Patent
Right

Date
Case number

October 30, 20192019 (Ne) 10014

Court

Intellectual
PropertyHigh
Court,First
Division- A case in which, with regard to the scope of claims including the constituent
features of "neutralizing" and "competing with an antibody", the court hascomprehensively taken the recitation of the scope of claims and the description ofeach of the specification into account and construed the constituent features.
- A case in which, with regard to the patent titled "ANTIGEN BINDING PROTEINAGAINST PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 9 (PCSK9)",
the court has determined that it does not violate the support requirement and theenablement requirement.
- A case in which the court has determined that it cannot be said that the injunctive
relief of the production. transfer, etc. of antibody and pharmaceutical product is an
abuse of right.
Case type: Injunction
Result: Appeal Dismissed
References: Article 70, paragraph (1) and paragraph (2), Article 104 -3, Article 100,
paragraph (1) and paragraph (2) of the Patent Act
Number of related rights, etc.: Patent No. 5705288, Patent No. 5906333
Summary of the Judgment
1.

This case is a case where Appellee, who owns two patent rights titled"ANTIGEN-BINDING

PROTEINAGAINSTPROPROTEINCONVERTASE

SUBTILISIN KEXIN TYPE 9 (PCSK9)", seeks against Appellant an injunction of the
production, transfer, import, or offer to transfer of the Defendant's products andDefendant's monoclonal antibody by Appellant and a disposal of Defendant's products
and Defendant's monoclonal antibody, alleging that the above Appellant's acts
infringe each of the patent rights.
The judgment in prior instance ordered against Appellant an injunction of the
production, transfer, import, or offer to transfer of Defendant's products andDefendant's monoclonal antibody and dismissed the remaining claims from Appellee,
stating that Defendant's products and Defendant's monoclonal antibody fall within thetechnical scopes of Inventions 1 and 2 and Corrected Inventions 1 and 2, and none of
the reasons for invalidation as Appellant alleges has a point.
Appellant filed an appeal objecting to the judgment in prior instance.
2.

In summary, the court decision has dismissed the appeal, stating that

Defendant's product and Defendant's monoclonal antibody fall within the technicalscope of each of the Inventions, and it cannot be recognized that each of theⅰInventions should be invalidated for the reasons of nonconformance to the support
requirement, nonconformance to the enablement requirement, and lack of inventive
step, nor is it construed that the injunctive relief is not permitted due to abuse of right.
(1) Whether or not to fall within the technical scope of each of the Invention sA.

Comprehensively taking into account the recitation of the scope of claims andthe description of each of the specifications, "neutralizing" the binding of PCSK9 and
LDLR in each of the Inventions is to prevent the binding of PCSK9 to LDLR, and it isrecognized that "competing with an antibody" of each of the inventions is acompetition between antigen-binding proteins measured by competition assay, andmeans the binding to the same epitope to which a reference antibody binds to PCSK9,or an overlapping epitope, or the binding to an adjacent epitope that produces a sterichindrance for the binding of reference antibody with PCSK9.
The "antibody", a basis for the competition for the binding with PCSK9 in
Defendant's monoclonal antibody, further specifies reference antibody 1 of Invention
1 and reference antibody 2 of Invention 2 by an amino acid sequence of variable
region, and thus fulfills both reference antibody 1 and reference antibody 2.

Further,

Defendant's monoclonal antibody and Defendant's product respectively fulfill theremaining constituent features of each of the Inventions.
B.

Appellant alleges as follows: each of the Inventions is a functional claim

specifying the invention only by a function competing with reference antibody 1 or 2,
and thus the technical scope of the invention should be defined on the basis of thetechnical idea shown in the specific configuration that the Applicant disclos ed in thespecification, it should be limited to a scope within which a person ordinarily skilledin the art can perform from the description of the specification, and the technicalscope of each of the Inventions is limited to a specific antibody described in theexample of each of the specifications or an antibody having an amino acid sequence inwhich one or several amino acids at a specific position are substituted in the former
antibody.

Thus, Defendant's monoclonal antibody and Defendant's product having a

different amino acid sequence from them respectively do not fall within the technicalscope of each of the Inventions.
Setting aside the question of whether each of the Inventions should be called aso-called "functional claim", the technical scope of the patent invention must be
determined on the basis of the recitation of the scope of claims, and should beconstrued on the basis of a technical idea disclosed therein by taking the descriptionof the specification and drawings into account, and the Appellant's allegation should
be considered as a problem of support requirement or enablement requirement .
ⅱ

Atechnical idea disclosed in each of the specifications is that an isolated monoclonal
antibody competing with reference antibody 1 or 2 binds to PCSK9 in a location
and/or a manner that prevents PCSK9 from binding to LDLR, blocks (neutralizes) the
binding between PCSK9 and LDLR, and reduces LDL level in a subject to exert aneffect of causing the decrease of serum cholesterols in a subject.

Further, as

aforementioned, Defendant's monoclonal antibody and Defendant's product fall withina technical scope of each of the Inventions that are construed on the basis of the above
technical idea.

Each of the Inventions provides an isolated monoclonal antibody thatneutralizes the binding of PCSK9 and LDLR protein and competes with each ofreference antibodies, and has constituent features of both blocking the binding
between PCSK9 and LDLR for "neutralization" and "competing" with a reference
antibody with regard to the binding with PCSK9.

Further, it cannot be said that

there is a description in each of the specifications that makes us believe that each of
the Inventions is specified only by a function to compete with reference antibody 1 or
2.

Appellant's allegation of each of the Inventions being limited to the example on

the premise of that is not acceptable.
C.

As described above, Defendant's monoclonal antibody and Defendant's productrespectively fall within the technical scopes of Inventions 1 and 2.
(2) Nonconformance to support requirement
Each of the Inventions provides an isolated monoclonal antibody thatneutralizes the binding of PCSK9 and LDLR protein and competes with reference
antibody 1 or 2, and a pharmaceutical composition using the same.

It can be seenthat the problem lies in the provision of such novel antibody and the preparation of apharmaceutical composition using the same that can neutralize the binding of PCSK9and LDLR and increase the amount of LDLR, thereby resulting in a reduction in thesubject's serum cholesterol level and treating or preventing or reducing the risk of thediseases associated with increased cholesterol level such as hypercholesteremia.
Each of the specifications discloses that hybridomas have been prepared by useof immunized mice produced in accordance with the description of each of thespecifications, and 2441 stable hybridomas producing an antibody that binds to
PCSK9 have been established by screening, and it has been found that, of these, 39
antibodies in total were subjected to an epitope binning, which resulted in 15
neutralizing antibodies not competing with 31H4 but competing with 21B12 and 7
neutralizing antibodies not competing with 21B12 but competing with 31H4.
Further, each of the specifications also discloses that 21B12 and 31H4 have excellent
effects of blocking the binding of PCSK9 and EGFa domain of LDLR.
ⅲ

21B12 is included in reference antibody 1, and 31H4 is included in reference
antibody 2.

Thus, it can be seen that an antibody competing with 21B12 is anantibody competing with reference antibody 1 and an antibody competing with 31H4
is an antibody competing with reference antibody 2.

Consequently, it is recognizedthat a person ordinarily skilled in the art who read each of the specification s could
recognize that, in addition to the fact confirmed as a result of the above epitope
binning assay that the specific antibodies are obtained, neutralizing antibodies
competing with reference antibody 1 or 2 may be obtained through a similar epitope
binning assay for the above remaining antibodies obtained from the above 2441 stablehybridomas, and have an effect of causing the decrease of serum cholesterols in a
subject.

Furthermore,

each

of

the

specifications

describes

procedure

immunization program, a method of screening, and an epitope binning assay.

of
It is

recognized that based on these descriptions, a person ordinarily skilled in the art could
recognize that neutralizing antibodies competing with reference antibody 1 or 2 might
be obtained in addition to neutralizing antibodies competing with the reference
antibody specifically described in each of the specifications, by repetitively
implementing a series of procedures from the start.
It is recognized that based on the above, a person ordinarily skilled in the art
can obtain an isolated monoclonal antibody that neutralizes the binding of PCSK9 and
LDLR protein and competes with reference antibody 1 or 2 on the basis of thedescription of each of the specifications, and thus a novel antibody of monoclonal
antibody of each of the Invention is provided, and one can recognize the fact that a
pharmaceutical composition of each of the Inventions using them may treat or preventor reduce the risk of the diseases associated with increased cholesterol level such as
hypercholesteremia.

It is thus recognized that each of the Inventions conforms to the

support requirement.
(3) Nonconformance to enablement requirement
It can be seen from the description of each of the specifications that an
antibody and a pharmaceutical composition of each of the Inventions may be
produced and used, and it can be said that the description of Detailed Description of
Inventions in each of the specifications definitely and sufficiently describes to theextent that allows a person ordinarily skilled in the art to implement each of theInventions.

Thus, it is recognized that each of the Inventions conforms to theenablement requirement.
(4) Propriety of injunctive relief
A.

Appellant alleges that Appellant does not produce Defendant's products, norⅳ

does it produce, import, transfer, and offer to transfer its raw material of Defendant's
monoclonal antibody; however, it cannot be ruled out that Appellant might possibly
produce Defendant's product or transfer Defendant's monoclonal antibody following
the import or production of Defendant's monoclonal antibody, and thus it must be said
that Appellant is likely to produce Defendant's product or conduct each of an act of
production, import, transfer, and offer to transfer of Defendant's monoclonal antibody,and the necessity of injunction is recognized.
B.

Appellant alleges that Appellee's claim for injunction corresponds to the abuseof rights since the injunction of the production and transfer, etc. of Defendant's
product and Defendant's monoclonal antibody causes patients currently administeredor to be administered Defendant's product to have severe health risk or anxiety for
future therapy.

In the field of pharmaceutical products, there might be the casewhere a right to seek injunction should be limited from a viewpoint of public
interests; however, it cannot be concluded that an injunction of the production,transfer, etc. of infringing products should not be permitted, without establishingconcrete facts, for a simple reason that it is desirable for patients to have a selectableoption.

ⅴ

Judgment rendered on October 30, 20192019 (Ne)10014

Appeal case of seeking injunction against patent infringement(court of Prior Instance: Tokyo District Court, 2017 (Wa) 16468)
Date of conclusion of oral argument: July 3, 2019
Judgment
Appellant:

Sanofi Incorporated

Appellee:Amgen Incorporated

Main text
1.
2.

The appeal shall be dismissed.

Appellant shall bear the cost of the appeal.
Facts and reasons

No. 1

Gist of the Appeal
1. A part where the Appellant was defeated in the prior instance judgment shallbe reversed.
2. All of the Appellee's claims according to the above rescinded part shall bedismissed.
3. Appellee shall bear the court costs for both the first and second instances.
No. 2

Outline of the case (unless otherwise specified, abbreviated names are inaccordance with those of the judgment in prior instance).
1. This case is a case where Appellee, who owns two patent rights titled"ANTIGEN-BINDING

PROTEINAGAINSTPROPROTEINCONVERTASE

SUBTILISIN KEXIN TYPE 9 (PCSK9)", seeks against Appellant an injunction of the
production, transfer, import, or offer to transfer of the Defendant's products andDefendant's monoclonal antibody by Appellant and a disposal of Defendant's products
and Defendant's monoclonal antibody, alleging that the above Appellant's acts
infringe each of the patent rights.
The judgment in prior instance ordered against Appellant an injunction of the
production, transfer, import, or offer to transfer of Defendant's products andDefendant's monoclonal antibody and dismissed the remaining claims from Appellee,
stating that Defendant's products and Defendant's monoclonal antibody fall within thetechnical scopes of the Inventions 1 and 2 and Corrected Inventions 1 and 2, and none1

of the reasons for invalidation as Appellant alleges has a point.
Appellant filed an appeal objecting to the judgment in prior instance.
2. Facts used as premise
Except for the following amendment, "Facts and reasons" of the judgment inprior instance, No. 2-1 is maintained.

