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February 8, 2019

Patent News

The Tokyo District Court interprets functional claim narrowly in a patent infringement case relating to Hemlibra(R) (emicizumab)

Asserting Japanese Patent No. 4313531 (the "Patent"), Baxalta Incorporated and Baxalta GmbH (correctively "Plaintiffs") sought an injunction prohibiting Chugai Pharmaceutical Co., Ltd, ("Chugai") from manufacturing, using, transferring, exporting, offering to transfer, and destruct Chugai's antibody drug Hemlibra(R) (emicizumab) ("the Products"). No damages were claimed in this lawsuit. The court ruled that the Products do not infringe the Patent, interpreting its functional claim narrowly.(The Tokyo District Court's judgement of March 28, 2018 (Case No. 2016 (wa) 11475))



1. Background

1.1. The Parties
Plaintiffs own Japanese Patent No. 4313531 ("the Patent"). Chugai manufactures the Products and the Plaintiffs allege that Chugai's activities infringe the Patent.

1.2. The Patent
The claims of the Patent were amended twice in the proceedings of trial for correction before the JPO. The claims of the Patent as amended are as follows, and the feature "except for antibody clone AHIX-5041... antibody derivatives thereof" was added in the second proceedings of trial for correction.

Claim 1 ("Invention 1")
  • Element 1A: An antibody or antibody derivative against factor IX or factor IXa,
  • Element 1C: wherein the antibody or antibody derivative (except for antibody clone AHIX-5041: manufactured by Haematologic Technologies, antibody clone HIX-1: manufactured by SIGMA-ALDRICH, antibody clone ESN-2: manufactured by American Diagnostica Co., and antibody clone ESN-3: American Manufactured by Diagnostica, as well as antibody derivatives thereof
  • Element 1B: increases the procoagulant activity.


Claim4 ("Invention 4")
  • Element 4D: An antibody or antibody derivative according to Claim 1,
  • Element 4F: wherein the antibody or antibody derivative
  • Element 4E: is selected from the group consisting of a monoclonal antibody, an antibody fragment, a chimeric antibody, a humanized antibody, a single chain antibody, a bispecific antibody, a diabody, and dimers, oligomers, or multimers thereof.


1.3. The Products
  • (1) Name of product: Hemlibra(R) / development code name: ACE910 / generic name: emicizumab
  • (2) Type: An antibody drug
  • (3) Manufacturer: Chugai
  • (4) Start of clinical trial: around August, 2012 at the latest
  • (5) Summary: bispecific antibody comprising activated factor IX and activated X factor
  • The amino-acid sequence of the Products is as follows.
    - An antibody comprising; an amino acid sequence of QVQLVESGGGLVQPGGSLRLSCAASGFTFSYYDIQWVRQAPGKGLEWVSSISPSGQSTYYRREVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRTGREYGGGWYFDYWGQGTLVTVSS ("IXa Side H Chain") and QVQLVQSGSELKKPGASVKVSCKASGYTFTDNNMDWVRQAPGQGLEWMGDINTRSGGSIYNEEFQDRVIMTVDKSTDTAYMELSSLRSEDTATYHCARRKSYGYYLDEWGEGTLVTVSS ("X Side H Chain") as an H chain; and an amino acid sequence of DIQMTQSPSSLSASVGDRVTITCKASRNIERQLAWYQQKPGQAPELLIYQASRKESGVPDRFSGSRYGTDFTLTISSLQPEDIATYYCQQYSDPPLTFGGGTKVEIK as a common L chain,
    wherein the antigen binding site ("lXa Binding Site") derived from the IXa Side H Chain and the above L chain binds to factor IXa, and
    wherein the antigen binding site ("X Binding Site") derived from the X Side H Chain and the above L chain binds to factor X.


2. Judgement

2.1. Rullings
The Court rejected the Plaintiffs' claims by finding that the Products do not fall within the technical scope of the Inventions for the reasons discussed hereafter.

2.2. Regarding interpretation of functional claims
With respect to the term "the antibody or antibody derivative... increases the procoagulant activity", there is no description defining this term in the current specification of the Patent ("the Specification"), and this term is only to indicate the purpose of the Inventions of "(providing) a preparation for the treatment of blood coagulation disorder" (paragraph [0010] of the Specification). Thus, this term concerned merely expresses the function or effect of the antibody or the antibody derivative of the Inventions and does not specify the specific configurations to achieve the purpose or effect of the Inventions.
In the case where claims are described only in a functional or abstract expression, it is not permissible to interpret that any configuration achieving the function or effect falls within the technical scope of a relevant patented invention.
In a case where claims are described in a functional or abstract expression, the technical scope of a relevant patented invention cannot be interpreted only by the description of the claims but must be interpreted also with the technical idea provided in the specific configurations disclosed in the specification of the patent. However, as long as persons skilled in the art can implement other configurations based on the specification of the patent, such configurations are included in the technical scope of the patented invention.

