC handed down 1decision on industrial design, and maintained the previous decision.