Thus, this is incorporated by reference.

(1) Page 5, lines 12 to 15 of the judgment in prior instance shall be modified asfollows:"A

Request for correction

In the case of request for invalidation trial of Patent 1 on May 8, 2017 (the caseof Invalidation Trial No. 2016-800004, hereinafter referred to as 'Case 1 forinvalidation trial') Appellee has made a request for correction to correct Claims 1 and
9 and delete Claims 2 to 4 from a group of claims consisting of Claims 1 to 4 and 9 of
the scope of claims, and to delete a group of claims consisting of Claims 5 to 8
(Exhibit Ko 11-1, hereinafter referred to as 'Correction 1').

In the case of request forinvalidation trial of Patent 2 (the case of Invalidation Trial No. 2016-800066,
hereinafter referred to as 'Case 2 for invalidation trial') Appellee has made a request
for correction to correct Claims 1 and 5 and delete Claim 2 from a group of claimsconsisting of Claims 1, 2, and 5 of the scope of claims, and delete a group of claimsconsisting of Claims 3 and 4 (Exhibit Ko 11-2, hereinafter referred to as 'Correction
2').
The Japan Patent Office accepted Correction 1 with respect to Case 1 forinvalidation trial on August 2 of the same year, and made a decision to the effect thatthe trial for the inventions according to Claims 1 and 9 was groundless, and the trial
for Claims 2 to 8 should be dismissed, and accepted Correction 2 with respect to Case
2 for invalidation trial, and the trial for the inventions according to Claims 1, 5 was
groundless, and the trial for Claims 2 to 4 should be dismissed.
On December 8, 2017, Appellant filed a suit against trial decision made by the
JPO seeking a rescission of a part according to Claims 1 and 9 of Patent 1 in the trial
decision with respect to Case 1 for invalidation trial (Japan Patent Office 2017(GyoKe)10225, hereinafter referred to as 'Suit 1 against trial decision made by JPO') andfiled a suit against trial decision made by JPO seeking a rescission of a part according
to Claims 1 and 5 of Patent 2 in the trial decision with respect to Case 2 forinvalidation trial (2017(Gyo-Ke)10226, hereinafter referred to as 'Suit 2 against trial
decision made by JPO').
On December 27, 2018 the Intellectual Property High Court made a court
decision to dismiss Appellant's claims for both Suits 1 and 2 against trial decision2

made by the JPO, and Appellant has petitioned for acceptance of final appeal.
B. Patent 1 after correction"(2) "B. Patent 2" of the judgment in prior instance, page 6, line 3 is modified to"C. Patent 2 after correction".
(3) Page 6, lines 16 to 26 of the judgment in prior instance shall be modified asfollows:"(5) Hereinafter, 'an antibody comprising: a heavy chain comprising CDR1, 2, and 3
respectively consisting of the amino acid sequences of SEQ ID NOS. 368, 175, and180; and a light chain comprising CDR1, 2, and 3 respectively consisting of the aminoacid sequences of SEQ ID NOS. 158, 162, and 395' of Invention 1 (Constituent
Feature 1B) is referred to as 'reference antibody 1'.

'An antibody comprising: aheavy chain comprising CDR1, 2, and 3 respectively consisting of the amino acidsequences of SEQ ID NOS. 247, 256, and 265; and a light chain comprising CDR1, 2,
and 3 respectively consisting of the amino acid sequences of SEQ ID NOS. 222, 229,
and 238' of Invention 2 (Constituent Feature 2) is referred to as 'reference antibody 2'.
'An antibody comprising: a heavy chain comprising a heavy chain variable region
consisting of the amino acid sequence of SEQ ID NO. 49; and a light chain
comprising a light chain variable region consisting of the amino acid sequence of SEQ
ID NO. 23' of Corrected Invention 1 (constituent feature 1B') is referred to as'reference antibody 1'.

'An antibody comprising: a heavy chain comprising a heavy

chain variable region consisting of the amino acid sequence of SEQ ID NO. 67; and alight chain comprising a light chain variable region consisting of the amino acidsequence of SEQ ID NO. 12' of Corrected Invention 2 (constituent feature 2B') is
referred to as 'reference antibody 2'.
Further, in some cases, Invention 1 and Invention 2 are collectively referred toas 'each of the Inventions', and Corrected Invention 1 and Corrected Invention 2 arecollectively referred to as 'each of the Corrected Inventions'."
3. Issues(1) Whether or not to fall within the technical scopes of each of the Inventions
and each of the Corrected Inventions
Whether Defendant's products and Defendant's monoclonal antibody fall within
the technical scopes of each of the Inventions and each of the Corrected Inventions.
(2) Presence or absence of reasons for invalidation
Whether each of the Patents should be invalidated for the reasons of thefollowing A to D.
A. Nonconformance to support requirement
3B. Nonconformance to enablement requirement
C. Lack of inventive step on the basis of the invention described in Thomas A.
Lagace et al., "Secreted PCSK9 decreases the number of LDL receptors inhepatocytes and in livers of parabiotic mice", The Journal of Clinical Investigation,
Vol. 116, No. 11, pp. 2995-3005 (Exhibit Otsu 1, published on November 2006)
D. Yue-Wei Qian et al., "Secreted PCSK9 downregulates low density
lipoprotein receptor through receptor-mediated endocytosis" Journal of Lipid
Research, Vol. 48, pp. 1488-1498 (Exhibit Otsu 27, published on April 2007,
hereinafter referred to as "Exhibit Otsu 27 Document"). (Issues added in this appellate
instance)(3) Propriety of injunctive relief
A. Necessity of injunction
B. Abuse of rights (Issues added in this appellate instance)(omitted)
No. 4

Judgment of this court
The court has also determined that Defendant's monoclonal antibody falls

within a technical scope of Inventions 1-1 and 2-1, Defendant's product falls within atechnical scope of Inventions 1-2 and 2-2, and further each of the Patents should beinvalidated by a trial for patent invalidation.

The reason is set forth as below.

1. The Invention(1) The description of each of the specifications
Except for the following amendment to the description of each of thespecifications, the description from page 22, line 22 to page 36, line 7 of the judgmentin prior instance is maintained.

Thus, this is incorporated by reference.

A. Following "has the following description" of page 22, line 23 of thejudgment in prior instance, "(See the attachment with regard to Table 2 and Table 3
cited by the following description)" shall be added, and Table 2 and Table 3 shall be
attached to the attachment.
B. Add as below with a carriage return to the end of page 29, line 15 of thejudgment in prior instance:" 'Antigen binding region' means a protein, or a portion of a protein, thatspecifically binds a specified antigen (e.g., a paratope).

For example, that portion ofan antigen binding protein that contains the amino acid residues that interact wi th an
antigen and confer on the antigen binding protein its specificity and affinity for the4

antigen is referred to as 'antigen binding region'.

An antigen binding region typically

includes one or more 'complementary binding regions' ('CDRs').
binding regions also include one or more 'framework' regions.

Certain antigen

A 'CDR' is an aminoacid sequence that contributes to antigen binding specificity and affinity. 'Framework'
regions can aid in maintaining the proper conformation of the CDRs to promotebinding between the antigen binding region and an antigen.
regions can be located in antibodies between CDRs.

Structurally, framework

Examples of framework and

CDR regions are shown in FIGs. 2A-3D, 3CCC-JJJ, and 15A-15D. ..."
"The variable regions typically exhibit the same general structure of relatively
conserved framework regions (FR) joined by three hyper variable regions, (also called
complementarity determining regions or CDRs).

The CDRs from the two chains ofeach pair typically are aligned by the framework regions, which can enable binding toa specific epitope.

From N-terminal to C-terminal, both light and heavy chain

variable regions typically comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3 ,and FR4. ..." (paragraphs [0123], [0127])"The term 'light chain' includes a full-length light chain and fragments thereof
having a sufficient variable region sequence to confer binding specificity.

A full-length light chain includes a variable region domain, V L, and a constant region
domain, C L.

The variable region domain of the light chain is at the amino-terminusof the polypeptide.

Light chains include κ chains and λ chains.""The term 'heavy chain' includes a full-length heavy chain and fragments
thereof having sufficient variable region sequence to confer binding specificity.

A

full-length heavy chain includes a variable region domain, V H, and three constantregion domains, C H1, C H2, and C H3.

The V H domain is at the amino-terminus of thepolypeptide, and the C H domains are at the carboxyl-terminus, with the C H3 being
closest to the carboxy-terminus of the polypeptide.

Heavy chains can be of any

isotype, including IgG (including IgG1, IgG2, IgG3, and IgG4 subtypes), IgA(including IgA1 and IgA2 subtypes), IgM, and IgE." (paragraphs [0132] to [0133])
C. Add as below with a carriage return to the end of page 32, line 23 of thejudgment in prior instance:" 'Antigen-binding protein against PCSK9Proprotein convertase subtilisin kexin type 9 (PCSK9) is a serine proteaseinvolved in regulating the levels of the low density lipoprotein receptor (LDLR)
protein (Horton et al, 2007; Seidah and Prat, 2007).

PCSK9 is a prohormone-proprotein convertase in the subtilisin (S8) family of serine proteases (Seidah et al,2003). ...

The structure of the PCSK9 protein has recently been solved by two
5groups (...).

PCSK9 includes a signal sequence, an N-terminal prodomain, asubtilisin-like catalytic domain, and a C-terminal domain.' (paragraph [0154])"
D. Add as below with a carriage return to the end of page 33, line 22 of thejudgment in prior instance:" '...

In some embodiments, ABP binds to any one of epitope to be bonded byan antibody discussed in the specification.

In some embodiments, this can bemeasured by competing assay between an antibody disclosed in the specification andthe other antibody. ...' (paragraph [0157])'Specific examples of some of the variable regions of the light and heavy chainsof the antibodies that are provided and their corresponding amino acid sequ ences are
summarized in TABLE 2.''Again, each of the exemplary variable heavy chains listed in Table 2 can be
combined with any of the exemplary variable light chains shown in Table 2 to form an
antibody.

Table 2 shows exemplary light and heavy chain pairings found in severalof the antibodies disclosed herein. ...' (paragraphs [0170], [0172])"
E. Add as below with a carriage return to the end of page 34, line 6 of thejudgment in prior instance:" 'In some embodiments, ABP 21B12 binds to an epitope including residues
162-167 (e.g., residues D162-E167 of SEQ ID NO: 1). ...'
(paragraph [0268])"
F. Add as below with a carriage return to the end of page 36, line 7 of thejudgment in prior instance:" '(Example 3) Selection of PCSK9 antibody ...

