News & Topics

 

      The Defendant (Amgen) filed a patent application with regard to an invention titled “Antigen Binding Proteins to Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9)” on September 20, 2013 by dividing a part of a patent application (Patent Application No. 2010-522084) for which the international filing date was August 22, 2008 (Priority date: August 23, 2007, December 21 of the same year, January 9, 2008, and August 4 of the same year, Priority country: United States of America). The Defendant obtained a registration of establishment of a patent right (Patent No. 5705288, this patent is hereinafter referred to as “the present patent”) on March 6, 2015.

      The Plaintiff (Regeneron) filed a request for a trial for invalidation of the present patent with regard to Claims 1 and 9 (Invalidation Trial No. 2020-800011) on February 12, 2020, and received a decision that “The request for a trial is dismissed” (hereinafter referred to as “the trial decision of the present case”) on April 7, 2021. Accordingly, the Plaintiff instituted a lawsuit to seek rescission of the trial decision of the present case.

      In this lawsuit, multiple grounds for invalidation were asserted, such as challenging the inventive step, the support requirement and the enablement requirement, but only a judgment on the support requirement was made.

 

      The recitations of Claims 1 and 9 after the correction are as follows (hereinafter, the invention according to Claim 1 is referred to as “Present Invention 1”, the invention according to Claim 9 is referred to as “Present Invention 9”, and Present Invention 1 and Present Invention 9 are collectively referred to as “the present invention,” and in addition, “an antibody which comprises: a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence of SEQ ID NO: 49; and a light chain comprising a light chain variable region consisting of an amino acid sequence of SEQ ID NO: 23” is referred to as the “21B12 antibody” and is also referred to as the “reference antibody.”).

 

An isolated monoclonal antibody, which can neutralize binding between PCSK9 and LDLR protein and which competes for binding to PCSK9 with an antibody which comprises: a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence of SEQ ID NO: 49; and a light chain comprising a light chain variable region consisting of an amino acid sequence of SEQ ID NO: 23. 

A pharmaceutical composition, comprising the isolated monoclonal antibody as claimed in Claim 1. 

 

      It can be understood that a problem of the present invention is to neutralize the binding between PCSK9 and LDLR and increase an amount of LDLR in a subject, and then reduce the risk of disease by treating or preventing the diseases associated with elevated cholesterol levels such as hypercholesterolemia by providing such a novel antibody and preparing a pharmaceutical composition containing it.

      The present specification specifically describes a method for producing an anti-PCSK9 monoclonal antibody, a method for screening for an antibody that neutralizes the binding of PCSK9 to LDLR, and a method for screening for an antibody that competes with the 21B12 antibody.

      In addition, in the examples, it is concretely shown that the screening of the present invention can repeatedly identify a number of antibodies of the present invention with a sufficiently high probability by two screenings such as “screening to choose those that can neutralize the binding between PCSK9 and LDLR” and “screening to choose those that compete with the 21B12 antibody”.

      The present specification then describes a mechanism of action wherein neutralizing the binding of PCSK9 to LDLR increases an amount of LDLR, resulting in reducing serum cholesterol in a subject.

      Therefore, it can be reasonably recognized that the antibody of the present invention, which has a property of “neutralizing the binding of PCSK9 to LDLR protein”, has the effect of reducing serum cholesterol in the subject, resulting in treating, preventing and reducing the risk of disease associated with elevated cholesterol such as hypercholesterolemia. 

      Therefore, a person ordinarily skilled in the art can recognize from the description of the present specification that the antibody of the present invention can solve the above problems. Thus, the patent in question satisfies the support requirement.

 

4-1. Basic Concept of Support Requirement

      Whether or not the descriptions of the claims satisfy the support requirement should be determined by comparing the claims and the detailed description of the invention and considering whether or not the invention of the claims is the invention described in the detailed description of the invention, and then whether or not the detailed description of the invention is such that a person ordinarily skilled in the art can recognize that the problem of the invention can be solved, or whether or not it is such that a person ordinarily skilled in the art can recognize that the problem of the invention can be solved in light of the common general technical knowledge at the time of filing, even without a statement or suggestion in the detailed description of the invention.

 

4-2. Determination of Present Invention

(1) Claim 1 of Present Invention

     Claim 1 of the present invention contains invention specifying matters (1) “which can neutralize binding between PCSK9 and LDLR protein”, (2) “which competes for binding to PCSK9 with an antibody (21B12 antibody, reference antibody) which comprises: a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence of SEQ ID NO: 49; and a light chain comprising a light chain variable region consisting of an amino acid sequence of SEQ ID NO: 23”, and (3) “An isolated monoclonal antibody”. Invention specifying matters (1) and (2) determine the properties of the monoclonal antibody in invention specifying matter (3). 

