Judgment rendered on April 13, 20182016 (Gyo-Ke) 10182

The case of seeking rescission of JPO decision (Hereinafterreferred to as "First case.")2016 (Gyo-Ke) 10184

The case of seeking rescission of JPO decision (Hereinafterreferred to as "Second case.")Date of conclusion of Oral argument: February 2, 2018
Judgment
Plaintiff of First case:Nippon Chemiphar Co., Ltd.

Counsel attorney

Tomoki IHARA
Takaharu KAKO

Counsel patent attorney

Masazumi IMAMURA
Yoshinobu MUROFUSHI
Satoshi HASHIMOTO

Plaintiff of Second case:

X

Counsel patent attorney for Plaintiffs

Tomoko TSUJITA
Daisuke MURAMATSU

Defendant of First and Second cases

SHIONOGI & CO., Ltd.

Counsel attorney

Seiji OHNO
Keiko KANAMOTO

Counsel patent attorney

Yuko MATSUTOYA
Shinsuke UMEDA

Supporting Intervener for Defendant of First and Second cases
Astra Zeneca UK. LimitedCounsel attorney

Tsuyoshi SUEYOSHI

Counsel patent attorney

Takumi TERACHI
Main text

1. All the Claims from Plaintiffs shall be dismissed.
2. The court costs shall be borne by Plaintiffs.
Facts and reasons1No. 1 Claims
1 First caseA trial decision for Invalidation Trial No. 2015-800095 that JPO made on July 5,2016 shall be rescinded.
2 Second case
The same as in the above item 1.
No. 2

Outline of the caseThis case is a suit against a trial decision that dismissed a request for aninvalidation trial. The issues are the presence or absence of: the legal interest for
litigation; inventive step; and the noncompliance of the support requirement.
1 Outline of procedures at the JPO
Defendant of First case and Second case (hereinafter simply referred to as"Defendant") filed a patent application with a filing date of May 28, 1992 (hereinafterreferred to as "the filing date") (priority claiming on: July 1, 1991 <Hereinafterreferred to as "the priority date".>) titled "PYRIMIDINE DERIVATIVES" (Japanese
Patent Application No. 1992-164009) and registered the same on May 16, 1997
(Exhibit Ko 65.

Patent No. 2648897.

Number of claims: 12.

Hereinafter thispatent is referred to as "the Patent").
Plaintiff of Second case (hereinafter referred to as "Plaintiff X") made a request
for an invalidation trial on March 31, 2015 with regard to Claims 1 to 5 and 7 to 12 of
the Patent as of the date (Exhibit Ko 79.
Hereinafter referred to as "the trial").

Invalidation Trial No. 2015-800095.

Supporting Intervener for Defendant of First

case and Second case (hereinafter simply referred to as "Supporting intervener")
applied for intervention to assist defendant in the trial, and after the permission was
granted, Plaintiff of First case applied for the intervention as a demandant in the trial
and obtained permission (according to the entire import of the oral argument).
Defendant requested for correction including the correction of the scope of claims by awritten correction request on August 3, 2015 (Exhibit Ko 80; cancels Claims 3, 4, 7
and 8, and adds Claims 13 to 17, which resulted in the number of the claims after
correction of 13. Number of claims after correction: 13.).
The Japan Patent Office made a trial decision on July 5, 2016 to the effect that"the demand for the trial was groundless," certified copies of which were sent toPlaintiffs on July 14.

In addition, after the trial decision of the other trial case became

final and binding (Invalidation Trial No. 2014-800022), a patent right was deemed to2

be registered with the scope of claims and the description after the correction made by
Defendant with a written correction request on June 30, 2014, which involved thecorrection of the scope of claims (hereinafter referred to as "the correction of the case").
Accordingly, no further correction has been made by the correction made by thewritten correction request on August 3, 2015, which has the same content as thecorrection of the case.

Therefore, the Japan Patent Office dismissed the lattercorrection made by the written correction request on August 3, 2015, since thecorrection was not to be made for any purpose provided in the each items of Article134-2, paragraph (1) of the Patent Act, and also dismissed the amendment made by thedemandant to the object of the demand to invalidate the patents according to Claims 13
and 15 to 17 after the correction of the case for a reason that the original object of thedemand is to invalidate patents according to Claims 1, 2, 5, and 9 to 12 after thecorrection of the case, and made a determination about Claims 1, 2, 5, and 9 to 12 andthe description after the correction of the case.
2 Recitation of the scope of claims
The recitation of the scope of claims according to Claims 1, 2, 5, and 9 to 12 of
the Patent after the correction of the case is set forth as below. (The inventions ofClaims 1, 2, 5, and 9 to 12 of the Patent after the correction of the case are hereinafterreferred to as "the Invention 1," etc. corresponding to the claim number, and theInventions 1, 2, 5, and 9 to 12 are collectively referred to as "the Invention,"
Hereinafter the descriptionattached to the written correction request (Exhibit Ko 81) isreferred to as "the description".)[Claim 1] (The Invention 1)
A compound represented by the following formula (I):[Formula 1](whereR1 is a lower alkyl;
R2 is a phenyl substituted with halogen;3R3 is a lower alkyl;
R4 is hydrogen or a calcium ion forming a hemicalcium salt;
X is an imino group substituted with an alkylsulfonyl group;
the dashed line represents the presence or absence of a double bond.)or a ring-closed lactone body thereof.
[Claim 2] (The Invention 2)(+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-Nmethylsulfonylaminopyrimidin)-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenoic acid.
[Claim 5] (The Invention 5)
A compound represented by the following formula (I):[Formula 2](the chemical formula is omitted since it is the same as formula (I) of Claim 1.)(whereR1 is a lower alkyl;
R2 is a phenyl substituted with a halogen;
R3 is a lower alkyl;
R4 is a calcium ion forming a hemicalcium salt;
X is an imino group substituted with a methylsulfonyl group;
the dashed line represents the presence or absence of a double bond).
[Claim 9] (The Invention 9)
A compound represented by the following formula (I):[Formula 4](the chemical formula is omitted since it is the same as formula (I) of Claim 1.)(whereR1 is a lower alkyl;
R2 is a phenyl substituted with a halogen;
R3 is a lower alkyl;
R4 is a calcium ion forming a hemicalcium salt;
X is an imino group substituted with a methylsulfonyl group;
the dashed line represents the presence of a double bond.).
[Claim 10] (The Invention 10)
An optically active compound represented by the following formula (I) obtained4

by a step of reacting a compound represented by formula (b) with a (3R)-3-(tertbutyldimethylsilyloxy)-5-oxo-6-triphenylphosphoranylidene hexanate derivative to
produce a compound represented by formula (c);[Formula 5][Formula 6]

a step of causing tert-butyldimethylsilyl group to leave the compound
represented by formula (c) so as to produce a compound represented by formula (d);[Formula 7]

and a step of reducing the compound represented by formula (d):[Formula 8](whereR1 is a lower alkyl;
R2 is a phenyl substituted with a halogen;
R3 is a lower alkyl;
R4 is a calcium ion forming a hemicalcium salt;
X is an imino group substituted with an alkylsulfonyl group;5the dashed line represents the presence of a double bond;t-Bu is tert-butyl;
C* is an asymmetric carbon atom).
[Claim 11] (The Invention 11)A

calciumsaltof(+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-

methylsulfonylaminopyrimidin)-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenoic acid.
[Claim 12] (The Invention 12)
A HMG-CoA reductase inhibitor comprising a compound of Claim 1 as anactive ingredient.
3

Invalidation Reason as alleged by Plaintiffs(1)

Invalidation Reason 1 (Lack of Inventive Step with Exhibit Ko 1 withprimarily cited reference)
The Inventions 1, 2, 5, and 9 to 12 were easily conceivable on the basis of theinventions described in Exhibit Ko 1 (Publication of Japanese Translation of PCT
International Application No. 1991-501613) (hereinafter referred to as "Exhibit Ko 1
Invention") and Exhibit Ko 2 (Japanese Unexamined Patent Application Publication
No. 1989-261377) (hereinafter referred to as "Exhibit Ko 2 Invention";

hereinafter

documentary evidence with branch number includes all branch numbers, unlessotherwise mentioned) and the common general technical knowledge as of the priority
date, before the priority date by a person who had an ordinary knowledge in a technicalfield to which the invention pertains (hereinafter referred to as "a person ordinarily
skilled in the art") (Article 29, paragraph (2) of the Patent Act).
(2)

Invalidation reason 2 (noncompliance of support requirement)

It cannot be said that the Inventions 1, 2, 5, and 9 to 12 had significantly highactivity compared to the conventional technique, and thus a person ordinarily skilled in
the art could not understand that the problem to be solved by the Invention might besolved.

It cannot be said that the invention for which a patent is sought recited in thescope of claims is described in the Detailed Description of the Invention (Article 36,
paragraph (5), item (i) of the Patent Act prior to amendment by Act No.116 of 1994).
4 Reasons of trial decision
Reason of trial decision is as described in a copy of the written trial decision in
the Appendix, and the gist thereof is set forth as below:
6

(1)
A

Invalidation reason 1
Invention 1(A) Exhibit Ko 1 Invention"

A compound (M=Na)"(B) Common features and differences between Invention 1 and Exhibit Ko
1 Invention[Common features]"A compound represented by the following formula (I):(whereR1 is a lower alkyl;
R2 is a phenyl substituted with a halogen;
R3 is a lower alkyl;
the dashed line represents the presence or absence of a double bond)or a ring-closed lactone body thereof"[Difference](1-i)
In Invention 1, X is an imino group substituted with an alkylsulfonyl group,
whereas in the Exhibit Ko 1 Invention it is an imino group substituted with a methyl
7group.
(1-ii)In Invention 1, R4 is hydrogen or a calcium ion forming a hemicalcium salt,
whereas in the Exhibit Ko 1 Invention it is a sodium ion forming a sodium salt.
(C) Determination whether or not the difference from the cited invention
can be easily conceived
a Difference (1-i)(a) Motivation from Exhibit Ko 1 Invention
The Exhibit Ko 1 invention is one selected from
"Formula I",
which is described in the scope of claims of Exhibit Ko 1, in which "R1" is"isopropyl" of "C1-6 alkyl not including asymmetric carbon," "R2" is "-N(R8)2,"
supposing that R8 is "methyl" to be "selected independently from a C1-4 alkyl notincluding asymmetric carbon atom," and "Q" is "Q"a" of "Q""; i.e., the following
structure:"", and any two of the "R3," "R4," and "R5," are "hydrogen" and one is "fluoro,"and "X" is "vinylene," and "Y" is the following structure:"8

", where "R6" is "hydrogen" and "R7" is a "cation" of a "sodium ion,"
Further, the compound of the Exhibit Ko 1 Invention is obtained from Working
Example 1b). Therefore, data support the pharmacological activity inhibiting "HMGCoA reductase." On the other hand, the compound of Formula I recited in the scopeof claims of Exhibit Ko 1 is prima facie described in a manner that allows us to expect
such pharmacological activity, although it is not supported that the whole range of thecompound of Formula I recited in the scope of claims of Exhibit Ko 1 has
pharmacological activity similar to that of Exhibit Ko 1 Invention.
Further, it can be seen from the relationship between Invention 1 and formula I
described in the scope of claims of Exhibit Ko 1 that Invention 1 selects "-N(R8)2" as"R2" of the above formula I, and further selects alkylsulfonyl group (-SO2R'; R' is alkyl
group) for one "R8," not "methyl" of "C1-4 alkyl, not including asymmetric carbon
atom" as in the Exhibit Ko 1 Invention, but a compound selected from such substituent
group that does not fall within the range of the above formula I.
Consequently, it cannot be said that the compound not included in formula I of
Exhibit Ko 1 may be expected to have pharmacological activity inhibiting "HMG-CoA
reductase activity." Therefore, it cannot be said that there is a motivation to replace"dimethylamino group" of Exhibit Ko 1 Invention with "-N(CH3)(SO2R')," which is analternative not included into the scope of formula I.
(b) Motivation from Exhibit Ko 2 Invention
Exhibit Ko 2 discloses that the "general formula"9

includes: "alkyl" for "R1," "aryl" for "R2," "-NR4R5" for "R3," "alkyl" and"alkylsulfonyl" for "R4," and "R5," "-CH=CH-" for "X," "" for "A," "hydrogen" for "R6," and "cation" for "R7," respectively as their alternatives.
Further, it discloses that a "particularly preferable compound of general formula (I)"includes "isopropyl" for "R1," "one monosubstituted with "phenyl" or "fluorine" for"R2," "-NR4R5" for "R3," "methyl" and "methylsulfonyl" for "R4" and "R5,"
respectively as their alternatives, and further includes "calcium cation" for "R7" as analternative.
The compound of general formula I of Exhibit Ko 2 also provides an HMGCoA reductase inhibitor with a pyrimidine ring as a basic skeleton and substituents atthe 2-, 4-, and 6- positions, which is in common with the Invention, like the compoundof formula I of Exhibit Ko 1.

The compounds included in both might partiallyoverlap depending on a selected substituent group, but the compound of generalformula (I) of Exhibit Ko 2 does not have exactly the same selectable range ofsubstituent groups of the pyrimidine ring as the compound of the formula I of Exhibit
Ko 1, but is respectively specified as a compound having a separate chemical structural
formula. Given the chemical structural formula of the compound, it may become acandidate for HMG-CoA reductase inhibitor.
Further, it cannot be said that compounds with different structures may have thesame HMG-CoA reductase inhibiting activity.

Therefore, even if the above conceptof the dimethylamino group of the Exhibit Ko 1 Invention corresponds to "-NR4R5" of"R3" of the general formula of Exhibit Ko 2, there is no motivation in the first place tosubstitute the dimethylamino group of the Exhibit Ko 1 Invention with the substituent
group not disclosed in Exhibit Ko 1 on the basis of the description of Exhibit Ko 2.
Further, each of "R1," "R2," and "R3" of the compound of general formula (I) of
Exhibit Ko 2 has numerous alternatives.

In contrast, what is described as a specificworking example where at least "X" and "A" have the same structure as in the Exhibit
Ko 1 Invention is only "methylerythro-(E)-3,5-dihydroxy-7-[2,6-dimethyl-4-(4fluorophenyl)-pyrimid-5-yl]-hept-6-enoate" of Working Example 8 (R3 is methyl),"methylerythro-(E)-3,5-dihydroxy-7-[4-(4-fluorophenyl)-6-methyl-pyrimid-5-yl]-hept10

6-enoate" of Working Example 15 (R3 is phenyl), and methylerythro-(E)-3,5dihydroxy-7-[4-(4-fluorophenyl)-6-isopropyl-2-phenyl-pyrimid-5-yl]-hept-6-enoate"of Working Example 23 (R3 is phenyl).
453"-NR R " for "R ".

Exhibit Ko 2 fails to describe one that selects

Further, regarding the compounds in which "-NR4R5" issubstituted, Exhibit Ko 2 not does describe a production method thereof, norpharmacological tests of HMG-CoA reductase inhibiting activity, nor the descriptionof selecting a specific combination of "methyl" and "methylsulfonyl" for "R4" and "R5"in "-NR4R5."
Consequently, it cannot be said first of all that the specification technicallysupports the compound in which "methyl" and "methylsulfonyl (SO2CH3)" are selected
for "R4" and "R5" just in a possible substituent group of "-NR4R5" that could beselected from numerous alternatives for "R3" of the general formula (I) described in
Exhibit Ko 2.

It cannot be deduced from this description that there is a motivation to

replace "dimethylamino group" of the Exhibit Ko 1 Invention with "N(CH3)(SO2CH3)."(c)

Motivation on the basis of the common general technicalknowledge
It can be seen from the description of Exhibit Ko 7, Ko 10, and Ko 11 that mostcholesterols are synthesized in the liver, and HMG-CoA reductase inhibitor inhibits thebiosynthesis of these cholesterols. Therefore, it can be said that as of the priority datea person ordinarily skilled in the art could have recognized the technical problem toobtain a HMG-CoA reductase inhibitor with high selectivity by the liver in view of theside effects.
Subsequently, it can be deduced from the description of Exhibit Ko 7 and Ko 20
that a hydrophilic compound in HMG-CoA reductase inhibitor may possibly improveliver selectivity, although there is an exception.

Thus a person ordinarily skilled in

the art could recognize prima facie a motivation as of the priority date to assess thecompound showing HMG-CoA reductase inhibiting activity with an indicator ofhydrophilicity and select a compound with high hydrophilicity (logP of 2 or less) inorder to obtain a HMG-CoA reductase inhibitor with high selectivity in the liver.
On the other hand, although both Exhibit Ko 7 and Ko 20 assessedhydrophilicity of a compound having HMG-CoA reductase inhibiting activity, they arecompletely silent about chemical structure to make a compound showing HMG-CoA
reductase inhibiting activity hydrophilic.
Exhibit Ko 9 discloses that logP value of a target compound may be
11theoretically calculated as well as πx value corresponding to a specific substituent
group, which allows us to predict relative lipophilicity of a compound to besynthesized. The πx value in the case of X being "3-SO2CH3" (methylsulfonyl group)is -1.26 in an aromatic substituent with R and X being a substituent.

It does notdescribe the means for modifying a compound to convert methyl group into
methylsulfonyl group in order to make a compound hydrophilic, but methylsulfonylgroup used herein is directly substituted with an aromatic ring, which is different in
structure from the Invention 1 where the pyrimidine ring is substituted with an iminogroup substituted with an alkylsulfonyl group (including -N(CH3)(SO2CH3)).
Consequently, although there is a motivation to measure hydrophilicity ofcompounds that have already been known to have HMG-CoA reductase inhibiting
activity and select from them a compound with high hydrophilicity, it cannot always be
expected that replacing a specific substituent of the Exhibit Ko 1 Invention with theother substituent may maintain HMG-CoA reductase inhibiting activity.

Therefore,

first of all, it cannot be said that there is a motivation in the Exhibit Ko 1 Invention to
replace the specific substituent group with a methylsulfonyl group to make ithydrophilic only relying on the fact that a logP value of a compound having
methylsulfonyl group becomes small (becomes hydrophilic).
Further, it is a common practice in the development of pharmaceuticalcompounds to change little by little the structure of a compound having a specificpharmacological activity and investigate the effect thereof.

It is indefinite, however,as to what change in pharmacological effects takes place by the change of chemical
structure. Therefore, it is natural to obtain a compound that may become hydrophilic
within a range where at least HMG-CoA reductase inhibiting activity is maintained if
one tries to obtain a compound that may become a hydrophilic HMG-CoA reductase
inhibitor by modifying a chemical structure of the Exhibit Ko 1 Invention.
Exhibit Ko 16 is an article that describes synthesis of lactone of pyridine- andpyrimidine-substituted 3,5-dihydroxy-6-heptenoate and investigation of the structureactivity relationship with regard to the inhibiting activity against HMG-CoA.

It

discloses that the substitution at the 2-, 4- and 6- positions of the central aromatic ring(pyrimidine ring) may cause a strong biological activity in the following structural
formula (omitted), and that the introduction of an isopropyl group at the 6-position (R1)
may maximize the biological activity, and that the polar substituent group at the 4position (R2) of 4-chlorophenyl and 4-fluorophenyl may become a strong inhibitor, andthat the substitution at the 2-position (R3) is the most important for the optimal
biological activity, and the introduction of not only a bulky alkyl group but also a12phenyl moiety may achieve a significant increase of titer.
Consequently, a person ordinarily skilled in the art who read the description of
Exhibit Ko 16 could not have a motivation to replace "dimethylamino group" of the
Exhibit Ko 1 Invention with "-N(CH3)(SO2R')", which is not at all disclosed in Exhibit
Ko 1 and Ko 16, while there is motivation to replace it with an alkyl group or phenylgroup in view of the fact that the compound substituted with isopropyl group at the 6position and 4-fluorophenyl at the 4-position of the pyrimidine ring, which is similar tothe case of the Exhibit Ko 1 Invention, has high inhibiting activity when the substituent
group at the 2-position is a bulky alkyl group or phenyl group, in combination with thefact that "C1-C6 alkyl not including an asymmetric carbon atom" may be selected for"R2" of formula I of Exhibit Ko 1. Further, it cannot be said that a person ordinarily
skilled in the art could conceive of selecting "-N(CH3)(SO2CH3)" from them on thebasis of the description of Exhibit Ko 2 that is irrelevant to Exhibit Ko 1 or Exhibit Ko
16. Further, Exhibit Ko 16 discloses that a bulky lipophilic substituent group at the 2position of the central aromatic ring (pyrimidine ring) contributes to the biologicalactivity of synthesized HMG-CoA reductase inhibitor.

Therefore, it cannot berecognized first of all that there is any suggestion of a substituent group or substitution
moiety for making the Exhibit Ko 1 Invention lipophilic.
Exhibit Ko 29 describes a search result of a compound with a substituent groupof a methylsulfonyl group, which was present before the priority date.

Exhibit Ko 30

also describes a compound with a substituent group of a methylsulfonyl group.

It iseven indefinite as to whether they are HMG-CoA reductase inhibitors. Further, it issilent about how the substituent group of the methylsulfonyl group changes theproperties of the compound.

Therefore, even if a compound having a substituent

group of a methylsulfonyl group was present before the priority date, a person
ordinarily skilled in the art could not easily conceive of modifying the dimethylaminogroup of the Exhibit Ko 1 Invention so as to replace the methyl group thereof with amethylsulfonyl group.
Further, referring to the other evidences distributed before the priority date,there is no description of the technical significance to replace a methyl group with amethylsulfonyl group.

There is no description to motivate a person ordinarily skilledin the art to replace "dimethylamino group" at the 2-position of the Exhibit Ko 1
Invention with "-N(CH3)(SO2R')" for making a compound of the Exhibit Ko 1
Invention hydrophilic.
Consequently, even if a person ordinarily skilled in the art could conceive ofmodifying a chemical structure of the Exhibit Ko 1 Invention to obtain a hydrophilic
13

compound, it cannot be said that there is a motivation to replace only one methyl groupof the "dimethylamino group" present at a specific position (2-position of pyrimidinering) with a methylsulfonyl group (alkylsulfonyl group) to make "-N(CH3)(SO2R')" formaking a compound of the Exhibit Ko 1 Invention hydrophilic.
(d) Summary
Therefore, in the Exhibit Ko 1 Invention, it cannot be said that a person
ordinarily skilled in the art could easily conceive of adopting the structure of thedifference (1-i). Therefore, without considering the difference (1-ii), it cannot be said
that the Invention 1 was easily conceivable on the basis of the Exhibit Ko 1 Invention
and the Exhibit Ko 2 Invention as well as the common general technical knowledge asof the priority date.
b

The effect of the Invention 1

The effect of Invention 1 is to provide a compound that may become aneffective drug showing strong HMG-CoA reductase inhibiting activity.
On the other hand, Exhibit Ko 1 discloses that the compound of the Exhibit Ko
1 Invention shows HMG-CoA reductase inhibiting activity; however, the Exhibit Ko 1
Invention fails to disclose the effect on the HMG-CoA reductase inhibiting activity if"dimethylamino group" at 2-position of pyrimidine ring is replaced with "N(CH3)(SO2CH3)," which is not included into the range of formula I.

Exhibit Ko 1

discloses a compound where the 2-position of pyrimidine ring is substituted with a "4morpholinyl group." This is just a compound where "-N(R8)2" is selected for "R2" offormula I of Exhibit Ko 1 and further "both R8, together with a nitrogen atom, form
part of a 5-,6- or 7-membered optionally substituted ring optionally containing one ormore further heteroatoms (ring B)" in the definition is selected for "R8."It fails todisclose the effect on the activity if "-N(CH3)(SO2CH3)", which does not fall within therange of formula I, is selected for "R2."
Subsequently, Exhibit Ko 2 describes "-NR4R5" is selected for "R3" of formula I,
and describes both methyl and methylsulfonyl for "R4" and "R5" as alternatives, but itlacks any description suggesting that a methyl group and a methylsulfonyl group areequivalent substituent groups in pharmacological activity, and does not even provide
any working example of a compound where "-NR4R5" was selected for "R3." Thus
the pharmacological activity of such compound cannot be expected from thedescription of Exhibit Ko 2.
Furthermore, similar to the compound of Invention 1, Exhibit Ko 16 describes a
14

compound with an isopropyl group at the 6-position and a 4-fluorophenyl group at the
4-position of a pyrimidine ring. The substitution at the 2-position is an alkyl group ora phenyl group.

The group "-N(CH3)(SO2CH3)" is not described.

Therefore, itcannot be said that any compound with an isopropyl group at the 6-position and a 4fluorophenyl group at the 4-position of a pyrimidine ring may achieve a similar levelof activity without relation to the substituent group at the 2-position.
Further, pharmacological activity is closely related to the structure of acompound.

If a substituent group of a compound with pharmacological activity ischanged, the pharmacological activity might be lost in some cases. Therefore, itcannot be seen from not only Exhibit Ko 1, Ko 2, and Ko 16 but also the otherevidences that a person ordinarily skilled in the art could have expected the effect on
HMG-CoA reductase inhibiting activity of replacing a "dimethylamino group" at the 2position of the pyrimidine ring of the Exhibit Ko 1 Invention with "-N(CH3)(SO2CH3)"
in a compound.
The pharmacological activity of the HMG-CoA reductase inhibiting activity of
the Invention 1 being higher than that of Mevinolin sodium salt can be inferred fromthe description of the specification, and Exhibit Ko 3 also supports this. Therefore,
the effect of the Invention 1 may not be negated.
c Summary
Therefore, it cannot be said that Invention 1 was easily conceivable by a person
ordinarily skilled in the art before the filing (priority date) on the basis of the Exhibit
Ko 1 Invention (main cited invention) and the Exhibit Ko 2 Invention distributed
before the filing (priority date) as well as a common general technical knowledge as ofthe priority date.
B The Inventions 2, 5, and 9 to 12
Similarly, it cannot be said that the Inventions 2, 5, and 9 to 12 were also easily
conceivable by a person ordinarily skilled in the art on the basis of the Exhibit Ko 1
Invention and the Exhibit Ko 2 Invention as well as the common general technicalknowledge as of the priority date.
(2)

Invalidation reason 2

A Problem to be solved by the Invention
The compound represented by the following general formula (I)"15(wherein R1 is a lower alkyl, aryl, or an aralkyl, each of which may have one or more
substituents; each of R2 and R3 is independently hydrogen, a lower alkyl, or an aryl,
and each of said lower alkyl and aryl may have one or more substituents; R 4 ishydrogen, a lower alkyl, or a cation capable of forming a non-toxic pharmaceutically
acceptable salt; X is sulfur, oxygen, or a sulfonyl group, or an imino group which may
have a substituent; the dashed line represents the presence or absence of a doublebond)"
includes the compounds of the Inventions 1, 2, 5, and 9 to 11, and the Invention
12 is directed to an HMG-CoA reductase inhibitor including the compound of theInvention 1 as an active ingredient. Therefore, the problem to be solved by theInventions 1, 2, 5, and 9 to 11 lies in the provision of a compound having excellent
HMG-CoA reductase inhibiting activity, and the problem to be solved by the Invention
12 lies in the provision of an HMG-CoA reductase inhibitor including such acompound.
Further, the Detailed Description of the Invention discloses that the Invention is
directed to a "3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase
inhibitor," and for such HMG-CoA reductase inhibitor there were developed
synthesized HMG-CoA reductase inhibitors such as Fluvastatin and BMY22089 otherthan Mevinolin, Pravastatin, and Simvastatin that are obtained from fungal metabolites
or their partially-modified compounds, but it fails to disclose that there is any problem
for these HMG-CoA reductase inhibitors that have already been developed.
Therefore, the Invention does not require more excellent HMG-CoA reductase
inhibiting activity compared to the existing HMG-CoA reductase inhibitors including
Mevinolin, Pravastatin, Simvastatin, Fluvastatin etc.