The selection of antibodies

was based on binding data and inhibition of PCSK9 binding to LDLR and affinity. ...'
(paragraph [0325])'Large Scale Receptor Ligand Blocking Screen

To screen for the antibodies

that block PCSK9 binding to LDLR, an assay was developed using the D374Y PCSK9
mutant.... The screen identified 384 antibodies that blocked the interaction between
PCSK9 and the LDLR well, 100 antibodies blocked the interaction strongly....'(paragraph [0332])'(Example 11) Efficacy of 31H4 and 21B12 for Blocking D374Y PCSK9/LDLR
Binding
This example provides the IC50 values for two of the antibodies in blocking
PCSK9 D374Y's ability to bind to LDLR....' (paragraph [0377])"(2) According to the description of each of the specifications of the above (1),
it is recognized that each of the Inventions is summarized as set forth below.
6Specifically, PCSK9 (Proprotein convertase subtilisin kexin type 9) binds to
LDLR (low density lipoprotein receptor) and interacts to be incorporated into liver
cells together with LDLR and decrease LDLR level in liver, and further decrease an
amount of LDLR available for the binding to LDL on the cell surface (extracellular)
to increase an amount of LDL in a subject ([0002], [0003], [0071]).

An isolated

monoclonal antibody "competing" with reference antibody 1 (Invention 1) or
reference antibody 2 (Invention 2) is a neutralization antigen binding protein(neutralizing ABP) that binds to PCSK9 in a location and/or a manner that preventsPCSK9 from binding to LDLR and blocks or reduces and "competitively neutralizes"
the interaction (binding) between PCSK9 and LDLR ([0138], [0140], [0155], [0157],[0261], [0262], [0269], Table 2).

This neutralizing ABP against PCSK9 canneutralize 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 therisk of the diseases associated with increased cholesterol level such as
hypercholesteremia, and thus may be therapeutically beneficial ([0155], [0270],[0271], [0276]).
2. Issue (1) (Whether or not to fall within the technical scope of each of theInventions)(1) Construction of each of the Inventions
A. Meaning of "neutralization"
The scope of claims of each of the Patents (Claim 1) describes that "capable ofneutralizing the binding of PCSK9 and LDLR proteins" (constituent features 1A, 2A).
Further, each of the specifications describes that "the term 'neutralizing antigen
binding protein' or 'neutralizing antibody' refers to an antigen binding protein or
antibody, respectively, that binds to a ligand and prevents or reduces the biologicaleffect of that ligand.... In the case of PCSK9 antigen binding proteins, such aneutralizing molecule can diminish the ability of PCSK9 to bind the LDLR. ... theantibodies or antigen binding proteins neutralize by binding to PCSK9 and preventing
PCSK9 from binding to LDLR (or reducing the ability of PCSK9 to bind to LDLR). "([0138]).

In addition, it describes in Examples "(Example 3) Selection of PCSK9

Antibodies ...

Selection of antibodies was based on binding data and inhibition of

PCSK9 binding to LDLR and affinity." ([0325]), "Large Scale Receptor Ligand
Blocking Screen

To screen for the antibodies that block PCSK9 binding to LDLR,

an assay was developed using the D374Y PCSK9 mutant ....

The screen identified

384 antibodies that blocked the interaction between PCSK9 and the LDLR well,7among which 100 antibodies blocked the interaction strongly" ([0332]), "(Example
11) Efficacy of 31H4 and 21B12 for Blocking D374Y PCSK9/LDLR BindingThis

example provides the IC50 values for two of the antibodies in blocking PCSK9D374Y's ability to bind to LDLR...." ([0377]).
Consequently, it can be seen that "neutralizing" the binding of PCSK9 and
LDLR is to prevent the binding of PCSK9 and LDLR protein or block the binding of
PCSK9 to LDLR.
Therefore, it is recognized that "neutralizing" the binding of PCSK9 and LDLR
in each of the Inventions is to prevent the binding of PCSK9 to LDLR.
B. Meaning of "competition"
The scope of claims of each of the Patents (Claim 1) recites that "competing"with reference antibody 1 or 2 "for binding with PCSK9".

This suggests thecompetition with a specific reference antibody for binding with PCSK9.

This does

not describe the meaning of "competing with an antibody".
Further, each of the specifications discloses that "The term 'compete' whenused in the context of antigen binding proteins (e.g., neutralizing antigen binding
proteins or neutralizing antibodies) that compete for the same epitope meanscompetition between antigen binding proteins as determined by an assay in which theantigen binding protein ... being tested prevents or inhibits (e.g., reduces) specificbinding of a reference antigen binding protein (e.g., a ligand, or a reference antibody)to a common antigen (e.g., PCSK9 ...). ...

Antigen binding proteins identified bycompetition assay (competing antigen binding proteins) include antigen binding
proteins binding to the same epitope as the reference antigen binding proteins andantigen binding proteins binding to an adjacent epitope sufficiently proximal to theepitope bound by the reference antigen binding protein for steric hindrance to occur."([0140]), "the neutralizing ABP binds to PCSK9 in a location and/or manner thatprevents PCSK9 from binding to LDLR.

Such ABPs can be specifically described as'competitively neutralizing' ABPs." ([0155]),"In some embodiments, ABP binds toany one of epitope to be bonded by an antibody discussed in the specification.

Insome embodiments, this can be measured by competing assay between an antibody
disclosed in the specification and the other antibody." ([0157]).

In addition, it

describes in Examples that "there is provided antigen binding proteins that competewith one of the exemplified antibodies ... binding to the epitope described herein for
specific binding to PCSK9.

Such antigen binding proteins can also bind to the same

epitope as one of the herein exemplified antigen binding proteins, or an overlapping
epitope." ([0269]).
8

Comprehensively taking into account the recitation of the scope of claims andthe description of each of the specifications, it is recognized that "competing with anantibody" of each of the inventions is a competition between antigen-binding proteinsmeasured by competition assay, and means the binding to the same epitope to which areference antibody binds to PCSK9, or an overlapping epitope, or the bindi ng to an
adjacent epitope that produces a steric hindrance for the binding of reference antibody
with PCSK9.
In addition, Encyclopedia of Immunology, 2nd Edition describes that"competition inhibition test" is "also referred to as competition inhibitory test.

It

may include, for example, a type of inhibition in which something competes with an
antigen molecule to compete for a site of an antibody molecule, and a type of
inhibition in which something competes with an antibody molecule to compete for an
antigen determinant of an antigen molecule".

Encyclopedia of Biochemistry, 4th

Edition describes that "competitive inhibition" is "also referred to as antagonistic
inhibition or competition inhibition.

Catalytic activity of enzymes may be frequently

subjected to reversible inhibition by various compounds.
enzymatic activity has various forms.

The inhibition ofParticularly, a type of inhibition in which an

inhibitor molecule competes with a substrate molecule to compete for a substrate binding site is a competitive inhibition".
competing for a binding site.

"Competition" is used in the sense of

As aforementioned, however, it is obvious in each of

the specifications that "competing" means a competition between antigen-binding
proteins measured by competition assay, and is not limited to a case of competing fora same binding site, but includes the binding to an adjacent epitope that produces asteric hindrance for the binding between the reference antibody and PCSK9.
(2) Fulfillment of the constituent feature of each of the inventions in question
A. Constitution of Defendant's monoclonal antibody and Defendant's products
Obviously, Appellant does not object to the fact that Defendant's monoclonal
antibody is"c. an isolated monoclonal antibody
a. capable of inhibiting the binding of PCSK9 and LDLR protein,b. competing with the antibody comprising: a heavy chain comprising a heavy chain
variable region consisting of the amino acid sequence of SEQ ID NO. 49; and a lightchain comprising a light chain variable region consisting of the amino acid sequenceof SEQ ID NO. 23 for binding with PCSK9,b'. competing with the antibody comprising: a heavy chain comprising a heavy chain
variable region consisting of the amino acid sequence of SEQ ID NO. 67; and a light9

chain comprising a light chain variable region consisting of the amino acid sequenceof SEQ ID NO. 12 for binding with PCSK9."and further Defendant's product is"d. A pharmaceutical composition comprisingc. an isolated monoclonal antibody
a. capable of inhibiting the binding of PCSK9 and LDLR protein,b. competing with the antibody comprising: a heavy chain comprising a heavy chain
variable region consisting of the amino acid sequence of SEQ ID NO. 49; and a lightchain comprising a light chain variable region consisting of the amino acid sequenceof SEQ ID NO. 23 for binding with PCSK9,b'. competing with the antibody comprising: a heavy chain comprising a heavy ch ain
variable region consisting of the amino acid sequence of SEQ ID NO. 67; and a lightchain comprising a light chain variable region consisting of the amino acid sequenceof SEQ ID NO. 12 for binding with PCSK9."
B. Fulfillment of the constituent feature of the invention in question(A) Defendant's monoclonal antibody binds to PCSK9 and inhibits the bindingof PCSK9 to LDLR (the above a), and thus "neutralizes" the binding of PCSK9 and
LDLR, and fulfills the constituent features 1A and 2A.
(B) In Defendant's monoclonal antibody, an antibody that can be a basis for thecompetition for binding with PCSK9 is an antibody comprising a heavy chain
comprising a heavy chain variable region consisting of the amino acid sequence of
SEQ ID NO. 49; and a light chain comprising a light chain variable region consistingof the amino acid sequence of SEQ ID NO. 23 (the above b) and an antibody
comprising: a heavy chain comprising a heavy chain variable region consisting of theamino acid sequence of SEQ ID NO. 67; and a light chain comprising a light chain
variable region consisting of the amino acid sequence of SEQ ID NO. 12 (the aboveb').
As aforementioned, "competing" means the binding to the same epitope towhich a reference antibody binds to PCSK9, or an overlapping epitope, or the binding
to an adjacent epitope that produces a steric hindrance for the binding of the reference
antibody with PCSK9.

Thus, it becomes a point of issue as to whether or not"antibody" which is the basis for competition for binding with PCSK9 fulfills thereference antibody of each of the Inventions in Defendant's monoclonal antibody.
The reference antibody of Invention 1 is reference antibody 1 (an antibody
comprising: a heavy chain comprising CDR1, 2, and 3 respectively consisting of theamino acid sequences of SEQ ID NOS. 368, 175, and 180; and a light chain
10

comprising CDR1, 2, and 3 respectively consisting of the amino acid sequences of
SEQ ID NOS. 158, 162, and 395).

The reference antibody of Invention 2 isreference antibody 2 (an antibody comprising: a heavy chain comprising CDR1, 2 ,and 3 respectively consisting of the amino acid sequences of SEQ ID NOS. 247, 256,and 265; and a light chain comprising CDR1, 2, and 3 respectively consisting of theamino acid sequences of SEQ ID NOS. 222, 229, and 238).

The above antibody bfurther limits reference antibody 1 to an amino acid sequence in a variable region.
The above antibody b' further limits reference antibody 2 to an amino acid sequencein a variable region (No issue between parties), thus it is recognized that antibody b
fulfills reference antibody 1, and antibody b' fulfills reference antibody 2.
Therefore, Defendant's monoclonal antibody competes with reference antibody
1 and reference antibody 2 for binding with PCSK9, and thus fulfills the constituent
features 1B and 2B.
(C) Defendant's monoclonal antibody is an isolated monoclonal antibody fromwhich impurities derived from any production step are sufficiently removed in the
production step of Defendant's product (the above c), and fulfills the constituent
features 1C and 2C.
(D) Defendant's product is a pharmaceutical product composition comprising
Defendant's monoclonal antibody (the above d), and thus fulfills the constituent
features 1D and 2D in addition to the constituent features 1A to C and 2A to C.
(E) As described above, Defendant's monoclonal antibody fulfills

all theconstituent features of Inventions 1-1 and 2-1, and Defendant's products fulfill all theconstituent features of Inventions 1-2 and 2-2.
(3) Appellant's allegation
A.

