Patent
Right

Date
Case number

June 17, 20202019 (Gyo-Ke) 10118

CourtIntellectual
Property
High Court, Second
Division- A case in which, in a lawsuit for a rescission of a JPO decision with regard to an
invention titled "TOPICAL OPHTHALMIC FORMULATIONS CONTAININGDOXEPIN DERIVATIVES FOR TREATING ALLERGIC EYE DISEASES", in acourt to which the case was remanded, an invention step was acknowledged, basedon the determination that it can be acknowledged that an effect of the invention isremarkable beyond the scope of effects that a person ordinarily skilled in the art
could have predicted as being achieved by the configuration of the invention.
Case type: Rescission of Trial Decision to Maintain
Result: Dismissed
References: Article 29, paragraph (2) of the Patent Act
Related rights, etc.: Patent No. 3068858
Decision of JPO: Invalidation Trial No. 2011-800018 (trial decision rendered on
December 1, 2016)
Summary of the Judgment
1. Outline of Procedures at the JPO and History of Lawsuit, etc.
(1) Previous Lawsuit Judgment
On January 22, 2013, the JPO rendered a trial decision to maintain the patent of
the present case (hereinafter referred to as "the Second Trial Decision"), regarding
Invalidation Trial No. 2011-800018 case filed by the Plaintiff, based on thedetermination that it cannot be deemed that the invention of the present case would
have been motivated from the invention disclosed in Exhibit Ko 1 (hereinafterreferred to as "Invention of Exhibit Ko 1") and the invention disclosed in Exhibit Ko
4 (hereinafter referred to as "Invention of Exhibit Ko 4").

However, on July 30,

2014, the Intellectual Property High Court rendered a judgment to rescind the Second
Trial Decision (hereinafter referred to as "the Previous Lawsuit Judgment").
Thereafter, the Previous Lawsuit Judgment became final and binding.
(2) Decision and Judgment, etc., after the Previous Lawsuit Judgment
On December 1, 2016, the JPO rendered a trial decision to accept the request for acorrection filed on February 1, 2016 (hereinafter referred to as "the Present
Correction", the invention according to Claim 1 after the correction is referred to as"Present Invention 1", the invention according to Claim 5 after the correction isreferred to as "Present Invention 2", and these inventions are collectively referred toas "the Present Inventions") and to maintain the patent of the present case.
ⅰ

However,

on November 21, 2017, the Intellectual Property High Court rendered a judgment torescind the trial decision of the present case (hereinafter referred to as the "theJudgment before the Remand").

The Judgment before the Remand held that on thepremise that the configuration of each of the Present Inventions would have been
easily conceivable from the Invention of Exhibit Ko 1 and the Invention of Exhibit Ko
4 to a person ordinarily skilled in the art, it cannot be deemed that an effect of each of
the Present Inventions is a remarkable effect which would have been difficult topredict by a person ordinarily skilled in the art, and thus, held that the trial decision of
the present case erred in the determination concerning the effect of each of the Present
Inventions.
The final appellate court quashed the Judgment before the Remand, and remanded
the present case to the Intellectual Property High Court on the grounds that the
Judgment before the Remand was unlawful in interpreting and applying the laws andregulations, because the Judgment before the Remand rescinded the trial decision of
the present case due to the fact that the Judgment before the Remand denied that theeffect of each of the Present Inventions is remarkable and unpredictable.
2. Reason 1 for Rescission (Reason 2 for Invalidation: Erroneous Determinations ofInventive Step Based on Invention of Exhibit Ko 1)(1) The Previous Lawsuit Judgment determined that with regard to each of the
Present Inventions, there would have been a motivation to arrive at the configurationof the invention.

In this regard, even when there would have been a motivation toarrive at the configuration of the invention, in the case where an effect of theinvention is remarkable to the extent that the effect of the invention exceeds the effectthat a person ordinarily skilled in the art could have predicted as being achieved by
the configuration of the invention at the time of the priority date, it cannot be
acknowledged that such invention could have been easily made by a person ordinarily
skilled in the art.