It is recognized that a problem

to be solved is to provide an HMG-CoA reductase inhibitor including a compound
having "excellent HMG-CoA reductase inhibiting activity" or the compound as anactive ingredient to the extent that it may become a pharmaceutical product for"suppressing the production of cholesterols."
16

B Decision(A) Manufacture
The Detailed Description of the Invention describes in Working Examples 1
and 2 a specific production method of "calcium salt" of "(+)-7-[4-(4-fluorophenyl)-6isopropyl-2-(N-methyl-N-methylsulfonylaminopyrimidin)-5-yl]-(3R,5S)-dihydroxy(E)-6-heptenoic acid," which is encompassed into Invention 1, the method comprising
the

steps

of:

producing"(+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-

methylsulfonylaminopyrimidin)-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenoic acid sodiumsalt" from the starting raw material (III-3); and changing from it to "(hemi)calciumsalt" thereof.

Further, a specific production method of the starting raw material of thecompound (III-3) is also described in the reference examples 1 to 4.
The "calcium salt" of "(+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-Nmethylsulfonylaminopyrimidin)-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenoic

acid"

specifically described in the working examples corresponds to the case of formula (I)of the Invention 1 where R1 is methyl, R2 is phenyl substituted with fluorine, R3 isisopropyl, R4 is a calcium ion, X is an imino group substituted with a methylsulfonylgroup, and the double bond exists. The Detailed Description of the Invention has ageneral description of a production method of formula (I) as well as a production
method when R4 is H in Invention 1.

Further, it also discloses that the following

compound a:""
is a starting material thereof. This corresponds to the above compound (III-3).

A

person ordinarily skilled in the art can recognize from the production examples ofreference examples 1 to 4 that a partial change of the agents described therein allows
for the production of compounds of formula (I) where R1 may be not only methyl but
also another lower alkyl, R2 may be phenyl substituted with not only fluorine but also
another halogen, R3 may be not only isopropyl but also another lower alkyl, and X may
be an imino group substituted with not only methylsulfonyl group but also anotheralkylsulfonyl group.
Consequently, it can be said that a person ordinarily skilled in the art could
understand from the Detailed Description of the Invention that the compound of17

Invention 1 can be actually produced; i.e., can be provided.
Inventions 2, 5, and 9 relate to a compound that confines the scope of theformula (I) of Invention 1, and the compound may be produced in a range of theformula (I) of Invention 1.

Therefore, a person ordinarily skilled in the art canunderstand that the compounds of Inventions 2, 5, and 9 may also be produced.
Invention 10 is produced by a specific production method.

The generalproduction method as well as a specific working example are described in the Detailed
Description of the Invention. Therefore, a person ordinarily skilled in the art could
recognize that the compound of Invention 10 may also be produced.
Invention 11 was actually produced in the above Working Examples 1 and 2.
Therefore, the Detailed Description of the Invention is described to the extent
that allows a person ordinarily skilled in the art to produce the compounds of Claims 1,
2, 5, and 9 to 11.
(B)

HMG-CoA reductase inhibiting activity

The Detailed Description of the Invention discloses a measurement method of
HMG-CoA reductase inhibiting activity, mixing a test compound with a mixture of a
rat liver microsome solution and a solution of [3-14C]HMG-CoA solution, andsubsequent to incubation, applying to thin-layer chromatography plate, and scraping apart with an Rf value of 0.45 to 0.60, and measuring the specific radio-activity thereof
to measure a relative activity thereof, with the relative activity of sodium Mevinolin
given as 100.
1)ofFurther, as a result of the measurement, it discloses that compound (Ia-"sodiumsalt"of"(+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-

methylsulfonylaminopyrimidin)-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenate"

hasarelative HMG-CoA reductase inhibiting activity of 442, with the inhibiting activity of
sodium Mevinolin given as 100.
Compound (Ia-1) described in the Detailed Description of the Invention is asodium salt, which is not included into Invention 1 of free acid or hemicalcium salt,
but it is construed as performing a similar drug efficacy in view of the pharmacologicalaction mechanism without relation to the form of salt. Therefore, it can be deduced
that Invention 1 shows a similar HMG-CoA reductase inhibiting activity as in the caseof sodium salt.

In fact, according to Exhibit Ko 3, a hemicalcium salt of "S-4522"

also shows a stronger HMG-CoA reductase inhibiting activity than sodium Mevinolin,which thus supports the above deduction.
Further, Invention 1 includes in its range a compound of formula (I) where R1 is
a lower alkyl, R2 is a phenyl substituted with a halogen, R3 is a lower alkyl, and X is an18imino group substituted with an alkylsulfonyl group. These substituent groups arevery similar to those of the compound in the working examples where R1 is methyl, R2
is a phenyl substituted with fluorine, R3 is isopropyl, and X is an imino group
substituted with a methylsulfonyl group. The compound (Ia-1) has a higher level ofactivity compared to a pharmaceutical product of sodium Mevinolin. Therefore, aperson ordinarily skilled in the art can recognize that Invention 1 with a very similar
chemical structure will also become a compound showing a similar HMG-CoA
reductase inhibiting activity, and will have an "excellent HMG-CoA reductase
inhibiting activity" to the extent that it may become a pharmaceutical product"suppressing the production of cholesterols."
Consequently, it can be said that the Detailed Description of the Invention
discloses to the extent that allows a person ordinarily skilled in the art to recognize that
Invention 1 can solve the problem.
Inventions 2, 5, and 9 to 11 are included within the scope of Invention 1.
Therefore, similarly, it can be said that the Detailed Description of the Invention
discloses to the extent that allows a person ordinarily skilled in the art to recognize thatthese Inventions can solve the problem.
Invention 12 is an HMG-CoA reductase inhibitor including Invention 1 as anactive ingredient.

Therefore, similarly, it can be said that the Detailed Description of

the Invention discloses to the extent that allows a person ordinarily skilled in the art torecognize that the Invention can solve the problem.
C

Summary

As seen above, it cannot be said that the inventions for which a patent is soughtrecited in Inventions 1, 2, 5, and 9 to 12 are not described in the Detailed Descriptionof the Invention.

Therefore, it cannot be said that the recitation of the scope of claimsof the specification does not comply with Article 36, paragraph (5), item (i) of the
Patent Act before the revision in Heisei 6.
No. 3

Defendant's Defense against the Complaint prior to the pleading on the merits
1

Tokyo High Court judgment on December 26, 1990 (1990 (Gyo-Ke)77, acollection of civil and administrative court decisions relating to intangible property
rights, Vol. 22, No. 3, page 864) rules that "The case requests for rescission of trial
decision to the effect that the request for an invalidation trial of the Patent made by
Plaintiff should be dismissed. Therefore, Plaintiff obviously has a standing under theprovision of Article 178, paragraph (2) of the Patent Act.
19

It cannot be seen from thefacts that Plaintiff has a legal interest for litigation with regard to the case.
Specifically, the trial decision to the effect that the request for an invalidation trial
according to the demand of Plaintiff should be dismissed is formally an administrative
measure against Plaintiff's interest; however, a legal interest for litigation as arequirement for a suit against trial decision made by the JPO is not satisfied by theexistence of such a formal disadvantage, but required for a substantial legal interest to
be recovered by the rescission of the trial decision in such circumstances where
Plaintiff suffers a substantial legal disadvantage, or faces a risk of so suffering as aresult of, as a legal effect, from the establishment of the JPO decision. Therefore,
even if one has a legal interest for litigation to sue for the rescission of trial decisionthat dismissed a demand for trial to invalidate a patent during the life of the patentsince he might face a risk of suffering disadvantage from the patent protection of theinvention that should have been invalidated, he does not have a legal interest for
litigation to sue for the rescission of trial decision that dismissed a request for aninvalidation trial of the patent when the life of the patent is lapsed without causing any
dispute that poses a problem as to whether the patent is valid or invalid, without any
factual relationship that might possibly become a cause for escalating into such disputein the future, and without any legal disadvantage due to the existence of the patentright being realistically or potentially substantiated."
2

The patent right has been expired due to the lapse of May 28, 2017 (Exhibit

Otsu 76).
Plaintiffs did not implement any act corresponding to the acts of work of thepatent right, and thus Defendant obviously has no right to demand compensation fordamage, nor does Defendant have a right for litigation, etc. Therefore, a legal interestfor litigation of Plaintiffs has already diminished, and thus the litigation should bedismissed.
3(1) Plaintiffs had suffered the effect of prohibitive right during the valid
period of patent right, which legal disadvantage may not be recovered by the rescissionof the trial decision.
Suit Against Trial Decision made by the JPO is a kind of administrative caselitigation. Under the Administrative Case Litigation Act, if there is no legal interest
to cancel an official action due to lapse of period, no legal interest for litigation ispresent.

This is the precedent and the commonly accepted theory.

20

(2) Article 123, paragraph (3) of the Patent Act only confirms that thetermination of patent right does not result in the immediate loss of legal interest for
litigation. The article does not specify the ability to conduct invalidation trial or suitagainst trial decision made by the JPO even in the absence of legal interest for
litigation.
No. 4

Argument by Plaintiffs against the defense prior to the pleading on the merits
One can request for invalidation trial even if the life of a patent is expired,

which is obvious from the Patent Act.

If there is any dispute between competing

pharmaceutical companies on the validity of the patent for an invention regarding drug
like the present case, things are different from the case of Tokyo High Court judgment
on December 26, 1990 where a consultant, having almost no realistic and specificpossibility for himself to be able to work an invention during a life of a patent,
contended against the validity of the patent.
Plaintiffs did not conduct any act that might be seen as an infringing act of thepatent right during the life of the patent right.

In this sense, it is true that Defendant

has no legal rights to pursue a variety of liabilities that premise the infringement of thepatent right such as a right to demand compensation for damage and a right for
litigation. However, it is the case where Plaintiffs had realistically and substantiallysuffered the effect of the prohibitive right of the Patent, and furthermore data
influencing the establishment of the Patent is also doubtful. Therefore, it is natural toseek a judicial ruling in a suit against trial decision made by the JPO with regard to thevalidity of the Patent.
No. 5

Grounds for rescission of the JPO decision presented by Plaintiffs

1 Ground 1 for rescission (Errors in the determination of inventive step)(1) Error in the determination of lack of motivation
A Motivation from Exhibit Ko 1
(A) The compound of the Exhibit Ko-1 Invention (the compound of Working
Example 1b) of Exhibit Ko 1) and the structure of the compound of the Invention are
shown in the following figures. The only difference (red circle part) is whether asubstituent group of N atom at the 2-position of a pyrimidine ring is a methyl group ora methylsulfonyl group (Indeed there is also a difference between a sodium salt and a
calcium salt, but this difference does not at all contribute to the inventive step of thecompound of the Invention.).

21

Compound of
Exhibit Ko 1 Invention

Compound of the Invention(Rosuvastatin)(B) The compound of the Exhibit Ko 1 Invention has excellent in vivo activityof about 125 times higher than that of Compactin whose utility was found in humansubjects, and about 15 times higher than that of Mevinolin (Lovastatin) that had beensold as a drug for lowering cholesterols as of the priority date (Test B, described in
Exhibit Ko 1, page 11, right bottom column, line 21 to page 12, left upper column, line
6 (in vivo animal experiment test)).
Therefore, there was a motivation for a person ordinarily skilled in the art tomake a compound of the Exhibit Ko 1 Invention a lead compound.
(C) There was an attempt as of the priority date to obtain an HMG-CoA
reductase inhibitor with high liver selectivity, in view of side effects.

Thus, there wasa motivation for a person ordinarily skilled in the art to introduce a hydrophilic
substituent group for selectively transferring a compound to the liver, the target organof an HMG-CoA reductase inhibitor, by increasing hydrophilicity of the compound of
the Exhibit Ko 1 Invention, which was a lead compound.
Further, in view of the common general technical knowledge as of the priority
date, the introduction at 2-position of pyrimidine ring was essential to introduce ahydrophilic substituent group into the compound of the Exhibit Ko 1 Invention, andthere was a motivation for a person ordinarily skilled in the art to introduce ahydrophilic substituent group at the 2-position of the pyrimidine ring of the compoundof the Exhibit Ko 1 Invention.
In other words, the compound of the Exhibit Ko 1 Invention is shown as below,
dihydroxyheptenoic acid at the 5-position of the pyrimidine ring is a so-calledpharmacophore essential for activity (Exhibit Ko 15). Therefore, a person ordinarily
skilled in the art would not conceive of the change of this part.
Further, in view of the fact that the combination of a p-fluorophenyl group at22

the 4-position of the pyrimidine ring and an isopropyl group at the 6-position resulted
in a strong activity (Comparison between Compounds 2t to 2w and 2r to 2s of "Table
I" of Exhibit Ko 16, Exhibit Ko 26, Ko 27, Ko 76) and many of compounds developed
at that time had this combination (Exhibit Ko 8), a person ordinarily skilled in the art
would not conceive of the change of the 4-position and 6-position of the pyrimidine
ring.
Therefore, a person ordinarily skilled in the art would be motivated to introduce
a hydrophilic substituent group at the 2-position of the pyrimidine ring of thecompound of the Exhibit Ko 1 Invention.

Isopropyl
Parafluorophenyl
Dihydroxyheptenoic acid

(Dimethylamino group surrounded by a dashed line binds to 2-position of pyrimidine
ring.

Parafluorophenyl

group

binds

to

4-positionofDihydroxyheptenoic acid binds to 5-position of pyrimidine ring.

pyrimidine

ring.

Isopropyl groupbinds to 6-position of pyrimidine ring.)(D)a

In modifying a lead compound, a principle is to modify it little by little,

while maintaining a chemical structure of a lead compound as much as possible(Exhibit Ko 56 to Ko 58). Therefore, a person ordinarily skilled in the art who
conceived of introducing a hydrophilic substituent group at the 2-position of thepyrimidine ring of the compound of the Exhibit Ko 1 Invention would substitute only
one methyl group (CH3) of the dimethylamino group at the 2-position of thepyrimidine ring of the compound of the Exhibit Ko 1 Invention with a hydrophilicgroup so that a structural change caused by the modification might be as small as
possible.
b

It is publicly known that a methylsulfonyl group is the substituent group that23contributes to hydrophilicity the most (e.g. Exhibit Ko 9, Ko 28, Ko 56, Ko 59, Ko 60).
Therefore, it is easy to substitute one methyl group of a dimethylamino group at the 2position of the pyrimidine ring of the compound of the Exhibit Ko 1 Invention with amethylsulfonyl group.
c Taking into consideration general formula (I) of Exhibit Ko 2, it is all themore easy to substitute one methyl group of a dimethylamino group at the 2-position of
the pyrimidine ring of the compound of the Exhibit Ko 1 Invention with amethylsulfonyl group.
In other words, general formula (I) of Exhibit Ko 2 includes the compound of
the Exhibit Ko 1 Invention as an HMG-CoA reductase inhibitor, and thus there is asufficient motivation to consider Exhibit Ko 2 for modification of the compound of the
Exhibit Ko 1 Invention.

General formula (I) of Exhibit Ko 2 only describes six

candidates (alkyl group, aryl group, aralkyl group, acyl group, alkylsulfonyl group,arylsulfonyl group) for the substituent group of the N atom of a dimethylamino groupat the 2-position of the pyrimidine ring of the compound of the Exhibit Ko 1 Invention,and it is extremely easy to select from them a methylsulfonyl group, an alkylsulfonylgroup having hydrophilicity, and a small change of molecule size from a methyl group.
(E)a The relationship between general formula I of Exhibit Ko 1 and generalformula (I) of Exhibit Ko 2 is shown as in the following schematic drawing:

24

The substituent groups at 4-,5-,6-positions
are isopropyl, dihydroxyheptenoic acid(or its closed ring) and parafluorophenyl

Pyrimidine skeleton

ExhibitKo 2

Exhibit Ko 1 (Note)

Exhibit Ko 1,
Working Example 2

ExhibitKo 1,
Working
Example 11d

Hydrophilicity

The substituent group at
2-position is hydrophilic

The substituent group at
2-position is hydrophobic

Exhibit Ko 2,
Working Example 8

Exhibit Ko 1,
Working Example 1b)(Exhibit Ko 1 Compound)

Compound of
the Invention(Rosuvastatin)

The substituent group at 2-position is
amine
ExhibitKo 2,
Working
Example 23

ExhibitKo 75,
Compound 1, 3

Exhibit Ko 16

Exhibit Ko 16,

ExhibitKo 73,
1-15-16

Hydrophobicity

Exhibit Ko 73

Exhibit Ko 74, 13k(Exhibit Ko 16, 2r)

Exhibit Ko 74(Exhibit
Ko 16, 2v)

Pyrimidine skeleton

Exhibit Ko 74

Exhibit Ko 74

Quinoline
skeleton

Pyrrole skeleton

Indole skeleton

Pyrimidine
skeleton

Hexahydronaphthalene
skeleton

Pitavastatin

Atorvastatin

Fluvastatin

Cerivastatin

Compactin
Pravastatin
Lovastatin
Simvastatin(Note) There are few compounds of working examples, for which Exhibit Ko 1 actually confirmed the activity.
There are no working examples sufficient to cover the group of compounds encompassed into the broad scopeof general formula (I). Therefore, it cannot be seen that the outer edge of the range of general formula (I) of
Exhibit Ko 1 was defined as a boundary between the region where the activity was confirmed and the region
where the activity was not confirmed by the compounds of the working examples.

The compound of the Invention is not encompassed into the scope of generalformula I of Exhibit Ko 1, but the former has common features with the compound of
the Exhibit Ko 1 Invention in that the former has isopropyl, dihydroxyheptenoic acid(or its closed ring), and parafluorophenyl at the 4-, 5-, 6-positions of pyrimidine ring,and has a structure expected to exhibit a strong HMG-CoA reductase inhibiting activity.
Further, both the compound of the Invention and the compound of the Exhibit
Ko 1 Invention have a hydrophilic substituent group at the 2-position of the pyrimidine
ring that is expected to have a high liver selectivity, and have the common substituent
25

group at the 2-position of an amine having at least one methyl group.
Therefore, the compound of the Invention is not included in the scope ofgeneral formula I of Exhibit Ko 1; however, it is a compound located in the vicinity ofthe outer edge of the scope of general formula I.
b

The scope of the claims is a scope that the applicant seeks for a patent as of

the filing date, which is not consistent with a scope in which pharmacological activity
may be expected.
As of the priority date, the research on the HMG-CoA reductase inhibitor of socalled statin was progressed, and it was at least known that dihydroxyheptenoic acid(or a lactone thereof) at the 5-position of the pyrimidine ring of the Exhibit Ko 1
Invention was a pharmacophore necessary for activity (Exhibit Ko 15). Therefore, aperson ordinarily skilled in the art would reasonably expect pharmacological activityof a compound having the pharmacophore, even if the compound were slightly out of
the scope of claims.
As set forth below, it was publicly known before the priority date that thecompound slightly out of the scope of the general formula I described in the scope ofclaims of Exhibit Ko 1 actually had a sufficiently strong HMG-CoA reductase
inhibiting activity.
(a) Compound 1-5-16 described in Exhibit Ko 73, which was publicly known
before the priority date, is out of the scope of general formula I of Exhibit Ko 1 in thatthe 2-position of the pyrimidine ring is 4-phenyl-phenyl, but 4-phenoxy-phenyl falls
within the scope of the general formula I of Exhibit Ko 1.

Therefore, it is acompound that does not fall within the scope of general formula I of Exhibit Ko 1, but
has a very similar structure, and is slightly out of the scope of general formula I of
Exhibit Ko 1.
Exhibit Ko 73 shows that the above compound has an HMG-CoA reductase
inhibiting activity comparable to or higher than that of CS-514 (Pravastatin) that had
been developed as a pharmaceutical product.
(b) Except that compounds 13a to 13e and 13g to 13j described in Exhibit Ko
74, which was publicly known before the priority date, are not pyrimidine but pyridine,these compounds fall within the scope of formula I of Exhibit Ko 1. Thus, thesecompounds have very similar structures although they do not fall within the scope ofgeneral formula I of Exhibit Ko 1, and thus are slightly out of the scope of general26

formula I of Exhibit Ko 1.
Exhibit Ko 74 discloses data showing that the above compound has an HMGCoA reductase inhibiting activity.
c

It is confirmed that a number of compounds included in a region surrounded

by a dashed-dotted line in the above schematic drawing have an HMG-CoA reductase
inhibiting activity (e.g. Compounds 2t to 2w of Exhibit Ko 16, Compound 1-5-8 of
Exhibit Ko 73, and Compound 13o of Exhibit Ko 74).

It is also confirmed that thecompounds of the Exhibit Ko 1 Invention included in a region surrounded by dashedtwo dotted line in the above schematic drawing and the compound of Working
Example 11d of Exhibit Ko 1 also have an HMG-CoA reductase inhibiting activity.
Therefore, the compound of the Invention included in a region where these dotted lines
overlap should be one where pharmacological activity may be reasonably expected,
even if the compound is out of the scope of general formula I of Exhibit Ko 1.
dTherefore, a person ordinarily skilled in the art would have reasonably

expected a pharmacological activity (HMG-CoA reductase inhibiting activity) from acompound having a pharmacophore as an HMG-CoA reductase inhibitor, but slightly
out of a scope of the claims even if the compound does not fall within a scope of theclaims of Exhibit Ko 1.

In view of this, the determination of the trial decision iserroneous in that it found lack of motivation because a pharmacological activity of"HMG-CoA reductase inhibiting activity" might not be expected if replaced with "N(CH3)(SO2R')," which was an alternative not included into scope of general formula I
of Exhibit Ko 1.
B Motivation from Exhibit Ko 2
(A) Exhibit Ko 2 describes a method of producing the whole range of thecompounds of general formula (I) and HMG-CoA reductase inhibiting activity as in
the following. Therefore, it can be seen as a technical support of the compound of thegeneral formula (I) where "NR4R5" was selected for "R3." Accordingly, the findingof the trial decision to the effect that "Exhibit Ko 2 fails to describe a production
method thereof or pharmacological tests of HMG-CoA reductase inhibiting activity
with respect to compounds where 'NR4R5' was selected for 'R3'" is erroneous.
a Exhibit Ko 2 describes a method for the synthesis of the compound ofgeneral formula (I) (page 13, left bottom column, line 8 to page 19, right bottom
27

column, line 1). Thus a person ordinarily skilled in the art could understand themethod for the synthesis of compound where "NR4R5" was selected for "R3."b

Exhibit Ko 2 discloses that the compound of general formula (I) has anactivity to the extent that it may be a pharmaceutical product capable of suppressing
the biosynthesis of cholesterols (page 19, right bottom column, lines 2 to 11). Thus, aperson ordinarily skilled in the art could understand that the compound where "NR4R5"
was selected for "R3" might have an activity to the extent that it might be apharmaceutical product capable of suppressing the biosynthesis of cholesterols.
(B)

As set forth below, it can be seen from publicly known documents before

the priority date that a plurality of compounds in a scope of general formula (I) of
Exhibit Ko 2 may have an activity.

Therefore, a person ordinarily skilled in the art

could recognize from Exhibit Ko 2 as of the priority date that there is a technicalsupport of the compound of general formula (I) having an HMG-CoA reductase
inhibiting activity.
a Exhibit Ko 16, which was publicly known before the priority date, discloses
Compounds 2r to 2w as compounds within a scope of general formula (I) of Exhibit
Ko 2 having a pharmacophore of an HMG-CoA reductase inhibitor of
dihydroxyheptenoic acid structure, and having the same structures in "X" and "A" asthe Exhibit Ko 1 Invention. All of these compounds have an HMG-CoA reductase
inhibiting activity, which is shown as data (Table I).Further, the production method is
also described (page 54 to page 55, left column).
bRegarding the compounds of Working Examples 8 and 23 in the working

examples of Exhibit Ko 2 with the same structure in "X" and "A" as the Exhibit Ko 1
Invention, Exhibit Ko 16 and Ko 73 to Ko 75, which were publicly known before thepriority date, respectively describe compounds with very similar structures.
In other words, the compound of Working Example 8 of Exhibit Ko 2 is only
described as a compound where Compound 2r of "Table I" of Exhibit Ko 16 andCompound 13k of Table 1 of Exhibit Ko 74 have been modified by changing the partof A of the general formula (I) of Exhibit Ko 2 from a methyl ester to a free carboxylic
acid or a salt thereof, otherwise described as a compound where a compound at thebottommost of "TABLE 1" of Exhibit Ko 75 has been modified by changing the partof A of general formula (I) of Exhibit Ko 2 from methyl ester of the compound ofWorking Example 8 of Exhibit Ko 2 to lactone, both of which respectively have28

demonstrated an HMG-CoA reductase inhibiting activity.

Further, the compound ofWorking Example 23 of Exhibit Ko 2 is only described as a compound where
Compound 2v of "Table I" of Exhibit Ko 16, Compound 13o of Table 1 of Exhibit Ko
74, and Compound I-5-8 of Exhibit Ko 73 have been modified by changing the part of
A of general formula (I) of Exhibit Ko 2 from a methyl ester to a free carboxylic acidor a salt thereof, otherwise described as a compound where a compound at the top of"TABLE 1" of Exhibit Ko 75 has been modified by changing the part of A of generalformula (I) of Exhibit Ko 2 from methyl ester of the compound of Working Example 8of Exhibit Ko 2 to lactone, both of which respectively have demonstrated HMG-CoA
reductase inhibiting activity.
In view of this publicly known information, it can be recognized that there is all
the more technical support of the compound of general formula (I) of Exhibit Ko 2
having an HMG-CoA reductase inhibiting activity.
c Therefore, it can be seen from the publicly known documents before thepriority date that a plurality of compounds in the scope of general formula (I) of
Exhibit Ko 2 have data showing an activity.

Thus it should be found that every

compound represented by general formula (I) of Exhibit Ko 2 is a compound in which
HMG-CoA reductase inhibiting activity is prima facie expected in the whole scope,
similarly to Exhibit Ko 1.
(C) Accordingly, there is a motivation to substitute "dimethylamino group" of
Exhibit Ko 1 Invention with "-N(CH3)(SO2CH3)" on the basis of the description of
Exhibit Ko 2 to obtain a compound of the Invention.
C

Motivation from the common general technical knowledge(A)

In view of the common general technical knowledge, a person ordinarily

skilled in the art would introduce a hydrophilic group at the 2-position of thepyrimidine ring of the compound of the Exhibit Ko 1 Invention and selectmethylsulfonyl as a hydrophilic group, as mentioned in the aforesaid A(C) and (D).
Further, Exhibit Ko 16 describes the improvement of HMG-CoA reductase
inhibiting activity due to the introduction of a bulky lipophilic substituent group at the
2-position of the pyrimidine ring.

It fails to disclose, however, that strong HMG-CoA

reductase inhibiting activity may not be obtained in the absence of a bulky lipophilic
substituent group at the 2-position of the pyrimidine ring. Therefore, the descriptionof Exhibit Ko 16 does not prevent a person ordinarily skilled in the art from29

introducing a hydrophilic group at the 2-position of the pyrimidine ring of thecompound of the Exhibit Ko 1 Invention.
Rather, Exhibit Ko 1 introduces a hydrophilic dimethylamino group at the 2position of the pyrimidine ring, and thus it was supposed to be a matter of common
general technical knowledge that the introduction of a hydrophilic substituent group at
the 2-position of the pyrimidine ring would also achieve high activity.
Further, a methylsulfonyl group was a substituent group publicly known as agroup imparting hydrophilicity as of the priority date (Figure 6 of Exhibit Ko 60), anda substituent group of which a person ordinarily skilled in the art of drug discovery
chemistry would easily conceive.
(B)

It is recognized from the description of Exhibit Ko 1 that the Exhibit Ko 1

Invention does not necessarily maintain a current level of HMG-CoA reductase
inhibiting activity, supposing a problem to be solved by the Invention to be "to provide
a compound having excellent HMG-CoA reductase inhibiting activity to the extent that
may become a pharmaceutical product for suppressing the production of cholesterols,
or to provide an HMG-CoA reductase inhibitor including the compound as an active
ingredient."
In other words, Exhibit Ko 1 describes a result of in vivo cholesterol
biosynthesis inhibition test together with in vitro HMG-CoA reductase inhibition testof the Exhibit Ko 1 Invention (a product of Working Example 1b)). According to this,the Exhibit Ko 1 Invention (a product of Working Example 1b)) has an ED50 value of
0.028 mg/kg, whereas Mevinolin has an ED50 value of 0.41 mg/kg, Compacting has an
ED50 value of 3.5 mg/kg.