Appellant alleges that each of the Inventions is a functional claim thatspecifies the invention only by a function to compete with reference antibody 1 or 2,
and in such a functional claim, if it should be construed that the entire constitution
capable of causing the function and effect should fall within a technical scope, the one
having a technical concept different from that disclosed in the specification might beencompassed into the technical scope of the invention, which results in the protection
by a patent right beyond what the Applicant has invented, and thus when it comes to afunctional claim, the technical scope of the invention should be defined on the basisof the technical idea shown in the specific configuration that the Applicant disclosed
in the specification by taking into account the description of the Detailed Descriptionof the Invention of the specification in addition to the recitation of the claims, andthus a functional claim should be narrowly construed to have a scope within which a11person ordinarily skilled in the art can perform from the description of thespecification.

Further, Appellant alleges that a scope where a person ordinarily

skilled in the art can perform from the description of the specificatio n is limited to a
specific antibody described in the example of each of the specifications or an antibody
having an amino acid sequence in which one or several amino acids at a specificposition are substituted in the former antibody, and thus the technical scope of each of
the inventions is limited to each of the above antibody or an amino acid sequence inwhich one or several amino acids at a specific position is substituted in the antibody,
Defendant's monoclonal antibody and Defendant's product having a different aminoacid sequence from them respectively do not fall within a technical scope of each of
the Inventions.
Setting aside the question of whether each of the Inventions should be called aso-called "functional claim", the technical scope of the patent invention must be
determined on the basis of the recitation of the scope of claims, and should beconstrued on the basis of a technical idea disclosed therein by taking the descriptionof the specification and drawings into account, and the Appellant's allegation should
be considered as a problem of support requirement or enablement requirement.

A

technical idea disclosed in each of the specifications is that an isolated monoclonal
antibody competing with reference antibody 1 or 2 binds to PCSK9 in a location
and/or a manner that prevents PCSK9 from binding to LDLR, blocks (neutralizes) the
binding between PCSK9 and LDLR, and reduces LDL level in a subject to exert aneffect of causing the decrease of serum cholesterols in a subject.

Further, as

aforementioned, Defendant's monoclonal antibody and Defendant's product fall withina technical scope of each of the Inventions that are construed on the basis of the above
technical idea.
Each of the Inventions provides an isolated monoclonal antibody thatneutralizes the binding of PCSK9 and LDLR protein and competes with each ofreference antibodies, and has constituent features of both blocking the binding
between PCSK9 and LDLR for "neutralization" (constituent features 1A, 2A) and"competing" with a reference antibody for binding with PCSK9 (constituent features
1B, 2B).

Further, it cannot be said that there is a description in each of thespecifications that makes us believe that each of the Inventions is specified only by afunction to compete with reference antibody 1 or 2.

Appellant's allegation of each of

the Inventions being limited to the example on the premise of that is not acceptable.
Further, each of the Inventions is not specified by amino acid sequence.

Thus,

there is no reason to construe as being limited to a specific antibody described in each12

of the specifications or an antibody having an amino acid sequence in which one orseveral amino acids are substituted at a specific position in the former antibody.
Furthermore, each of the specifications describes: the production of an
immunized mouse in compliant with the procedure and schedule of an immunization
program; the production of hybridoma for which an immunized mouse is used; and amethod of screening and epitope binning assay for identification of antibody thatstrongly blocks the binding of PCSK9 and LDLR that competes with reference
antibody 1 or 2 (the below-mentioned 3(2)).

It can be recognized from thesedescriptions that a neutralizing antibody competing with reference antibody 1 or 2
may be obtained by repetitively implementing a series of procedures in addition to theneutralizing antibodies competing with a reference antibody specifically described ineach of the specifications, and that the result of the above epitope binning assay has
confirmed that 15 specific antibodies of the Invention 1 and 7 specific antibodies of
the Invention 2 are obtained, and neutralizing antibodies competing with reference
antibody 1 or 2 may be obtained through a similar epitope binning assay for the above
remaining antibodies obtained from 2441 stable hybridomas, as per the below mentioned 3, 4.
Consequently, it cannot be said that a scope of the invention within which aperson ordinarily skilled in the art could implement from the description of each of
the specifications is limited to a specific antibody described in each of thespecifications or an antibody having an amino acid sequence in which one or severalamino acids are substituted at a specific position in the former antibody, and theAppellant's allegation is unacceptable also in this point.
B. Appellant alleges that one could not read a technical idea that an antibody
competing with reference antibody 1 or 2 can neutralize the binding of PCSK9 and
LDLR from each of the specifications, nor can it be inferred from antibodies in only
three groups or two groups described in the examples of each of the specifications thatan enormous number of antibodies competing with reference antibody 1 or 2 are all
PCSK9-LDLR binding neutralizing antibodies.
As per the aforesaid A, however, each of the specifications discloses atechnical idea that an isolated monoclonal antibody competing with reference
antibody 1 or 2 binds to PCSK9 in a location and/or a manner that prevents PCSK9from binding to LDLR, blocks (neutralizes) the binding between PCSK9 and LDLR ,and reduces LDL level in a subject to exert an effect of causing the decrease of serum
cholesterols in a subject.

There is a disclosure that a neutralizing antibody

competing with reference antibody 1 or 2 may be obtained by repeatedly carrying out
13

a series of procedures described, in addition to the neutralizing antibodies competingwith reference antibody specifically described in each of the speci fications.

Thus,

neutralizing antibody competing with reference antibody 1 or 2 is not limited to threegroups or two groups described in the examples of each of the specifications.
Further, Invention 1 has constituent features of being PCSK9-LDLR binding
neutralizing antibody and being an antibody competing with reference antibody 1, andInvention 2 has constituent features of being PCSK9-LDLR binding neutralizing
antibody and being an antibody competing with reference antibody 2.

Therefore,

first of all, one competing with reference antibody 1 or 2 but which is not a PCSK9LDLR binding neutralizing antibody does not fall within a technical scope ofInvention 1.

Thus, the Appellant's allegation is not reasonable.

C. Appellant alleges that an antibody competing with reference antibody 1 or 2,
which is a specific example of PCSK9-LDLR binding neutralizing antibody in each of
the specifications, only binds to LDLR binding site on a surface of PCSK9 with its
part being overlapped,

Defendant's monoclonal antibody is an antibody (EGFa

mimic) that recognizes the most part of amino acids on PCSK9 that LDLR recognizes,
and thus Defendant's monoclonal antibody and Defendant's product do not fall within
the technical scopes of each of the Inventions.
However, each of the Inventions is not specified by a binding site on PCSK9that an antibody recognizes.

Thus, even if the example disclosed in each of thespecifications differs from Defendant's monoclonal antibody in their binding site on
PCSK to be recognized, it cannot be said to not fall within a technical scope of eachof the Inventions, and the Appellant's allegation is not reasonable.
D. Therefore, none of the Appellant's allegation is acceptable.
(4) In addition, both Correction 1 and Correction 2 had not yet been made final
and binding as of the conclusion of oral proceeding.

In view of the nature of thecase, a consideration is given as to whether or not to fall within a technical scope ofeach of the Corrected Invention of Defendant's monoclonal antibody and Defendant's
product.
Constituent features 1A, 1C, and 1D of the Corrected Invention 1 are identicalto Constituent features 1A, 1C, and 1D of Invention 1, and Constituent features 2A,
2C, and 2D of Corrected Invention 2 are identical to Constituent features 2A, 2C, and
2D of Invention 2, respectively.

Thus, Defendant's monoclonal antibody and

Defendant's product fulfill Constituent features 1A, 2A, 1C, and 2C.

Further,

Defendant's product fulfills Constituent features 1D and 2D.
In Defendant's monoclonal antibody, an antibody that can be a basis for the14

competition for binding with PCSK9 is "an antibody comprising a heavy chain
comprising a heavy chain variable region consisting of the amino acid sequence of
SEQ ID NO. 49; and a light chain comprising a light chain variable region consistingof the amino acid sequence of SEQ ID NO. 23" (the above b) and "an antibody
comprising: a heavy chain comprising a heavy chain variable region consisting of theamino acid sequence of SEQ ID NO. 67; and a light chain comprising a light chain
variable region consisting of the amino acid sequence of SEQ ID NO. 12 " (the aboveb').

The above b is identical to reference antibody 1' and the above b' is identical toreference antibody 2'.

It is thus recognized that Defendant's monoclonal antibody

and Defendant's product fulfill the constituent features 1B' and 2B'.
As described above, Defendant's monoclonal antibody fulfills all theconstituent features of Corrected Inventions 1-1 and 2-1, and Defendant's products
fulfill all the constituent features of Corrected Inventions 1-2 and 2-2.
(5) Summary
As described above, Defendant's monoclonal antibody falls within the technicalscopes of Inventions 1-1 and 2-1 and Corrected Inventions 1-1 and 2-1, andDefendant's products fall within the technical scopes of Inventions 1-2 and 2-2 andCorrected Inventions 1-2 and 2-2.
3. Issues (2) A (Violation of Support Requirement)(1) Each of the specifications has the following description with regard to eachof the Inventions (see the attachment for Table 8.3, Table 37.1 cited in the following
description).
A. PCSK9 (Proprotein convertase subtilisin kexin type 9) is a serine proteasethat binds to LDLR (low density lipoprotein receptor) and interacts to be incorpora ted
into liver cells together with LDLR and decrease LDLR level in the liver, and further
decrease an amount of LDLR available for the binding to LDL on a cell surface(extracellular) to increase an amount of LDL in a subject ([0002], [0003], [0071]).
The term "neutralizing antibody" represents an antibody that binds to a ligand
and prevents or reduces the biological effects of the ligand.

In the anti -PCSK9

antibody, it involves neutralization by prevention of the binding of PCSK9 and LDLR,
and neutralization by prevention of PCSK9-mediated decomposition of LDLR without
preventing the binding of PCSK9 and LDLR ([0138]).
The term "competing" means the competition between antibodies determinedby various assays that measure the degree of a test antibody preventing or inhibiting a
specific binding of the reference antibody to an antigen.