The Previous Lawsuit Judgment did not determine to the extent

whether or not each of the Present Inventions has such an unpredictable andremarkable effect, and therefore, it is construed that the binding effect of the Previous
Lawsuit Judgment (Article 33, paragraph (1) of the Administrative Case LitigationAct) does not extend to this issue.
(2) Present Invention 1
A. According to the description of the present case, in an experiment to measure
an inhibition rate of histamine release from human conjunctival mast cells byadministering a drug to a cell population in which human conjunctival mast cells were
cultured, with regard to the compound of the Present Invention (hereinafter referred toⅱ

as "the present compound"), it can be acknowledged that an inhibition rate ofhistamine release from human conjunctival mast cells increased in a concentration dependent manner between 30 μM and 2000 μM, to a maximum value of 92.6%, andbetween these concentrations, unlike the cases of cromolyn sodium and nedocromil
sodium, a phenomenon of decreasing the inhibition rate did not occur with higher
doses (concentrations) than the dose (concentration) at which the maximum inhibition
rate was reached.
B(A) With regard to the present compound, there is no evidence that it can be
acknowledged that the above A was clear at the time of the priority date of the present
case.
(B) It can be acknowledged that ketotifen has an application as a hum an
conjunctival mast cell stabilizing agent in humans, in contrast to the results ofexperiments in guinea pigs (Exhibit Ko 1), where the inhibition rate of histamine
release was 67.5% at 5 minutes after the induction and 67.2% at 10 minutes after the
induction.

However, there is no evidence that it can be acknowledged that, at thetime of the priority date of the present case, it was clear whether or not ketotifen has aconcentration-dependent effect on an inhibition rate of histamine release from human
conjunctival mast cells between 30 μM and 2000 μM.
In addition, there is no evidence that it can be acknowledged that it was known toa person ordinarily skilled in the art at the time of the priority date of the present casethat Chlorpheniramine (chlorpheniramine), which is stated in Exhibit Ko 1 as nothaving an inhibitory effect on histamine release in the conjunctiva in guinea pigs aswell as Ketotifen (ketotifen) and the present compound, has a stabilizing effect onhuman conjunctival mast cells.
Further, anti-allergic drugs with a tricyclic skeleton include amelexanox(Amelexanox in Exhibit Ko 1) and nedocromil sodium as well as the present
compound and ketotifen.

However, only the fact that the compounds are common to

the extent that they are tricyclic compounds does not provide a basis for a person
ordinarily skilled in the art to expect the same kind and the same level of efficacy instabilizing human conjunctival mast cells.
Therefore, it cannot be deemed that a person ordinarily skilled in the art, who hadread the disclosure of Exhibit Ko 1, could have predicted from the effect of ketotifen
that the present compound would have the effect on human conjunctival mast cells as
mentioned in the above A.
(C) At the time of the priority date of the present case, even if there were
documents on inhibitory effects of eye drop solutions containing procaterolⅲ

hydrochloride, disodium cromoglycate, and pemirolast potassium on the reaction topatients with cedar pollen allergy (Exhibits Ko 20, 34, and 37), the chemical structureof the present compound is remarkably different from those of procaterolhydrochloride (Exhibit Ko 20), disodium cromoglycate (Exhibit Ko 34), andpemirolast potassium (Exhibit Ko 37).

In addition, from the experimental results as

disclosed in Exhibits Ko 20, 34, and 37, it cannot be acknowledged that it is clear
whether or not procaterol hydrochloride (Exhibit Ko 20), disodium cromoglycate(Exhibit Ko 34), and pemirolast potassium (Exhibit Ko 37) have concentration dependent effects between 30 μM and 2000 μM on the inhibition rate of histamine
release from human conjunctival mast cells.
Therefore, from each disclosure of Exhibits Ko 20, 34, and 37, it cannot be
deemed that it would have been possible to predict that the present compound would
have the effect on inhibiting histamine release from human conjunctival mast cells as
mentioned in the above A.
C. According to the above, it can be acknowledged that the effect of Present
Invention 1 is remarkable beyond the scope of effects that a person ordinarily skilledin the art could have predicted as being achieved by the configuration of the invention.
Therefore, it cannot be acknowledged that Present Invention 1 could have been easily
made by a person ordinarily skilled in the art.
(3) Present Invention 2
Present Invention 2 is limited to the Z form (cis isomer) of the present compoundof Present Invention 1.