It can be seen that the Exhibit Ko 1 Invention has an invivo activity 15 times as strong as that of Mevinolin (0.41/0.028 = 14.6), and 125 times(3.5/0.028 = 125) as strong as that of Compactin.

Mevinolin was commerciallyavailable as a hyperlipidemia drug of Lovastatin as of the filing. Compactin was also
known as having a drug efficacy sufficient to decrease blood cholesterol in humans(Exhibit Ko 14 and Ko 26).

Therefore, the Exhibit Ko 1 Invention does notnecessarily maintain a current level of HMG-CoA reductase inhibiting activity for the
purpose of solving the above problem, and the problem may be solved even if HMGCoA reductase inhibiting activity should be decreased by a factor of 125 times.
Further, it can be seen that the improvement in pharmacokinetics including the target
tissue selectivity of compounds may solve the problem even if the activity is loweredby a factor of more than 125 times.
Therefore, given maintenance of the current level of inhibiting activity, it is30unknown whether the substitution at the 2-position of the pyrimidine ring of the
Exhibit Ko 1 Invention may maintain a current level of HMG-CoA reductase inhibiting
activity of the Exhibit Ko 1 Invention.

Therefore, the determination of the trial

decision is erroneous in that it determined lack of motivation to substitute the 2position of the pyrimidine ring of the compound of the Exhibit Ko 1 Invention.
Further, in the determination of the support requirement, the trial decision
determined by formulating a problem to provide a compound having "excellent HMGCoA reductase inhibiting activity" to the extent that it may become a pharmaceuticalproduct capable of "suppressing the production of cholesterols" or an HMG-CoA
reductase inhibitor including the compound as an active ingredient, whereas in thedetermination of a motivation with respect to the inventive step, it is determined byformulating a criteria "to maintain a current level of HMG-CoA reductase inhibiting
activity of the compound of Exhibit Ko 1 Invention," which goes beyond a level
required by the problem to provide a pharmaceutical product "capable of suppressing
the production of cholesterols."

Thus it is not reasonable to determine support

requirement and motivation with such a double standard.
D Summary
Therefore, the determination of the trial decision made an error in that it
affirmed the inventive step of Invention 1.
The same can also apply to Inventions 2, 5, and 9 to 12.
E Counterargument against Defendant and Supporting Intervener (hereinafterreferred to as "Defendants and others".)(A) Selection of main cited referenceaInventive step supposes a person ordinarily skilled in the art anddetermines whether or not a person ordinarily skilled in the art could have easily
conceived of an invention on the basis of the invention disclosed in a distributed
publication (Article 29, paragraph (2), Article 29, paragraph (1), item (iii) of the PatentAct).
If Defendant's argument is an argument that a documentarily publicly known
invention should not be the only requirement for the selection of main cited reference,and it is not possible without the fact that the publicly known invention had practicallyconstituted a basis for the development by a person ordinarily skilled in the art to raisea document as main cited reference, such argument is equivalent to saying that thestate of art should not be established on the basis of a person ordinarily skilled in the31

art, but on the actual act of the development, which seems to disregard the literal
construction of Article 29, paragraph (2) of the Patent Act that premises publicly
known invention provided in Article 29, paragraph (1) for the discussion of inventive
step, and introduce a new and different construction in the determination of theinventive step, which might result in the breach of Article 29, paragraph (2).
bPlaintiffs do not fix main cited reference with the Exhibit Ko 1 Invention

only in view of the structural similarity to the compound of the Invention. Taking
into account that Exhibit Ko 1 discloses that the Exhibit Ko 1 Invention has a highpharmacological activity, the Exhibit Ko 1 Invention is fixed with a main citedreference.
The technical field to which the Invention pertains is directed to a
hypercholesteremia drug, more specifically, a statin-based pharmaceutical compound.
A person ordinarily skilled in the art has a goal to develop a useful hypercholesteremia
drug by creating a statin-based pharmaceutical compound.

A person ordinarily

skilled in the art has the above goal, and thus he absorbs all information of the publicly
known documents before the filing and matters known to researchers in the same fieldas common general technical knowledge with respect to statin-based pharmaceuticalcompounds.
Exhibit Ko 1 discloses that the compound of Working Example 1b) (Exhibit Ko
1 Invention) has an in vivo activity 15.8 times that of Mevinolin.

It is thus natural fora person ordinarily skilled in the art to focus on a compound of the Exhibit Ko 1
Invention, which is very promising from a viewpoint of activity in a living body.
Therefore, even if it premises the Defendant's understanding of the qualification
for the main cited reference, there is no particular problem in the case to fix the maincited reference with the Exhibit Ko 1 Invention.
(B)

According to Exhibit Otsu 12 submitted by Defendant, HR780 has a p-

fluorophenyl group and an isopropyl group at respective sides of a heterocyclic moiety
to which dihydroxyheptenoic acid (or a lactone thereof) binds.

Thus, it rather

reinforces the argument about the conventional technique presented by Plaintiffs.
In other words, from 10 HMG-CoA reductase inhibitors that were commerciallyavailable or developed before the priority date, seven compounds excluding
BMY22089 (BMY21950) and Pitavastatin had a p-fluorophenyl group and an
isopropylgroup atrespective sides of a heterocyclic moiety todihydroxyheptenoic acid (or a lactone thereof) bound.
32

which

It was a conventional

technique as of the priority date that a p-fluorophenyl group and an isopropyl group at
respective sides of a heterocyclic moiety to which dihydroxyheptenoic acid (or alactone thereof) bound exhibited excellent HMG-CoA reductase inhibiting activity.
(C)

Defendant's argument on the basis of Exhibit Ko 7 about thecorrelation between liver selectivity and hydrophilicity only picks up an exceptional
result, and is not reasonable as set forth below.
a

It can be seen from Exhibit Ko 84 (Exhibit Otsu-15) that the compounds

such as Lovastatin and Simvastatin, in which a dihydroxyheptenoic acid moiety
essential for HMG-CoA reductase inhibiting activity is a lactone body, is effectivelytransported to the liver and metabolized and converted into an active main body of
dihydroxyheptenoic acid, and thus the compound selectively accumulates in the liver;i.e., an HMG-CoA reductase inhibitor having a lactone body is effectively transported
to the liver when administered to a living body, and thus is liver-selective.

It can berecognized that only Pravastatin is a compound having (an active moiety of)dihydroxyheptenoic acid structure in the compounds tested in Exhibit Otsu 11 (andExhibit Otsu 12 where its structural formula is described for reference) and Otsu-19(Exhibit Ko 85), and all of Lovastatin, HR780, and Simvastatin are compounds inwhich a dihydroxyheptenoic acid moiety is (a prodrug of) a lactone body.
The tests of Exhibit Otsu 11 (Otsu 12) and Exhibit Otsu 19 (Exhibit Ko 85) are
the test systems that are inherently unable to detect the effect of hydrophilicity ofcompound against liver selectivity, because the lactone bodies administered to a rat
living body of Lovastatin, HR780, and Simvastatin are effectively transported to theliver due to lactone body and become liver-selective.
Therefore, it cannot be deduced from Exhibit Otsu 11 (Exhibit Otsu 12) and
Exhibit Otsu 19 (Exhibit Ko 85) that there is no correlation between hydrophilicity andtissue selectivity.
b

Exhibit Otsu 13 was not a publicly known document before the priorityc

In addition, Exhibit Ko 7 is cited by Exhibit Ko 83, and the inventor ofdate.

the compound of the Invention himself created the compound of the Invention byintroducing a hydrophilic substituent group with reference to Exhibit Ko 7. Thus,
Exhibit Ko 7 constitutes common general technical knowledge before the priority date.

33

(D) As set forth below, it was common general technical knowledge as ofthe priority date that the order of the degree of inhibiting activity varies depending on
the test.
a Data in the table of Exhibit Ko 31 was cited by an article (Exhibit Ko 83)
in which the inventor of the compound of the Invention had published his research.
Thus, it is a test result implemented before the priority date, and represents a techniqueitself as of the priority date.
b

The order of the degree of inhibiting activity of Fluvastatin andLovastatin is changed between Exhibit Ko 7 and Ko-8. The order of the degree of
inhibiting activity of Pravastatin and Lovastatin is changed between Exhibit Ko 31 andKo 7. The order of the degree of inhibiting activity of Rosuvastatin salt and BMY21950 is changed between Exhibit Ko 7 and Ko 15.
c Therefore, it was common general technical knowledge as of the priority
date that the order of the degree of inhibiting activity varies depending on the test.
(E) The argument on the basis of domestic records (Exhibit Otsu 21 to
Otsu 27) of Sand is not reasonable, because these records were not publicly known asof the filing.
(F)

It can be seen from Exhibit Ko 16 that "increased lipophilicity results

in a significant increase of inhibiting activity"; however, this does not lead to thefinding that "the shift to hydrophilicity results in a significant decrease of activity."
For example, in "Table I" of Exhibit Otsu 17, when CLOGP is calculated as anindicator of lipophilicity for each compound in which a substituent group is introduced,
and the compounds are listed in the order of higher to lower lipophilicities, its relative
activity (relative (CSI) efficacy) is described as in the following.

34

No.

R

CLOGP

Relative(CSI)
efficacy

Descendingorder oflipophilicity

Descendingorder ofrelative (CSI)
efficacy30

1-naphthyl

5.166

19.6

1

5

26

4-methylphenyl

4.491

49.0

2

4

25

4-fluorophenyl

4.208

62.0

3

3

28

4-methoxyphenyl

4.155

75.8

4

2

29

benzyl

4.011

12.6

5

6

10

phenyl

3.992

83.0

6

1

27

4-tolylsulfonyl

2.782

4.5

7

7

With increasing lipophilicity from the compound of No. 10 in the above table
where R is a phenyl to the compound where R is 1-naphthyl, the inhibiting activity
generally gets lowered; i.e., it can be recognized that "as the lipophilicity increases
from the compound where R is phenyl, the inhibiting activity lowers."
However, with increasing hydrophilicity from the compound (10) where R is aphenyl to a compound (27) where R is 4-trisulfonyl, the inhibiting activity lowers.
Therefore, it is erroneous understanding that "imparting hydrophilicity may increase
inhibiting activity."
Since hydrophilicity and lipophilicity are relative indicators, the Defendant's
argument of if "high lipophilicity results in a significant increase of inhibiting activity,"
then "hydrophilicity results in a significant decrease of activity" is not reasonable.
Rather, Exhibit Ko 1 shows that the compound of the Exhibit Ko 1 Invention(Compound of Working Example 1b)) and the compound of Working Example 11d
exhibited strong HMG-CoA reductase inhibiting activity due to the introduction ofhydrophilic amine at the 2-position of the pyrimidine ring (see test A and test B of
Exhibit Ko 1).
Therefore, there is no disincentive in Exhibit Ko 16 to introduce a hydrophilicgroup at the 2-position of the pyrimidine ring of the compound of the Exhibit Ko 1
Invention, but it is rather natural for a person ordinarily skilled in the art to conceive of
introducing a hydrophilic group at the 2-position of the pyrimidine ring in view of
Exhibit Ko 1 etc.
(G) The compound of Exhibit Otsu 17 (Exhibit Ko 76) is a compound witha pyrazole skeleton. Thus the description of the structure-activity relationship by the35substitution of a nitrogen atom of the pyrazole ring in Exhibit Otsu 17 does not provide
any suggestion to modify the compound of the Exhibit Ko 1 Invention.
(H)a Plaintiff X argues in the written request for trial (Exhibit Ko 79) that
"Substituted pyrimidine compound of general formula (I) of Exhibit Ko 2 has technicalsupport. A person ordinarily skilled in the art would expect an excellent HMG-CoA
reductase inhibiting effect for the compound of the Invention where dimethylaminogroup at the 2-position of the pyrimidine ring of the compound of the Exhibit Ko 1
Invention is substituted with a methylsulfonyl group. Therefore, there is a motivation
to substitute a dimethylamino group at the 2-position of the pyrimidine ring of thecompound of the Exhibit Ko 1 Invention with a methylsulfonyl group.", and also
argues that " Exhibit Ko 16 shows data of HMG-CoA reductase inhibiting activity of
the compound of formula (I) of Exhibit Ko 2." Therefore, taking into account the factthat it is the compound of general formula (I) of Exhibit Ko 2, for which Exhibit Ko 16
has confirmed pharmacological activity, the compound of general formula (I) of
Exhibit Ko 2 has a technical support. The substitution of a dimethylamino group at
the 2-position of the pyrimidine ring of the Compound of the Exhibit Ko 1 Invention
maintains the activity.

Therefore, there is a motivation for such a substitution.

In response to the argument, the trial decision determined that "Since there is no
description of the production method or pharmacological activity, it cannot be said thata person ordinarily skilled in the art could conceive of replacing a specific substituent
group of the Exhibit Ko 1 Invention on the basis of the description of Exhibit Ko 2
without such a technical support." Thus this argument was considered in the trial
proceeding.
b

The argument of "Both the compound of Invention 1 and the compoundof the Exhibit Ko 1 Invention are selection inventions of the compound of generalformula (I) of Exhibit Ko 2," which was presented by Plaintiffs , means that a
motivation should not be negated on the presumption that "activity might possibly belost" when the structure activity relationship of compounds has been clarified at a highlevel and a number of analogous compounds actually having an activity (equivalent toor higher than that of Mevinolin) have been known, but should be rather affirmed on
the presumption that one can "reasonably expect an activity" in accordance with theconcept of selection invention. From the viewpoint of the effects, this means that themaintenance of the effects is not a sufficient condition for advantageous effects on thepresumption that "activity might possibly be lost," but the significantly high effects
36

compared to those of the cited invention are a sufficient condition for advantageous
effects on the presumption that one can "reasonably expect an activity" in accordancewith the concept of selection invention.
The argument by Plaintiffs does not change the primarily cited reference, butposes a question about the determination criteria of the inventive step that wasconsidered in the proceeding of the trial.
c Plaintiff X argues in the written request for trial (Exhibit Ko 79) that
"Patentee misunderstood that the compound Ia-1 of the Invention (the compound of
Invention 1) had a significantly high activity compared to the conventional technique,and completed 'the patent invention' and described the Detailed Description of theInvention of the specification.""The patent invention" used herein is acomprehensive expression of "the invention recited in the claims according to therequest for an invalidation trial" (Exhibit Ko 79, page 2, lines 10 to 11), and thus
includes the whole range of the compounds of Claim 1 of the Patent.
Therefore, Plaintiff X did not only present an argument that the calcium salt of
the compound Ia-1 of the specification was not supported among the compounds ofInvention 1. The argument in this case to the effect that the whole range of thecompound of the Invention 1 is not supported does not correspond to the addition of
the argument.
(2) Errors in the determination of the effect of the Invention
A There is a motivation to conceive of the compound of the Invention from
Exhibit Ko 1 and Ko 2.

Therefore, it is necessary for the compound of the Invention

to cause significant effects unexpected from Exhibit Ko 1 and Ko 2 in view of thecommon general technical knowledge to involve an inventive step, but such significant
effects are not found.
Further, given that the Invention 1 is a selection invention of the compound of
the general formula (I) of Exhibit Ko 2, it is all the more necessary to perform
significant activity compared to a compound out of the selected range.
B As set forth below, the effects of Invention 1 should be compared withthose of the compound of the Exhibit Ko 1 Invention. Thus the determination of thetrial decision is erroneous in that it affirmed the effects of Invention 1 by comparing
the effects of sodium Mevinolin with the effects of Invention 1.
(A)

Prior to the priority date, there were developed and commercially37

available HMG-CoA reductase inhibitors having a hexahydronaphthalene skeletonsuch as Lovastatin, Simbastatin, and Pravastatin.

A number of HMG-CoA reductase

inhibiting compounds in which the hexahydronaphthalene was converted into anotherskeleton were publicly known (Exhibit Ko 8).
There were numerous reports before the priority date on the HMG-CoA
reductase inhibiting compound of the Invention in which hexahydronaphthalene wasconverted into pyrimidine (Exhibit Ko 1, Ko 2, Ko 16, and Ko 73 to Ko 75). Amongthem, the compound of the Exhibit Ko 1 Invention has a very similar structure to thecompound of Invention 1. The structural difference was only a methyl group (thecompound of the Exhibit Ko 1 Invention) or an alkylsulfonyl group (the compound of
Invention 1) binding to amine at the 2-position of the pyrimidine ring.
(B)

Both the compound of the Exhibit Ko 1 Invention and the compound of

the Invention are included in general formula (I) of Exhibit Ko 2.

It is thus a so-called selection invention of the compound of general formula (I) of Exhibit Ko 2
(setting aside whether the effects are significant, it is the case where the compound
falls within the scope of the general formula of the patent specification of an earlier
application, but the patent specification of the earlier application fails to describe thespecific compound).
The selection invention is at least required to have a significantly high HMGCoA reductase inhibiting activity compared to the compound of the Exhibit Ko 1
Invention that was a specific publicly known compound falling within the scope ofgeneral formula (I) of Exhibit Ko 2, not compared to sodium Mevinolin, in order tofind the inventive step of the compound of Invention 1 over the Exhibit Ko 2 Invention
which constitutes the above concept.
(C) Patentee had known of the existence of Exhibit Ko 1 and Ko 2 before
the filing of the U.S. application having the same content and being filed at almost thesame time as the application of this case, and thus had known of Exhibit Ko 1 and Ko
2 as of the filing, and had recognized that the compound of Invention 1 and thecompound of the Exhibit Ko 1 Invention were selection inventions of the Exhibit Ko 2
Invention. Further, the Patentee had also recognized that the compound of Invention
1 needed to cause a significant HMG-CoA reductase inhibiting activity compared tothe compound of the Exhibit Ko 1 Invention in order to find the inventive step of thecompound of Invention 1 over the Exhibit Ko 2 Invention.
It is believed that the Patent was established by preparing the specification as if
38

the Patentee had not known that the Invention was a selection invention, regardless of
the recognition of the Invention being a selection invention as of the filing, and, in
response to the assertion of lack of inventive step in the notice of reasons of refusal,
deliberately submitting data showing unreliably high effects in a written opinion, anddemonstrating that the significant effects qualified for the selection invention
compared to the compound of the Exhibit Ko 1 Invention to obtain a decision to granta patent.
If the standard for comparison of the effects of the compound of Invention 1
should be recognized as sodium Mevinolin, not a compound of the Exhibit Ko 1
Invention after the registration of the Patent and the determination should be made to
the effect that "it does not necessarily require a higher HMG-CoA reductase inhibiting
effect compared to the Exhibit Ko 1 Invention," this might endorse the way oftentatively acquiring a patent by arguing an inventive step on the basis of extremely
unreliable data, instead of presenting an argument about the effects on the basis ofreliable data in the written opinion against a notice of reasons of refusal without thedescription of comparative data on the effects with a compound having the mostanalogous structure in the specification of the application.
C

As set forth below, even if it were appropriate to compare the compound of

Invention 1 with sodium Mevinolin, it cannot be deduced from the description of thespecification that the compound of Invention 1 has a higher HMG-CoA reductase
inhibiting activity compared to sodium Mevinolin.
(A) A person ordinarily skilled in the art fails to understand what thenumerical values of Table 4 in the specification mean.
The specification describes a method for the measurement and an assay result of
HMG-CoA reductase inhibiting activity of the compound of Invention 1.

It discloses

that "the activities of the compounds of the Invention measured by the method areshown in Table 4 as comparative data, based on the assumption that the inhibiting
activity of Mevinolin (sodium salt) as the reference drug is 100" ([0042]), and Table 4shows data of relative activity of the test compound.
The pharmacological activity of the compound is specifically shown only in
Table 4 in the specification.

In the table, HMG-CoA reductase inhibiting activities ofcompounds Ia-1, Ia-3, Ia-5, and Ia-7 are shown by use of rat liver microsome; however,the compound likely to support Invention 1 is only compound Ia-1. Table 4 discloses
that compound Ia-1 has a relative activity of 442 with the inhibiting activity of sodium
Mevinolin given as 100.
39

However, the inhibiting activity varies depending on the condition, mainly theconcentration of compound. A person ordinarily skilled in the art fails to understandfrom the description of "on the assumption that the inhibiting activity of Mevinolin(sodium salt) as the reference drug is 100" in what condition the inhibiting activity of
Mevinolin (sodium salt) was set to 100.
For example, a person ordinarily skilled in the art fails to understand which of
the following is true: a) Measurement was made for the inhibiting activity of
Mevinolin (sodium salt) at a certain level of concentration, and given the activity be
100, a relative value of inhibiting activity of test compound at the same concentration
was shown in Table 4, or b) Measurement was made for the inhibiting activity of
Mevinolin (sodium salt) at two or more levels of concentration, and from the results
the IC50 value of inhibiting rate of test compound was calculated, and given the value
be 100, a relative value of IC50 value of test compound was shown in Table 4, or other
another procedure was made.
Further, for example, when the HMG-CoA reductase inhibiting activity is 1%,
50%, and 90%, respectively for 1 nM, 10 nM, and 100 nM of the compound A, and the
HMG-CoA reductase inhibiting activity is 5%, 30%, and 50% respectively for 1 nM,
10 nM, and 100 nM of the compound B, given that the HMG-CoA reductase inhibiting
activity for 1 nM of the compound A (1%) is 100, the HMG-CoA reductase inhibiting
activity for 1 nM of the compound B is 5%. Therefore, the activity of the compoundB relative to the compound A is 500 in the case of the above b). On the other hand,the compound A has an IC50 value of 10 nM, and the compound B has an IC50 value of
100 nM. Therefore, in the case of the above a), a relative activity of the IC 50 value ofthe compound B is 10, given that the IC50 value of the compound A is 100.

In otherwords, the order of the degree of activity of the compounds is reversed between thecase of the above a) and the case of the above b), and the order of the degree of activityof the compounds cannot be understood unambiguously.
(B)

It was known as of the filing that the method for the measurement of invitro HMG-CoA reductase inhibiting activity by use of rat liver microsome describedin the specification caused varied results, and the order of the degree of inhibiting
activity also varied (Exhibit Ko 7, Ko 8, Ko 31, Ko 35, Ko 75). Therefore, a person
ordinarily skilled in the art fails to understand which of the compounds has a higher
inhibiting activity and which of the compounds has a lower inhibiting activity unlessthe results of implementing at least multiple separate same experimentations are shown.
The result of Table 4 is only a measurement result for one time (Exhibit Ko 5), and it
40

cannot be thus deduced for a person ordinarily skilled in the art from the description of
the specification that the compound of the Invention 1 has a higher HMG-CoA
reductase inhibiting activity compared to sodium Mevinolin.
Most patent applications for HMG-CoA reductase inhibiting compound having
a pyrimidine skeleton did not demonstrate the HMG-CoA reductase inhibiting activityof a compound by showing data of a one-time test result of only one kind of test of invitro HMG-CoA reductase inhibiting test by use of liver microsome like the Patent(Exhibit Ko 1, Ko 73, Ko 74, Ko 77, Ko 78). This fact supports the recognition of aperson ordinarily skilled in the art that results for one kind and one-time test system are
not sufficient, but results of a plural kinds of tests must be shown as data in view of thevariation of test results in the discussion about the degree of HMG-CoA reductase
inhibiting activity among compounds.
D As set forth below, Exhibit Ko 3 fails to support the fact that the Invention
1 has a significant effect.
(A)

It cannot be seen from the documents submitted after the filing that aperson ordinarily skilled in the art could not understand from the specification.
Therefore, the determination of the trial decision to the effect that "Exhibit Ko 3
supports the significant effects of the Invention 1.

Therefore, the effects of theInvention 1 cannot be negated" is erroneous.
(B)

Data of S-4522 (Invention 1) and SDZ-65129 (Exhibit Ko 1 Invention)of Exhibit Ko 3 summarize the results of the measurements 1 to 3 of Exhibit Ko 5.

It

can be seen that these data had been obtained by August 1, 1996. Exhibit Ko 3 andKo 5 disclose that compound Ia-1 of the specification has in vitro HMG-CoA
reductase inhibiting activity only about two times higher than that of the compound ofWorking Example 1b) of Exhibit Ko 1. They fail to describe activity about ninetimes higher.
Patentee submitted the written amendment and the written opinion on August
12, 1996 in response to the reason for refusal due to the lack of novelty and the lack ofinventive step with Exhibit Ko 1 as a cited document, in an attempt to overcome thelack of novelty and the lack of inventive step to obtain a decision to grant a patent.

In

the above written opinion, Patentee argued that compound Ia-1 of the specification had
an in vitro HMG-CoA reductase inhibiting activity about nine times higher than that of
the compound of Working Example 1b) of Exhibit Ko 1, and was thus particularly
superior.
41

Patentee did not submit experimental results allegedly having about two-time
activity that he should have recognized as reliable results as of the submission of theabove written opinion, but submitted an experimental result allegedly having aboutnine-time activity, and only argued about the significant effects of the compound of
Invention 1 (without the argument about the structure) in an attempt to overcome thereasons for refusal due to lack of inventive step.

Therefore, Patentee actuallyadmitted that the significant effects did not mean "about two-time activity," but meant"about nine-time activity" compared to the compound of the Exhibit Ko 1 Invention.
At this late date, this is not permitted because of estoppel and the violation of fair andequitable principle to argue that the significant effects may be even caused by "about
two-time activity," and that "about nine-time activity" is not a requirement for thesignificant effects.
Further, Patentee had known as of the submission of the above written opinion
that the patentability might not be ensured unless Invention 1 caused significant effects
as a selection invention of Exhibit Ko 2 Invention. Therefore, it is believed that heargued about significant effects sufficient for patentability. The above argument is all
the more not permitted due to estoppel.
E As set forth below, the description fails to disclose that Invention 1 has asignificant effect.
(A) The compound of the Exhibit Ko 1 Invention having a very similar
structure to the compound of Invention 1 falls within the scope of the general formula(I) of Exhibit Ko 2, but is out of the scope of Invention 1. Taking into account theIC50 value (0.068 μM) of the HMG-CoA reductase inhibiting activity of sodium
Mevinolin described in Table 1 of Exhibit Ko 8 and the IC50 value (0.026 μM) of
HMG-CoA reductase inhibiting activity as a result of test A of Exhibit Ko 1, it could
be presumed that the compound of the Exhibit Ko 1 Invention would have an in vitro
HMG-CoA reductase inhibiting activity by use of rat liver microsome 2.6 times higher
than that of sodium Mevinolin.
Further, compounds 2t, 2u, 2v and 2w of Exhibit Ko 16 are compounds fallingwithin the scope of general formula (I) of Exhibit Ko 2, but are out of the scope ofInvention 1.

These compounds have an in vitro HMG-CoA reductase inhibiting

activity by use of rat liver microsome 2.6 to 8 times higher than that of sodium
Mevinolin (Compound 1b of Exhibit Ko 16).
(B)

However, it is failed to describe anywhere in the description and it
42

cannot be seen from anywhere in the description that the compound of Invention 1
from which its high HMG-CoA reductase inhibiting activity compared to sodium
Mevinolin cannot even be seen had had significant activity (sufficiently significant
activity compared to the compound of the Exhibit Ko 1 Invention and compounds 2t,
2u, 2v and 2w of Exhibit Ko 16) appropriate for a selection invention of the Exhibit Ko
2 Invention in view of Exhibit Ko 1 and Exhibit Ko 2, which describes the generalformula of the above concept of Exhibit Ko 1.
(C) Referring to Exhibit Ko 3, which is a document after the filing, Exhibit
Ko 3 shows that S-4522 (Rosuvastatin), a calcium salt of compound Ia-1 of Table 4 ofthe description, has an activity 2.0 times higher than that of sodium Mevinolin
according to the measurement results of HMG-CoA reductase inhibiting activity
obtained by multiple measurements. Therefore, it can only be seen from Exhibit Ko 3that compound Ia-1 has about two-times higher the activity of sodium Mevinolin.
On the other hand, the compounds of Exhibit Ko 16 (2t, 2u, 2v and 2w) and thecompound of the Exhibit Ko 1 Invention falling within general formula (I) of Exhibit
Ko 2 and out of Invention 1 might have or might be expected to have an in vitro HMGCoA reductase inhibiting activity by use of rat liver microsome 2.6 to 8 times higher
than that of sodium Mevinolin.
Therefore, even if Exhibit Ko 3 should be considered, it is not supported inview of Exhibit Ko 1 and Ko 2 that the compound of the Invention 1 had had asufficiently significant activity.
(D)

The trial decision determined that "Whether or not the Invention

causes significant effects should be determined with a criterion of whether or not to
expect the effect of the Invention from the Exhibit Ko 1 Invention and the common
general technical knowledge as of the priority date.