An antibody identified by acompetitive assay includes an antibody binding to an epitope identical to the reference
15

antibody, and an antibody binding to an adjacent epitope sufficiently close to interfere
sterically with the binding of the reference antibody to the epitope ([0140]).
The term "epitope" is a region of an antigen that is bound by an antibody, andwhen the antigen is a protein, includes specific amino acids that directly contact theantibody ([0142]).
B. An isolated monoclonal antibody "competing" with an antibody ("21B12")
comprising: a heavy chain variable region consisting of the amino acid sequence of
SEQ ID NO. 49; and a light chain variable region consisting of the amino acidsequence of SEQ ID NO. 23, an isolated monoclonal antibody "competing" with anantibody ("31H4") comprising: a heavy chain variable region consisting of the aminoacid sequence of SEQ ID NO. 67; and a light chain variable region consisting of theamino acid sequence of SEQ ID NO. 12 is a neutralization antigen binding protein(neutralizing ABP) that binds to PCSK9 in a location and/or a manner that preventsPCSK9 from binding to LDLR and blocks, reduces and "competitively neutralizes"
the interaction (binding) between PCSK9 and LDLR. ([0138], [0140], [0155], [0269],
Table 2).
Neutralizing ABP against PCSK9 can 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 , andthis effect may treat or prevent or reduce the risk of the diseases associated withincreased cholesterol level such as hypercholesteremia, and thus may betherapeutically beneficial ([0066], [0155], [0270], [0271], [0276]).
C. A human PCSK9 antigen was injected 11 times to mice in two groups
containing human immunization globulin gene to prepare immunized mice and selectmice (10 mice) that produce an antibody specific to PCSK9 according to a procedureand schedule of an immunization program described in Table 3 (Example 1, [0312],[0313], [0320], Table 3).
Hybridomas producing antigen binding proteins to PCSK9 were produced byuse of these selected immunized mice (Example 2, [0322] to [0324]), a total of 3104
antigen specific hybridomas were obtained by "Primary Screen" by ELiSA with acapture sample of biotinylated-PCSK9, without a V5 tag, binding to a plate coatedwith neutravadin (Example 3, [0325] to [0328]).
The 3000 positives in total were rescreened from the above hybridomas
obtained by "Primary Screen" and further the 2441 positives in total were thenrescreened ("Confirmatory Screen") to confirm that stable hybridomas were
established, and then it was confirmed that 579 antibodies could bind to both human16and mouse PCSK9 by "mouse cross-reactivity screening" ([0329], [0330]).
Furthermore, "large scale receptor ligand blocking screening" was implemented forscreening antibody that blocks the binding of PCSK9 to LDLR, identif ying 384
antibodies that strongly blocked the interaction between PCSK9 and the LDLR well,among which 100 antibodies blocked the binding interaction of PCSK9 and LDLR by
90% or more ([0332]).
For the 384 member subset of neutralizers (blockers) identified in this manner,"a receptor ligand binding assay for a subset of blockers" was implemented, and 85
antibodies blocking the interaction between PCSK9 mutant enzyme an d LDLR by
90% were identified ([0333], [0334]).
Identified on the basis of the results of these assays, several hybridoma lines
producing antibodies with desired interactions with PCSK9 included a reference
antibody (21B12, 31H4) ([0336], Table 2), which is a neutralizing antibody thatstrongly blocks the binding of PCSK9 and LDLR (Example 11, [0138], [0377],[0378]).
D. From 32 antibodies in Table 2 (several hybridoma lines that produce anantibody having a desired interaction with PCSK9), 27B2, 13H1, 13B5, and 3C4 are
non-neutralizing antibodies, and 3B6, 9C9, and 31A4 are weak neutralizing antibodies,and the others (including a reference antibody) are strong neutralizing antibodies([0138], [0336]).
According to the result of epitope binning for the above 32 antibodies, the ones
competing with 21B12 (bin 1) total 19, and the ones competing with 31H4 (bin 3)
total 7.

They are mutually exclusive.

One was identified as competing with both

21B12 and 31H4 (bin 2), and one was identified as competing with neither 21B12 nor
31H4 (bin 4) (Example 10, [0373], [0494], Table 8.3).
In addition to the above set of Example 10, according to the result of epitope
binning implemented for the other set (39 antibodies in total), the ones not competingwith 31H4 but competing with 21B12 (bin 1) total 19, and the ones competing withboth 21B12 and 31H4 (bin 2) total 3.

The ones not competing with 21B12 butcompeting with 31H4 (bin 3) total 10.

Further, it has been confirmed that 16 out of

the antibodies included in BIN 1 are antibodies listed in Table 2, and of these, 15
except for 27B12 antibody are neutralizing antibodies, and 7 out of the antibodies
included in BIN 3 are antibodies listed in Table 2 and are neutralizing antibodies(Example 37, [0138], [0489] to [0495], Table 37.1).
(2) According to the finding of the above (1), Invention 1 provides an isolated
monoclonal antibody that neutralizes the binding of PCSK9 and LDLR protein and17

competes with reference antibody 1, and a pharmaceutical composition using the sa me.
Invention 2 provides an isolated monoclonal antibody that neutralizes the binding of
PCSK9 and LDLR protein and competes with reference antibody 2, and apharmaceutical composition using the same.

Further, it can be seen that a problem

to be solved by each of the Inventions lies in the provision of such novel antibody andthe preparation of a pharmaceutical composition using the same that can neutralize thebinding of PCSK9 and LDLR and increase the amount of LDLR, thereby resulting ina reduction in the subject's serum cholesterol level and treating or preventing or
reducing the risk of the diseases associated with increased cholesterol level such as
hypercholesteremia.
Each of the specifications discloses that hybridomas have been prepared by useof immunized mice produced in accordance with the description of each of thespecifications, and 2441 stable hybridomas producing an antibody that binds to
PCSK9 have been established by screening, and it has been found that, of these, 39
antibodies in total were subjected to epitope binning, which resulted in 19 antibodies
not competing with 31H4 but competing with 21B12 (BIN 1), out of which 15
antibodies were found to be neutralizing antibodies, and resulted in 10 antibodies notcompeting with21B12 but competing with 31H4 (BIN 3); of these, 7 antibodies were
found to be neutralizing antibodies.

Further, each of the specifications also discloses

that 21B12 and 31H4 have excellent effects of blocking the binding of PCSK9 and
EGFa domain of LDLR.
21B12 is included in reference antibody 1, and 31H4 is included in reference
antibody 2.

Thus, it can be seen that an antibody competing with 21B12 is anantibody competing with reference antibody 1 and an antibody competing with 31H4
is an antibody competing with reference antibody 2.

Consequently, it is recognizedthat a person ordinarily skilled in the art who read each of the specification s would
recognize that, in addition to the fact confirmed as a result of the above epitope
binning assay that 15 specific antibodies of Invention 1 and 7 specific antibodies ofInvention 2 are obtained, neutralizing antibodies competing with reference antibody 1
or 2 may be obtained through a similar epitope binning assay for the above remaining
antibodies obtained from the above 2441 stable hybridomas and have an effect of
causing the decrease of serum cholesterols in a subject.
Furthermore, each of the specifications describes the manufacture and selectionof immunized mouse in accordance with a procedure and a schedule of immunization
program in the description, the production of hybridomas using an immunized mouse,a screening, and an epitope binning assay for identifying an antibody that strongly
18

blocks the binding of PCSK9 and LDLR and competes with 21B12 or 31H4.

It isrecognized that based on these descriptions, a person ordinarily skilled in the art could
recognize that neutralizing antibodies competing with reference antibody 1 or 2 might
be obtained in addition to neutralizing antibodies competing with the reference
antibody specifically described in each of the specifications, by repetitively
implementing a series of procedures from the start.
As aforementioned, a person ordinarily skilled in the art can obtain an isolated
monoclonal antibody that neutralizes the binding of PCSK9 and LDLR protein andcompetes with reference antibody 1 or 2 on the basis of the description of each of thespecifications.

Thus, novel antibodies of monoclonal antibodies of Inventions 1-1

and 2-1 are provided.

Further, one can recognize the fact that a pharmaceuticalcomposition of Inventions 1-2 and 2-2 using them may treat or prevent or reduce therisk of the diseases
hypercholesteremia.

associated with increased cholesterol level such as

Therefore, it is recognized that each of the Inventions conforms

to the support requirement.
(3) Appellant's allegation
Appellant alleges that each of the Inventions is an invention of an antibody
specified only by a parameter requirement of "competing with reference antibody"and a problem to be solved by the invention (desired effect) "capable of neutralizing
the binding" and a pharmaceutical composition using the same, but it cannot be said
that a problem can be solved only by the competition, and thus the Inventions do notconform to the support requirement.
However, it cannot be said from the description of each of the specification sthat "capable of neutralizing the binding" and "competing with reference antibody"are the relationship between a problem and a means for solving the problem, nor canit be said that the constituent feature to compete with reference antibody is aparameter requirement.

Further, it is a matter of common general knowledge thatamino acid sequence is identified in a process of identifying an antibody having
specific binding properties.

Therefore, it is not recognized as essential to specify the

structure of the antibody (amino acid sequence) in advance for obtaining an antibody
having specific binding properties (Exhibits Ko 34, 35).
As aforementioned, each of the Inventions provides an isolated monoclonal
antibody that neutralizes the binding of PCSK9 and LDLR protein and competes witheach of the reference antibodies, and has constituent features of being an isolated
monoclonal antibody that "competes" with reference antibody and being capable ofblocking ("neutralizing") the interaction (binding) between PCSK9 and LDLR.
19

Thus,

the Appellant's allegation is not acceptable.
(4) Conformance to the support requirement of each of the corrected inventions
Note that Corrected Invention 1 further specifies reference antibody 1 ofInvention 1 (constituent feature 1B) as reference antibody 1' (constituent feature 1B')by an amino acid sequence in a variable region.

Note that Corrected Invention 2

further specifies reference antibody 2 of Invention 2 (constituent feature 2B) as
reference antibody 2' (constituent feature 2B') by an amino acid sequence in a variable
region, it is recognized that each of the corrected inventions conforms to the support
requirement.
(5) Summary
As described above, it must be said that each of the Inventions and each of thecorrected inventions conform to the support requirement.
4. Issue (2)B (Violation of Enablement Requirement)(1) According to the finding of said 3(1), it can be seen from the description ofeach of the specifications that an antibody of Inventions 1-1 and 2-1 and apharmaceutical composition of Inventions 1-2 and 2-2 may be produced and used, andthus it can be seen from the description of Detailed Description of the Invention ofeach of the specifications that a person ordinarily skilled in the art could definitely
and sufficiently describe each of the Inventions to the extent that allows a person
ordinarily skilled in the art to implement each of the Inventions.
Therefore, it is recognized that each of the Inventions conforms to theenablement requirement.
(2) Appellant's allegation
Appellant alleges that each of the Inventions does not identify the antibody
structure, but defines only functionally, and includes an extremely broad range ofantibodies, whereas it takes enormous time and effort as well as many trial s and errors
for a person ordinarily skilled in the art to obtain an antibody included in the whole
range of each of the Inventions that does not specify the structure, and thus each of
the Inventions fails to satisfy the enablement requirement.
However, the description of Detailed Description of the Invention of thespecification is required to conform with the requirement that it should describe
definitely and sufficiently to the extent that allows a person ordinarily skilled in theart to implement the invention, because in the absence of the description of theconstitution of the invention, etc. in Detailed Description of the Invention of thespecification to the extent that allows a person ordinarily skilled in the art to easily
implement the invention, it can be traced to the non-disclosure of the invention, which
20

leads to lack of the prerequisite for granting to the inventor an exclusive rightprovisioned by the Patent Act.
Each of the Inventions is a technical idea for an isolated monoclonal antibody
that competes with a reference antibody for binding with PCSK9 and is capable ofneutralizing the binding of PCSK9 and LDLR protein.
defined only functionally.

It cannot be said to be

Further, if the description of the Detailed Description of

the Invention should have such a description that allows us to make an antibody
which embodies a technical idea of an isolated monoclonal antibody that canneutralize the binding of PCSK9 and LDLR protein and competes with reference
antibody 1 or 2 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 fallwithin a technical scope of the patent invention may be obtained.
Further, each of the Inventions is an invention of an antibody in which anamino acid to be recognized on an antigen is not specified.