2.3. The Products do not fall within the technical scope of the Inventions
The Court, in judging the technical scope of the Inventions, mentioned as follows:
  • (1) In this case, in the description of the Specification, more than one monoclonal antibody (monospecific antibodies) having factor VIII-like activity was prepared by screening antibodies against factor IXa and by pigmentation assay (Examples 4 and 9). Among them, an antibody (193/AD3) which causes blood clotting of factor VIII inhibitor has also been confirmed (Example 7). Therefore, persons skilled in the art can manufacture a monoclonal antibody (monospecific antibody) which increase procoagulant activity at a constant rate by screening antibodies against factor IXa without excessive trial and error.
  • (2) In addition, more than one derivative from monoclonal antibodies (monospecific antibodies) that increases procoagulant activity was also produced (for example, peptides derived from the CDR3 region and its derivatives (Examples 11 and 12), chimeric antibodies (Example 13), Fab fragments (Example 15), single chain antibodies (scFv. Examples 10, 16, 18), mini-antibodies (Example 17)). Therefore, persons skilled in the art can manufacture derivatives from monoclonal antibodies (monospecific antibodies) that increase procoagulant activity.
  • (3) In connection with the extent of "increas(ing) procoagulant activity", little increase in procoagulant activity cannot be evaluated as "increas(ing) procoagulant activity". The extent of such increase must be substantial, and "increas(ing) procoagulant activity" must be that the ratio with the negative control exceeds about 2 at least.
  • (4) In terms of a bispecific antibody, according to the common technical knowledge at the filing date, it is possible to manufacture a bispecific antibody against factor IX or factor IXa. Thus, it is possible to predict that a bispecific antibody derived from a monospecific antibody against factor IX or factor IXa can maintain the activity of increasing the procoagulant activity of the monospecific antibody. Therefore, a bispecific antibody is also included in "antibody derivatives" as one embodiment of antibody derivatives obtained by modifying the antibody while maintaining the activity of the monospecific antibody. Consequently, a bispecific antibody can be deemed one embodiment of the "antibody derivatives".
  • (5) Consequently, to be covered by the technical scope of the Inventions, it is necessary that a monoclonal antibody (monospecific antibody) be against factor IX or factor IXa that increases substantially the procoagulant activity of the factor IXa, or an antibody derivative which maintains this activity and is modified from said antibody. A bispecific antibody will be included in them as one form of the "antibody derivative".


The Court further compared the technical scope of the Inventions with the Products and denied infringement a follows.
  • (1) Concerning the Products, the ratio of the monospecific antibody that comprises an arm binding to factor IXa of the Products (Qhomo) with the negative control is 1.36 to 1.48, and therefore, the Qhomo is not a monospecific antibody which increases substantially the procoagulant activity of the factor IXa. Since the Products is a monospecific antibody (an antibody derivative) which is made by modifying one arm of the Qhomo to be against factor X, it can be said that the Products are antibody derivatives which do not increase substantially the procoagulant activity of factor IXa.
  • (2) Accordingly, the Products have the effect of increasing procoagulant activity by extracting factor IXa binding site from a monospecific antibody which does not substantially increase the procoagulant activity of factor IXa and by converting to a bispecific antibody in combination with a specific factor X binding site. Therefore, the Products do not fall under "monoclonal antibody (monospecific antibody) against factor IX or factor IXa which substantially increases the procoagulant activity of factor IXa or an antibody derivative obtained by modifying the antibody while maintaining its activity", and thus, do not fall within the technical scope of the Inventions.


3. Comments

3.1. Since the technical idea of the Invention and the Products are quite different, the conclusion of the Judgement itself is quite reasonable.
Haemophilia A is the most frequent congenital coagulation disorder caused by deficiency of coagulation factor VIII.
At the time of filing the Patent, the treatment was so-called "Supplementary Therapy", which supplements deficient factor VIII. However, because of the existence of anti-Factor VIII antibodies (inhibitors), a treatment other than "Supplementary Therapy" was desired at the time of filing.
The Invention has a technical idea of enhancing the enzymatic activity of factor IXa and increasing the procoagulant activity by an antibody having an arm binding to factor IX or factor IXa (except for known antibodies).
On the other hand, the Products have a technical idea, namely substituting a bispecific antibody (one of which recognizes active factor IX and the other recognizes factor X) for factor VIII.
As such, the ideas (including its mechanism of action) are clearly different.

3.2. Whether to treat this case with infringement issue or invalidation issue.
In this case, functional claims are patentable but interpreted narrowly.
On the other hand, in the small molecule medicine field, functional claims are not patentable, due to a violation of the description requirement.
Some people question why in the Antibody field functional claims are patentable.
Based on this perspective, some would argue that this case should be treated as a matter of invalidation.

3.3. There were other issues argued in this case as below; however the Court did not address these issues.
  • (1) Whether Chugai's manufacture of the Products infringes or is likely to infringe the Patent right in light of the Products being under investigation in clinical trials conducted outside Japan
  • (2) Whether manufacture of the Products for clinical trials conducted outside Japan falls under "implementation of invention for testing or research" and the Patent is not enforceable against such testing or research (Article 69 (1) of the Patent Act)
  • (3) Whether the Patent shall be invalidated in an invalidation action (Issue 4)

Regarding implementation of invention for testing or research, clinical trials for regulatory approval conducted in Japan are exempt from patent infringement (Supreme Court's Judgement dated April 16, 1999 (Ono Pharmaceutical v. Kyoto Pharmaceutical). Article 69(1) of the Patent Act in Japan provides a testing or research use exemption from patent infringement. However, this does not encompass economic or commercial research (conducted by any party including universities) and whether the manufacturing of drugs in Japan for clinical trials conducted outside Japan are also exempted was never tested. The Court did not decide on this issue.
While clinical trials for regulatory approval shall be included in "implementation of invention for testing or research", manufacturing stocks for sale after expiration of the patent duration shall not be included in "implementation of invention for testing or research".

3.4. This Tokyo District Court judgment is the first court decision regarding the technical scope of antibody claims expressed functionally, and can practically be of reference to a pharmaceutical company who manufactures antibody drugs.

Written by: Mr. Yuichiro Suzuki (Attorney at Law and Patent Attorney)