The Invention needs notnecessarily have a high HMG-CoA reductase inhibiting activity compared to the
Exhibit Ko 1 Invention." In view that both the Exhibit Ko 1 Invention and Invention 1
were selection inventions of the Exhibit Ko 2 Invention, the determination of the above
trial decision is erroneous.
F Summary
Therefore, the effects are not considered.

From this viewpoint, it is notsupported that Invention 1 involves an inventive step over Exhibit Ko 1 and Ko 2.
The same can also apply to Inventions 2, 5, and 9 to 12.
432 Ground 2 for rescission (Errors in the determination of the support requirement)(1) Finding of a problem to be solved by Invention 1
A As set forth below, the problem found in the trial decision is inappropriate
in view of the common general technical knowledge as of the filing.
(A) What was found first as a compound having "excellent HMG-CoA
reductase inhibiting activity" to the extent that may become a pharmaceutical productis Compactin (Exhibit Ko 14, Ko 26). Compactin had been already publicly known
more than a decade before the filing of the Patent (Exhibit Ko 66).
It is inappropriate to formulate a problem to be solved by the Invention "toprovide an HMG-CoA reductase inhibitor including a compound having 'excellent
HMG-CoA reductase inhibiting activity' or the compound as an active ingredient to theextent that may become a pharmaceutical product for 'suppressing the biosynthesis ofcholesterols'" at the same level as the state of art more than a decade before.
(B)

As of the filing date of the patent, there were already a plurality of

HMG-CoA reductase inhibitors in the market as pharmaceutical products.
Further, a plurality of the compounds with a pyrimidine skeleton, which was thesame as the Invention 1, were publicly known (Exhibit Ko 16, and Ko 73 to Ko 75),
and a compound showing a higher HMG-CoA reductase inhibiting activity comparedto sodium Mevinolin was also publicly known (Exhibit Ko 16).
In view of such common general technical knowledge as of the filing, "theextent that may become a pharmaceutical product for 'suppressing the biosynthesis ofcholesterols'" in the problem formulated by the trial decision is a lower level comparedto the common general technical knowledge, and thus inappropriate.
B

As set forth below, the problem formulated by the trial decision isinappropriate in view that the compound of Invention 1 is a compound within thescope of general formula (I) of Exhibit Ko 2.
(A)Invention 1 includes the scope of general formula (I) of Exhibit Ko 2.

If the compound of Invention 1 should have patentability (in particular inventive step)in such circumstances, it would be the case of a selection invention.

If so, thecompound of Invention 1 needs to have a significant effect over the other compoundsof general formula (I) of Exhibit Ko 2.
Here, compounds 2t, 2u, 2v and 2w of Exhibit Ko 16 are compounds fallingwithin the scope of general formula (I) of Exhibit Ko 2, but out of the scope of44

Invention 1. These compounds were publicly known as of the filing to have an invitro HMG-CoA reductase inhibiting activity by use of rat liver microsome 2.6 to 8
times higher than that of sodium Mevinolin (Compound 1b) of Exhibit Ko 16) (Exhibit
Ko 16).
Further, the compound specifically described as Working Example 23 of
Exhibit Ko-2 is a methyl ester of carboxylic acid of compound 2v of Exhibit Ko 16,
and a compound having HMG-CoA reductase inhibiting activity comparable to a socalled prodrug of compound 2v of Exhibit Ko 16.

It can be seen that Exhibit Ko 2

had described a compound having a HMG-CoA reductase inhibiting activity 2.6 times
higher than that of sodium Mevinolin (the activity of the compound 2v of Exhibit Ko
16 is 2.6 times higher than that of sodium Mevinolin (the compound 1b of Exhibit Ko2)) as a specific compound in the working examples.
(B) The compound of the Exhibit Ko 1 Invention having a very similar
structure to the compound of Invention 1 also falls within the scope of general formula(I) of Exhibit Ko 2, but out of the scope of Invention 1. Taking into account the IC50
value (0.068 μM) of HMG-CoA reductase inhibiting activity of sodium Mevinolin
described in Table 1 of Exhibit Ko 8 and the IC50 value (0.026 M) of HMG-CoA
reductase inhibiting activity as a result of test A of Exhibit Ko 1, a person ordinarily
skilled in the art could presume as of the filing that the compound of the Exhibit Ko 1
Invention would have an in vitro HMG-CoA reductase inhibiting activity by use of rat
liver microsome, 2.6 times higher than that of sodium Mevinolin.
(C) As seen above, what was publicly known as of the filing was thecompound having an in vitro HMG-CoA reductase inhibiting activity by use of rat
liver microsome 2.6 to 8 times higher than (or reasonably expected to be higher than)that of sodium Mevinolin in the compounds encompassed into general formula (I) of
Exhibit Ko 2.
Therefore, in order that the compound of Invention 1 may involve an inventive
step in view of the compound of general formula (I) of Exhibit Ko 2, it is contemplated
that the compound needs to have an HMG-CoA reductase inhibiting activity 2.6 to 8
times higher than that of sodium Mevinolin.
(D) Exhibit Ko 1 describes the result of an in vivo cholesterol biosynthesis
inhibiting test using rat, and shows that Compactin has an in vivo cholesterol
biosynthesis inhibiting effect about 8.5 times lower than that of Mevinolin (3.5/0.41 =45

8.53).
Compactin was a publicly known, and authorized HMG-CoA reductase
inhibitor, and was known to have a drug efficacy sufficient to lower blood cholesterolin human (Exhibit Ko 14, Ko 26). Therefore, it can be recognized that a problem
formulated by the trial decision "to provide a compound having 'excellent HMG-CoA
reductase inhibiting activity' to the extent that may become a pharmaceutical productfor 'suppressing the biosynthesis of cholesterols'" may be solved, even if Compactin
had an HMG-CoA reductase inhibiting activity about 8.5 times lower than that of
Mevinolin.
Consequently, it can be recognized that a problem formulated by the trial
decision may be solved by Compactin that has an HMG-CoA reductase inhibiting
activity about 8.5 times lower than that of sodium Mevinolin.
However, in order that the compound of Invention 1 may involve an inventive
step as a selection invention in view of the compound of general formula (I) of Exhibit
Ko 2, it can be seen that the compound needs to have an HMG-CoA reductase
inhibiting activity 2.6 to 8 times or more higher than that of sodium Mevinolin.
Therefore, even if the problem formulated by the trial decision should be solved, it
may not involve an inventive step as a selection invention, and thus the invention
cannot be granted a patent.
As seen above, even if the problem formulated by the trial decision should be
solved, it may not involve an inventive step and thus cannot be a patented invention.
This is only because the problem formulated by the trial decision is of a significantly
low level relative to the common general technical knowledge at that time, and thus
inappropriate.
C

As set forth below, the problem formulated by the trial decision isinappropriate in view of the situation as of the filing.
Patentee had recognized Exhibit Ko 1 and Ko 2 as of the filing (May 28, 1992),
and that the compounds of Invention 1 and the Exhibit Ko 1 Invention fell within thescope of general formula (I) of Exhibit Ko 2.
Given such recognition, regardless of Exhibit Ko 1 describing compound 1b)(Compound of the Exhibit Ko 1 Invention) showing an in vivo strong HMG-CoA
reductase inhibiting activity comparable to that of Mevinolin (may have the sameactivity as sodium Mevinolin metabolized in a living body), it is unlikely to formulate
a problem to be solved by the Invention "to provide an HMG-CoA reductase inhibitor
including a compound having 'excellent HMG-CoA reductase inhibiting activity' or the46

compound as an active ingredient to the extent that it may become a pharmaceuticalproduct for 'suppressing the biosynthesis of cholesterols,'" which may be solved evenby a compound with an HMG-CoA reductase inhibiting activity about 8.5 times lower
than that of sodium Mevinolin.
D Therefore, the problem of the Invention formulated by the trial decision isincorrect.
(2) A person ordinarily skilled in the art fails to recognize that Invention 1
may solve a problem "to provide a compound having an excellent HMG-CoA
reductase inhibiting activity"
A A plurality of HMG-CoA reductase inhibitors having pyrimidine skeleton
like Invention 1 were known as of the filing date of this case (Exhibit Ko 1, Ko 2, Ko
73 to Ko 75). Among them, compounds having an HMG-CoA reductase inhibiting
activity 2.6 to 8 times higher than that of sodium Mevinolin were publicly known, likethe compounds 2t to 2w of Exhibit Ko 16.
Further, regarding the compound of the Exhibit Ko 1 Invention, taking into
account the IC50 value (0.068 μM) of HMG-CoA reductase inhibiting activity of
sodium Mevinolin described in Table 1 of Exhibit Ko 8 and the IC50 value (0.026 μM)
of HMG-CoA reductase inhibiting activity as a result of test A of Exhibit Ko 1, aperson ordinarily skilled in the art could presume as of the priority date that thecompound of the Exhibit Ko 1 Invention would have an HMG-CoA reductase
inhibiting activity 2.6 times higher than that of sodium Mevinolin.

Furthermore,according to Defendant's argument, the compound of Working Example 11d of Exhibit
Ko 1 is allegedly a compound having a higher activity as compared to the compoundof the Exhibit Ko 1 Invention if a racemic body thereof is divided into a single
enantiomer.
In such circumstances where there is common general technical knowledge, andthe test result of activity measurement described in the description varies so that theorder of the degree of activity sometimes switches, the average value and the standard
deviation are not shown, but only a one-time test result with sodium Mevinolin(positive control) is shown, which can be seen from the disclosure of Table 4 in thedescription.

It cannot be seen from the disclosure that a compound with "excellent"

HMG-CoA reductase inhibiting activity is disclosed. The description fails to disclosethat Invention 1 has a strong HMG-CoA reductase inhibiting activity comparable tothat of sodium Mevinolin.
47

Further, the description does not disclose anywhere that the compound of
Invention 1 causes significant effects in view of Exhibit Ko 1 and Ko 2.
A person ordinarily skilled in the art may not recognize from such content of
the description that a problem of Invention 1 "to provide a compound having an
excellent HMG-CoA reductase inhibiting activity" may be solved.
B The compound of the Invention is a selection invention of general formula(I) of Exhibit Ko 2, and its structure has already been disclosed.

Thus, theidentification of the structure is not at all the disclosure of a novel technique.
The description only discloses activity that cannot be said to be significant incomparison to sodium Mevinolin, which is only a positive control (measurement for astandard compound to be measured for verifying the normality of each measurement
and comparing test results between measurements) regarding a compound withidentified structure. Therefore, the description fails to disclose any novel technique.
C

Plaintiff X pointed out in the written request for trial (Exhibit Ko 79) the

Patentee's dishonest behavior to obtain a decision to grant a patent by submitting selfserving data of compound Ia-1 of the description having about 9 times higher activity
in the written opinion of the prosecution of the Patent (Submitted on August 12, 1996.
Exhibit Ko 6.), regardless of his knowledge of the compound having only two-times
higher activity than the compound of the Exhibit Ko 1 Invention, and argued about thenonconformance to so-called support requirement.
In contrast, Patentee argued in the written reply (Exhibit Ko 80) that "The
Correction has rendered compound Ia-1 (corresponding to the sodium salt of
Rosuvastatin) out of the scope of claims. Accordingly, the argument in the written
request for invalidation trial on the basis of data of the compound Ia-1 in the written
opinion (Exhibit Ko 6) is no longer an argument of the noncompliance of support
requirement"; i.e., "Data of compound Ia-1 do not support the Corrected Invention (theInvention).

Thus there is no room to doubt the conformance to the support

requirement, regardless of whether or not the Examiner misunderstands that theactivity of compound Ia-1 is high."
This is the Patentee's admission that Invention 1 is not supported by data ofcompound Ia-1 of the description. The description lacks any other data of HMG-CoA
reductase inhibiting activity that supports Invention 1.

Therefore, it cannot berecognized that a person ordinarily skilled in the art may recognize that a problem tobe solved by the Invention "to provide a compound having an excellent HMG-CoA
48

reductase inhibiting activity" may be solved.
(3) A person ordinarily skilled in the art could not understand that the overall
range of compounds of the Invention 1 had higher activity compared to sodium
Mevinolin
A person ordinarily skilled in the art could understand that compound Ia-1
described in the description had a higher activity compared to sodium Mevinolin, but
could not understand that the overall range of compounds of the Invention 1 had higher
activity compared to sodium Mevinolin.
In other words, for example, when the isopropyl group at the moiety
corresponding to R3 of formula (I) of Invention 1 in compound Ia-1 (compound 2t of
Exhibit Ko 16) is substituted with a methyl group (the compounds 2r, 2s of Exhibit Ko16), it is inferred from the comparison between 2r to 2s and 2t to 2w of Exhibit Ko 16
that HMG-CoA reductase inhibiting activity is lowered by a factor of 100 times ormore. Therefore, it can be said that the substitution of an isopropyl group with amethyl group results in the decrease of activity by a factor of 100 times or more.

Itcannot be seen from the common general technical knowledge as of the filing that,
although compound Ia-1 has an HMG-CoA reductase inhibiting activity 4.42 times
higher than that of sodium Mevinolin, the whole range of the compounds of theInvention 1 has HMG-CoA reductase inhibiting activity higher than that of sodium
Mevinolin like compound Ia-1.
In addition, compounds 2r to 2s and compounds 2t to 2w of Exhibit Ko 16 aredifferent from each other in that the moiety corresponding to "-X-R1" of formula (I) of
Invention 1 is isopropyl (i-C3H7), etc. for 2t to 2w and a methyl group (CH3) for 2r to
2s.
However, the above difference is presumed to reduce HMG-CoA reductase
inhibiting activity by a factor of about three times at most when comparing compound
2f and compound 2e of Exhibit Ko 16, both of which are compounds with a pyridine
skeleton. Most of the reduction in HMG-CoA reductase inhibiting activity may be
attributed to the difference in the above R3. Therefore, the difference in the moiety
corresponding to -X-R1 does not contribute to the reduction of HMG-CoA reductase
inhibiting activity by a factor of more than 100 times.
(4) Summary
Therefore, it cannot be seen for a person ordinarily skilled in the art from thedescription of the Detailed Description of the Invention that the problem to be solved
49

might be solved by Invention 1, and thus the determination of the trial decision thataffirmed the conformance to the support requirement is erroneous.
Further, regarding the aforesaid items (1) and (2), the same can also apply toInventions 2, 5, and 9 to 12. Therefore, the determination of the trial decision thataffirms the conformance to the support requirement for these Inventions is erroneous.
No. 6

Argument by Defendant and others

1 Ground 1 for rescission(1) Selection of primarily cited reference
A(A) The compound of the Exhibit Ko 1 Invention that Plaintiffs see as a socalled lead compound in the primarily cited reference was selected as the mostanalogous compound in structure to the compound of the subject of the Invention withthe knowledge of the content of the Invention in hindsight.
If there is no reasonable reason other than the similarity of structure to theInvention in hindsight to select a lead compound in the primarily cited reference, aperson ordinarily skilled in the art would not easily conceive of the selection itself ofthe primarily cited reference. That is enough to establish an inventive step.
Plaintiffs fail to show any reasonable reason other than the similarity of thestructure of the Invention in hindsight for the selection of the compound of Exhibit Ko
1 Invention as a lead compound.

Therefore, the Invention is construed as involving

an inventive step without discussing ground 1 for rescission.
(B)

At least five competing companies had begun to research and develop astatin with a pyrimidine skeleton by the priority date of the Patent (Exhibit Ko 8, Ko73); however, none of the companies could place it on the market.

The inventors of

the Invention made a success in creating a novel compound with the world's highest
level of HMG-CoA reductase inhibiting activity through research and development ofa statin with a pyrimidine skeleton.
Therefore, the compound of the Exhibit Ko 1 Invention is not appropriate forthe lead compound.
Even if a person ordinarily skilled in the art should give importance to the resultof the test B of Exhibit Ko 1 as Plaintiffs argued, a single enantiomer of an active bodyof the compound of Working Example 11d is expected to have a higher activity
compared to the compound of the Exhibit Ko 1 Invention from the result of the test B.
Therefore, a person ordinarily skilled in the art would select the compound of Working
Example 11d, not the compound of the Exhibit Ko 1 Invention, as a lead compound.
50

B(A)

When a primarily cited invention belongs to the category where aperson ordinarily skilled in the art ceased to research and develop as of the filing date,
the adverse effect of the post-facto analysis cannot be overlooked in specifying the
primarily cited invention.

Therefore, this situation should be considered in thedetermination of the difference related to inventive step.
Further, when an inventor should achieve an invention causing superior effects
starting from a primarily cited invention in which many persons ordinarily skilled in
the art did not show any interest, many persons ordinarily skilled in the art could haverecognized that he could not achieve an excellent invention even if one should try to
improve starting from the primarily cited invention.

Therefore, the effects should be

evaluated as beyond expectation.
According to the fact of aforesaid A(B), the effects of the Invention should be
evaluated as unexpected and significant ones.

Thus the inventive step of theInvention should be affirmed.
If the Exhibit Ko 1 Invention should have superior effects and be suitable for alead compound as Plaintiffs argue, the Invention should be all the more evaluated as
causing unexpected and significant effects, since the Invention causes effects
exceeding the Exhibit Ko 1 Invention.
(B)

In a lawsuit of the U.S., the inventive step of the U.S. Patentcorresponding to the Patent (nonobviousness) was affirmed in comparison to the
publicly known documents and an argument of invalidation similar to the trial of thecase (Exhibit Otsu 7, Otsu 8).
The determination of inventive step should have elements to be considered incommon in each jurisdiction from a viewpoint of international harmonization.
(2) Errors in the determination of lack of motivation
A Motivation from Exhibit Ko 1
(A)

It cannot be recognized that the overall range of the compound

represented by general formula I of Exhibit Ko 1 has a pharmacological activity
similar to that of the Exhibit Ko 1 Invention, and a person ordinarily skilled in the art
could not reasonably expect the pharmacological activity for a compound out of therange.
It was a matter of common general technical knowledge as of the priority datethat a pharmacological activity might be lost in many cases if a part of a substituent
51

group of a compound having pharmacological activity is changed (an example ofLovastatin and Pravastatin in Exhibit Ko 7, Exhibit Otsu 65, Otsu 66). Exhibit Ko 1
fails to suggest that the difference 1-i may drastically improve the HMG-CoA
reductase inhibiting activity.
(B)

Although a compound out of the range of the general formula I of

Exhibit Ko 1 might possibly show the HMG-CoA reductase inhibiting activity, one
cannot establish that "HMG-CoA reductase inhibiting activity may be expected for all
the compounds out of the range of general formula I of Exhibit Ko 1," nor that "HMGCoA reductase inhibiting activity may be expected for the compound of the Invention
among the compounds out of the range of general formula I of Exhibit Ko 1."
A number of the compounds are present out of the range of the general formula
I of Exhibit Ko 1. Among them, there are a number of compounds with a poor HMGCoA reductase inhibiting activity. Exhibit Ko 1 gives no hint as to what compoundshows a superior HMG-CoA reductase inhibiting activity.
General formula I of Exhibit Ko 1 fails to comprise the structure of thedifference (1-i) (for example, N(CH3)(SO2R')(R': alkyl group) as a substituent group at
the 2-position of the pyrimidine ring).
(C)

It was known as of the priority date that liver selectivity did notnecessarily have a correlation with hydrophilicity (Exhibit Ko 7, Exhibit Otsu 11 to
Otsu 13, Otsu 19), and it was well-known that the hydrophilicity of statin does nothave a correlation with HMG-CoA reductase inhibiting activity (Exhibit Ko 7).
Therefore, a person ordinarily skilled in the art would not have a motivation to simply
improve the hydrophilicity of a statin.
If the argument by Plaintiffs were correct in that the tests of Exhibit Otsu 11
and Otsu 19 are test systems unable to detect the effect of hydrophilicity of acompound on the liver selectivity, since the effect of liver selectivity caused by thehydrophilicity of a compound is hidden by the effect of a lactone body, a person
ordinarily skilled in the art who read the results of Exhibit Otsu 11 and Otsu 19 could
be motivated to change a compound into a prodrug (lactone body), rather thanrendering the compound hydrophilic for the purpose of improving the liver selectivityof a statin.

Further, if the above argument were correct, an in vivo test system would

be a test system that inherently fails to detect the effect of hydrophilicity of acompound on liver selectivity. Therefore, even if a person ordinarily skilled in the art
could recognize from the result of the test B of Exhibit Ko 1 that the compound of52

Exhibit Ko 1 Invention had good in vivo activity, he could not understand that itcorrelated with the improvement of hydrophilicity.
(D) Exhibit Ko 1 lacks description considering the correlation of HMGCoA reductase inhibiting activity with degree of hydrophilicity. Therefore, it cannot
be said that it discloses the correlation of the inhibiting activity of the compounds ofWorking Example 1b) and Working Example 11b with hydrophilicity of thesubstituent group at 2-position.
First of all, test B is a test for the measurement of the inhibiting activity ofcholesterol biosynthesis, not a test for the measurement of HMG-CoA reductase
inhibiting activity.
Even if a person ordinarily skilled in the art would focus on the hydrophilicityof the substituent group, the highly hydrophilic pyridyl group is introduced at the 4position (4-pyridyl) of the pyrimidine ring of the compound of Working Example 11d,
and a person ordinarily skilled in the art could understand that a single enantiomer ofan active body of Working Example 11d had a higher activity compared to thecompound of the Exhibit Ko 1 Invention. Therefore, a person ordinarily skilled in theart could focus on a substituent group at the 4-position, not the 2-position.
(E) Hydrophilicity is a relative concept, and is determined by comparison
between two substituent groups. When the atom -H of an aromatic compound issubstituted with a dimethylamino group, it shows hydrophobicity (Exhibit Ko 9).
Therefore, it cannot be said that a dimethylamino group is hydrophilic.
(F) Of course, it is naturally an alternative for a person ordinarily skilled in
the art to modify both methyl groups of a dimethylamino group with a hydrophilicgroup having smaller contribution to hydrophilicity compared to a methylsulfonylgroup, rather than to modify only one methyl group of a dimethylamino group at the 2position of the pyrimidine ring with a publicly known hydrophilic group of amethylsulfonyl group.
Besides a methylsulfonyl group, there are many hydrophobic groups having asmall contribution (Exhibit Otsu 4). Therefore, there was no motivation to select amethylsulfonyl group among these groups.
(G) The schematic drawing is drawn by Plaintiff as if general formula I of
Exhibit Ko 1 and general formula (I) of Exhibit Ko 2 overlap across a wide range, but
53

actually the overlapping range is limited. Further, the above schematic drawing is
drawn as if only the Invention is located in the vicinity of the Exhibit Ko 1 Invention,
but actually Exhibit Ko 2 describes a number of substituent groups equivalently as a
substituent group at the 2-position of the pyrimidine ring, and thus the schematic
drawing by Plaintiffs is misleading.
B Motivation from Exhibit Ko 2(A)aIn the trial, Plaintiff failed to present any argument that Exhibit Ko 2

describes the manufacturing method and HMG-CoA reductase inhibiting activity for
the whole range of the compounds of general formula (I) or that Exhibit Ko 16 shows
data of HMG-CoA reductase inhibiting activity for a compound of general formula (I)of Exhibit Ko 2, none of which was a subject for trial examination. Therefore, it is
not permitted for Plaintiffs to present in this lawsuit the argument of the aforesaid No.
5, 1(1)B, and the argument about the error in the determination to the effect that there
is no motivation from Exhibit Ko 2 of the trial decision.
The written request for trial argues that Exhibit Ko 16 describes the compoundof Working Example 23 of Exhibit Ko 2 as compound 2i having a pyrimidine ringskeleton. Compound 2i of Exhibit Ko 16 is not a compound having a pyrimidine ringskeleton, and thus is not the compound of Working Example 23 of Exhibit Ko 2.
Therefore, the description of the written request for trial is incorrect, and the above
argument has not been subjected to the trial examination of the trial.
b

The written request for trial argues that the Invention does not involve an

inventive step by the combination of Exhibit Ko 1 and Ko 2 (Exhibit Ko 79). The
above argument of No. 5, 1(1)B is intended to negate the inventive step of theInvention by combining Exhibit Ko 1 with Exhibit Ko 2 and Ko 16, which corresponds
to the change of the gist of the statement of the demand. Therefore, it is not permitted.
(B) Even if the aforesaid argument of No. 5, 1(1)B should be approved, theargument by Plaintiffs is not reasonable as in the following items a and b.
In addition, the trial decision stated that it cannot be said that Exhibit Ko 2
"describes a compound where 'R4' and 'R5' are 'methyl' and 'methylsulfonyl (SO2CH3)'
for '-NR4R5' so as to be technically supported," and "... -NR4R5 is described as one of agreat number of alternatives for 'R3', and none of these compounds is described in theworking examples, nor are the manufacturing method and pharmacological activity
described. Therefore, on the basis of the description of Exhibit Ko 2 having no54

technical support, ...."The trial decision does not mention that "the compound of thegeneral formula (I) has no technical support."a(a) The Invention is not X in the following drawing, but R1-X(R1: lower
alkyl) is a substituent group at the 2-position, and corresponds to -NR4R5 of the Exhibit
Ko 2 Invention.

In the Invention, X is an imino group substituted with analkylsulfonyl group, whereas in the Exhibit Ko 1 Invention it is an imino group
substituted with a methyl group.

Exhibit Ko 2 lists a great number of alternatives for R1, R2, and R3 in thecompounds of general formula (I). There are at least 21.2 million species for a
substituent group listed for R3 of "particularly preferable compound" (Exhibit Ko 80).
"Particularly extremely preferable compound" includes methyl, isopropyl, tert-butyland substituted or non-substituted phenyl for substituent group (R3) at the 2-position of
the pyrimidine ring, all of which are the groups with no hydrophilicity, not including NR4R5.
Further, in NR4R5 of Exhibit Ko 2, R4 and R5 may be the same or different fromeach other, and "particularly preferable compound" is "methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, tert-butyl, phenyl, benzyl, acetyl, methylsulfonyl, ethylsulfonyl,
propylsulfonyl, isopropylsulfonyl or phenylsulfonyl."
4 5specific examples of NR R is disclosed.

Furthermore, none of the

In Working Examples, the substituent

group at the 2-position of the pyrimidine ring is methyl (Working Example 8) andphenyl (Working Example 23). A compound with -NR4R5 is not disclosed.
As seen above, Exhibit Ko 2 lacks any specific description of even a compound
having -NR4R5, let alone a compound having -N(CH3)(SO2CH3) at the 2-position of
the pyrimidine ring. Therefore, there is no motivation to focus on -NR4R5, which is
not included in "particularly extremely preferable compound" of R3, and further
intentionally select a methyl group and a methylsulfonyl group for R4 or R5 of -NR4R5
from numerous substituent groups.
(b) According to the argument by Plaintiffs, a person ordinarily skilled in
the art would recognize that the compound manufactured by a manufacture working
55example other than Working Examples 8, 15, and 23 of Exhibit Ko 2 might not exhibit
the HMG-CoA reductase inhibiting activity.