Thus, it must be said thatit has nothing to do with the enablement requirement as to whether a specific antibody(EGFa mimic) that recognizes the most part of amino acids on PCSK9 that LDLR
recognizes is described to work from the description of the Detailed Description of
the Invention.
Further, as per the aforesaid (1), a person ordinarily skilled in the art can obtaina neutralizing antibody that competes with a reference antibody included in the scopeof the claims of each of the Patents (Claim 1) in addition to the neutralizing
antibodies that compete with a reference antibody described in each of thespecifications in compliance with the description of each of the specifications.

Thus,

it cannot be said that it would take many trials and errors that go beyond the level thatcan be expected for a person ordinarily skilled in the art to obtain an antibody
encompassed into the technical scope of each of the Inventions.
Therefore, the Appellant's allegation is not acceptable.
(3) Conformance to the enablement requirement of each of the corrected
inventions
As per the aforesaid 3(4), it should be noted that Corrected Invention 1 further
specifies reference antibody 1 of Invention 1 (constituent feature 1B) as reference
antibody 1' (constituent feature 1B') by an amino acid sequence of a variable region.
Note that Corrected Invention 2 further specifies reference antibody 2 of Invention 2(constituent feature 2B) as reference antibody 2' (constituent feature 2B') by an aminoacid sequence of a variable region.

Therefore, a person ordinarily skilled in the art
21

can produce and use an antibody of Corrected Inventions 1-1 and 2-1 and apharmaceutical composition of Corrected Inventions 1-2 and 2-2 from the descriptionof each of the specifications.

It is recognized that each of the Corrected Inventions

conforms to the enablement requirement.
(4) Summary
As described above, it must be said that each of the Inventions and each of thecorrected inventions conform to the enablement requirement.
5. Issues (2)C (Lack of Inventive step over Exhibit Otsu 1 Document)(1) Described matters in Exhibit Otsu 1 document
The description from page 42, line 22 to page 46, line 23 of the judgment inprior instance is maintained.

Thus, this is incorporated by reference.

(2) Finding of Exhibit Otsu 1 invention
A. According to the finding of the above (1), it is recognized that Exhibit Otsu
1 document discloses that [i] By an experiment adding a purified PCSK9 to a mediumof cultured HepG2 cells, it was demonstrated that the purified PCSK9 reduced thenumber of cell-surface LDLRs of HepG2 cells in a dose- and time-dependent manner(Figures 2 and 3), [ii] We conclude from the experimental result of [i] that secreted
PCSK9 associates with the LDLR and reduces hepatic LDLR protein levels, [iii]Genetic data from humans with loss-of-function mutations in PCSK9 combined withthe studies in knockout mice that lack PCSK9 would be sufficient to inhibit the abilityof an inhibitor of the protease activity of PCSK9 in cells to decrease LDLR level forthe treatment of hypercholesterolemia; however, as suggested by data of this study, an
additional method for neutralizing the activity of PCSK9 including the developmentof an antibody blocking the interaction (binding) between PCSK9 and LDLR and thedevelopment of an inhibitor blocking the activity in plasma may be sought as atreatment of hypercholesteremia.
Therefore, Exhibit Otsu 1 document describes "PCSK9 protein binding to
LDLR" (hereinafter referred to as "Exhibit Otsu 1 Invention").
B. Appellant alleges that Exhibit Otsu 1 document discloses a PCSK9-LDLR
binding neutralizing antibodies, which shares this point with each of the Inventions.
As in the aforesaid item (1)(cited Judgment in the prior instance, page 46, lines
19 to 23), however, Exhibit Otsu 1 document discloses an additional method forneutralizing the activity of PCSK9 including the development of an antibody blocking
the interaction (binding) between PCSK9 and LDLR may be sought as a treatment ofhypercholesteremia, whereas it fails to describe or suggest a specific antibody havingsuch effect.

Therefore, Exhibit Otsu 1 document fails to disclose an antibody itself
22that blocks the interaction (binding) between PCSK9 and LDLR.

Appellant 's

allegation is not acceptable.
(3) Comparison between each of the Inventions and Exhibit Otsu 1 invention
Comparing each of the Inventions with Exhibit Otsu 1 invention, they have incommon that they are proteins, and have the following different features:(Different Feature 1) Each of the Inventions is an "isolated monoclonal
antibody", and an antibody "capable of neutralizing the binding of PCSK9 and LDLR
protein" (constituent features 1A, 1C, 2A, 2C), whereas Exhibit Otsu 1 invention is
not an isolated monoclonal antibody capable of neutralizing the binding of PCSK9and LDLR protein.
(Different Feature 2A) Invention 1-1 is an antibody "competing" with reference
antibody 1 "with respect to the competition with PCSK9" (constituent feature 1B'),
whereas Exhibit Otsu 1 invention is silent about the competition with reference
antibody 1 with respect to the competition with PCSK9.
(Different Feature 2B) Invention 2-1 is an antibody "competing" with reference
antibody 2 "with respect to the competition with PCSK9" (constituent feature 2B'),
whereas Exhibit Otsu 1 invention is silent about the competition with reference
antibody 2 with respect to the competition with PCSK9.
(4) Well-known art as of the priority date
A. Exhibits Otsu 15 to 19 have the following descriptions:(A) Exhibit Otsu 15 (Antibodies A LABORATORY MANUAL, 1988 (Showa
63-nen))"For manipulating and adopting the reactivity against a certain antigen, there is
only a little room left for researchers to be able to intervene.
interventions are categorized into two categories.
or change the condition of infusion. ...

The types of suchSpecifically, to modify the antigen,

The second kind of intervention includes theselection of animals, dose amount and forms of antigen, the use of immunoadjuvant,infusion path and times, and an interval between infusions." (page 92, lines 1 to 11)"For the preparation of monoclonal antibody, both mouse and rat may be used.
(...)" (page 94, lines 14 to 15)(B) Exhibit Otsu 16 (Antibody Engineering Methods and Protocols, 2004
(Heisei 16-nen))"A transgenic mouse in which a human immune globulin gene is introduced
provides researchers with an opportunity to obtain complete human antibody by use ofa well-established hybridoma technique.

Several different strains of such mouse areavailable and accessible in a certain condition from various businesses.
23

Brand

names of these mice are XenoMouse®, HuMAb mouse®, ..., and KM TM mouse." (page191, main text, lines 1 to 6)"3.

Methods

3. 1

Preparation of all cells for immunization ...

3. 2

Immunization ...

3. 3

Preparation of lymphoid cell ...

3. 4

Isolation of B cell ...

3. 5

Cell Fusion ...

3. 6

Primary Screen of Antigen Binding...

3. 7

Secondary ELISA Screen...

3. 8

Hybridoma Cloning ..." (page 194, line 4 from the bottom to page 198, line 9)"3.6 Primary Screen of Antigen Binding
1.

An appropriate number of ELISA plates is ... into plate coating buffer (abuffer covering a plate surface) and in a case of using a plate (...) coated (a surface iscovered) with a soluble antigen or streptoavidin, 100 to 300 ng/mL biotinylated
antigen is coated (a surface is covered) at 50 uL/well." (page 197, lines 12 to 17)"3.7 Secondary ELISA Screen
1.

By use of a similar condition to Primary Screen (...), ELISA plates in double thenumber of cultivation plates are coated with 50 uL/well soluble or biotinylated
antigen (a surface is covered)." (page 197, lines 33 to 36)(C) Exhibit Otsu 17 (Phage Display of Peptides and Proteins A Laboratory
Manual, 1996 (Heisei 8-nen))"An antibody is a functional protein of cells that has been displayed on asurface of phage subsequent to the first demonstration (...) of peptide display (...). .. .
A region for the determination of binding specificity of antibody is a part called
variable regions of heavy chain and light chain, and it is present at the N-terminal ofeach chain.

The binding of heavy chain and light chain variable regions(respectively, VH and VL) results in the production of heterodimer molecule called
Fv fragment and retains the binding specificity of the original antibody ....
The antibody may be expressed by Escherichia coli in the form of Fv fragment
due to the other expression of VH and VL domains under the influence of signal
peptide." (page 79, lines 1 to 12)"In the other method, an antibody can express the form of FAb fragment inwhich various heavy chains bind to the whole light chain in addition to the first
constant region." (page 80, lines 1 to 3)"Preparation of the production of antibody gene and library ...
24Preparation of PCR template ...
Protocol 2

Preparation of human peripheral blood lymphocyte ...

Protocol 3

Preparation of mouse or human antibody cDNA ...

Constructionof human V-gene repertoireProtocol 4

Preparation of primary VH and VL PCR production ...

Protocol 11

Selection of phage antibody library by the selection (panning) in‘immune tube’...
Protocol 12

Selection of phage-antibody library by biotin selection ..." (page 81,

line 34 to page 101, line 5 from the bottom)"Screen and Expression of selected clone
Following selection (panning), individual colonies may be directly assayed forthe ability to bind to a specific antigen.

These may be screened by an immunoassay

technology like ELISA as a phage particle or a soluble fragment." (page 105, lines 24
to 27)(D) Exhibit Otsu 18 (REVIEW Selecting and screening recombinant antibody
libraries, September 2005 (Heisei 17-nen))"During the past decade several display methods and other library screening
techniques have been developed for isolating monoclonal antibodies (mAbs) fromlarge collections of recombinant antibody fragments.

These technologies are now

widely exploited to build human antibodies with high affinity and specificity. " (page1105, Abstract, lines 1 to 3)"Phage Display
Antibody display on a surface of two kinds of bacteriophage fd and M13 is the mostcommonly used method for the display and selection of a large number of collectionsof antibodies and for the engineering of selected antibodies (...)." (page 1106, left
column, line 10 to right column, line 2)"FIG. 3
Method for ex vivo (in vitro) selection for binding.

The selection fromdisplay library is implemented with several methods (or a combination thereof).
(...)(b) Biotinylated antigen (Biotin (red) is captured via beads (gray) coated with
Streptoavidin)" (page 1111)(E) Exhibit Otsu 19 (REVIEWS Potent antibody therapeutics by design, May
2006 (Heisei 18-nen))"Table 1

Monoclonal antibody approved for the therapeutic use in the

United States" (page 344)
25

"The use of transgenic mouse for the manufacture of human antibody isrelatively simple, and based on a widely used technique." (page 347, left column,
lines 18 to 19)"Human antibody from phage display library" (page 347, left column, line 9
from the bottom)"After isolating from phage display library, several antibody fragments havesufficiently high binding affinity and biological effect for the indication of treatment. "(page 347, the right column, lines 30 to 33)"Affinity mature of the current antibody and the subsequent functional
screening are widely used for promoting the effectiveness of antibodies, and are
strategies that make a success at a high frequency." (page 350, right column, line 2
from the bottom to page 351, left column, line 2).
B. Comprehensively taking the description of the aforesaid A into account, it isrecognized as a well-known technical matter that there were a method of utilizing
hybridoma (Exhibits Otsu 15, 16) and a phage display method (Exhibits Otsu 17 to19) as a method for producing monoclonal antibody having a specific binding to an
antigen, and hybridoma method adopts the means of producing a number ofhybridomas by use of cells sampled from a subject animal immunized by an antigen,and selecting an antibody having an ability to bind to an antigen by screening fromantibodies produced by these hybridomas, and a phage display method adopts themeans of preparing antibody genes and libraries on the basis of antibody geneobtained from human and animals and selecting an antibody having an ability to bindto an antigen as of the priority date.
(5) Determination about the different features
A. Different Feature 1
As aforementioned, Exhibit Otsu 1 document discloses that "an inhibitor of theprotease activity of PCSK9 in cells would be sufficient to inhibit the ability todecrease LDLR level for the treatment of hypercholesterolemia; however, as issuggested by data of this study, an additional method for neutralizing the activity of
PCSK9 including the development of an antibody blocking the interaction (binding)between PCSK9 and LDLR and the development of an inhibitor blocking the activity
in plasma may be sought as a treatment of hypercholesteremia".