Further, in Present Invention 2, the matter "inhibits

histamine release from a human conjunctival mast cell by 66.7% or more" for defining
the invention is added to Present Invention 1.
same effect as Present Invention 1.

Then, Present Invention 2 achieves the

According to the above (2), it can be deemedthat the effect of Present Invention 2 is remarkable beyond the scope of effects that aperson ordinarily skilled in the art could have predicted from Exhibits Ko 1 and 4, andthe common general technical knowledge at the time of the priority date of the present
case.
Further, it cannot be acknowledged that a person ordinarily skilled in the art co uld
have predicted the effects of the present compound on the basis of the effect of
ketotifen and Exhibits Ko 20, 34, and 37, as mentioned in the above (2).
Therefore, it cannot be acknowledged that Present Invention 2 could have been
easily made by a person ordinarily skilled in the art.

ⅳ

Judgment rendered on June 17, 20202019 (Gyo-Ke) 10118 A case of seeking rescission of the JPO decision
Date of conclusion of oral argument: February 17, 2020
Judgment
Plaintiff:

X

Defendant: Alcon Research, Ltd.
Former Trade Name: Kyowa Hakko Kirin Co., Ltd.
Defendant: Kyowa Kirin Co., Ltd.

Main Text
1. The Plaintiff's claim shall be dismissed.
2. The court costs shall be borne by the Plaintiff.
Facts and ReasonsNo. 1 Claim
A trial decision for Invalidation Trial No. 2011-800018 rendered by the JPO on
December 1, 2016 shall be rescinded.
No. 2 Outline of the Case
The present case is a lawsuit seeking rescission of the JPO decision to maintainwith regard to a request for a trial for patent invalidation.

The issue is whether or

not the inventions of Claims 1 and 5 after the correction of the patent of the present
case have an inventive step (a remarkable effect).
1. Outline of Procedures at the JPO and History of Lawsuit, etc.
(1) The Defendants are patentees of a patent right for an invention titled"TOPICALOPHTHALMIC

FORMULATIONSCONTAININGDOXEPINDERIVATIVES FOR TREATING ALLERGIC EYE DISEASES" (Patent No.
3068858, hereinafter referred to as "the present patent right", the patent concerning
the present patent right is referred to as "the present patent", Exhibit Ko 81).
The patent application for the present patent was filed on May 3, 1996,
claiming priority based on a patent application filed in the United States of America
1on June 6, 1995 (this filing date, which forms the basis for the priority claimed, ishereinafter referred to as "the priority date of the present case").

The establishmentof the present patent was registered on May 19, 2000 (Exhibit Ko 81).
(2) First Trial Decision
A. On February 3, 2011, the Plaintiff filed a request for a trial forinvalidation of the present patent with the JPO, and this case became pending as
Invalidation Trial No. 2011-800018.
B. On May 23, 2011, the Defendants filed a request for a correction of the
Scope of Claims of the present patent (hereinafter also referred to as "the First
Correction").
C. On December 16, 2011, the JPO rendered a trial decision (hereinafterreferred to as "the First Trial Decision") to accept the First Correction and toinvalidate the patent concerning the inventions of Claims 1 to 12 (Exhibit Ko 82).
D. On April 24, 2012, the Defendants instituted a lawsuit for seeking of a
rescission of the First Trial Decision (The Intellectual Property High Court, 2012
(Gyo-Ke) 10145).

Thereafter, on June 29, 2012, the Defendants filed a request for acorrection trial for correcting the Scope of Claims of the present patent.
E. On July 11, 2012, the Intellectual Property High Court rendered a rulingto rescind the First Trial Decision on the basis of Article 181, paragraph (2) of the
Patent Act prior to the revision made by Act No. 63 of 2011.
(3) Second Trial Decision
A. The JPO resumed the proceedings of Invalidation Trial No. 2011-800018
in response to the ruling mentioned in the above (2)E.