All the statins manufactured byWorking Examples 8, 15, and 23 are compounds having a methyl or phenyl (lipophilic
substituent group) at the 2-position of the pyrimidine ring.
Therefore, according to the argument by Plaintiffs, a person ordinarily skilled in
the art should construe the compounds specifically disclosed as an active compound;i.e., a compound having a methyl or phenyl as a substituent group R3 at the 2-positionof the pyrimidine ring, as meaning the best mode of the invention disclosed in Exhibit
Ko 2, and would not be motivated to select -NR4R5 as R3, for which none of specificcompounds is disclosed.
b(a) The description of "manufacturing method of the compound of thegeneral formula (I)" of Exhibit Ko 2 that Plaintiffs pointed out relates to a method of
producing a compound where "phenyl (C6H5)" is selected as "R3," and does not relate
to a method for producing a compound where "-NR4R5" is selected as "R3."
Furthermore, there was common general technical knowledge as of the priority
date that a method for producing a compound with a phenyl for "R3" was applicable to
the whole range of the compound of general formula (I).
Therefore, it cannot be said that a person ordinarily skilled in the art could
understand the method for synthesizing a compound where "-NR4R5" is selected as"R3" from the description of the manufacturing method as Plaintiffs pointed out.
(b) The difficulty in predicting the pharmacological activity of a compoundfrom only a structure of the compound was a matter of common general technicalknowledge as of the priority date.
Exhibit Ko 2 fails to disclose any specific data for HMG-CoA reductase
inhibiting activity, and thus a person ordinarily skilled in the art could not understandthat the compound of general formula (I) of Exhibit Ko 2 exhibits an HMG-CoA
reductase inhibiting activity.
Furthermore, as in the aforesaid item a(b), a person ordinarily skilled in the art
would recognize that the compounds manufactured in the manufacture working
examples other than Working Examples 8, 15, and 23 of Exhibit Ko 2 might notexhibit HMG-CoA reductase inhibiting activity, and thus would understand that thedescription of "The active compounds of Working Examples 1 to 23 showed higher
activity compared to Mevinolin." of Working Example 24 of Exhibit Ko 2 wasincorrect.
56

(c) The compounds 2r to 2w of Exhibit Ko 16 lack "-NR4R5" for "R3."
Thus it cannot be said that there is a technical support for the case where "-NR4R5" isselected as "R3."(d)

Plaintiffs argue that "one can find technical support of HMG-CoA

reductase inhibiting activity for the compounds of general formula (I) of Exhibit Ko
2," since Exhibit Ko 16, and Ko 73 to Ko 75 disclosed before the priority date that "acompound with a very similar structure" to the compounds of Working Examples 8
and 23 of Exhibit Ko 2 had a HMG-CoA reductase inhibiting activity. However, it is
not permissible to argue as if the inhibiting activity of a compound with a different
structure might apply to the compound of Working Examples of Exhibit Ko 2 by useof ambiguous language such as "a compound with a very similar structure."(C)

European Patent Application No. 330057 (Exhibit Otsu 10)

corresponding to Exhibit Ko 2 had already been withdrawn before the priority date
(Exhibit Otsu 6); however, if Bayer intended to continue the development of thecompound disclosed in Exhibit Ko 2, Bayer could aim to obtain a patent for thisapplication as a matter of course.
Consequently, the fact of the withdrawal of the application shows that Bayerceased to develop the compound disclosed in Exhibit Ko 2; i.e., Bayer determined that
it was not promising for an HMG-CoA reductase inhibitor.
So long as such circumstances were known before the priority date, a person
ordinarily skilled in the art would naturally avoid a compound that Bayer determined
to be not promising. Also from this viewpoint, a person ordinarily skilled in the art
would not select the substituent group disclosed in Exhibit Ko 2.
(D) The trial decision mentioned that "the compound of formula I is 'prima
facie' expected to have an HMG-CoA reductase inhibiting activity." This descriptionmeans that, if a person ordinarily skilled in the art who reads Exhibit Ko 1 should
modify the Exhibit Ko 1 Invention, the candidate would fall within the scope of
formula I.

Similarly, if one selects a substituent group at the 2-position of thepyrimidine ring from Exhibit Ko 2, the candidate falls within the range of R3.
However, R3 extends to a large number of substituent groups.

In order to overcome

the difference (1-i), -NR4R5 (R4: methyl, R5: methylsulfonyl) should be selected from
them.
57

Exhibit Ko 2 lists a large number of functional groups for R3. To select thefunctional group making a difference (-NR4R5, R4: lower alkyl, R5: alkylsulfonyl) fromthese functional groups and combine with the Exhibit Ko 1 Invention, some suggestionor motivation of the combination is necessary.

Even if a person ordinarily skilled in

the art should try to increase hydrophilicity of the compound of the Exhibit Ko 1
Invention, a person ordinarily skilled in the art could not select the functional groupmaking the above difference only on the basis of the generalized property ofhydrophilicity.
There is no suggestion or motivation in Exhibit Ko 2 for a person ordinarily
skilled in the art to select particularly -NR4R5 from R3, and a functional group making
the above difference therefrom, and combine with Exhibit Ko 1 Invention.
(E) Therefore, there is no motivation to replace "dimethylamino group" ofthe Exhibit Ko 1 Invention with "-N(CH3)(SO2CH3)" on the basis of the description of
Exhibit Ko 2.
C

Motivation from the common general technical knowledge(A)a As in the following, there was no motivation to modify the Exhibit

Ko 1 Invention or increase hydrophilicity.
(a)Five companies who had started the research and development of astatin with a pyrimidine skeleton ceased by the priority date. Therefore, it was wellknown as of the priority date that a statin with a pyrimidine skeleton was not promising
for an HMG-CoA reductase inhibitor.
Therefore, a person ordinarily skilled in the art who tried to develop an
excellent HMG-CoA reductase inhibitor would not be motivated to modify the Exhibit
Ko 1 Invention of a statin with a pyrimidine skeleton.
(b)

The Invention and the Exhibit Ko 1 Invention both relate to apharmaceutical product to be administered for chronic diseases such as
hypercholesteremia and hyperlipidemia.

It was a matter of common general technicalknowledge as of the priority date that a dose period of the pharmaceutical product was
longer than that of other pharmaceutical products, and thus low toxicity was strongly
desired (Exhibit Otsu 20).
Therefore, if a person ordinarily skilled in the art should intend to modify thecompound of the Exhibit Ko 1 Invention, he would first confirm the toxicity as amatter of course.

If toxicity of the compound of the Exhibit Ko 1 Invention is found,58

he should stop the modification.
Further, the compound of the Exhibit Ko 1 Invention is omitted from thecandidates for development of Sandoz due to the problem of liver toxicity (Exhibit
Otsu 21). Therefore, a person ordinarily skilled in the art would not intend to develop
a new HMG-CoA reductase inhibitor by modifying the compound of the Exhibit Ko 1
Invention (Exhibit Otsu 4).
(c) As in the aforesaid A(C), it was known as of the priority date that liver
selectivity did not necessarily have a correlation with hydrophilicity, and it was wellknown that the hydrophilicity of statin did not have a correlation with HMG-CoA
reductase inhibiting activity. Therefore, a person ordinarily skilled in the art would
not conceive that excellent HMG-CoA reductase inhibiting activity may be achievedby improving the hydrophilicity of a statin.
b

Even if there were a motivation to improve hydrophilicity of an HMG-

CoA reductase inhibitor, there was no motivation to improve hydrophilicity with thefixed substituent group of methyl at the 2-position of the pyrimidine ring as set forth
below.
(a)Exhibit Ko 1 itself discloses that a compound with increasedhydrophilicity through the introduction of a substituent group other than pfluorophenyl at the 4-position of the pyrimidine ring was manufactured in Working
Example 11d as "a preferable compound," and its excellent inhibiting activity wasconfirmed.
A person ordinarily skilled in the art who intended to modify the compound of
the Exhibit Ko 1 Invention would always refer to the disclosure of Exhibit Ko 1, andthus would naturally try to introduce a hydrophilic substituent group at the 4-positionof the pyrimidine ring, not at the 2-position.
(b) There was no common general technical knowledge as of the priority
date that the introduction of a dihydroxyheptenoic acid structure at the 5-position, a pfluorophenyl group at the 4-position, and an isopropyl group at the 6-position in apyrimidine skeleton statin resulted in excellent HMG-CoA reductase inhibiting activity.
As of the priority date, there were numerous statins with different substituent
groups at the positions corresponding to the 4- and 6-positions of the pyrimidine ring,
including Pitavastatin, BMY21950, BMY22089, and HR780.
Exhibit Ko 1 and Ko 2 disclose a combination other than a combination of a59parafluorophenyl group at the 4-position and an isopropyl group at the 6-position as acompound with a pyrimidine ring skeleton that might have HMG-CoA reductase
inhibiting activity.
Two cases out of three cases where HMG-CoA reductase inhibiting activity
may be demonstrated in the compounds synthesized by the manufacture working
examples 1 to 23 of Exhibit Ko 2 have a methyl group at the 6-position, not an
isopropyl group (Working Examples 8 and 15).
Further, Exhibit Ko 26, Ko 27, and Ko 76 are not documents of a statincompound containing a pyrimidine ring. There is no description that, "regarding a pfluorophenyl group at the 4-position of the pyrimidine ring and an isopropyl group at
the 6-position of the pyrimidine ring," "these combinations have a strong activity."
Therefore, a person ordinarily skilled in the art would not necessarily fix a pfluorophenyl group at the 4-position and an isopropyl group at the 6-position inmodifying the compound of the Exhibit Ko 1 Invention, nor focus only on thesubstituent group at the 2-position of the pyrimidine ring.
If a person ordinarily skilled in the art tries to modify the Exhibit Ko 1
Invention with reference to Exhibit Ko 1, the range should fall within a range ofgeneral formula I of Exhibit Ko 1.
Exhibit Ko 1 describes a C1-6 alkyl, C1-6 cycloalkyl, (CH2)m-substituted or nonsubstituted phenyl, benzyloxy, benzylthio, and disubstituted amino group as substituent
groups at the 2-position of the pyrimidine ring in the compound of general formula I(Claim 1).

In Working Examples, in addition to a disubstituted amino group such as -N(CH3)2, there used were a phenyl (Working Examples 3 to 8), an isopropyl (Working
Examples 9, 11a and 10f), a tert-butyl group (Working Examples 10a, 11b, 11e, and11g), and a methyl (Working Examples 10b, 10e, 10h, 11c, 11f, and 11i) for a
substituent group at the 2-position.
Therefore, a person ordinarily skilled in the art who read Exhibit Ko 1 should
understand that the substituent group at the 2-position of the pyrimidine ring was notnecessarily fixed, but might be the above substituent group.
To change the Exhibit Ko 1 Invention into the Invention, it should undergo thefollowing steps: [i] Fix nitrogen atom binding to the 2-position of the pyrimidine ringand two methyl groups binding to the nitrogen atom of the Exhibit Ko 1 Invention; [ii]Fix one nitrogen-methyl group bond, insert the other functional group between anothernitrogen-methyl group bond; and [iii] Focus on NR4R5 suitable for the purpose of [ii]among R3 of Exhibit Ko 2 and further specify R5 as an alkylsulfonyl group. This
process may not be implemented without a priori recognition of the Invention.
60

Even if a person ordinarily skilled in the art should try to improvehydrophilicity, he could modify a methyl group (e.g. -CH2OH), or substitute a methylgroup with the other group. Thus there is no certainty to fix the methyl group.
In pyrimidine skeleton statins that a person ordinarily skilled in the art actually
manufactured and tested by the priority date, almost all the statins introduced alipophilic group at the 2-position (Exhibit Ko 1, Ko 2, Ko 80, Otsu 5, Otsu 28, andOtsu 29). Therefore, also from this viewpoint, there was no motivation to select the
2-position for the improvement of hydrophilicity.
c As set forth below, there was a disincentive to introduce a methylsulfonylgroup at the 2-position of pyrimidine ring as of the priority date (Exhibit Ko 80 and
Otsu 4).
(a) Exhibit Ko 16 discloses that a substituent group at the 2-position of thepyrimidine ring is the most important for biological activity such as HMG-CoA
reductase inhibiting activity, and furthermore the activity may be significantly
increased by rendering the substituent group at the same position lipophilic, and thesubstituent group at the same moiety may be assumed to become an additional anchor
by interacting with the hydrophobic region of an enzyme to strengthen the bonding,and the lipophilic substituent group specifically includes an alkyl group and a phenylgroup.
On the contrary, a person ordinarily skilled in the art would naturally expectthat the increased hydrophilicity of the substituent group at the 2-position would resultin the decrease of HMG-CoA reductase inhibiting activity.

Even if a person

ordinarily skilled in the art should try to increase hydrophilicity of the compound of the
Exhibit Ko 1 Invention, he would not try to introduce a highly hydrophilic substituent
group at the 2-position, which would compromise the most important factor of the
enzyme inhibiting activity for an HMG-CoA reductase inhibitor, but would naturally
introduce the substituent group at a position other than the 2-position.
Since hydrophilicity and lipophilicity are relative indicators, it was a matter ofcommon knowledge for a ordinarily person skilled in the art as of the priority date tounderstand that if "higher lipophilicity results in a significant increase of inhibiting
activity," then "the shift to hydrophilicity results in a significant decrease of activity."
In addition, Plaintiffs argue that the order of ClogP for various compounds of
Exhibit Ko 16 does not necessarily coincide with the order of relative (CSI) efficacy(HMG-CoA reductase inhibiting activity), but these compounds are not arranged at anequal interval for ClogP. When a number of compounds are distributed in a narrow61

range of ClogP, the order of relative (CSI) efficacy tends to be changed.

Therefore,

comparing the order of ClogP and the order of relative (CSI) efficacy, no accurate
findings may be obtained with respect to the correlation between ClogP and relative(CSI) efficacy.
(b) As of the priority date, a sulfonamide structure was an extremely rare
substituent group among statin-based compounds (Exhibit Otsu 18).

The onlycompound with a lactone structure specific to a statin-based compound or a free acidstructure thereof is compound No. 27 of Exhibit Ko 76 (Exhibit Otsu 17) in thefollowing drawing.

The biological activity of the compound is less than 10%

compared to a compound without a sulfonyl group (No. 26; R=tolyl group (4methylphenyl group)).

The introduction of a sulfonyl group into compound No. 26

resulted in a decrease of HMG-CoA reductase inhibiting activity to a factor of about
one-eleventh.

(R=4-tolylsulfonyl group)
Even if there was a motivation to improve hydrophilicity of the Exhibit Ko 1
Invention, a person ordinarily skilled in the art would naturally avoid the introductionof a methylsulfonyl group at the 2-position of the compound of the Exhibit Ko 1
Invention.
dExhibit Ko 16 recommends a bulky, lipophilic substituent group(including an alkyl group) for the substituent group at the 2-position of the pyrimidine
ring (R3 in Exhibit Ko 16), not a hydrophilic substituent group.
Therefore, a person ordinarily skilled in the art should focus on a lipophilicalkyl group, in particular, bulky groups such as isopropyl, tert-butyl, and phenyl,
although he would consider Exhibit Ko 16 in addition to Exhibit Ko 1 and Ko 2.
(B) Even if it is a common general technical knowledge to change thecompound by stages, in the modification of a lead compound, the research is62

conducted to replace a substituent group with another substituent group withsimilarities in size or electronic properties so as not to drastically change a size of thesubstituent group or electronic properties of the substituent group of the compound of
the Exhibit Ko 1 Invention (Exhibit Otsu 67). Therefore, the introduction of anelectron-withdrawing, high polarity group (Exhibit Ko 56) of a methylsulfonyl groupthat has a great impact on steric structure with electronic properties largely different
from those of a methyl group does not change the structure of compound by stages, nor
is it a modification that avoids changing a size of the substituent group.

There is no

motivation for a person ordinarily skilled in the art to select this. On the contrary, aperson ordinarily skilled in the art should avoid selecting the substituent group.
(C) The inhibiting activity of cholesterol biosynthesis (ED50) and HMGCoA reductase inhibiting activity (IC50) are not the same activity, but differ inmeasurement method.

Therefore, it cannot be said that HMG-CoA reductase

inhibiting activity would be 125 times that of Compactin even if the inhibiting activityof cholesterol biosynthesis were 125 times.
(D) Since inventive step and the support requirement are different patentrequirements, it cannot be a ground for rescission of the JPO decision that thedetermination criteria are different from each other.

Therefore, the argument by

Plaintiffs is incorrect on its premise.
(3) Errors in the determination of the effect of the Invention
A With regard to the invalidation reason 1 of the trial, the specific compoundof Working Example 1b) of Exhibit Ko 1 is the primarily cited invention (Exhibit Ko 1
Invention) (Exhibit Ko 79, Otsu 67 etc.), whereas the argument by Plaintiffs isintended to negate the inventive step of the more specific concept of Invention 1 with acriterion of selection invention on the premise that the above concept of the compoundof general formula (I) of Exhibit Ko 2 be a primarily cited invention.

This

corresponds to the substitution of the primarily cited invention.
The trial decision finds the Exhibit Ko 1 Invention to be the invention of a
specific compound in accordance with Plaintiff X's argument.

Therefore, no room isleft for argument about the selection invention in invalidation reason 1 argued by
Plaintiffs.
In the trial of the case, such argument is not presented.
trial examination as a matter of course.

It is not a subject of

It is not permitted for Plaintiffs to argue in63this manner in this lawsuit.
First of all, the compound of Exhibit Ko 1 Invention is not a selection inventionof general formula (I) of Exhibit Ko 2.
B(A)a(a)From the test results of HMG-CoA reductase inhibiting activity

described in Exhibit Ko 3 and Ko 5, four-times tests show that the compound of theInvention 1 of Rosuvastatin calcium has a two-time to nine-time higher activity
compared to the compound of the Exhibit Ko 1 Invention.
Therefore, it is recognized that there are at least two times or more ofsignificant difference in activity between Invention 1 and the Exhibit Ko 1 Invention
even in view of the test errors (Exhibit Ko 64, Otsu 4. 3.2 times for Exhibit Ko 64).
Given that the compound of Exhibit Ko 1 Invention is a standard for comparison, it has
a superior HMG-CoA reductase inhibiting activity compared to the compound of the
Exhibit Ko 1 Invention.
(b) The compound of the Exhibit Ko 1 Invention has high liver toxicity(Exhibit Otsu 21 to Otsu 27), whereas the compound of Invention 1 of Rosuvastatin
calcium has low toxicity (Exhibit Otsu 42).
It was a matter of common general technical knowledge as of the priority datethat higher liver selectivity might accordingly result in higher load on the liver, andmight possibly increase liver toxicity.

According to the argument by Plaintiffs,

Rosuvastatin calcium has a higher hydrophilicity compared to the compound of the
Exhibit Ko 1 Invention, and thus has high liver selectivity, and is thus expected to
impose a heavy load on the liver. Nevertheless, the liver toxicity of Rosuvastatin
calcium is much lower than that of the compound of the Exhibit Ko 1 Invention.
(c) Rosuvastatin calcium is expected to show a comparable effect with adose amount in a living body one-half or less that of the compound of the Exhibit Ko 1
Invention, and thus has a further broader range of safety dose.
Such excellent effect of low toxicity of Invention 1 is a particularly significant effectthat goes beyond the scope predictable from the Exhibit Ko 1 Invention in view of thestate of the art as of the priority date.
b

Further, it was known as of the priority date that the introduction of ahydrophilic substituent group at the 2-position of the pyrimidine ring of a statin or the
introduction of a sulfonamide structure into a statin resulted in a significant decrease of64

HMG-CoA reductase inhibiting activity (Exhibit Ko 16, Otsu 17).

Therefore, aperson ordinarily skilled in the art would expect that HMG-CoA reductase inhibiting
activity would be decreased if one methyl group of a dimethylamino group at the 2position of the pyrimidine ring of the Exhibit Ko 1 Invention should be substituted
with a more hydrophilic sulfonyl group to form a sulfonamide structure.
c Consequently, it cannot completely be expected from the Exhibit Ko 1
Invention or common general technical knowledge that Rosuvastatin calcium has an
inhibiting activity at least two times higher than that of the compound of the Exhibit
Ko 1 Invention.
(B)

The effect of the Invention may be evaluated by comparing withsodium Mevinolin that had been known as an HMG-CoA reductase inhibitor, once thedifficulty of the structure should be affirmed. What is used for a positive control is acompound whose effectiveness has already been confirmed.

If it is not inferior to thepositive control, the effectiveness of the test compound may be demonstrated. This isa matter of common general technical knowledge for a person ordinarily skilled in theart.

It does not necessarily have a higher HMG-CoA reductase inhibiting activity

compared to the Exhibit Ko 1 Invention, nor is the compound of the Exhibit Ko 1
Invention the only comparative control.
(C) HMG-CoA reductase inhibiting activity is a property different fromcell permeability. Even if increasing the hydrophilicity of compound may result in
the decrease of permeability into non-hepatic cells (and as a result, increase theselectivity of liver cell with regard to permeability), the effect on HMG-CoA reductase
inhibiting activity is not predictable.
For the purpose of increasing hydrophilicity of a compound, various substituent
groups may be used.

In addition, a person ordinarily skilled in the art may find many

parts to be substituted with another group for the purpose of increasing thehydrophilicity of a compound in the compound.

Therefore, there are many

alternatives to increase hydrophilicity. When the 2-position of the pyrimidine ring of
the Exhibit Ko 1 Invention among the alternatives was substituted with N(CH3)(SO2CH3), the HMG-CoA reductase inhibiting activity was improved, which
was unexpected.
Consequently, if the compound of Invention 1 should have an inhibiting activity
comparable to the Exhibit Ko 1 Invention, it is just a particularly significant effect that65

goes beyond the scope predictable from the Exhibit Ko 1 Invention in view of the stateof the art as of the priority date. Even only with this fact, the inventive step would be
affirmed.
A compound with an HMG-CoA reductase inhibiting activity comparable tothat of the conventional HMG-CoA reductase inhibitors may contribute to theimprovement of the industry from a viewpoint of increasing the alternatives of new
HMG-CoA reductase inhibitors.
(D) Rosuvastatin calcium of the compound according to Invention 1 has avery strong HMG-CoA reductase inhibiting activity compared to the existing HMGCoA reductase inhibitors (Fluvastatin, Simvastatin, Pravastatin, Cerivastatin, andAtorvastatin) (Exhibit Otsu 34 to Otsu 36).
Rosuvastatin calcium realizes a lower level of LDL-C (Low Density
Lipoprotein Cholesterol) in a wide range of doses as compared to the other approved
statins (specifically, Atorvastatin, Simvastatin, and Pravastatin).
Furthermore, the existing statin-based HMG-CoA reductase inhibitors could notcontrol LDL-C to a targeted value for many patients (in particular high-risk patients)(Exhibit Hei 10). Rosuvastatin calcium provided great therapeutic effects for thesepatients.
As seen above, the HMG-CoA reductase inhibiting activity of Rosuvastatin
calcium has a clinically significantly important value.
This is also a particularly significant effect that goes beyond the scope expectedfrom the Exhibit Ko 1 Invention in view of the state of the art as of the priority date.
C(A) Rat liver microsome method was commonly used as of the priority dateas the standard method to measure in vitro inhibiting activity of HMG-CoA reductase
inhibitors (Exhibit Ko 1, Ko 2, Ko 7, Ko 8, Ko 15, Ko 16, Ko 19, Ko 26, Ko 27, andKo 64). Even if absolute value of activity of the test compound might sometimes
vary between different measurement trials, it was common general technicalknowledge as of the priority date that this method allowed us to clearly show a relative
relationship of inhibiting activity between test compounds in the same measurement
trial.
Further, it was common general technical knowledge as of the priority date that,when the HMG-CoA reductase inhibiting activity is measured by rat liver microsome
method, IC50 was used as an indicator of "inhibiting activity" (Exhibit Ko 1, Ko 2, Ko
7, Ko 8, Ko 15, Ko 16, Ko 19, Ko 26, and Ko 27).
66

The description details an experimental method by use of liver microsome
fraction ([0040], [0041]). A person ordinarily skilled in the art would thus naturally
understand that "IC50" was an indicator of "inhibiting activity," and the numericalvalues of Table 4 showed a relative activity of each compound, given that the
inhibiting activity of Mevinolin assessed by IC 50 is 100, from the description inparagraph [0041] of "The activities of the compounds of the Invention are shown in
Table 4 as comparative data, based on the assumption that the activity of Mevinolin(sodium salt) as the reference drug is 100."(B) Table 4 discloses that the inhibiting activity of the test compound Ia-1
(sodium salt of the compound according to the Invention 1) was "442," given that the
inhibiting activity of sodium salt of Mevinolin is "100."

Therefore, a person

ordinarily skilled in the art would instantly recognize that Mevinolin sodium salt andtest compound Ia-1 were measured under the same conditions, and a result of theinhibiting activity of the test compound Ia-1 being higher than that of Mevinolin
sodium salt was obtained.
Further, Table 4 describes at the bottom that "As seen above, it is believed thatparticularly the compounds of the present invention exhibit HMG-CoA reductase
inhibition activities superior to that of Mevinolin." ([0042]). A person ordinarily
skilled in the art could recognize from this description that the result of Table 4
exhibits a stronger HMG-CoA reductase inhibiting activity of the test compound Ia-1
as compared to Mevinolin.
Therefore, a person ordinarily skilled in the art could understand the meaning of
the numerical values of Table 4, and deduce from the result that the compound of theInvention 1 had a higher HMG-CoA reductase inhibiting activity compared to sodium
Mevinolin.
D(A)It is evident from the result of Exhibit Ko 3 that the compound of

Invention 1 has a higher HMG-CoA reductase inhibiting activity as compared tosodium Mevinolin.
Exhibit Ko 3 describes an experimental result of HMG-CoA reductase
inhibiting activity conducted after the filing.

In Exhibit Ko 3, the compound of theInvention 1 had a HMG-CoA reductase inhibiting activity about two times higher thanthat of the compound of the Exhibit Ko 1 Invention.
The activity is objectively determined without relation to the prosecution
history.

The description describes the relative activity of sodium Rosuvastatin
67

(Sodium Mevinolin is a standard for comparison) as well as the assessment method.
It is naturally acceptable to make an additional comparison with a publicly known
compound other than sodium Mevinolin by a method for assessment similar to thatcited in the description.
(B) The Patentee has never argued in the examination process that "about 2times" is not a significant effect.

The Exhibit Ko 2 Invention was not cited as areference in the notice of reasons of refusal (Exhibit Ko 71). Therefore, the Patentee
did not have to argue in the written opinion about the effect as a selection invention inorder to establish the inventive step over the Exhibit Ko 2 Invention.
Therefore, the argument by Plaintiffs that "the standard for comparison of
Invention 1 is the Exhibit Ko 1 Invention, and Invention 1 cannot be seen as having
significant effects unless the Invention is about 9 times stronger in HMG-CoA
reductase inhibiting activity" is incorrect on its premise.
E(A) The compound according to Invention 1 of Rosuvastatin calcium has avery strong inhibiting activity of cholesterols biosynthesis as compared to the existing
HMG-CoA reductase inhibitors and also has a long sustained time of synthesis
inhibitory effect (Exhibit Otsu 34 to Otsu 36).
Rosuvastatin calcium has strong effects of increasing HDL cholesterol anddecreasing triglycerides, and exhibits excellent improvement on clinical state ofatherosclerosis, and is thus clinically superior to the other statin-based HMG-CoA
reductase inhibitors (Exhibit Otsu 35 to Otsu 41).
(B)

Both the Invention and the Exhibit Ko 1 Invention have a longer

administration period than the other pharmaceutical products, and thus a poor result ofpharmacokinetics makes their clinical use difficult.
Rosuvastatin calcium provided extremely excellent results compared to thecompound of Exhibit Ko 1 Invention in the non-clinical Pharmacokinetic Studies forthe assessment of disposition (Exhibit Otsu 45 and Otsu 46).
a

Cytochrome P450 (CYP) enzyme is composed of various molecularspecies that differ in substrate specificity, and was well known as a primary drug
metabolic enzyme as of the priority date (Exhibit Otsu 47).
The inhibition of the activity of any CYP molecular species by one drug resultsin the delayed metabolism of other drug(s) that may become a substrate of the CYP
68

molecular species (i.e. decomposition by the CYP molecular species).

Therefore, it

was a matter of common general technical knowledge as of the priority date that a drugwith a low inhibiting activity against various CYP molecular species was desirable.
Defendant measured the inhibiting activity for Rosuvastatin calcium and thecompound of the Exhibit Ko 1 Invention against various CYP enzymes that were wellknown as of the priority date. Thus the compound of the Exhibit Ko 1 Invention
showed a very strong CYP2C9 inhibiting activity as compared to Rosuvastatin calcium(Exhibit Otsu 45).
b

It is confirmed by a comparative test that Rosuvastatin calcium has avery high level of metabolic stability as compared to the compound of the Exhibit Ko 1
Invention (Exhibit Otsu 46).
The stability against oxidative metabolism of Rosuvastatin calcium and thecompound of Exhibit Ko 1 Invention was measured in human liver cells microsome.
The results show that the stability of Rosuvastatin calcium is very high (100%), andthe kinetic profiles (in particular sustainability) in human are expected to be good.
On the contrary, the compound of the Exhibit Ko 1 Invention has a fairly low
stability (69%), and the kinetic profiles (in particular sustainability) are expected to bepoor, which poses a problem in maintaining the effective blood level important forpharmaceutical products.