This disclosuresuggests the possibility of usefulness of antibody blocking the interaction (binding)between PCSK9 and LDLR and neutralizing the PCSK9 activity for the treatment ofhypercholesteremia, and is thus recognized as a motivation for a person ordinarily
skilled in the art who read Exhibit Otsu 1 to obtain a binding neutralizing antibody of26

PCSK9 and LDLR.
Further, as per the aforesaid (4), it is recognized that a common method for the
preparation of monoclonal antibody was well known by a hybridoma method or aphage display method as of the priority date.
Consequently, it is feasible to obtain any isolated monoclonal antibody capableof neutralizing the binding of PCSK9 and LDLR protein by applying well-known art
to Exhibit Otsu 1 invention.
B. Different features 2A and 2B
However, Exhibit Otsu 1 document neither describes nor suggests competingwith reference antibody 1 or 2 for binding with PCSK9, nor do they describe
information that gives a clue for obtaining an antibody competing with reference
antibody 1 or 2 from antibodies neutralizing the binding of PCSK9 and LDLR.
Further, as discussed in the aforesaid (4)B, it is recognized that every common
means for obtaining monoclonal antibody of the well-known art comprises a step of
producing a number of antibodies and a step of selecting an antibody by scre ening
from these numerous antibodies, and a specific monoclonal antibody is obtained forthe first time when an antibody is selected by screening.

There is no evidence

sufficient to find the fact that reference antibody 1 or 2 had been obtained before thepriority date.

It cannot be said that an antibody competing with reference antibody 1

or 2 could be selected by screening through competition assay.
Therefore, it cannot be recognized that a person ordinarily skilled in the art
could have easily conceived of obtaining an antibody that competes with reference
antibody 1 or 2 on the basis of Exhibit Otsu 1 invention and well-known art.
C. Based on the above fact, although a person ordinarily skilled in the art who
read Exhibit Otsu 1 document could have easily conceived of obtaining any
monoclonal antibody (Different Feature 1) capable of neutralizing the binding of
PCSK9 and LDLR on the basis of Exhibit Otsu 1 invention and the above well-known
art, it cannot be recognized that an antibody "competing" with reference antibody 1 or
2 was easily conceivable (different features 2A, B).
D. Appellant alleges that [i] each of the specifications describes that when aplurality of PCSK9-LDLR binding neutralizing antibodies are prepared without abarometer of whether or not to compete with reference antibody 1 or 2, almost all theantibodies compete with reference antibody 1 or 2; and [ii] According to thedeclaration statement by A, when PCSK9-LDLR binding neutralizing antibodies are
obtained, of these, many antibodies competing with reference antibody 1 or 2 arecontained, and this is why a person ordinarily skilled in the art could have easily
27

conceived of binding neutralizing antibodies competing with reference antibody 1 or 2
only by preparing several PCSK9-LDLR binding neutralizing antibodies on the basis
of Exhibit Otsu 1 and well-known art as of the priority date.
However, each of the specifications describes in Table 37.1 that 2441 stablehybridomas had been established by confirmatory screening to produce an antibody
binding to PCSK9 ([0329]), a part of which (39 antibodies in total) were subjected toepitope binning, and the results were summarized ([0489] to [0493]), and when thistable is analyzed, it is difficult to derive a proportion of antibodies competing with areference antibody in binding neutralizing antibody of PCSK9 and LDLR, and thus it
cannot be said that most of PCSK9-LDLR binding neutralizing antibodies competedwith reference antibody 1 or 2.
Further, the declaration statement by A stated that “most of anti-PCSK9
antibodies neutralizing the binding of PCSK9 and LDLR obviously compete witheither of 21B12 or 31H4 in view of the binding site on PCSK9 surface of LDLR andthe binding manner of these antibodies as depicted in Figure 27D (of each of thespecifications)." (Exhibit Otsu 4).

It only mentions that anti-PCSK9 antibodies

neutralizing the binding of PCSK9 and LDLR compete with either of reference
antibody 1 or 2, and it is not shown that most of PCSK9-LDLR binding neutralizing
antibodies compete with reference antibody 1 or 2.
Therefore, as Appellant alleges, it cannot be said that Invention 1 -1 or 2-1 wasconceivable only by making PCSK9-LDLR binding neutralizing antibody.
In this regard, according to the description of Exhibit Otsu 15, it is recognizedthat in producing an antibody with an animal immunization method, antibodies withdifferent reactivities against an antigen may be obtained by the difference in "aninfusion condition" (for animals) including the selection of animals, a dosage amountand a dosage form of an antigen, the use of immunization adjuvant, the infusion routeand times, and an interval between infusions (aforesaid (4)A(A)).

It can be seen that

this can apply similarly to animals for obtaining antibody gene used for the
production of antibody in a phage display method.

Incidentally, Exhibit Otsu 1

document does not at all describe the process for obtaining an antibody competingwith reference antibody included in a specific condition of animal immunization.
Thus, it cannot be said that it was easy to obtain reference antibody 1 or 2, which wasan antibody having a specific amino acid sequence in a variable region even by
applying general well-known art regarding the production of monoclonal antibody,nor can it be said that an antibody competing with reference antibody 1 or 2 could beobtained.
28

Therefore, the Appellant's allegation is not acceptable.
(6) Inventive step of each of the Corrected Inventions
A. Comparison between each of the Corrected Inventions and Exhibit Otsu 1
invention
Comparing each of the Corrected Inventions with Exhibit Otsu 1 invention,
they have in common that they are proteins, and have the following different featuresin addition to Different Feature 1 between each of the Inventions and Exhibit Otsu 1
invention:(Different feature 2A') Corrected Invention 1-1 is an antibody "competing"with reference antibody 1' "with respect to the competition with PCSK9" (constituent
feature 1B'), whereas Exhibit Otsu 1 invention is silent about the competition withreference antibody 1' with respect to the competition with PCSK9.
(Different Feature 2B') Corrected Invention 2-1 is an antibody "competing"with reference antibody 2' "with respect to the competition with PCSK9" (constituent
feature 2B'), whereas Exhibit Otsu 1 invention is silent about the competition withreference antibody 2' with respect to the competition with PCSK9.
B. Whether Different Features 2A' and 2B' were easily conceivable
Reference antibody 1' further specifies reference antibody 1 by an amino acidsequence in a variable region.

Reference antibody 2' further specifies reference

antibody 2 by an amino acid sequence in a variable region.

Thus, for a similarreason for the fact that it is not easy to obtain an antibody competing with reference
antibody 1 or 2, it must be said that it is also not easy to obtain an antibody competingwith reference antibody 1' or 2'.
Therefore, it cannot be recognized that a person ordinarily skilled in the art
could have easily conceived of obtaining an antibody that competes with reference
antibody 1' or 2' on the basis of Exhibit Otsu 1 invention and well-known art.
(7) Summary
For the above reason, it cannot be said that each of the Inventions and each of
the Corrected Inventions was easily conceivable by a person ordinarily skilled in theart on the basis of Exhibit Otsu 1 invention and well-known technique.
6. Issues (2) D (Lack of Inventive step over Exhibit Otsu 27 Document)(1) Petition for dismissal of method of allegation or evidence Presented After
Its Time Without PrejudiceAppellee alleges that the Appellant's allegation of lack of inventive step on thebasis of the description of Exhibit Otsu 27 document and well-known art is asubmission of petition of method of allegation or evidence presented after its time29

without prejudice due to intention or serious fault that will delay the conclusion of
litigation, and thus should be dismissed.
However, this suit had concluded oral proceeding on the date for oral argument
when the above allegation was presented (Facts obvious to the court).

It cannot be

said that the above allegation will delay the conclusion of litigation.

Therefore, theabove Appellee's allegation is not acceptable.
(2) Described matters in Exhibit Otsu 27 document
Exhibit Otsu 27 document has the following descriptions:A. When excreted PCSK9 is added to HEK293 cell, the decomposition of
LDLR on cell surface was caused in a concentration-dependent and time-dependent
manner.

Accordingly, intracellular uptake of LDR was significantly decreased .

When purified human PCSK9 was directly infused to C57B6 mice, LDLR protein
level in liver is substantially decreased, thereby causing a result of elevating LDLcholesterol level in plasma. (page 1488, left column, lines 7 to 14)
B. PCSK9 interacts with LDLR extracellular domain.
... caused LDLR extracellular domain to be expressed as an excretion type, andthe protein was purified (Figure 6A).

After incubation together with recombinant

PCSK9, LDLR was ... co-immuneprecipitated.

A western blot analysis using PCSK9

antibody definitely shows the co-immuneprecipitation of PCSK9, which suggests the
direct binding of PCSK9 to LDLR extracellular domain (Figure 6B). (page 1493, rightcolumn, line 1 to page 1494, left column, line 2)
C. In an additional experiment, we have demonstrated that the inhibition of thebinding of PCSK9 to cell surface LDLR was sufficient to significantly weaken thefunction of PCSK9 through overexpression of LDLR extracellular domain, thereby
being capable of characterizing the deterministic role of this direct interaction.
Therefore, the binding of PCSK9 to LDLR extracellular domain is an essential step inthe process of PCSK9 acting thereby to decrease LDLR protein level. (page 1497, left
column, lines 8 to 15)
D. The drug inhibiting the specific function of PCSK9 will be developed as amethod suitable for decreasing LDL and atherosclerosis. (page 1497, right column,
lines 1 to 4)(3) Finding of Exhibit Otsu 27 invention
According to the finding of the above (2), it is recognized that Exhibit Otsu 27
document demonstrates that the function of PCSK9 is significantly weakened by useof a protein that inhibits PCSK9 from binding to LDLR on cell surface by binding to
PCSK9 outside the cell, and describes, as a result, proposing the use of a drug that30