On August 10, 2012, theDefendants filed a request for a correction of the Scope of Claims of the present
patent (hereinafter also referred to as "the Second Correction").
B. The Scope of Claims after the Second Correction is stated as follows(Exhibit Ko 83).
[Claim 1] A human conjunctival mast cell stabilizing agent for ophthalmic us e, whichis topically administrable and is prepared as an eye drop for the treatment of allergic
eye diseases in humans, comprising a therapeutically effective amount of 11-(3dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic

acid

or

a

pharmaceutically acceptable salt thereof.
[Claim 2] A topically administrable composition for ophthalmic use, which is for thetreatment of allergic eye diseases in humans, comprising a therapeutically effective
amount of 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic
acid

or

a

pharmaceutically

acceptable2

salt

thereof,whereinthe11 -(3-

dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid is (Z)-11-(3dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic
substantially

free

of

acid,

and

is

(E)-11-(3-dimethylaminopropylidene)-6,11-

dihydrodibenz[b,e]oxepin-2-acetic acid, and wherein the topically administrable
composition achieves a human conjunctival mast cell stabilizing effect.
(Hereinafter,"11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-

acetic acid" may be referred to as "the present compound").
C. On January 22, 2013, the JPO rendered a trial decision to accept theSecond Correction and to maintain the present patent (hereinafter refer red to as "theSecond Trial Decision"), based on the determination as follows: it cannot be deemedthat the matter "human conjunctival mast cell stabilizing" for defining the invention ineach of the inventions after the Second Correction would have been motivated fromthe invention disclosed in Exhibit Ko 1 (KAMEI Chiaki et al. "Morumotto no Jikken
teki Arerugi sei Ketsumakuen ni taisuru Ko Arerugi Yaku no Eikyo (Effects ofAntiallergic Drugs on Experimental Allergic Conjunctivitis in Guinea Pigs)" Atarasi i
Ganka (New Ophthalmology), Vol. 11, No. 4, Pages 603-605, 1994 (in Japanese))(hereinafter referred to as "Invention of Exhibit Ko 1") and the invention disclosed in
Exhibit Ko 4 (Unexamined Patent Application Publication No. 1988-10784)(hereinafter referred to as "Invention of Exhibit Ko 4"); and thus, Reason forInvalidation asserted by the Plaintiff; i.e., lack of an inventive step based on theInvention of Exhibit Ko 1 as the primary cited document, is unfounded (Exhibit Ko
83).
D. On March 1, 2013, the Plaintiff instituted a lawsuit seeking a rescissionof the Second Trial Decision (The Intellectual Property High Court, 2013 (Gyo-Ke)
10058).
E. On July 30, 2014, the Intellectual Property High Court rendered a
judgment (hereinafter referred to as "the Previous Lawsuit Judgment") to rescind theSecond Trial Decision.

The Previous Lawsuit Judgment held that the Second Trial

Decision erred in determining that "it cannot be deemed that the matter 'human
conjunctival mast cell stabilizing' for defining the invention in each of the inventions
after the Second Correction would have been motivated from the Invention of Exhibit
Ko 1 and the Invention of Exhibit Ko 4, and thus, the Reason for Invalidation asserted
by the Plaintiff; i.e., lack of an inventive step based on Invention of Exhibit Ko 1 as
the primary cited document, is unfounded", because it can be acknowledged that aperson ordinarily skilled in the art, who had read Exhibits Ko 1 and 4, would havebeen motivated to apply an eyedrop containing KW-4679 (hydrochloride of the cis
3isomer of the present compound) for inhibiting allergic conjunctivitis as disclosed in
Exhibit Ko 1 to an eye drop for allergic eye diseases in humans, and that whenattempting to apply KW-4679, the person ordinarily skilled in the art would haveconfirmed that KW-4679 has an effect of inhibiting histamine release from human
conjunctival mast cells (human conjunctival mast cell stabilizing effect), and would
have easily conceived of an idea of applying it to a human conjunctival mast cellstabilizing agent (Exhibit Ko 84).