A person ordinarily skilled in the art would conceive thatthe compound of the Exhibit Ko 1 Invention has a great barrier in proceeding with
development (Exhibit Otsu 46).
F As aforementioned, the compound according to Invention 1 of Rosuvastatincompound causes excellent HMG-CoA reductase inhibiting activity unexpected fromthe Exhibit Ko 1 Invention or the common general technical knowledge, and exhibitshigh inhibiting activity of cholesterol synthesis as well as excellent clinical effects.
Furthermore, the compound according to Invention 1 of Rosuvastatincompound has low liver toxicity and excellent pharmacokinetics compared to thecompound of the Exhibit Ko 1 Invention. Such effects are particularly significant
effects that go beyond the scope predictable from the Exhibit Ko 1 Invention in viewof the state of art as of the priority date.
It is very difficult to develop a drug for the treatment of hypercholesterolemiawith an effective and low toxic pyrimidine skeleton statin (Exhibit Otsu 48 to Otsu 50).
Further, the other pharmaceutical companies did not regard pyrimidine skeleton statins
as promising.

Regardless of these factors, Rosuvastatin calcium according to69

Invention 1 has achieved worldwide revenue as a drug for the treatment ofhypercholesterolemia (Exhibit Otsu 51 to Otsu 55), and the other pharmaceuticalcompanies are developing analogous compounds (Exhibit Otsu 48). Furthermore, in
two lawsuits in the United States, the inventive step of the invention similar toInvention 1 has been affirmed (Exhibit Otsu 8 and Otsu 9).
These facts support the inventive step of Invention 1.
2 Ground 2 for rescission(1)

In the test example of the specification, the evaluation result of HMG-CoA

reductase inhibiting activity by use of liver microsome is described for sodium salt of
Rosuvastatin, and for sodium salt of Mevinolin as a comparative control.
The compound of formula (I) of Invention 1 corresponds to a statin.

Statinshave common features of dihydroxyheptenoic acid (or dihydroxyheptanoic acid) or aderivative thereof ("HMG-like moiety") and a skeleton binding to the HMG-likemoiety.

In an active type circulating plasma, HMG-like moiety is in the form ofopened-ring dihydroxyheptanoic acid (or dihydroxyheptenoic acid) (Exhibit Ko 7 andKo 8).
When a statin compound is administered to a human body, the compound is
dissolved into aqueous media in the body. For example, when a statin compound isorally administered, the compound is dissolved into a gastrointestinal fluid.

In thedissolution process, the statin compound forms a cation (e.g. sodium cation andcalcium cation) and an anion (e.g. Rosuvastatin anion) according to the original
structure. Once a statin compound is dissolved, a statin anion freely interacts with theother ions present in a gastrointestinal fluid. Gastrointestinal fluid includes a numberof ions, such as hydrogen, sodium, potassium, and magnesium cations.

Therefore,

Rosuvastatin anion may associate with all these cations to be liberated.

Afterdissolution into gastrointestinal fluid, Rosuvastatin anion penetrates into the blood
system by passing through the intestinal tract.

In the blood system, Rosuvastatinanion may associate with all the cations (sodium is domestic) in the blood system to beliberated.
As aforementioned, it is no longer possible to find what kind of salt
Rosuvastatin anion was derived from (Exhibit Hei 13).
Therefore, the recitation of the scope of claims is supported by the test
examples of the description.
(2) Problem to be solved by the Invention
70

A(A)

An active ingredient of a pharmaceutical product requires

pharmacological activity to the extent that it may become a pharmaceutical product.
Even if the pharmacological activity of a new active ingredient is at the same level asthat of an active ingredient that has been commercially available, the new active
ingredient has a technical value in that it provides an alternative means for solution.
For example, if two active ingredients show a similar level of pharmacologicalactivity, this might cause a difference between patient groups to be administered fromanother viewpoint (e.g. difference in pharmacokinetics and adverse events).

In thiscase, two active ingredients both have technical value.
Therefore, a pharmacological activity beyond that of all the conventional active
ingredients is not required as a problem of the support requirement.
(B)

If the argument by Plaintiffs is correct, the inventor is obliged to

conduct comparative tests with any and all of the publicly known compounds for theclaimed compounds of an invention and establish its superior activity compared to the
publicly known compounds.

Such conclusion is not reasonable.

B(A) The compounds of Inventions 1, 2, 5, and 9 to 11 are encompassed into
the compound represented by the general formula (I) described in paragraph [0004] ofthe description. Therefore, the problem to be solved by Inventions 1, 2, 5, and 9 to 11
lies in the provision of a compound having an excellent HMG-CoA reductase
inhibiting activity, and the problem to be solved by Invention 12 lies in the provisionof an HMG-CoA reductase inhibitor including such a compound.

This can be seenfrom the description in paragraphs [0003] and [0004] of the description.
Further, it can be seen from the description of paragraph [0003] that the degreeof the HMG-CoA reductase inhibiting activity is sufficient if it is the extent that thecompound may become a pharmaceutical product "for suppressing the synthesis ofcholesterols."
Consequently, the objective of the Invention is to provide an excellent HMGCoA reductase inhibiting compound, or an HMG-CoA reductase inhibitor comprising
the compound.

The sufficiency of the support requirement should be determined bywhether the compounds of Inventions 1, 2, 5, and 9 to 11 may be obtained (may be
manufactured) and whether the Detailed Description of the Invention is described tothe extent that allows a person ordinarily skilled in the art to recognize that theobtained compound has an excellent HMG-CoA reductase inhibiting activity.

71

(B)

Setting aside this point, Mevinolin is a representative statin-based

HMG-CoA reductase inhibitor that was commercially available as of the priority date,and it was a common general technical knowledge as of the priority date to use
Mevinolin as a comparative control for the activity assessment of a new statin-based
HMG-CoA reductase inhibitor (Exhibit Ko 1, Ko 2, Ko 7, Ko 15, Ko 19, Ko 27, etc.).
(C) The argument by Plaintiffs relying on Exhibit Ko 16 compares anabsolute value of HMG-CoA reductase inhibiting activity IC50 obtained in different
experimental systems via Mevinolin, and is thus not reasonable.
Further, in vivo cholesterol biosynthesis inhibiting activity and in vitro HMGCoA reductase inhibiting activity are not the same activity, and the measurement
method is different.

The argument by Plaintiffs tries to apply an activity ratio

obtained with respect to one activity to a different activity, and is thus not reasonable.
C

The problem to be solved by the invention should be formulated on thebasis of the content of the description in view of the common general technicalknowledge as of the filing, and the prosecution history should not be considered.
Thus it is not affected by the subjective view of the patent applicant.
(3) The fact that a person ordinarily skilled in the art could recognize that the
problem to be solved by Invention 1 might be solved
A The description discloses in paragraphs [0040] to [0042] that the compoundof (Ia-1), a sodium salt of Rosuvastatin calcium according to Invention 1, has a HMGCoA reductase inhibiting effect of a relative activity of 442 with the inhibiting activityof sodium Mevinolin given as 100. A person ordinarily skilled in the art could
recognize that the compound Ia-1 (sodium salt) shows a similar activity to its calcium
salt in a living body.

Therefore, the specification discloses that Invention 1 has astrong HMG-CoA reductase inhibiting activity as compared to sodium Mevinolin.
Furthermore, Exhibit Ko 3 actually shows that its calcium salt of Rosuvastatin
calcium has a higher HMG-CoA reductase inhibiting activity as compared to sodium
Mevinolin, which supports that the above deduction is correct.
B Defendant definitely argues in the written statement dated March 24, 2016
for trial that Invention 1 is supported by data of compound Ia-1 of the specification(Exhibit Otsu 69).
First of all, the prosecution history should not be considered in considering72

"whether or not the inventions recited in the Claims might fall within the scope, inwhich a person ordinarily skilled in the art could recognize that the object of theinvention might be solved by the description of the Detailed Description of theInvention, or in view of common general technical knowledge as of the filing without
such description or suggestion." Therefore, it is not affected by the subjective viewof the Patentee (Exhibit Otsu 62).
(4) A person ordinarily skilled in the art could understand that the overall
range of compounds of Invention 1 have a higher HMG-CoA reductase inhibiting
activity compared to sodium MevinolinA

In the trial, the argument about the noncompliance of support requirement(invalidation reason 2) only focuses on the point that the calcium salt of compound Ia1 of the specification is not supported among the compounds of Invention 1.
Therefore, it is not permitted to add in the suit against trial decision a new argument to
the effect that the overall range of the compound of Invention 1 is not supported.
B Compounds 2r and 2s of Exhibit Ko 16 are different from compounds 2t, 2u,
2v, and 2w not only in a substituent group at the 6-position of the pyrimidine ring(corresponding to R1 of Exhibit Ko 16), but also in a substituent group at the 2-position(corresponding to R3 of Exhibit Ko 16). Therefore, the argument by Plaintiffs thatemphasizes only the difference in a substituent group at the 6-position is notreasonable.
Rosuvastatin has achieved improved HMG-CoA reductase inhibiting activity by
the modification of a substituent group at the 2-position of the pyrimidine ring (-XR1;
R1 is methyl, X is -N(SO2CH3)-) in the case of R2 being parafluorophenyl and R3 being
isopropyl in formula (I).
The following formula (I):(R1 is a lower alkyl; R2 is a phenyl substituted with a halogen; R3 is a lower alkyl; thedashed line represents the presence or absence of a double bond.)
The improved HMG-CoA reductase inhibiting activity due to the modificationof this substituent group at the 2-position may be reasonably expected not only in73

Rosuvastatin but also in the other compounds within the above limited scopes of R2
and R3.
Therefore, Invention 1 falls within such a scope that allows a person ordinarily
skilled in the art to recognize that the objective of the invention may be solved in viewof the specification and the common general technical knowledge.
Accordingly, a person ordinarily skilled in the art could understand that thecompound of Invention 1 might become a compound showing a comparable HMGCoA reductase inhibiting activity from the disclosure of the specification thatcompound Ia-1 had a higher HMG-CoA reductase inhibiting activity compared tosodium Mevinolin.
(5) As seen above, the Invention conforms to the support requirement.
Further, the argument of ground 2(3) for rescission with respect to Invention 1
presented by Plaintiffs may not apply to Inventions 2 and 11.
No. 7

Judgment of this court

1 Defense prior to the pleading on the merits(1)A The request for trial was made on March 31, 2015, and thus the Patent
Act as of that date (the Patent Act prior to amendment by Act No.36 of 2014) shall beapplied to the request for trial.

Article 123, paragraph (2) of the Patent Act at thattime specified that "a trial for invalidation of a patent may be demanded by anyone(hereinafter omitted)," which means the permission of trial for invalidation of a patent
regardless of the presence or absence of proprietary interest.

(Additionally, there is aseparate provision with regard to a misappropriated application or violation of joint
application, but it has nothing to do with this case. Thus no reference is made to thisprovision.

This can apply to the following determination.)

The spirit of such provision is construed such that a patent right is an exclusive
right, which prohibits the use of technique according to a patent by anyone without
permission of the patentee, and it is an action that becomes beneficial for all the people
and it serves the public interest to invalidate an erroneously registered patent, and inview of such nature, a person entitled to demand for invalidation trial of the patent is
not limited to a private proprietary interests, but extends to the public.
Further, the trial for invalidation of a patent may be demanded even after the
expiration of the life of a patent (Article 123, paragraph (3) of the Patent Act).
Therefore, even if the life of a patent is expired, it is obvious that an interest to make arequest for an invalidation trial, and thus a legal interest for litigation to rescind a trial
74decision that dismissed the request for an invalidation trial, would not diminish.
B Regarding a suit for rescission of a trial decision that dismissed the request
for an invalidation trial after the expiration of a life of a patent, Defendant cites a
Tokyo High Court judgment made on December 26, 1990 and argues that a legal
interest for litigation is affirmed only in the case where there is any substantial legal
disadvantage for demandant of the trial due to the existence of the patent right.
However, if the case where a legal interest for litigation to rescind a trial
decision that dismissed the request for an invalidation trial of a patent is affirmed after
the termination of the patent right is limited to: the case where there is a dispute
between the patentee and the demandant for trial such as a claim for compensation fordamage that poses a problem as to whether the patent is valid or invalid, or there is any
factual relationship that might possibly become a cause developing such dispute in the
future even after the expiration of a life of a patent, and there is any substantial legal
disadvantage for the demandant of the trial due to the existence of the patent right, alegal interest for litigation is an ex officio search matter, and thus a court should searchand determine the presence or the absence of dispute that poses a problem as towhether the patent is valid or invalid, or the presence or the absence of a factual
relationship that might possibly become a cause developing such dispute in the futureeven after the expiration of the life of the patent. Further, for such a goal, a court
should request parties concerned to argue about the existence of an actual dispute as towhether or not a product manufactured by himself might be an infringing product of a
specific patent, or the existence of a factual relationship that might possibly become acause developing such dispute in the future. Such argument may include an argumentof a fact that might possibly be harmful to himself, including a fact that a productmanufactured by himself might have a structure that might be evaluated as an worked
product of the patent invention.
It is not reasonable to oblige a party concerned to argue such fact.
C

Indeed, if there are special circumstances where the complete loss of

possibility of anyone being subjected to a claim for damages or gaining unjust
enrichment from, or being imposed criminal penalties for, conduct within the lifetimeof patent right and after the expiration of patent right, e.g. the case where 20 years has
already passed after the expiration of the life of a patent, it means that no one runs arisk of suffering disadvantage from the existence of the patent right any longer, andthus it is meaningless to invalidate the patent.
75

Therefore, in such case, it is construed that a legal interest for litigation torescind a trial decision that dismissed the request for an invalidation trial would also
diminish.
D Based on the above fact, under the Patent Act prior to amendment by Act
No.36 of 2014, the legal interest for litigation against a trial decision that dismissed arequest for an invalidation trial would not be lost in the absence of special
circumstances such as the complete loss of possibility of anyone being subjected to aclaim for damages or gaining unjust enrichment from, or being imposed criminal
penalties for, conduct within the lifetime of patent right even after the expiration ofpatent right.
E Taking this case into consideration in view of the above fact, there are no
special circumstances in this case as described above. Therefore, the legal interest for
litigation has not yet been lost.
(2) Further, pursuant to the amendment by Act No.36 of 2014, those who canmake a request for an invalidation trial have been limited to only an "interested
person," and a patent opposition system that can be made by "anyone" has been
introduced instead. Taking this into account, it can't help but construe that a person
who is entitled to make a request for an invalidation trial has been currently limited toonly a person who has a private proprietary interest with regard to invalidating thepatent.
However, as long as there is the slightest possibility that a patent infringement
issue may be raised, a person who might possibly get involved with such a problem
obviously has a private proprietary interest to invalidate the patent, as well as aninterest to make a request for an invalidation trial (therefore, a legal interest for
litigation to rescind a trial decision that dismissed the request for an invalidation trial).
Therefore, in order to establish the fact that a legal interest for litigation has diminished,
it is construed as necessary to find that the possibility of questioning patent right
infringement against Plaintiff has been objectively completely lost, and find special
circumstances such as the complete loss of possibility of Plaintiff being subjected to aclaim for damages or unjust enrichment from, or being imposed criminal penalties for,
conduct within the lifetime of patent right and after the expiration of patent right.
2 The Invention76

(1) The Invention is set out as in the foregoing No. 2, item 2. The Detailed
Description of the Invention of the description (Exhibit Ko 81) has the following
description:
A

Industrially applicable field[0001]The present invention relates to 3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) reductase inhibitors. More specifically, the invention is effective for thetreatment of hypercholesteremia, hyperlipoproteinemia, and further atherosclerosis byspecifically inhibiting HMG-CoA reductase, a rate-limiting enzyme of cholesterol
biosynthesis, to thereby suppress the synthesis of cholesterols.
B Background Art[0002]
Hypercholesteremia is a severe risk factor of atherosclerosis, a frequently foundcardiovascular disease.

Therefore, for the development of novel drug for thetreatment of atherosclerosis, it is necessary to investigate the effects on the activity of
HMG-CoA reductase, which is a key enzyme for cholesterol synthesis that catalyzes
the synthesis of mevalonic acid from 3-hydroxy-3-methyl glutaryl CoA. For suchdrugs, there are known the first generation HMG-CoA reductase inhibitors, including
mevinolin (...), pravastatin (...), and simvastatin (...), which are fungal metabolites orpartially modified derivatives thereof.

In contrast, recently, synthetic inhibitors of

HMG-CoA reductase such as fluvastatin (...) and BMY 22089 (...) have beendeveloped and are expected as the second generation drugs.
C

Problem to be solved by the invention[0003]As seen above, the suppression of cholesterol production is essential for theprevention and treatment of atherosclerosis. Taking this into consideration, there is
still a need for the development of useful pharmaceutical products.
D Means for solving the problem[0004]The inventors have investigated in view of the aforesaid situation, and foundthat the compound represented by the following general formula has an excellent
HMG-CoA reductase inhibiting activity, to thereby complete the present invention.
Specifically, the present invention relates to an HMG-CoA reductase inhibitor
77

represented by the formula (I):[Formula 9](wherein R1 is a lower alkyl, an aryl, or an aralkyl, each of which may have one ormore substituents; each of R2 and R3 is independently hydrogen, a lower alkyl, or anaryl, and each of said alkyl and aryl may have one or more substituents; R4 is hydrogen,a lower alkyl, or a cation capable of forming a non-toxic pharmaceutically acceptable
salt; X is sulfur, oxygen, or sulfonyl group, or imino group which may have asubstituent; the dashed line represents the presence or absence of a double bond), or
the corresponding ring-closed lactone body.
E Working Examples[0029]
Working Example 1
sodium(+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-

methylsulfonylaminopyrimidin)-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenate (Ia-1)...
[0033](5)...

methyl7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-

methylsulfonylamino)pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenate (Ib-1) was
obtained as 11.4 g of sugar paste (yield: 85.2%).
[Formula 21]...
78

[0034](6) To a solution of 11.4 g of the compound (Ib-1) in 160 ml of ethanol, 223
ml of 0.1 N sodium hydroxide was added under ice-cooling. The reaction mixture
was gradually warmed to room temperature and stirred for 1 hour. The solvent was
distilled off under reduced pressure, and ether was added to the resulting residue andthe mixture stirred to give 11.0 g (yield: 95.0%) of the objective compound (Ia-1) as
powdery crystals.
[Formula 22]...
[0039]
Working Example 8
Method of synthesizing calcium salt of compound (Ia-1)
Compound (Ia-1) (sodium salt) 1.50 g (3.00 mmol) was dissolved in 15 ml ofwater and stirred at room temperature under a nitrogen atmosphere. Successively
3.00 ml of 1 mol/L calcium chloride aqueous solution (3.00 mmol) was added
dropwise thereto over 3 minutes.

The reaction mixture was stirred at the same

temperature for 2 hours, and the resulting precipitate was collected, washed with water,and dried to give 1.32 g of calcium salt as powder. This compound started to melt at
a temperature of 155°C, but the definitive melting point is ambiguous.
...
[0040]
Biological activity assay[Test example]
HMG-CoA reductase inhibiting effect(1) Production method of rat liver microsome
Sprague-Dawley rats, which were given ordinary diets containing 2%cholestyramine and water for 2 weeks ad libitum, were used for the preparation of rat
liver microsomes. The thus obtained microsomes were then purified according to themanner described by Kuroda et al., Biochim. Biophys. Acta, 486, 70 (1977). The
microsomal fraction obtained by centrifugation at 105000 × g was washed once with a79

solution containing 15 mM nicotinamide and 2 mM magnesium chloride (in a 100 mM
potassium phosphate buffer, pH 7.4). The fraction was homogenized with a buffer
containing nicotinamide and magnesium chloride at the same weight as the liver
employed. The thus obtained homogenate was cooled down and kept at -80°C.
[0041](2) Measurement method of HMG-CoA reductase inhibiting activity
The rat liver microsome sample (100 µl), which was preserved at -80°C, wasfused at 0°C and diluted with 0.7 ml of a cold potassium phosphate buffer (100 mM,
pH7.4). This was mixed with 0.8 ml of 50 mM EDTA solution (buffered with theaforementioned potassium phosphate buffer) and 0.4 ml of 100 mM dithiothreitol
solution (buffered with the aforementioned potassium phosphate buffer), and the
mixture was kept at 0°C. The microsome solution (1.675 ml) was mixed with 670 μlof 25 mM NADPH solution (buffered with the aforementioned potassium phosphatebuffer), and the solution was added to 670 μl solution of 0.5 mM [3-14C]HMG-CoA (3mCi/mmol). A solution (5 μl) of sodium salt of the test compound dissolved inpotassium phosphate buffer was added to 45 μl of the mixture of the microsome and
HMG-CoA. The resulting mixture was incubated at 37°C for 30 minutes and cooled.
After termination of the reaction by addition of 10 μl of 2N-HCl, the mixture wasincubated again at 37°C for 15 minutes.

30 μl of this mixture was applied to thin-layer chromatography on silica gel of 0.5 mm in thickness (manufactured by Merck,
Merck AG, trade name: Art 5744).

Chromatograms were developed intoluene/acetone (1/1) and the spot, whose Rf value was between 0.45 to 0.60, wasscraped. The obtained products were put into a vial containing 10 ml of scintillator tomeasure specific radio-activity with a scintillation counter.

The activities of thecompounds of the Invention are shown in Table 4 as comparative data, based on theassumption that the inhibiting activity of Mevinolin (sodium salt) as the reference drug
is 100.
[0042]
Table 4
Tested compound

Relative activity

Ia-1

442

Ia-3

385

Ia-5

279

80

Ia-7

260

Mevinolin Na

100

As seen above, it is believed that the compounds of the Invention are
particularly effective drugs that exhibit HMG-CoA reductase inhibiting activities
superior to that of Mevinolin.
(2)

According to the recitation of the scope of claims of the Patent (theaforesaid No. 2, item 2) and the content of the description of the aforesaid item (1), theInvention is recognized as follows:
The Invention relates to a 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitor effective for the treatment of hypercholesteremia,
hyperlipoproteinemia, and furthermore atherosclerosis by specifically inhibiting HMGCoA reductase, a rate-limiting enzyme of cholesterol biosynthesis to suppress thesynthesis of cholesterols ([Claim 12], [0001]).
Mevinolin, Pravastatin, and Simvastatin obtained from fungal metabolites orpartially modified derivatives thereof are known as first-generation HMG-CoA
reductase inhibitors. Further, recently, synthesized HMG-CoA reductase inhibitors
such as fluvastatin and BMY22089 have been developed and are expected as secondgeneration HMG-CoA reductase inhibitors ([0002]). The suppression of cholesterol
production is essential for the prevention and treatment of atherosclerosis.

Takingthis into consideration, there is still a need for the development of usefulpharmaceutical products ([0003]).
The Inventors have found that the compound represented by the following
formula (I):(whereR1 is a lower alkyl;
R2 is a phenyl substituted with halogen;81

R3 is a lower alkyl;
R4 is hydrogen or a calcium ion forming hemicalcium salt;
X is an imino group substituted with a alkylsulfonyl group;
the dashed line represents the presence or absence of a double bond)or its ring-closed lactone body has an excellent HMG-CoA reductase inhibiting
activity, and have completed the Invention ([Claim 1], [0004]).
Further, the compound (Ia -1) ([0029], [0034]), which was a "sodium salt" of"(+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-Nmethylsulfonylaminopyrimidin)-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenoic

acid"([Claim 2]) encompassed into the Invention, was subjected to the measurement of
HMG-CoA reductase inhibiting effect with the measurement method by use of rat liver
microsome fraction ([0040], [0041]).

It had a relative activity of 442, with the

inhibiting activity of sodium salt of Mevinolin given as 100. Therefore, it is believedthat the compound of the Invention is an effective drug that exhibits HMG-CoA
reductase inhibiting activities superior to that of Mevinolin ([0042]).
3 Ground 1 for rescission(1) Determination of inventive step
Article 29, paragraph (1) of the Patent Act specifies that "An inventor of an
invention that is industrially applicable may be entitled to obtain a patent for said
invention, except for the following cases." and as the case of item (iii), it specifies"inventions that were described in a distributed publication" "in Japan or a foreigncountry prior to the filing of the patent application."

Article 29, paragraph (2)specifies that an invention easily conceivable before the filing of the invention by aperson ordinarily skilled in the art on the basis of an invention provided in each item of
Article 29, paragraph (1) should not be granted a patent, which specifies that aninvention not involving inventive step cannot be granted a patent.
The above inventive step requirement is established by finding an invention
according to patent application (hereinafter referred to as "the present invention") on
the basis of the scope of claims, comparing the invention with a certain invention
provided in each item of Article 29, paragraph (1) of the Patent Act, finding a common
feature and a difference, and if there is a difference, determining whether a person
ordinarily skilled in the art could easily conceive of the present invention
corresponding to the difference on the basis of the state of the art as of the filing (orpriority) date. The same shall apply to "3 Ground 1 for rescission."In the determination of such inventive step, a certain invention provided in each82

item of Article 29, paragraph (1) of the Patent Act to be compared with the present
invention (hereinafter referred to as "the primarily cited invention," and referred to as"cited invention" together with the following "auxiliary cited invention") is usually
selected from the inventions that are relevant to the present invention in their technicalfield and falling within a range where a person ordinarily skilled in the art in thetechnical field targets for consideration.

In particular, "an invention described in a

Publication" of Article 29, paragraph (1), item (iii), should be a basis for thedetermination of whether a person ordinarily skilled in the art could easily conceive of
the present invention on the basis of the state of the art as of the filing.

Therefore, it

must be a specific technical concept to be extracted from the description of a
Publication. Further, if a compound is described in a form of a general formula in a
publication and the general formula has an enormous number of alternatives, a person
ordinarily skilled in the art fails to extract a specific technical concept according to a
specific alternative from the description of the publication in the absence of
circumstances where the specific technical concept according to the specific alternative
should be positively or preferentially selected.
Therefore, it is reasonable to find that, if an invention as allegedly claimed to bea cited invention is the "invention described in a publication" and a compound is
described in a form of general formula in the publication and the general formula hasan enormous number of alternatives, a specific technical concept according to a
specific alternative cannot be extracted in the absence of circumstances where thetechnical concept according to the specific alternative should be positively or
preferentially selected, and such invention is not qualified for a cited invention.
This logic shall also apply to the finding of, from publications, an auxiliary
cited invention, which is another "invention described in a publication" provided in
Article 29, paragraph (1), item (iii) corresponding to a difference between the present
invention and the primarily cited invention (hereinafter referred to as "the auxiliary
cited invention"), in the case of determining whether the present invention is easily
conceivable by applying the auxiliary cited invention to a primarily cited invention.
Therefore, it is reasonable to find that, if an auxiliary cited invention is the "invention
described in a publication" and a compound is described in the form of a generalformula in the publication and the general formula has an enormous number ofalternatives, a specific technical concept according to a specific alternative cannot be
extracted in the absence of circumstances where the specific technical concept
according to the specific alternative should be positively or preferentially selected, andsuch invention is not qualified for an auxiliary cited invention.
83

Further, as aforementioned, in the case of determining whether the present
invention is easily conceivable by applying the auxiliary cited invention to a primarily
cited invention, it is determined by: [i] Comprehensively considering the suggestions
in a primarily cited invention or an auxiliary cited invention, the relevance in technicalfield, and the commonality in problem, effect, and function, a determination is made as
to whether there is a motivation to apply the auxiliary cited invention to the primarily
cited invention and arrive at the present invention, and [ii] Considering the presence or
the absence of factors inhibiting the application as well as the presence or the absenceof unexpected significant effects in combination.