inhibits this specific function of PCSK9 as a pharmaceutical composition.
Therefore, it is recognized that Exhibit Otsu 27 document describes "LDLR
extracellular protein binding to PCSK9" (hereinafter referred to as "Exhibit Otsu 27
invention".).
(4) Comparison between each of the Inventions and Exhibit Otsu 27 invention
Comparing Exhibit Otsu 27 invention with Inventions 1-1 and 2-1, they have incommon that they are proteins binding to PCSK9, and have the followin g different
features:(Different Feature 1) Each of the Inventions is an "isolated monoclonal
antibody", and a binding neutralizing antibody "capable of neutralizing the binding of
PCSK9 and LDLR" (constituent features 1A, 1C, 2A, 2C), whereas Exhibit Otsu 27
invention is not an isolated monoclonal antibody capable of neutralizing the bindingof PCSK9 and LDLR protein.
(Different Feature 2A) Invention 1-1 is an antibody "competing" with reference
antibody 1 "with respect to the competition with PCSK9" (constituent feature 1B),
whereas Exhibit Otsu 27 invention is silent about the competition with reference
antibody 1 with respect to the competition with PCSK9.
(Different Feature 2B) Invention 2-1 is an antibody "competing" with reference
antibody 2 "with respect to the competition with PCSK9" (constituent feature 2B),
whereas Exhibit Otsu 27 invention is silent about the competition with reference
antibody 2 with respect to the competition with PCSK9.
(5) Determination about the different features
A. Exhibit Otsu 27 document does not describe an antibody neutralizing thebinding of PCSK9 and LDLR, nor does it suppose replacing a protein binding to an
LDLR extracellular domain with an antibody, and thus it must be said that there is no
motivation to replace LDLR extracellular domain protein binding to PCSK9 of
Exhibit Otsu 27 invention with PCSK9-LDLR binding neutralizing antibody.
Therefore, it cannot be recognized that a person ordinarily skilled in the art
could easily conceive of the constitution according to the above Different Feature 1.
Therefore, it is obvious that Inventions 1-1 and 2-1 were not easily conceivable
by a person ordinarily skilled in the art on the basis of Exhibit Otsu 27 invention, norwere Inventions 1-2 and 2-2, which relate to a pharmaceutical composition includingthese antibodies, easily conceivable by a person ordinarily skilled in the art on thebasis of Exhibit Otsu 27 invention.
B. Appellant alleges that it was a well-known matter as of the priority date thata representative example of inhibitor capable of inhibiting the binding of one protein
31

and another protein outside the cell (in blood) may include an antibody (usuallymonoclonal antibody particularly for pharmaceutical use), and Exhibit Otsu 1
document and Exhibit Otsu 28 document explicitly propose an antibody as a PCSK9LDLR inhibitor, and thus there was a motivation for replacement.
However, as aforementioned, Exhibit Otsu 1 document discloses that anadditional method of neutralizing the activity of PCSK9, involving the developmentof antibody blocking the interaction of PCSK9 and LDLR or an inhibitor blocking theactivity in plasma, may be sought for the treatment of hypercholesteremia.

Further,

Exhibit Otsu 28 document describes "an antibody or small molecule binding to
PCSK9 in plasma to inhibit the binding of PCSK9 and LDLR may be an effective
inhibitor for the function of PCSK9"; however, it does not disclose the replacement
itself of an inhibitor with an antibody.

Therefore, it cannot be said from thesedescriptions that it was a well-known art to replace an inhibitor with an antibody.
Thus, the Appellant's allegation is not acceptable.
C. Even if the replacement of an inhibitor with an antibody was a well-known
art and it was possible to obtain PCSK9-LDLR binding neutralizing antibodies(Different Feature 1) by applying such well-known art or well-known art for the
method of producing common monoclonal antibody as found in said 5(4), Exhibit
Otsu 27 document neither describes nor suggests competing with reference antibody 1
or 2 for binding with PCSK9, nor does it describe information that gives a clue forobtaining an antibody competing with reference antibody 1 or 2 from antibodies
neutralizing the binding of PCSK9 and LDLR.

Further, there is no evidence

sufficient to find the fact that reference antibody 1 or 2 had been obtained before thepriority date.

It cannot be said that an antibody competing with reference antibody 1

or 2 could be selected by screening through competition assay by applying the meansfor obtaining a common monoclonal antibody in well-known art, as per the aforesaid
5(5)B.
Therefore, it cannot be said that a person ordinarily skilled in the art could have
easily conceived of obtaining reference antibody 1 or 2, nor can it be recognized thatthe constitution according to Different Feature 2 was easily conceivable.
(6) Inventive step of each of the Corrected Inventions
A. Comparison between each of the Corrected Inventions and Exhibit Otsu 27
invention
Comparing each of the Corrected Inventions with Exhibit Otsu 27 invention,
they have in common that they are proteins binding to PCSK9, and have the following
different features in addition to Different Feature 1 between each of the Inventions
32

and Exhibit Otsu 27 invention:(Different Feature 2A') Corrected Invention 1-1 is an antibody "competing"with reference antibody 1' "with respect to the competition with PCSK9" (constituent
feature 1B'), whereas Exhibit Otsu 27 invention is silent about the competition withreference antibody 1' with respect to the competition with PCSK9.
(Different Feature 2B') Corrected Invention 2-1 is an antibody "competing"with reference antibody 2' "with respect to the competition with PCSK9" (constituent
feature 2B'), whereas Exhibit Otsu 27 invention is silent about the competition withreference antibody 2' with respect to the competition with PCSK9.
B. Whether Different Features 2A' and 2B' were easily conceivable
Reference antibody 1' further specifies reference antibody 1 by an amino acidsequence in a variable region.

Reference antibody 2' further specifies reference

antibody 2 by an amino acid sequence in a variable region.

Thus, for a similarreason for the fact that it is not easy to obtain an antibody competing with reference
antibody 1 or 2, it must be said that it is also not easy to obtain an antibody competingwith reference antibody 1' or 2'.
Therefore, it cannot be recognized that a person ordinarily skilled in the art
could have easily conceived of obtaining an antibody that competes with reference
antibody 1' or 2' on the basis of Exhibit Otsu 27 invention and well-known art.
(7) Summary
For the above reason, it cannot be said that each of the Invention s and each of
the Corrected Inventions were easily conceivable by a person ordinarily skilled in theart on the basis of Exhibit Otsu 27 invention and well-known technique.
7. Issues (3) (Propriety of injunctive relief)(1) According to the aforesaid findings 1 to 6, it is not recognized that
Defendant's monoclonal antibody falls within a technical scope of Inventions 1-1 and
2-1, Defendant's product falls within a technical scope of Inventions 1-2 and 2-2, andfurther each of Patent 1 and 2 should be invalidated by a trial for patent invalidation.
As aforementioned, there is no dispute between parties concerned that
Appellant imports, transfers, and offers to transfer Defendant's products (cited
Judgment in prior instance, page 7, line 2).

These acts correspond to infringing actsof patent rights 1 and 2.
(2) Necessity of injunction of production of Defendant's products andproduction, import, transfer, and offer to transfer Defendant's monoclonal antibody
Appellant alleges that Appellant does not produce Defendant's products, nordoes it produce, import, transfer, and offer to transfer its raw material of Defendant's
33monoclonal antibody.
According to the entire import of the oral argument, however, it is recognizedthat Appellant can import Defendant's monoclonal antibody, which is an active
pharmaceutical ingredient of Defendant's product, from the parent company Sanofi,
etc. of France, and Defendant's monoclonal antibody may be easily produced bysubjecting a cell strain for the production of Defendant's monoclonal antibody toclonal culture.

Thus, it cannot be ruled out that Appellant might possibly produce

Defendant's product or transfer Defendant's monoclonal antibody following the importor production of Defendant's monoclonal antibody, and thus it must be said that
Appellant is likely to produce Defendant's product or conduct each of an act of
production, import, transfer, and offer to transfer of Defendant's monoclonal antibody.
Consequently, these acts possibly infringe Patent Rights 1 and 2.

Thus, thenecessity of the injunction is recognized.
(3) Abuse of rights
Appellant submits the expert opinion prepared by B (Exhibit Otsu 33), alleging
that Appellee's claim for injunction corresponds to the abuse of rights and thus is not
permitted since the injunction of the production and transfer, etc. of Defendant's
product and Defendant's monoclonal antibody causes patients currently administeredor to be administered Defendant's product to have severe health risk or anxiety for
future therapy.
Exhibit Otsu 33 points out the problem of decreasing options for patients andexpecting the bafflement of patients who use Defendant's product caused by the
injunction of transfer, etc. of Defendant's product; however, it does not go so far as topoint out the occurrence of concrete health risk for patients by use of products
produced and sold by Appellee in place of Defendant's product.

Thus, it cannot be

said that specific facts have been demonstrated that the injunction of the use of
Defendant's product is contrary to the public interest.
Further, in the field of pharmaceutical products, there might be the case wherea right to seek injunction should be limited from a viewpoint of public interests ;however, it cannot be concluded that an injunction of the production , transfer, etc. of
infringing products should not be permitted, without establishing concrete facts, for a
simple reason that it is desirable for patients to have a selectable option .

Therefore,

the Appellant's allegation is not acceptable.
(4) Summary
As seen above, all the Appellee's claims against Appellant for an injunction of
the production, transfer, import, and offer to transfer of Defendant's product and34

Defendant's monoclonal antibody and a disposal of Defendant's product under Article
100, paragraph (1) and (2) of the Patent Act on the basis of each of the patent right s
have a point.
8. Conclusion
As described above, the judgment in the prior instance that accepted a claim for
an injunction of the Appellee's production, transfer, import, and offer to transfer ofDefendant's product and Defendant's monoclonal antibody and a claim for disposal of
Defendant's product and dismissed the remaining claim is reasonable, and thus theappeal shall be dismissed, and a judgment shall be made as described in the main text.
Intellectual Property High Court, First Division
Presiding Judge TAKABE Makiko
Judge KOBAYASHI YasuhikoJudge SEKINE Sumiko

35

Attachment
Table 2
Typical heavy chain and light chain
variable regions
Antibody

Light chain /Heavy
chain variable regions
SEQ NO.

Table 3
Mouse strain
Number of animals
ImmunogenFirstenhanced

XMG2/k1
10
PCSK9-V5/His
Intraperitoneal injection
36

XMG4/k1
10
PCSK9-V5/His
Intraperitoneal injection

10 μg for each
Titermax Gold
Tail injection
5 μg for each
Alum/CpG ODNIntraperitoneal injection
5 μg for each
Titermax Gold
Tail injection
5 μg for each
Alum/CpG ODNIntraperitoneal injection
5 μg for each
Titermax Gold
Tail injection
5 μg for each
Alum/CpG ODNIntraperitoneal injection
5 μg for each
Titermax Gold
Tail injection
5 μg for each
Alum/CpG ODN

10 μg for each
Titermax Gold
Tail injection
5 μg for each
Alum/CpG ODNIntraperitoneal injection
5 μg for each
Titermax Gold
Tail injection
5 μg for each
Alum/CpG ODNIntraperitoneal injection
5 μg for each
Titermax Gold
Tail injection
5 μg for each
Alum/CpG ODNIntraperitoneal injection
5 μg for each
Titermax Gold
Tail injection
5 μg for each
Alum/CpG ODNBlood samplingNinthenhanced Intraperitoneal injection
immunization
5 μg for each
Titermax GoldTenthenhanced Tail injection
immunization
5 μg for each
Alum/CpG ODNEleventhenhanced BIP
immunization
5 μg for each
PBS
Sampling

Intraperitoneal injection
5 μg for each
Titermax Gold
Tail injection
5 μg for each
Alum/CpG ODN
BIP
5 μg for each
PBS

immunization
Secondimmunization

enhanced

Third
immunization

enhanced

Fourthimmunization

enhancedFifth
immunization

enhancedSixthimmunization

enhanced

Seventhimmunization

enhanced

Eighthimmunization

enhanced37

Table 8.3
Clone

Clone

BIN

BIN

38

Table 37.1
BIN 1

BIN 2

BIN 3

39

BIN 4

BIN 5