 

(2) As to “neutralize”

     The term “neutralize” in the present invention includes an aspect of altering a binding ability of PCSK9 to LDLR protein through indirect means (such as structural or energetic alterations in a ligand) in addition to interfering with, blocking, reducing, or modulating an interaction between PCSK9 and LDLR protein by directly blocking a protein binding site.

 

(3) As to “compete”

     It was interpreted that, in the present invention, “compete” with the reference antibody means preventing or inhibiting (e.g., reducing) the specific binding of the reference antibody by binding to the same or overlapping site on PCSK9 as the site where the reference antibody binds to PCSK9, or sterically hindering the binding of the reference antibody to PCSK9 to prevent or inhibit (e.g., reduce) specific binding of the reference antibody. It is evaluated as “competition” between antibodies if an assay determines that an antibody prevents or inhibits (e.g., reduces) a specific binding of a reference antibody to PCSK9. However, in the present invention, the degree of “competition” is not specified.

 

(4) Properties of Monoclonal Antibody of Present Invention

     A monoclonal antibody of the present invention which competes with a reference antibody to prevent or inhibit (e.g., reduce) specific binding of the reference antibody in various degrees encompasses a very wide variety of antibodies. It is determined that the monoclonal antibody of the present invention encompasses not only an antibody which prevents or inhibits (e.g., reduces) specific binding of the reference antibody by binding to the same site on PCSK9 as the site where the reference antibody binds to PCSK9, but also an antibody which prevents or inhibits (e.g., reduces) specific binding of the reference antibody by binding to a site which overlaps with the site where the reference antibody binds to PCSK9, and an antibody which prevents or inhibits (e.g., reduces) specific binding of the reference antibody by sterically hindering the binding of the reference antibody to PCSK9.

 

4-3. Problem to be Solved by Invention

(1) Technical Significance

     The problem of the present invention is to provide an antibody that neutralizes the binding between PCSK9 and LDLR protein, which reduces an amount of LDLR protein in a subject and increases an amount of LDL by binding to LDLR protein, or a pharmaceutical composition containing the same. In relation to solving this problem, competition with a reference antibody cannot have any unique meaning. Therefore, the technical significance of the present invention resides in the fact specified wherein any antibody that competes with the 21B12 antibody has functional properties as a binding neutralizing antibody through a mechanism similar to that of the 21B12 antibody.

 

(2) Functional Property (Position to bind to PCSK9)

     The present specification does not specifically describe a position where, among antibodies identified as those that compete as described above, the antibody stated to have a neutralizing activity binds on PCSK9. It can be deemed to be highly probable that a group of antibodies having an amino acid sequence that is highly identical to the 21B12 antibody bind to PCSK9 in a position similar to the 21B12 antibody. However, regarding several groups of antibodies having an amino acid sequence other than the above, the position where the above antibody binds to PCSK9 cannot be deemed to be apparent since there is no common knowledge that the position where the antibody binds to PCSK9 is apparent due to being estimated to compete in the assay such as epitope binning.

    The present specification describes that “antigen-binding proteins and their fragments that compete with or bind to the same epitope as the exemplified antigen-binding proteins are expected to have similar functional properties.” However, as mentioned above, “competing with the 21B12 antibody for binding to PCSK9” does not specify that the antibody binds to PCSK9 at the same position as the 21B12 antibody.  Therefore, it cannot be said that any antibody that competes with the 21B12 antibody is an antigen-binding protein (antibody) that competes with or binds to the same epitope as the 21B12 antibody. Since there is no particular explanation for the mechanism that supports the fact that such antibodies in general have functional properties similar to those of the 21B12 antibody, it cannot be said that the “antibody that competes with the 21B12 antibody for binding to PCSK9” of the present invention has functional properties which are to those of the 21B12 antibody. 

 

(3) Assertion of Defendant

     The Defendant asserts that there is no reason why the present invention does not comply with the support requirement, on the grounds that even if there exists an antibody which competes with the 21B12 antibody (the reference antibody) but which cannot neutralize the binding between PCSK9 and LDLR protein, such an antibody is literally excluded from the technical scope of Present Invention 1.

     However, the technical significance of the present invention should be identifying that an antibody which competes with the 21B12 antibody has a functional property as an antibody which neutralizes the binding between PCSK9 and LDLR protein by the mechanism similar to that of the 21B12 antibody. If an antibody which competes with the 21B12 antibody includes one which does not have a binding neutralizing activity, it is apparent that the assumption of the technical significance will collapse.

 

(4) Conclusion

     Thus, since Present Inventions 1 and 9 do not comply with the support requirement, the trial decision including a conclusion different from this involves an error.

     It is noted that some of the plaintiff’s claims regarding “EGFa mimic antibodies” are worthy of consideration and cast doubt on the defendant’s claim that the support requirement is satisfied. However, there is no need to make a judgment on this point, because both Present Inventions 1 and 9 are recognized as not satisfying the support requirement as mentioned above, so the IPHC refrains from making any further judgment.