The above judgment became final and binding on

January 12, 2016.
(4) Decision after the Previous Lawsuit Judgment
A. The JPO resumed the proceedings of Invalidation Trial No. 2011-800018
in response to the Previous Lawsuit Judgment.

On February 1, 2016, the Defendants

filed a request for a correction (hereinafter referred to as "the Present Correction" ,Claims 1 and 5 after the correction are as mentioned in 2 below, the invention
according to Claim 1 after the correction is referred to as "Present Invention 1" theinvention according to Claim 5 after the correction is referred to as "Present Invention
2", these inventions are collectively referred to as "the Present Inventions", and thedescription and the drawings after the correction are referred to as "the present
description") (Exhibit Ko 207).
B. On December 1, 2016, the JPO rendered a trial decision to accept the
Present Correction and to maintain the present patent (the summary of reasons
therefor is as mentioned in 4 below, hereinafter referred to as "the Present Trial
Decision").

On December 9, 2016, a certified copy of the Present Trial Decision wasserved on the Plaintiff.
C. On January 6, 2017, the Plaintiff instituted a lawsuit for seeking a
rescission of the Present Trial Decision.
(5) Judgment of the Intellectual Property High Court before the Remand
A. On November 21, 2017, the Intellectual Property High Court rendered a
judgment to rescind the Present Trial Decision (hereinafter referred to as the "theJudgment before the Remand").

The Judgment before the Remand held that on thepremise that the configuration of each of the Present Inventions would have been
easily conceivable from the Invention of Exhibit Ko 1 and the Invention of Exhibit Ko
4 to a person ordinarily skilled in the art, it cannot be deemed that an effect of each of
the Present Inventions is a remarkable effect which would have been difficult topredict by a person ordinarily skilled in the art, and thus, held that the Present Trial
Decision erred in the determination concerning the effect of each of the Present
Inventions.
4B. The Defendants filed a petition for acceptance of the final appeal against
the Judgment before the Remand.
(6) Determination by the Final Appellate Court
The final appellate court quashed the Judgment before the Remand, andremanded the present case to the Intellectual Property High Court on the grounds that
the Judgment before the Remand was unlawful in interpreting and applying the laws
and regulations, because the Judgment before the Remand rescinded the Present Trial
Decision due to the fact that the Judgment before the Remand denied that the effect ofeach of the Present Inventions is remarkable and unpredictable.
2. Statement of the Scope of Claims
After the Present Correction, the statement of Claims 1 and 5 in the Scope ofClaims of the present patent is as follows.
[Claim 1] A human conjunctival mast cell stabilizing agent for ophthalmic use, whichis topically administrable and is prepared as an eye drop for the treatment of allergic
eye diseases in humans, comprising a therapeutically effective amount of 11-(3dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic

acid

or

a

pharmaceutically acceptable salt thereof (the same as Claim 1 before the Present
Correction).
[Claim 5] A human conjunctival mast cell stabilizing agent for ophthalmic use, whichis topically administrable and is prepared as an eye drop for the treat ment of allergic
eye diseases in humans, comprising a therapeutically effective amount of 11-(3dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic

acid

or

pharmaceuticallythe

11-(3-

acceptable

salt

thereof,whereinadimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid is (Z)-11-(3dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic
substantially

free

of

acid,

and

is

(E)-11-(3-dimethylaminopropylidene)-6,11-

dihydrodibenz[b,e]oxepin-2-acetic acid, and wherein the human conjunctival mast cellstabilizing agent inhibits histamine release from a human conjunctival mast cell by
66.7% or more.
3. Reasons for Invalidation Asserted by the Plaintiff(1) Reason 1 for Invalidation (Lack of Novelty Based on Exhibit Ko 1 asPrimary Cited Document)
Each of the Present Inventions is the Invention of Exhibit Ko 1, which is a
publication distributed prior to the priority date of the present case.
(2) Reason 2 for Invalidation (Lack of Inventive Step Based on Exhibit Ko 1
as Primary Cited Document)
5Each of the Present Inventions could have been easily made by a person
ordinarily skilled in the art on the basis of the Invention of Exhibit Ko 1 and theInvention of Exhibit Ko 4.
(3) Reason 3 for Invalidation (Lack of Inventive Step Based on Exhibit Ko 3
as Primary Cited Document)
Each of the Present Inventions could have been easily made by a person
ordinarily skilled in the art on the basis of the invention disclosed in Exhibit Ko 3
(Unexamined Patent Application Publication No. 1987-45557) (hereinafter referred toas "Invention of Exhibit Ko 3") as well as the Invention of Exhibit Ko 1 and theInvention of Exhibit Ko 4.
4. Summary of Reasons of the Present Trial Decision(1) Reason 1 for Invalidation (Lack of Novelty Based on Exhibit Ko 1 asPrimary Cited Document)
It cannot be deemed that each of the Present Inventions is the Invention of
Exhibit Ko 1.