In a suit for the rescission against a

trial decision of trial for invalidation of a patent, it is a person who argues invalidationof patent (in a suit for the rescission against a trial decision of appeals against an
examiner's decision of refusal and a suit for the rescission of the decision of revoke
according to the opposition to a granted patent, it is the commissioner of the Japan
Patent Office) for the above [i]; and a patentee (in a suit for the rescission against a
trial decision of appeals against an examiner's decision of refusal, it is a patentapplicant) for the above [ii] that is required to argue and establish the facts that
underlie the existence of these factors.
(2) Exhibit Ko 1 Invention
A Content of Exhibit Ko 1
Exhibit Ko 1 (National Publication of International Patent Application No.
1991-501613) has the following descriptions:(A) The scope of claims"1. A compound of formula I in free acid form,

wherein R1 and R2 independently are:a C1-6 alkyl not containing an asymmetric carbon atom;
a C3-6 cycloalkyl; or84whereinm is 0, 1, 2, or 3;
R3 is hydrogen, a C1-3 alkyl, n-butyl, i-butyl, t-butyl, C1-3 alkoxy, n-butoxy, ibutoxy, trifluoromethyl, fluoro, chloro, phenoxy, or benzyloxy;
R4 is hydrogen, a C1-3 alkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro,
phenoxy or benzyloxy; and R5 is hydrogen, a C1-2 alkyl, C1-2 alkoxy, fluoro or chloro;
with the provisos thatnot more than one of R3 and R4 is trifluoromethyl;
not more than one of R3 and R4 is phenoxy; andnot more than one of R3 and R4 is benzyloxy; or
R1 is as defined above, andR2 is benzyloxy;
benzylthio;-N(R8)2 wherein either each R8 independently is a C1-4 alkyl not containing an
asymmetric carbon atom or both R8 together with the nitrogen atom form part of a 5,6- or 7-membered optionally substituted ring optionally containing one or more
further heteroatoms (ring B);
or Q wherein
Q is Q' or Q" wherein
Q' is a heterocyclic group optionally mono- or independently di-substituted by
C1-2 alkyl or C1-2 alkoxy andQ" is: Q"a, with the proviso that Q"a iswhere R3, R4, and R5 are as defined above, including the provisos thereto;orQ"b, with the provisos that Q"b is85where R4 and R5 are as defined above;
X is either ethylene or vinylene; andY is: a group Y' of formulawhereinR6 is hydrogen or a C1-3 alkyl; andR7 is hydrogen, an ester group (R7'), or a cation (M); a group Y" of formulawhere R6 is as defined above: or a group Y'" of formulawhere R6 and R7 are as defined above: with the proviso thatwhen Y is a group Y'",then X is vinylene and/or R6 is a C1-3 alkyl; in free acid form, or in the form ofan ester or δ-lactone thereof, or in salt form as appropriate." (Claim 1 of the scope ofclaims)86

(B)Description (page 11, right bottom column, line 9 to page 12, left uppercolumn, line 13)"In particular the compounds show activity in the following tests:
Test A.

In vitro microsomal assay of 3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) reductase inhibition: as described in EP 114027:
The following results are obtained by test A:
Product of Working Example 11d: IC50=0.039 μM;
Product of Working Example 1b): IC50=0.026 μM;
Compactin: IC50 = 1.01 μM;
Mevinolin: IC50 = 0.352 μM.
IC50 is the concentration of the test substance in the assay system calculated to
produce a 50% inhibition of HMG-CoA reductase activity.

The tests are run atconcentrations of test substance between 0.05 μM and 1000 μM.
Test B.

In vivo cholesterol biosynthesis inhibition test: as described in EP

114027:
The following results are obtained by test B:
Product of Working Example 11d: ED50=0.04 mg/kg;
Product of Working Example 1b): ED50=0.028 mg/kg;
Compactin: ED50 = 3.5 mg/kg;
Mevinolin: ED50 = 0.41 mg/kg.
ED50 is the dose of the test substance calculated to produce a 50% inhibition of
3β-hydroxysterol synthesis.

The tests are run to test doses of between 0.01 mg/kg and

10 mg/kg.
The above test data indicate that the compounds are competitive inhibitors of 3hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), the rate limiting enzyme incholesterol biosynthesis, and, therefore, they are inhibitors of cholesterol biosynthesis.
Consequently, they are indicated for use in lowering the blood cholesterol level inanimals, e.g. mammals, especially larger primates, and, therefore, are indicated for use
as hypolipoproteinemic and anti-atherosclerotic agents."(C) Description (page 12, left bottom column, line 3 to page 13, left uppercolumn, line 3)"Working

Example1:(3R,5S)-[E]-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-(dimethylamino)pyrimidine-5-yl]-3,5-dihydroxy-6-heptenoic acid, (1,1-dimethylethyl)
ester; and sodium salt87

(R1 = isopropyl; R2 = dimethylamino; Q = 4-fluorophenyl; X = (E)-CH = CH-; Y =group Y', wherein R4 = H, R7 = tert-butyl or Na and the steric configuration is 3R, 5S)[(Method c) (Deprotection) and recycle in a salt form]ora) Deprotection:
14.2 g of (3R,5S)-[E]-3,5-bis[[(1,1-dimethylethyl)-diphenylsilyl]oxy]-7-[4-(4fluorophenyl)-6-(1-methylethyl)-2-(dimethylamino)pyrimidin-5-yl]-6-heptenoic acid,
1,1-dimethylethyl ester (see below) dissolved in 350 ml of CH3CN was added to a
mixture of 47.2 g of tetra-n-butylammonium fluoride trihydrate and 350 ml ofacetonitrile and 9 g (8.6 ml) of glacial acetic acid.

This was stirred at 45-50°C underargon, and then stirred at 65°C for 24 hours. The reaction mixture was poured into
150 ml of saturated sodium chloride solution, 200 ml of saturated sodium carbonate
solution, and 1.35 liters of water (the pH was approximately 7.5-8.5 after the addition)and the mixture was extracted three times with diethyl ether.

The diethyl ether

extracts were combined, washed three times with 500 ml portions of water, dried overanhydrous MgSO4, filtered, and evaporated at a reduced pressure to yield an oil. The
crude product was flash chromatographed on a 230-400 ASTM silica gel using 6:4
mixed hexanes:ethyl acetate as the eluant.

A yellow oil was isolated, and thentriturated to a light yellow powder with hexanes.

(3R,5S)-[E]-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-(dimethylamino)pyrimidin-5-yl]-3,5-dihydroxy-6-heptenoic acid,(1,1-dimethylethyl) ester was obtained (M.P. 114-116°C; 25[α] D = + 7.7°, CHCl3)b) Hydrolysis:12.35 g of the product of step a) above, 26.0 ml of 1N NaOH, and 150 ml ofethanol were combined and stirred at room temperature for 3-4 hours.
was rotary evaporated.

The solvent

The residue was treated with approximately 150 ml of toluene

and the toluene rotary evaporated. This was repeated, and the final residue wastriturated to a light yellow solid with a mixture of hexane-ether. This was filtered and
dried

to

yield

sodium(3R,5S)-[E]-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-288

(dimethylamino)pyrimidin-5-yl]-3,5-dihydroxy-6-heptenoate(M.P.

231-233°C;

25[α]D = +33.3°, c = 20.625 mg in 1 ml H2O)."(D) Description (page 20, left bottom)"Working Example 11
In a similar manner to Working Example 5 (hydrolysis), starting from esters
corresponding to Working Example 9 or 10, the following sodium salt was obtained.

89Subexam
ple
No.

R1

11a isopropyl

11b isopropyl
11c isopropyl
11d isopropyl
11e isopropyl
11f isopropyl
11g isopropyl

11h isopropyl

11i

methylStarting fromesters
Melting2
RQX
Yof thepoint
following
No.
isopropy 4-pyridyl (E)Y', with the9
224 tol
CH=CH- provisos that
225°C
R6=H,
(decompo
7
R =ethyl, andsed)stericconfiguration
is mainly
erythro(>98%)(racemicbody)
tert4-pyridyl (E)Y'
10a
butyl
CH=CHmethyl 4-pyridyl (E)Y'
10b
CH=CH4-pyridyl (E)Y'10c
N(CH3)2
CH=CHtert4(E)Y'
10d
foam
butyl
fluorophey CH=CH(NMR1))lmethyl 4(E)Y'10efoam
fluorophey CH=CH(NMR2))lisopropy 4(E)Y'
10f
172 tolfluorophey CH=CH178°Cl(decompo
sed)
4(E)Y'
10g
210 toN(CH3)2 fluorophey CH=CH212°Cl(decompo
sed)methyl 4(E)Y'10h
foam
fluorophey CH=CH(NMR3))l"
B Finding of Exhibit Ko 1 Invention90

According to the aforesaid A, Exhibit Ko 1 Invention is recognized as "a compound of (M=Na)"
as in the finding of the trial decision.

In this respect, there is no dispute

between the parties.
(3) Selection of primarily cited invention
As discussed in the aforesaid item 2(2), the Invention relates to 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor effective for thetreatment of hypercholesteremia, hyperlipoproteinemia, atherosclerosis by specificallyinhibiting HMG-CoA reductase, a rate-limiting enzyme of cholesterol biosynthesis, tothereby suppress the synthesis of cholesterols. As discussed in the aforesaid item
(2)A, the Exhibit Ko 1 Invention also relates to a competitive inhibitor of 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA), a rate-limiting enzyme for the biosynthesisof cholesterols, and relates to a treating agent for hypolipoproteinemic and antiatherosclerotic agents that decrease a blood cholesterol level.

Therefore, it has atechnical field in common with the Invention, and falls within a range where a person
ordinarily skilled in the art in a technical field to which the Invention pertains would
consider.
Further, comparing Invention 1 and the Exhibit Ko 1 Invention as is found in
the aforesaid item (2)B, they are common in the following [Common features] as in thefinding of the trial decision.

In this regard, there is no dispute between the parties,

and thus they have similar structures.

Therefore, the Exhibit Ko 1 Invention iscomparable in structures to the Invention.
[Common features]"A compound represented by the following formula (I):91

(whereR1 is a lower alkyl;
R2 is a phenyl substituted with a halogen;
R3 is a lower alkyl;
the dashed line represents the presence or absence of a double bond.)or a ring-closed lactone body thereof"
Consequently, the Exhibit Ko 1 Invention is an underlying publicly known
technical idea in considering the inventive step of the Invention.
Based on the above fact, the Exhibit Ko 1 Invention is not construed as being
not qualified for the primarily cited invention in the determination of the inventive stepof Article 29, paragraph (2) of the Patent Act with respect to the Invention. The
argument presented by Defendant and others opposed to this is not acceptable.
(4) Comparison
Here, comparing Invention 1 and the Exhibit Ko 1 Invention as is found in the
aforesaid item (2)B, they are common in the [Common features] as in the finding of
the trial decision, as mentioned in the aforesaid item (3), and they are different in thefollowing [Difference]: In this respect, there is no dispute between the parties.
[Difference](1-i)
In the Invention 1, X is an imino group substituted with an alkylsulfonyl group,
whereas in the Exhibit Ko 1 Invention it is an imino group substituted with a methyl
group(1-ii)In the Invention 1, R4 is hydrogen or a calcium ion forming hemicalcium salt,
whereas in the Exhibit Ko 1 Invention it is a sodium ion forming sodium salt(5) Determination of differences between Invention 1 and the Exhibit Ko 1
92

Invention
A Determination whether or not the Difference (1-i) from the cited invention
can be easily conceived(A) Regarding the difference (1-i), Plaintiffs argue that the Invention 1 iseasily conceivable by combining the Exhibit Ko 1 Invention with the Exhibit Ko 2
Invention, specifically by replacing one of two methyl groups (-CH3) of thedimethylamino group (-N(CH3)2) at the 2-position of the pyrimidine ring of thecompound of the Exhibit Ko 1 Invention with an alkylsulfonyl group (-SO2R'(R' is analkyl group)) of the Exhibit Ko 2 Invention; i.e., a "dimethylamino group" at the 2position of the pyrimidine ring of the compound of the Exhibit Ko 1 Invention with "N(CH3)(SO2R').
Accordingly, the Exhibit Ko 2 Invention is considered in the following.
(B)

a Exhibit Ko 2 (Japanese Unexamined Patent Application Publication

No. 1989-261377) has the following descriptions:(a) Scope of claims"1. A substituted pyrimidine of the general formula:where R1 represents a cycloalkyl or
alkyl, and the group may be substituted with a halogen, cyano, alkoxy, alkylthio,
alkylsulfonyl,

trifluoromethyl,

trifluoromethoxy,

trifluoromethylthio,

trifluoromethylsulfonyl, alkoxycarbonyl, or acyl group, or formula -NR4R5, supposingthat R4 and R5 are the same or different from each other and represent an alkyl, aryl,
aralkyl, acyl, alkylsulfonyl, or arylsulfonyl,or may be substituted with a carbamoyl, dialkylcarbamoyl, sulfamoyl,
dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio
or aralkylsulfonyl, and the substituent groups of heteroaryl and aryl group mentioned
last may be substituted with one, two, or three substituent groups that are the same ordifferent from each other consisting of a halogen, cyano, trifluoromethyl,
trifluoromethoxy, alkyl, alkoxy, alkylthio, or alkylsulfonyl,
R2 represents a heteroaryl, and the group may be substituted with one, two, or93three groups, the same or different from each other, consisting of halogen, alkyl,
alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsufonyl, trifluoromethyl,
trifluoromethoxy, trifluoromethylthio, or alkoxycarbonyl, or formula -NR4R5, with theprovisos that R4 and R5 are as described above, or
R2 represents an aryl, and the group may be substituted with one to five groups,
the same or different from each other, consisting of an alkyl, alkoxy, alkylthio,
alkylsulfonyl, aryl, aryloxy, arylthio, arylsufonyl, aralkyl, aralkoxy, aralkylthio,
aralkylsufonyl,

halogen,cyano,

nitro,

trifluoromethyl,

trifluoromethoxy,

trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, or
dialkylcarbamoyl, or formula -NR4R5, with the provisos that R4 and R5 are as
described above, R3 represents hydrogen,a cycloalkyl or
alkyl, and the group may be substituted with a halogen, cyano, alkoxy, alkylthio,
alkylsulfonyl,

trifluoromethyl,

trifluoromethoxy,

trifluoromethylthio,

trifluoromethylsulfonyl, alkoxycarbonyl, or acyl group, or formula -NR4R5, with theprovisos thatR4 and R5 are as described above,or may be substituted with a carbamoyl, dialkylcarbamoyl, sulfamoyl,
dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkoxy, aralkylthio,or aralkylsulfonyl, and the substituent groups of heteroaryl and aryl group mentioned
last may be substituted with one, two, or three groups that are the same or different
from each other consisting of a halogen, cyano, trifluoromethyl, trifluoromethoxy,
alkyl, alkoxy, alkylthio, or alkylsulfonyl, orR3 represents a heteroaryl, and the group may be substituted with one, two, or
three groups that are the same or different from each other, consisting of a halogen,alkyl,

alkoxy,alkylthio,

alkylsulfonyl,

aryl,

aryloxy,

arylthio,

arylsufonyl,

trifluoromethyl, trifluoromethoxy, trifluoromethylthio, or alkoxy, or the formula-NR4R5, with the provisos thatR4 and R5 are as described above,or
R3 represents an aryl, and the group may be substituted with one to five groups,
the same or different from each other, consisting of an alkyl, alkoxy, alkylthio,
alkylsulfonyl, aryl, aryloxy, arylthio, arylsufonyl, aralkyl, aralkoxy, aralkylthio,
aralkylsufonyl,

halogen,cyano,

nitro,

trifluoromethyl,

trifluoromethoxy,

trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, or
dialkylcarbonyl, or formula -NR4R5, with the provisos that R4 and R5 are as described94

above, or
R3 represents an alkoxy, aryloxy, aralkoxy, alkylthio, arylthio, or aralkylthio, ora group formula -NR4R5, supposing thatR4 and R5 are as described above,
X represents a group of formula -CH2-CH2- or -CH=CH-, andA represents the formula or a group, whereinorR6 represents hydrogen or an alkyl, andR7 represents hydrogen,or a methyl, aralkyl, or aryl group, or a cation."(b) Detailed Explanation of the Invention (page 6, left bottom column,
lines 2 to 5)"Surprisingly, the substituted pyrimidine of the present invention shows a goodinhibiting effect in HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl coenzyme A
reductase)."(c) Detailed Description of the Invention (page 8, right upper column, line
11 to left bottom column, line 7)"When R7 represents a cation, it preferably means a physiologically acceptable
metal cation or ammonium cation.

In this regard, preferable ones include: alkali

metals or alkali earth metals, e.g. a sodium cation, potassium cation, magnesium cation,or calcium cation, and aluminum cation or ammonium cation, and non-toxic
ammonium cations substituted with amines usable for the production of salts: e.g. diloweralkylamines (C1 to about C6), tri-loweralkylamines (C1 to about C6),
dibenzylamine, N,N'-dibenzylethylenediamine,N-benzyl-β-phenylethylamine, N-

methylmorphorine,

dihydroabiethylamine,

N-ethylmorphorine,
95

N,N'-bis-diehydroabiethylethylenediamine, N-loweralkylpyperidine, and the other amines."(d) Detailed Description of the Invention (page 10, left upper column, line
9 from the bottom to page 11, right bottom column, line 10)"A particularly preferable compound of the general formula (I) is a compound
where
R1 represents a cyclopropyl, cyclopentyl or cyclohexyl, or methyl, ethyl, propyl,
isopropyl, butyl, sec-butyl, or tert-butyl, each may be substituted with fluorine,
chlorine, bromine, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy,tert-butoxy,

methylthio,

ethylthio,

propylthio,

isopropylthio,

methylsulfonyl,

ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, trifluoromethyl, trifluoromethoxy,
methoxycarbonyl,

ethoxycarbonyl,

butoxycarbonyl,

isobutoxycarbonyl,

tert-butoxycarbonyl, benzoyl, acetyl, pyridyl, pyrimidyl, thienyl, furyl, phenyl, phenoxy,
phenylthio, phenylsulfonyl, benzyloxy, benzylthio, or benzylsulfonyl,
R2 represents a pyridyl, pyrimidyl, quinolyl, or isoquinolyl, the groups may besubstituted with fluorine, chlorine, methyl, methoxy, or trifluoromethyl, or
R2 represents a phenyl, and the group may be substituted with one, two, or threegroups that are the same or different from each other, consisting of methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, tert-butoxy, methylthio, ethylthio, propylthio, isopropylthio,
methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, phenyl, phenoxy,
benzyl, benzyloxy, fluorine, chlorine, bromo, cyano, trifluoromethyl, trifluoromethoxy,
methoxycarbonyl,

ethoxycarbonyl,

propoxycarbonyl,

isopropoxycarbonyl,

butoxycarbonyl, isobutoxycarbonyl, or tert-butoxycarbonyl,
R3 represents hydrogen, a cyclopropyl, cyclopentyl, or cyclohexyl, or a methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, or, isohexyl,
and these groups include fluorine, chlorine, bromine, a cyano, methoxy, ethoxy,
propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methylthio, ethylthio, propylthio,
isopropylthio, butylthio, isobutylthio, tert-butylthio, methylsulfonyl, ethylsulfonyl,
propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl,
trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, or tert-butoxycarbonyl,
benzoyl, acetyl or ethylcarbonyl, or the formula -NR4R5, with the provisos thatR4 and R5 are the same or different from each other, and represent a methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, phenyl, benzyl, acetyl,
methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, or phenylsulfonyl,96

or may be substituted with a pyridyl, pyrimidyl, pyradinyl, pyridazinyl,
quinoline, isoquinoline, thienyl, furyl, phenyl, phenoxy, phenylthio, phenylsulfonyl,
benzyloxy, benzylthio, or benzylsulfonyl, the above heteroaryl and aryl groups may besubstituted with fluorine, chlorine, methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl,
methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, trifluoromethyl,or trifluoromethoxy,orR3 represents a thienyl, furyl, pyridyl, pyrimidyl, pyradinyl, pyridazinyl,oxazolyl,

isoxazolyl,

imidazolyl,

pyrazolyl,

thiazolyl,

isothiazolyl,

quinolyl,

isoquinolyl, benzoxazolyl, benzimidazolyl, or benzthiazolyl, wherein these groups may
be substituted with fluorine, chlorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy,
phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl,
isopropoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, or tertbutoxycarbonyl, orR3 represents a phenyl, and the group may be substituted with one, two, or threegroups that are the same or different from each other, consisting of methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl,
methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methylthio,
ethylthio,

propylthio,

methylsulfonyl,

isopropylthio,

ethylsulfonyl,

butylthio,

propylsulfonyl,

isobutylthio,

tert-butylthio,

isopropylsulfonyl,

butylsulfonyl,

isobutylsulfonyl, tert-butylsulfonyl, phenyl, phenoxy, phenylthio, phenylsulfonyl,
benzyl, benzyloxy, benzylthio, benzylsulfonyl, fluorine, chlorine, bromo, cyano,trifluoromethyl,

trifluoromethoxy,

trifluoromethylthio,

methoxycarbonyl,

ethoxycarbonyl,

propoxycarbonyl,

isopropoxycarbonyl,

butoxycarbonyl,

isobutoxycarbonyl, or tert-butoxycarbonyl or the group -NR4R5, with the provisos thatR4 and R5 are as described above,or
R3 represents an alkoxy, aryloxy, aralkoxy, alkylthio, arylthio, or aralkylthio, or
the formula -NR4R5, with the provisos that R4 and R5 are as described above,
X represents a group of formula -CH2-CH2- or -CH=CH-, andA is a group represented by the formula:

97

or

whereinR6 represents hydrogen, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or
tert-butyl, andR7 represents hydrogen, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or
tert-butyl, or benzyl, or sodium, potassium, calcium, magnesium, or ammonium ion."(e) Detailed Description of the Invention (page 11, right bottom column,
line 11 to page 12, right upper column, line 8.

[excluding the lines described in thedrawing; the same shall apply hereinafter]):"Substituted pyrimidine of the general formula (I) of the present invention has a
few asymmetric carbon atoms, and thus various stereochemical types.

The present

invention relates to both individual isomers and a mixture of isomers.
Different stereoisomers generate according to what the group X or the group A
represents.

This is further elaborated in the following:a)

If the group -X- represents the group of formula -CH=CH-, thecompound of the present invention may be present in two stereoisomer forms of E
steric configuration (II) and Z steric configuration (III) in double bond:( II ) E-type( III ) Z-typewhere R1, R2, R3, and A are as described above.
Esteric configuration (II) is preferable for the compound of the general98formula (I).
b)

If a group -A- represents the group of the following formula:

the compound of general formula (I) has at least two asymmetric carbon atoms;
i.e. two carbon atoms to which hydroxyl group binds.

According to a relative

position of these hydroxyl groups, the compound of the present invention may bepresent in either erythro steric configuration (IV) or threo steric configuration (V).

erythro type (IV)threo type (V)Further, in both cases of the compounds with erythro and threo stericconfigurations, there are two kinds of enantiomers; i.e. 3R,5S-isomer or 3S,5R-isomers(erythro type) and 3R,5R-isomer and 3S,5S-isomer (threo type).
In this regard, an isomer with erythro steric configuration is preferable, and
3R,5S-isomer and a 3R,5S-3S,5R-racemic body is particularly preferable."(f) Detailed Description of the Invention (page 13, right upper column, line
1 to left bottom column, line 7)"Particularly, the most preferable compound of the general formula (Ia) and (Ib)
is the compound where
R1 represents a cyclopropyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or
tert-butyl, andR2 represents phenyl that may be mono- or di-substituted with the same ordifferent groups consisting of a methyl, methoxy, phenoxy, fluorine, chlorine, or
trifluoromethyl,R3 represents a methyl, isopropyl, tert-butyl, or phenyl that may be mono- or di99

substituted with the same or different groups consisting of methyl, methoxy, fluorine
or chlorine,
X is a group represented by the formula:(E steric configuration)and
A is represented by the formula:orwhere, R6 represents hydrogen, andR7 represents hydrogen, a methyl or ethyl, or a sodium or potassium cation."(g) Detailed Description of the Invention (Working Examples)i

Working Example 8 (page 22, left bottom column, lines 12 to 15)"Working Example 8
methylerythro-(E)-3,5,-dihydroxy-7-[2,6-dimethyl-4-(4-fluorophenyl)-pyrimid-5-yl]hept-6-enoate

"

100

ii

Working Example 15 (page 24, right upper column, lines 1 to 5)"Working Example 15
methylerythro(E)-3,5,-dihydroxy-7-[4-(4-fluorophenyl)-6-methyl-2-phenyl-pyrimid-5yl]-hept-6-enoate"iii

Working Example 23 (page 26, left upper column, line 5 to last line fromthe bottom)"Working Example 23
methylerythro-(E)-3,5-dihydroxy-7-[4-(4-fluorophenyl)-6-isopropyl-2-phenyl-pyrimid5-yl]-hept-6-enoate"
iv

Working Example 24 (page 26, right upper column, line 6 from the bottom

to page 27, left upper column, line 10)"Use working example
Working Example 24
101

Enzymatic activity was measured in accordance with the modification by Ness,etc. to measure a relative suppression capability, with the IC50 value of a control
substance of Mevinolin given as 1, and compared with an IC50 value of test compound
measured simultaneously.
The active compounds of Working Examples 1 to 23 showed a higher effectcompared to Mevinolin."b

According to the aforesaid a, Exhibit Ko 2 describes a compound

represented by general formula (I).

The compound has a pyrimidine ring, andsubstituent groups at the 2-, 4-, and 6-positions of the pyrimidine ring, and shows goodinhibiting effects in HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl coenzyme A
reductase).
(C)a As in the aforesaid item (B), the compound of general formula (I) of
Exhibit Ko 2 is intended to provide an HMG-CoA reductase inhibitor, like thecompound of general formula I of Exhibit Ko 1.

They are common in that they havea pyrimidine ring and substituent groups at the 2-, 4-, and 6-positions of the pyrimidine
ring.

The compound of the Exhibit Ko 1 Invention is encompassed into thecompound represented by general formula (I) of Exhibit Ko 2.
Exhibit Ko 2 describes "-NR4R5" as an alternative of substituent group R3 at the
2-position of the pyrimidine ring of a "particularly preferable compound" among thecompounds represented by general formula (I) of Exhibit Ko 2, and also describes"methyl group" and "alkylsulfonyl group" as an alternative for R4 and R5.
Plaintiffs did not particularly argue however, that there are numerous
alternatives of R3 in "particularly preferable compound" of Exhibit Ko 2, and thenumber is at least 20 million.

The compound where R3 is "-NR4R5, and R4 and R5 are"methyl" and "alkylsulfonyl" is one alternative among 20 million or more.
Further, Exhibit Ko 2 not only describes "particularly preferable compound" butalso "particularly extremely preferable compound," which fails to describe "-NR4R5"
as an alternative of R3.
Furthermore, Exhibit Ko 2 describes Working Example 8 (R3 is methyl),
Working Example 15 (R3 is phenyl), and Working Example 23 (R3 is phenyl) as
working examples of the compound having the same structure as the Exhibit Ko 1
Invention in X and A of the general formula (I) of Exhibit Ko 2.

It fails to describe "-NR4R5" for R3.
Consequently, although Exhibit Ko 2 describes an alkylsulfonyl group, it is102

impossible for a person ordinarily skilled in the art to find from the description of
Exhibit Ko 2 any circumstances where "-NR4R5" is positively or preferentially selected
as R3 of the general formula (I) of Exhibit Ko 2.

It is difficult to find any

4 5circumstances to select "-NR R , and further select "methyl" and "alkylsulfonyl" for R4
and R5.
Therefore, it cannot be seen that the technical idea of changing the group at the
2-position of the pyrimidine ring into "-N(CH3)(SO2R')" may be extracted from
Exhibit Ko 2.

It cannot be said that Exhibit Ko 2 describes the structure according to

the above difference (1-i). The combination of the Exhibit Ko 1 Invention with the
Exhibit Ko 2 Invention may not result in the structure according to the difference (1-i)
of the Invention.
b

Plaintiffs argue that Exhibit Ko 2 describes a method of producing thewhole range of the compounds of general formula (I) and HMG-CoA reductase
inhibiting activity as in the following, and it can thus be seen as a technical support ofthe compound of the general formula (I) where "NR4R5" was selected for "R3, andtherefore the finding of the trial decision to the effect that " Exhibit Ko 2 fails to
describe a producing method thereof, nor pharmacological tests of HMG-CoA
reductase inhibiting activity with respect to compounds where 'NR4R5' was selected for'R3'" is erroneous.
As in the aforesaid item a, the compound represented by general formula (I) of
Exhibit Ko 2 is intended to provide a HMG-CoA reductase inhibitor. As in the
aforesaid item (B)a(g), Exhibit Ko 2 discloses that the compounds of Working
Examples 1 to 23 of Exhibit Ko 2 encompassed in the compound represented bygeneral formula (I) of Exhibit Ko 2 have a higher HMG-CoA reductase inhibiting
activity compared to Mevinolin.