 

      This judgment relates to a case in which the invention was defined using functional expressions of “which can neutralize binding between PCSK9 and LDLR protein” and “which competes for binding to PCSK9 with an antibody”. The basic concept of the support requirement is shown in court precedents (e.g., en banc decision of the IPHC on November 11, 2005 (2005 (Gyo-ke) No. 10042) on “Manufacturing Method of Polarizing Film”). The JPO examination guideline is also consistent with this concept.

      The IPHC stated that the technical significance of the present invention lies in the fact that any antibody that competes with the reference antibody has functional properties as a binding neutralizing antibody as to binding to PCSK9. The IPHC also stated that the present invention includes an antibody that competes with the reference antibody and does not have neutralizing binding properties, and the binding position on PCSK9 is not clear even in consideration of the present specification and the common technical knowledge. It is then determined that the support requirement was not satisfied, and the trial decision was reversed. The claims of the present invention grant exclusive rights to an invention based on properties different from the functional property disclosed in the specification, which may also cause a problem as a reach-through claim that covers inventions that will be made in the future. In this regard, this IPHC decision on the support requirement would be appropriate.

      In the future, when defining an invention using functional expressions, the technical significance of the invention should be clarified, and in order to satisfy the support requirement, it is important to consider thoroughly the disclosure of the specification regarding the functional expressions and the common technical knowledge. In particular, in antibody claims, when defining an invention using functional expressions such as “which can neutralize” or “which competes with a reference antibody,” it is important to identify the functional properties (e.g., to clarify the binding position of the antibody, etc.) in order to comply with the support requirement. For example, in case that “even if there exists an antibody which competes with the 21B12 antibody (the reference antibody) but which cannot neutralize the binding between PCSK9 and LDLR protein, such an antibody is literally excluded from the technical scope of the present invention” as the defendant asserted, if the functional properties have technical significance for the present invention, it is necessary to specifically clarify that the invention has those functional properties when the technical significance of the present invention lies in the functional properties.

      In order to further clarify the judgment on the support requirement in antibody patents, it is necessary to accumulate judicial precedents, and it is important to watch future trends of the judicial precedents. For example, this decision did not specifically address the plaintiff’s assertion regarding the “EGFa mimic antibody”, but cast possible doubt on the defendant’s claim that the support requirement is satisfied. It is necessary to watch future judicial precedents.

      It is noted that as a dispute between Amgen and Regeneron, a lawsuit was filed against a similar antibody patent (Patent No. 5906333, Patentee: Amgen) that differs from the present patent only in the reference antibody, and a similar decision was issued on the same date as this decision. (IP High Court Case on January 26, 2023 (2021 (Gyo-ke) No. 10094))

 

(1) IP High Court Decisions on December 27, 2019 (2019 (Gyo-ke) No. 10225 and 2019 (Gyo-ke) No. 10226)

     For the present patent (Patent No. 5705288, Patentee: Amgen), an invalidation trial was requested by Sanofi, and corrections were requested by Amgen. The JPO made a trial decision (Invalidation Trial No. 2016-800004) dismissing the request for the invalidation trial of the present patent and admitting the correction.

     Sanofi was dissatisfied with this trial decision and filed a lawsuit to cancel the trial decision at the Intellectual Property High Court, but the lawsuit was dismissed. In this lawsuit, all of the grounds for the cancellation asserted by Sanofi (errors in determining the inventive step, the support requirement, and the enablement requirement) were denied. Sanofi appealed this decision to the Supreme Court, but on April 24, 2020, the Supreme Court refused the appeal so that the decision was finalized. (IP High Court Decision on December 27, 2019 (2019 (Gyo-ke) No. 10225))

     It is noted that, as a dispute between Amgen and Sanofi, a lawsuit was filed against a similar antibody patent (Patent No. 5906333) that differs from the patent in question only in the reference antibody, and a similar decision was issued on the same date as this decision. (IP High Court Case on December 27, 2019 (2019 (Gyo-ke) No. 10226))

 

(2) Amgen Inc. v. Sanofi, Aventisub LLC (Fed. Cir. Feb.11, 2021)

     In 2014, Amgen, which owns patents (US 8,829,165, US 8,859,741) corresponding to the patent in question (Patent No. 5705288), sued Sanofi in a federal district court for patent infringement. Sanofi argued that the patent was invalid due to the failure to satisfy the enablement requirement, but the federal district court decided that the patent was valid. The decision was subsequently appealed to the CAFC, which reversed and remanded the federal district court’s decision. On the remand, the federal district court reviewed the compliance with the enablement requirement and decided that the enablement requirement was not satisfied. Amgen was dissatisfied with this remand decision, and appealed to the CAFC, but the CAFC affirmed the decision that the enablement requirement was not satisfied (February 11, 2021). This affirmation was then appealed to the Federal Supreme Court, but on May 18, 2023, the Supreme Court issued a decision affirming the CAFC’s decision.