Thus, Reason 1 for Invalidation is unfounded.

(2) Reason 2 for Invalidation (Lack of Inventive Step Based on Exhibit Ko 1
as Primary Cited Document)
A. Present Invention 1(a) The Plaintiff asserts the following different features between Present
Invention 1 and the Invention of Exhibit Ko 1.
a. Different Feature 1
With regard to allergic eye diseases, Present Invention 1 is specified as "inhumans".

In contrast, the Invention of Exhibit Ko 1 is not specified as such.
b. Different Feature 2

With regard to a composition (agent) for ophthalmic use, Present Invention 1 is
specified as "a human conjunctival mast cell stabilizing agent for ophthalmic use".
In contrast, the Invention of Exhibit Ko 1 is not specified as such.
c. Different Feature 3
Present Invention 1 is specified as "prepared as an eye drop".

In contrast, theInvention of Exhibit Ko 1 is not specified as such.
(b) Different Features 1 and 2
Under the binding effect of the Previous Lawsuit Judgment, it is deemed thatboth of the matter specified as "in humans" (Different Feature 1) and the matter
specified as "a human conjunctival mast cell stabilizing agent for ophthalmic use"
(Different Feature 2) in Present Invention 1 would have been easily conceivable to aperson ordinarily skilled in the art who had read Exhibits Ko 1 and 4.
6

(c) Different Feature 3
An eye drop is a dosage form commonly used as a topically administrable
formulation in the field of ophthalmology.

Therefore, the matter specified as"prepared as an eye drop" in Present Invention 1 is merely a design matter.
(d) Effect Achieved by Present Invention 1
a. Table 1 of the present description shows experimental results which
compare stabilizing effects of human conjunctival mast cells by comparing inhibition
rates of histamine release from human conjunctival mast cells.

Cromolyn sodium

and nedocromil sodium as disclosed in Table 1 are compounds which were widely
known to a person ordinarily skilled in the art at the time of the priority date of thepresent case as compounds having mast cell stabilizing actions.
Among the experimental results as shown in Table 1, inhibition rates ofhistamine release obtained after treatment of human conjunctival mast cells with eachof the above compounds 15 minutes before anti-human IgE stimulation are compared.
As for cromolyn sodium, an inhibition rate reached a maximum value of 10.6% at adose of 10 μM.

However, the inhibition rate decreased with further dose(concentration) increase, and the inhibition rate became a negative value at doses of
100 μM or more; that is, a phenomenon of promoting histamine release occurred.

In

addition, as for nedocromil sodium, an inhibition rate reached a maximum value of
28.2% at a dose of 100 μM.

However, the inhibition rate decreased with further dose(concentration) increase, decreasing to 7.2% at a dose of 1000 μM.
In contrast, as for the present compound, an inhibition rate of histamine release
increased in a dose-dependent manner up to a high dose (high concentration) of 2000
μM, such as 29.6% at a dose of 300 μM, 47.5% at 600 μM, 66.7% at 1000 μM, and92.6% at 2000 μM.

That is, after the inhibition rate of histamine release reached amaximum value, a phenomenon of decreasing the inhibition rate of histamine release
did not occur with further dose increase, in contrast to the case of cromolyn sodium
and nedocromil sodium.
b. Exhibit Ko 1 discloses that when "an effect of each drug on histamine
release from the conjunctiva caused by the antigen-antibody reaction wasinvestigated", "KW-4679 was ineffective."