Further, Exhibit Ko 16 discloses that a specificcompound within the general formula (I) of Exhibit Ko 2 has an HMG-CoA reductase
inhibiting activity, and according to the evidences (Exhibit Ko 16, and Ko 73 to Ko 75)
and the entire import of the oral argument, it is recognized that a person ordinarily
skilled in the art sometimes recognizes that a specific compound in which only a partof the working example of Exhibit Ko 2 is changed is likely to have an HMG-CoA
reductase inhibiting activity.
However, Working Examples 1 to 23 of Exhibit Ko 2 and the specificcompound of the above finding do not include a compound with a sulfonamide
structure. According to the evidence (Exhibit Otsu 65) and the entire import of theoral argument, it is a matter of common general technical knowledge that chemical
103substances possibly undergo change of their effects by a very small structural change.
Not all of numerous compounds represented by general formula (I) of Exhibit Ko 2 are
expected to have an HMG-CoA reductase inhibiting activity comparable to or higher
than those of Working Examples 1 to 23 or the specific compound in the above finding.
It is also possible to lose the HMG-CoA reductase inhibiting activity.
Therefore, it cannot be seen from Exhibit Ko 2 that all of numerous compounds
represented by general formula (I) of Exhibit Ko 2 are technically supported. The
above argument by Plaintiffs does not affect the determination of the aforesaid item a.
(D)a Even if Exhibit Ko 2 might be evaluated as describing the structure
according to the difference (1-i), as in the aforesaid item (2), a compound of Exhibit
Ko 1 Invention of "a compound of(M=Na)""sodium(3R,5S)-[E]-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-(dimethylamino)pyrimidine-5-yl]-3,5-dihydroxy-6-heptenoic acid" is a product ofWorking Example 1b) of Exhibit Ko 1 with an HMG-CoA reductase inhibiting activity,and is encompassed into the compound represented by the general formula I of Exhibit
Ko 1. Further, Exhibit Ko 1 describes "-N(R8)2" as an alternative of substituent group
R2 at the 2-position of the pyrimidine ring of formula I of Exhibit Ko 1. Furthermore,
it describes "methyl group" as an alternative of R8, but it fails to describe"alkylsulfonyl group" as an alternative of R8.
Consequently, it cannot be said that Exhibit Ko 1 has a motivation to replace"dimethylamino group" at the 2-position of the pyrimidine ring of the compound of the
Exhibit Ko 1 Invention with "-N(CH3)(SO2R')," which is not included in thealternatives of formula I of Exhibit Ko 1.
b(a)It was recognized as a matter of common general technical knowledgeof a person ordinarily skilled in the art as of the priority date that the most cholesterols
are synthesized by the liver, and HMG-CoA reductase catalyzes the biosynthesis of104cholesterols, and HMG-CoA reductase inhibitor inhibits the biosynthesis ofcholesterols (Exhibit Ko 7, Ko 10, Ko 11, and Ko 14).
"Many discussions are made on articles with regard to the properties and thepresence or the absence of tissue (liver) selectivity of various HMGR (HMG-CoA
reductase) inhibitors" as of the priority date (Exhibit Ko 7). Further, there was afinding that "Lovastatin and Simvastatin encompassed into HMG-CoA reductase
inhibitors might cause cataract in dog at high dose" (Exhibit Ko 24).
Consequently, it can be said that a person ordinarily skilled in the art could
recognize the technical problem as of the priority date to obtain an HMG-CoA
reductase inhibitor with high selectivity by the liver, by which most cholesterols aresynthesized, in view of the side effects.
(b) Exhibit Ko 7 (According to the entire import of the oral argument, it
was published on January 1, 1991.) discloses that, considering a hypothesis of "tissue
selectivity is mainly affected by relative lipophilicity of drug, and a compound withrelatively high hydrophilicity in an HMG-CoA reductase inhibitor may possibly
improve liver selectivity" with respect to the compound of HMG-CoA reductase
inhibitors such as Lovastatin and Pravastatin, "A 'cross' point where the selectivity
becomes equal in the liver and other tissue is CLOGP≈2," and "below this level, thecompound is liver-selective, and above this level, the compound is peripheral tissueselective."

Further, Exhibit Ko 20 discloses that the lipophilicity (logP) of four

HMG-CoA reductase inhibitors of Pravastatin, Lovastatin, Mevastatin, andSimvastatin was measured, and Pravastatin with a hydroxyl group has a lower logP
value compared to Lovastatin and Simvastatin with a methyl group at the 6-position ofhexahydronaphthalene ring, and Pravastatin is not so effectively taken by cells outside
the liver due to such physiochemical properties.
It can be deduced from the description of Exhibit Ko 7 and Ko 20 that acompound with relatively high hydrophilicity in an HMG-CoA reductase inhibitor may
possibly improve liver selectivity. Thus a person ordinarily skilled in the art could
recognize a motivation as of the priority date to assess the compound showing HMGCoA reductase inhibiting activity with an indicator of hydrophilicity and select acompound with high hydrophilicity (logP of 2 or less) in order to obtain an HMG-CoA
reductase inhibitor with high selectivity for the liver in view of side effects.
(c) On the other hand, Exhibit Ko 16, which describes the HMG-CoA
reductase inhibiting activity of lactone of pyridine and pyrimidine substituted 3,5105

dihydroxy-6-heptenoic acid, discloses that the bulky, lipophilic substituent group at the
6-position of the central aromatic ring greatly contributes to biological activity ofsynthetic HMG-CoA reductase inhibitors.

It also discloses that, in the following

structural formula (hereinafter referred to as "Exhibit Ko 16, structural formula") "CH for the numbers 2a to 2q of Y=Table II, N for the numbers 2t to 2w),"
the substitution at the 2-, 4-, and 6-positions (R1, R2, and R3) of the central
aromatic ring (pyrimidine ring) results in strong biological activity, and that the
introduction of an isopropyl group at the 2-position (R1) may maximize the biologicalactivity, and that an analogous structure at the 4-position (R2) of 4-chlorophenyl and 4fluorophenyl substitutions may become a comparably strong inhibitor, and that thesubstitution at the 6-position (R3) is the most important for the optimal biologicalactivity, and the introduction of a bulky alkyl group or a phenyl moiety may achieve asignificant increase of titer.
Here, although the compound of the Exhibit Ko 1 Invention is not a lactone
body of dihydroxyheptenoic acid, but a sodium salt of dihydroxyheptenoic acid, it
corresponds to one where "2:A-B=(E)-CH=CH" and the isopropyl group is introduced
into R1, and R2 is substituted with 4-fluorophenyl in the structural formula of Exhibit
Ko 16. Therefore, a person ordinarily skilled in the art who read Exhibit Ko 16
would recognize that the introduction of a bulky, lipophilic substituent group, inparticular a bulky alkyl group or phenyl moiety into a moiety of "dimethylaminogroup" at the 2-position of the pyrimidine ring of the compound of Exhibit Ko 1
Invention corresponding to R3 in the structural formula of Exhibit Ko 16 would
probably result in a significant increase of titer.
Consequently, even if there was a motivation to select a more hydrophiliccompound having an HMG-CoA reductase inhibiting activity in view of the side106

effects as of the priority date, whereas a person ordinarily skilled in the art would
recognize that the introduction of a bulky, lipophilic substituent group, in particular abulky alkyl group or phenyl moiety into a moiety of "dimethylamino group" at the 2position of the pyrimidine ring of the compound of the Exhibit Ko 1 Invention would
probably result in a significant increase of titer.

Therefore, it cannot be said that there

was a motivation for a person ordinarily skilled in the art as of the priority date to
replace "dimethylamino group" at the 2-position of the pyrimidine ring of thecompound of the Exhibit Ko 1 Invention with a more hydrophilic substituent group,and not a bulky, lipophilic substituent group.
(d) Further, Exhibit Ko 9 and Ko 60 describe a number of groups otherthan methylsulfonyl group (-SO2CH3) as a group more hydrophilic than a methyl group.
Even if there was a motivation for a person ordinarily skilled in the art as of thepriority date to replace the dimethylamino group at the 2-position of the pyrimidine
ring of the compound of the Exhibit Ko 1 Invention with a more hydrophilic
substituent group, it cannot be said from the common general technical knowledge asof the priority date that there was a motivation for a person ordinarily skilled in the art
to replace one of the methyl groups with a specific methylsulfonyl group as of thepriority date.
Further, for a similar reason to the fact that there is no motivation to replace one
methyl group of the dimethylamino group at the 2-position of the pyrimidine ring of
the compound of the Exhibit Ko 1 Invention with a methylsulfonyl group, there is no
motivation to replace one methyl group of the dimethylamino group at the 2-positionof the pyrimidine ring of the compound of the Exhibit Ko 1 Invention with analkylsulfonyl group (ethylsulfonyl group, propylsulfonyl group etc.) other than amethylsulfonyl group.
(e) Therefore, it cannot be said that there was a motivation to replace thedimethylamino group at the 2-position of the pyrimidine ring of the compound of the
Exhibit Ko 1 Invention with "-N(CH3)(SO2R')" even if Exhibit Ko 2 might beevaluated as describing the structure according to the difference (1-i).

It cannot be

said that there was a motivation to adopt the structure of the difference (1-i) in the
Exhibit Ko 1 Invention.
(E)

Further, Plaintiffs argue that, in the determination of the support

requirement, the trial decision determined by formulating a problem to provide a107compound having "excellent HMG-CoA reductase inhibiting activity" to the extent
that the compound may become a pharmaceutical product capable of "suppressing the
production of cholesterols" or an HMG-CoA reductase inhibitor including thecompound as an active ingredient, whereas in the determination of the inventive step, it
determined by formulating a criterion "to maintain a current level of HMG-CoA
reductase inhibiting activity of the compound of Exhibit Ko 1 Invention," which goesbeyond a level required by the problem to provide a pharmaceutical product capable of"suppressing the production of cholesterols." Thus it is not reasonable to determine
support requirement and motivation with such a double standard.
The above determination of the support requirement in the trial decision among
the above argument is correct as described in the following item 4. In contrast,
regarding the inventive step, as is already determined, Exhibit Ko 2 fails to describe
the structure according to the difference (1-i). Further, even if Exhibit Ko 2 might beevaluated as describing the structure according to the difference (1-i), it cannot be said
that there was a motivation to adopt the structure according to the difference (1-i), andthus the Invention was not easily conceivable.

The inventive step was not determinedwith a criterion as Plaintiffs argue. Thus no discrepancy is caused as Plaintiffs argue.
(F) As seen above, it cannot be said that it was possible to adopt thestructure of the difference (1-i) in the Exhibit Ko 1 Invention.
B SummaryConsequently, without considering the difference (1-ii), it cannot be recognizedthat Invention 1 was easily conceivable by a person ordinarily skilled in the art by
combining the Exhibit Ko 1 Invention and the Exhibit Ko 2 Invention.
Further, the compounds of Inventions 2, 5, and 9 to 11 are encompassed in
Invention 1, whereas Invention 1 was not easily conceivable by a person ordinarily
skilled in the art. Therefore, it cannot be said that Inventions 2, 5, and 9 to 11 withfurther limitation to the Invention 1 were also easily conceivable by a person ordinarily
skilled in the art.
Further, the HMG-CoA reductase inhibitor of Invention 12 is an HMG-CoA
reductase inhibitor including the compound of the Invention 1 as an active ingredient,whereas Invention 1 was not easily conceivable by a person ordinarily skilled in the art.
Therefore, it cannot be said that Invention 12 was also easily conceivable by a person
ordinarily skilled in the art.
Therefore, it cannot be recognized that Inventions 1, 2, 5, and 9 to 12 were108

easily conceivable by combining both the Exhibit Ko 1 Invention and the Exhibit Ko 2
Invention.

The ground 1 for rescission presented by Plaintiffs is groundless.

4 Ground 2 for rescission(1) Determination criteria
The determination of whether or not the recitation of the scope of claims might
conform to the support requirement should follow the steps of: comparing therecitation of the scope of claims with the description of the Detailed Descriptions of
the Invention; and considering whether or not the Invention recited in the scope ofclaims might be the invention described in the Detailed Description of the Invention
and fall within the range in which a person ordinarily skilled in the art could recognizethat the problem to be solved by the Invention might be solved, or considering whether
or not the Invention recited in the scope of claims might fall within the range in which
a person ordinarily skilled in the art could recognize without the explicit description orsuggestion in view of the common general technical knowledge as of the filing that the
problem to be solved by the Invention might be solved (see the judgment of IP High
Court, Special Division, made on November 11, 2005 for 2005 (Gyo-Ke) 10042).
(2) Problem to be solved by the Invention
A As seen in the aforesaid item 2(1)C and D, the description discloses inparagraph [0003] that "the suppression of cholesterol production is essential for theprevention and the treatment of atherosclerosis.

Taking this into consideration, there

is still a need for the development of useful pharmaceutical products.", and inparagraph [0004] that, in view of such circumstances, the inventors have completed theInvention "on the basis of the findings that the compound represented by the following
general formula (I):(wherein R1 is a lower alkyl, aryl, or aralkyl, each of which may have one or more
substituents; each of R2 and R3 is independently hydrogen, a lower alkyl, or aryl, andeach of said alkyl and aryl may have one or more substituents; R 4 is hydrogen, a lower
alkyl, or a cation capable of forming a non-toxic pharmaceutically acceptable salt; X is109

sulfur, oxygen, or a sulfonyl group, or imino which may have a substituent; the dashedline represents the presence or absence of a double bond) has excellent HMG-CoA
reductase inhibiting activity." The compound represented by this general formula (I)encompasses the compounds of Inventions 1, 2, 5, and 9 to 11, and Invention 12 isdirected to an HMG-CoA reductase inhibitor including the compound of the Invention
1 as an active ingredient. Therefore, the problem to be solved by Inventions 1, 2, 5,
and 9 to 11 lies in the provision of the compound having excellent HMG-CoA
reductase inhibiting activity, and the problem to be solved by Invention 12 lies in theprovision of an HMG-CoA reductase inhibitor including such compounds.
B As in the aforesaid 2(1)B, the specification discloses in paragraph [0002]
that there were first generation HMG-CoA reductase inhibitors such as Mevinolin,which were obtained from fungal metabolites or their partial modified compounds,
while synthesized HMG-CoA reductase inhibitors such as Pravastatin have beendeveloped and expected as the second generation.
However, the Detailed Description of the Invention of the specification does notdisclose any problem of these HMG-CoA reductase inhibitors that have already beendeveloped. As seen in the aforesaid item 2(1)C, it only discloses in paragraph [0003]
that "the suppression of cholesterol production is essential for the prevention and thetreatment of atherosclerosis. Taking this into consideration, there is still a need forthe development of useful pharmaceutical products."
According to the evidence (Exhibit Ko 36) and the entire import of the oral
argument, although the pharmacological activity of a new active ingredient is at thesame level as an active ingredient that has been commercially available in the field ofpharmaceutical products, the new active ingredient has a technical value in that itprovides an alternative means for solution.
Taking the above into consideration, it cannot be said that a problem to besolved by the Invention is to provide an HMG-CoA reductase inhibitor superior to theabove HMG-CoA reductase inhibitors that have already been developed.
C

Therefore, the problem to be solved by the Invention should be to provide acompound having excellent HMG-CoA reductase inhibiting activity to the extent thatthe compound may become a pharmaceutical product for suppressing the production ofcholesterols, and to provide an HMG-CoA reductase inhibitor including the compoundas an active ingredient.

110

(3) Means for solution
A

As in the aforesaid item 2(1)E, the specification discloses a specificprocedure of measuring HMG-CoA reductase inhibiting activity by use of rat liver
microsome fraction in paragraphs [0040] and [0041], and in paragraph [0042] that the
HMG-CoA reductase inhibiting activity of compound (Ia-1) is 442 given the HMGCoA reductase inhibiting activity of sodium Mevinolin be 100 as a measurement result.
This compound (Ia-1) is "(+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methylN-methylsulfonylaminopyrimidin)-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenoic
sodium salt" (the specification [0029]).

acid

It is not "(+)-7-[4-(4-fluorophenyl)-6-

isopropyl-2-(N-methyl-N-methylsulfonylaminopyrimidin)-5-yl]-(3R,5S)-dihydroxy(E)-6-heptenoic acid," nor its " hemicalcium salt," which are encompassed in Invention
1. Therefore, it is not encompassed in Invention 1; however, according to the entire
import of the oral argument, it is recognized that the difference of salt does not greatly
affect HMG-CoA reductase inhibiting activity.

Compound (Ia-1) and the compoundof Invention 1 have a comparable level of HMG-CoA reductase inhibiting activity.
Therefore, supposing that compound (Ia-1) has a higher level of HMG-CoA reductase
inhibiting activity compared to sodium Mevinolin, it can be said that a person
ordinarily skilled in the art would understand that "(+)-7-[4-(4-fluorophenyl)-6isopropyl-2-(N-methyl-N-methylsulfonylaminopyrimidin)-5-yl]-(3R,5S)-dihydroxy(E)-6-heptenoic acid" and its " hemicalcium salt" might also have a higher HMG-CoA
reductase inhibiting activity compared to sodium Mevinolin.
Although the above measurement result is a result of one-time measurement, it
does not influence the above determination, nor is there other evidence sufficient tofind circumstances which question the reliability of the above determination.
Further, Invention 1 includes a compound of formula (I) where R1 is a lower
alkyl, R2 is a phenyl substituted with halogen, R3 is a lower alkyl, and X is an iminogroup substituted with an alkylsulfonyl group.

These substituent groups haveanalogous chemical structure to the group of "(+)-7-[4-(4-fluorophenyl)-6-isopropyl-2(N-methyl-N-methylsulfonylaminopyrimidin)-5-yl]-(3R,5S)-dihydroxy-(E)-6heptenoic acid" and the group of its "hemicalcium salt" (where R1 is a methyl, R2 is aphenyl substituted with fluorine, R3 is an isopropyl, X is an imino group substituted
with a methylsulfonyl group).

Therefore, it can be said that a person ordinarily

skilled in the art would understand that the remaining compounds included in
Invention 1 might also have a higher HMG-CoA reductase inhibiting activity
compared to sodium Mevinolin, like the compound (Ia-1), or "(+)-7-[4-(4fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylaminopyrimidin)-5-yl]111

(3R,5S)-dihydroxy-(E)-6-heptenoic acid" and its "hemicalcium salt."

There is noevidence against this fact.
Consequently, it can be said that the Detailed Description of the Invention of
the specification discloses to the extent that allows a person ordinarily skilled in the art
to recognize that the compound of Invention 1 has an excellent HMG-CoA reductase
inhibiting activity to provide a pharmaceutical product suppressing the production ofcholesterols; i.e., the compound can solve the problem to be solved by the Invention.
B Further, the compounds of Inventions 2, 5, and 9 to 11 are encompassed in
the Invention 1, and the HMG-CoA reductase inhibitor of Invention 12 is an HMGCoA reductase inhibitor including the compound of Invention 1 as an active ingredient.
Similarly, it can be said that the Detailed Description of the Invention of thespecification discloses to the extent that allows a person ordinarily skilled in the art torecognize that the Invention can solve the problem to be solved by the Invention.
(4) The argument by Plaintiffs
A(A) Plaintiffs argue that the HMG-CoA reductase inhibitor of Compactin
had been publicly known more than a decade before the filing, and a plurality of
HMG-CoA reductase inhibitors were already commercially available as of the filing,
the compound showing a stronger HMG-CoA reductase inhibiting activity compared tosodium Mevinolin was also publicly known, and thus "to the extent that the compoundmight become a pharmaceutical product for suppressing the biosynthesis ofcholesterols" is inappropriate since it is a level lower than the common generaltechnical knowledge.
As discussed in the aforesaid item (2), however, it cannot be said that a problem
to be solved by the Invention is to provide a compound or a drug with an HMG-CoA
reductase inhibiting activity superior to the HMG-CoA reductase inhibitors that havebeen already developed.
Therefore, the above argument presented by Plaintiffs is not acceptable due tothe erroneous premise.
(B) Plaintiffs argue that Invention 1 is encompassed in the scope of generalformula (I) of Exhibit Ko 2, and thus the significant effects are necessary incomparison to the other compounds of general formula (I) of Exhibit Ko 2 in order tobe affirmed the inventive step, whereas a degree of "to the extent that the compoundmight become a pharmaceutical product for suppressing the biosynthesis of112cholesterols" is inappropriate, since it is such a level lower than the common generaltechnical knowledge as of the filing that could not involve the inventive step as aselection invention.
However, the support requirement is specified as a requirement for therecitation of the scope of claims to prevent the establishment of an exclusive right for
an invention not disclosed by reciting an invention not described in the Detailed
Description of the Invention in the scope of claims (Article 36, paragraph (5), item (i)of the Patent Act before the revision by Heisei 6 Act No. 116), whereas the inventive
step is specified as a patent requirement to eliminate an invention easily conceivable
by a person ordinarily skilled in the art as of the filing on the basis of a publicly known
technique from a target of the grant of a patent to prevent a grant of an exclusive rightfor such an invention (Article 29, paragraph (2) of the Patent Act). Consequently, thedetermination of whether or not to conform to the support requirement should be madefrom the above viewpoint, and the determination of the inventive step should not be
encompassed into the framework.
Therefore, the above argument presented by Plaintiffs is not acceptable.
(C) Plaintiffs argue that the applicant recognized that the compound of
Invention 1 and the Exhibit Ko 1 Invention falls within a range of the general formula(I) of Exhibit Ko 2, and thus could not formulate a problem to be solved to provide a
HMG-CoA reductase inhibitor including a compound having an excellent HMG-CoA
reductase inhibiting activity or the compound as an active ingredient "to the extent thatthe compound might become a pharmaceutical product for suppressing thebiosynthesis of cholesterols."
The determination of the support requirement should be made, however, withrespect to the recitation of the scope of claims and the description of the Detailed
Description of the Invention in view of the common general technical knowledge as of
the filing.

It cannot be construed that the determination varies depending on the

Applicant's subjective view as of the filing.
Therefore, the above argument presented by Plaintiffs is not acceptable.
B(A) Plaintiffs argue that the Detailed Description of the Invention of thespecification fails to show the significant HMG-CoA reductase inhibiting activity of
the Invention, and thus a person ordinarily skilled in the art could not recognize that"the problem to be solved by the Invention" might be solved.
As in the aforesaid item (2), however, the problem to be solved by the Invention
113

should be to provide a compound having excellent HMG-CoA reductase inhibiting
activity to the extent that the compound may become a pharmaceutical product for
suppressing the biosynthesis of cholesterols, and to provide an HMG-CoA reductase
inhibitor including the compound as an active ingredient.

It can be said that the

Detailed Description of the Invention of the specification discloses to the extent thatallows a person ordinarily skilled in the art to recognize that this problem can besolved. The above argument by Plaintiffs is premised on the fact that the Invention
needs to have a "significant" HMG-CoA reductase inhibiting activity.

But suchargument is based on an incorrect premise, and thus is not acceptable.
(B)

Plaintiffs argue that the compound of the Invention is a selection

invention of general formula (I) of Exhibit Ko 2, and thus no new technique isdisclosed by specifying a structure without the disclosure of significant activity.
However, the determination of whether or not to conform to the support
requirement should be made independent of the determination of the inventive step, asin the aforesaid item A(B).
Therefore, the above argument presented by Plaintiffs is not acceptable due tothe erroneous premise.
(C) Plaintiffs argue that the Patentee had admitted in the trial that Invention
1 was not supported by data of the compound (Ia-1) described in the Detailed
Description of the Invention of the specification, and thus a person ordinarily skilled in
the art could not recognize that the problem might be solved by Invention 1.
The determination of the support requirement should be made, however, withrespect to the recitation of the scope of claims and the description of the Detailed
Description of the Invention in view of the common general technical knowledge as of
the filing.

It cannot be construed that the determination varies depending on the

Patentee's argument in the trial stage.
Therefore, the above argument presented by Plaintiffs is not acceptable.
C

Plaintiffs argue that, even if compound Ia-1 of the Detailed Description of

the Invention of the specification has an HMG-CoA reductase inhibiting activity
higher than that of sodium Mevinolin, since Exhibit Ko 16 suggests that the HMGCoA reductase inhibiting activity decreases by a factor of 100 times or more by
substituting an isopropyl group corresponding to R3 of the formula (I) of the Invention
1 in compound Ia-1 with a methyl group, it cannot be recognized that a person
114

ordinarily skilled in the art could understand that the overall range of compounds of theInvention 1 has a higher HMG-CoA reductase inhibiting activity compared to sodium
Mevinolin, like compound Ia-1.
Indeed, there is a large difference in HMG-CoA reductase inhibiting activity
between compound 2t and compound 2r or 2s among the compounds of Exhibit Ko 16,
the moiety corresponding to R3 of formula (I) of Invention 1 is an isopropyl group for
2t, whereas it is a methyl group for 2r and 2s.

In addition to the above, however, 2t,

and 2r or 2s of Exhibit Ko 16 are different from each other in that the moiety
corresponding to "-X-R1" of formula (I) of the Invention 1 is an isopropyl group for 2t,
whereas it is a methyl group for 2r and 2s. As for this difference, Plaintiffs argue that
HMG-CoA reductase inhibiting activity may be reduced by at most a factor of threetimes as a result of the comparison between the compounds of pyrimidine ring skeleton,
2f and 2e, of Exhibit Ko 16. Exhibit Ko 16 only discloses that "In general, thestructure-activity relationship of pyrimidine (2r-w) is comparable to the structureactivity relationship of pyridines (2a-q) (e.g. 2i vs. 2v, 2a vs. 2r, 2j vs. 2w; Table 1)."
Exhibit Ko 16 may not be evaluated as describing that the effect of the difference in a
structure other than a ring structure on the HMG-CoA reductase inhibiting activity iscomparable between a compound with a pyridine ring skeleton and a compound with apyrimidine ring skeleton.

Therefore, it cannot be said that, regarding the compoundswith pyrimidine ring skeleton of the compound 2t and the compounds 2r and 2s of
Exhibit Ko 16, the effect of the difference in a moiety corresponding to "-X-R1" offormula (I) of the Invention 1 on the HMG-CoA reductase inhibiting activity is a factor
of about 3 times. Furthermore, compound Ia-1 has alkylsulfonyl group at a moiety
corresponding to "-X-R1" of formula (I) of Invention 1, which differs from the above 2t,
2r, and 2s.
Consequently, it is insufficient to find the common general technical knowledgeof a person ordinarily skilled in the art as of the filing from only Exhibit Ko 16 that the
HMG-CoA reductase inhibiting activity decreases by a factor of 100 times or more by
substituting an isopropyl group corresponding to R3 of formula (I) of the Invention incompound Ia-1 with a methyl group.
Therefore, the above argument presented by Plaintiffs is not acceptable.
(5) Summary
As seen above, it cannot be said that the Inventions 1, 2, 5, and 9 to 12 do notcomply with the provisions of Article 36, paragraph (5), item (i) of the Patent Act prior115

to amendment by Act No.116 of 1994, of which the provisions then in force shallremain applicable according to revision supplement Article 6, paragraph (2) of Act No.
116 of 1994.
Therefore, none of the ground 2 for rescission presented by Plaintiffs isreasonable.
No. 8

Conclusion
Accordingly, none of the argument of the ground for rescission presented by

Plaintiffs is reasonable.
Therefore, all the Plaintiffs' claims shall be dismissed, and the court renders as
in the main text.

Intellectual Property High Court, Special Division

Chief Judge
Misao SHIMIZU
Judge
Makiko TAKABE
Judge
Yoshiyuki MORI
Judge
Toshihiko TSURUOKA
Judge
Ayako MORIOKA

116