Thus, Exhibit Ko 1 discloses that KW-

4679 does not inhibit histamine release from the conjunctiva in guinea pigs; i.e., KW4679 does not have a stabilizing action on conjunctival mast cells in guinea pigs.
In

addition,"cis-11-(3-dimethylaminopropylidene)-6,11-

dihydrodibenz[b,e]oxepin-2-acetic

acid"

and

dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic
7"trans-11-(3acid"asdisclosed in Exhibit Ko 4 (Compound No. 20) correspond to the cis isomer and thetrans isomer of the present compound, respectively.

Further, Exhibit Ko 4 discloses

that these compounds have a PCA inhibitory action in rats and that the PCA inhibitory
action is considered to be based on an action of inhibiting release of a chemical
mediator such as histamine from skin mast cell in rats.
Thus, Exhibit Ko 1 discloses the results of the experiments using conjunctival
mast cells in guinea pigs, and Exhibit Ko 4 discloses the results of the experiments
using skin mast cells in rats.

However, neither Exhibit Ko 1 nor Exhibit Ko 4

discloses a result of an experiment using "conjunctival mast cells in humans."
The Previous Lawsuit Judgment held that it was common general technicalknowledge at the time of the priority date of the present case that a histamine releaseinhibitory action of a drug on a mast cell may be different for different mast cell
species or tissues, and that from an experimental result on a mast cell in one tissue of
one animal species, it is not necessarily possible to predict an experimental result on amast cell in another tissue of another animal species.
Taking the above common general technical knowledge into consideration, it
cannot be deemed that an action of KW-4679 of Exhibit Ko 1 on human conjunctival
mast cells could have been specifically predicted by a person ordinarily skilled in theart, on the basis of the results of the experiments using conjunctival mast cells inguinea pigs as disclosed in Exhibit Ko 1 and skin mast cells in rats as disclosed in
Exhibit Ko 4.
In addition, according to the disclosure of Exhibit Ko 1, KW-4679 does nothave a stabilizing action on conjunctival mast cells in guinea pigs.

Thus, a person

ordinarily skilled in the art could not have predicted that KW-4679 has a stabilizing
action on human conjunctival mast cells.
Further, the ''skin'' mast cells in rats used in Exhibit Ko 4 are mast cells of atissue which is different from the "conjunctiva".

Furthermore, Exhibit Ko 4 does notdisclose a result of an experiment using skin mast cells or conjunctival mast cells inrats to confirm an inhibitory effect of histamine release.

Therefore, a person

ordinarily skilled in the art could not have predicted that the compound of "CompoundNo. 20" in Exhibit Ko 4 (the cis isomer and the trans isomer of the present compound)
has a stabilizing action on human conjunctival mast cells.
c. The experiment to investigate an inhibition rate of histamine releasefrom human conjunctival mast cells in Exhibit Ko 39 (J. M. YANNI et al. "The In
Vitro and In Vivo Ocular Pharmacology of Olopatadine (AL-4943A), an Effective
Anti-Allergic / Antihistaminic Agent" Journal of Ocular Pharmacology and8Therapeutics Vol. 12, No. 4, pages 389-400, 1996) is an experiment using the same
conditions as in the experiment in Table 1 of the present description.
Exhibit Ko 39 shows an inhibition rate of histamine release of AL-4943A (thecis isomer of the present compound) and ketotifen (Ketotifen as disclosed in ExhibitKo 1) in Graph B of Figure 1.

Exhibit Ko 39 discloses the experimental results

showing that a concentration (dose) of AL-4943A increased in a dose-dependent
manner even when the concentration (dose) of AL-4943A reached approximately
2000 μM, and that an inhibition rate of approximately 90% was maintained even when
the concentration increased to 10000 μM, and that an IC 50 value (a concentration atwhich an inhibition rate reaches 50%) was 559 ± 277 μM.

These experimental

results disclosed in Exhibit Ko 39, in which "a concentration (dose) of AL-4943A
increased in a dose-dependent manner even when the concentration (dose) of AL4943A reached approximately 2000 μM" and in which "an IC 50 value (a concentration
at which an inhibition rate reaches 50%) was 559 ± 277 μM" are both equivalent to
the experimental results in Table 1 of the present description showing that the
inhibition rate of histamine release in human conjunctival mast cells by the present
compound increased in a dose-dependent manner up to 2000 μM and is 47.5% at 600
μM.
On the other hand, at the time of the priority date of the present case, ketotifen
was an active ingredient in a drug which was available on the market for the treatmentof allergic conjunctivitis as "Zaditen (R) Eye Drops Solution 0.05%".

Ketotifen had

been known for its pharmacological actions, including inhibition of PCA (Passive
Cutaneous Anaphylaxis) reactions and inhibition of the release of chemical mediatorssuch as histamine.

In addition, Exhibit Ko 32 (SAKUMA Yasuko et al. "Sugi

Kahunsho ni taisuru Ketotifen Tengan Yaku no Gan Yuhatu Hannou Yokusei Kouka(Inhibitory Effects of Ketotifen Eye Drops on Ocular-Induced Reaction to Cedar
Pollen Allergy)", Ringan (Japanese Journal of Clinical Ophthalmology), Vol. 43, No.
8, Pages 1251-1254, 1989 (in Japanese)) discloses that according to measurement of
histamine levels in tears of patients with cedar pollen allergy, "0.05% Ketotifen (HC)Eye Drops Solution" significantly achieved an inhibitory effect on histamine releaseas compared to "placebo eye drops solution", and this inhibitory effect on histamine
release is considered to be a result of the inhibition of histamine release from mast
cells which occurs after the induction of an allergic reaction by cedar antigen solution.
Thus, the results of the experiments with ketotifen disclosed in Exhibit Ko 39
merely confirm the significant inhibitory action of ketotifen on histamine release,which was known at the time of the priority date of the present case, by using "human9conjunctival mast cells".
According to the above, Exhibit Ko 39 is a publication distributed in 1996,
which is after the priority date of the present case.

However, the experimental

results on the inhibition rate of histamine release by ketotifen and AL-4943A (the cis
isomer of the present compound) on "human conjunctival mast cells" as disclosed in
Exhibit Ko 39 are the experimental results which should be taken into consideration in
determining the remarkable effect of Present Invention 1.
d. The present description shows in Table 1 that an inhibition rate ofhistamine release by the present compound on "human conjunctival mast cells"
increases in a dose-dependent manner up to a high dose (high concentration) of 2000
μM, and that the maximum inhibition rate of histamine release (92.6% at 2000 μM)
was significantly higher than the maximum values (10.6% and 28.2%) measured withthe control drugs, cromolyn sodium and nedocromil sodium, respectively.
Thus, although Exhibit Ko 1 discloses that KW-4679 does not have astabilizing action on conjunctival mast cells in guinea pigs, the present compound has
a very high inhibition rate of histamine release on "human conjunctival mast cells".
Therefore, it can be deemed that the present compound has a particularly remarkableeffect which could not have been predicted by a person ordinarily skilled in the art.
On the other hand, Exhibit Ko 1 discloses that ketotifen as well as KW -4679
was "ineffective" in inhibiting histamine release from the conjunctiva in guinea pigs;i.e., ketotifen does not have a stabilizing action on conjunctival mast cells in guinea
pigs.
According to the experimental results in Exhibit Ko 39, ketotifen also showed aremarkably high inhibition rate of histamine release on "human conjunctival mast
cells" with a maximum value of approximately 90%, to the same extent as AL-4943A.
However, ketotifen causes a rapid decrease in the inhibition rate of histamine releaseand severe histamine release at concentrations three times higher than theconcentration (approximately 100 μM) which achieves the maximum inhibition rate ofhistamine release on "human conjunctival mast cells".

In contrast, AL-4943A

maintains a maximum inhibition rate of histamine release without decreasing evenwhen reaching 10000 μM, which is a concentration several times the concentration(2000 μM) which achieves the maximum inhibition rate of histamine release on"human conjunctival mast cells."
According to these, it cannot be deemed that a person ordinarily skilled in theart could have predicted the experimental results showing that AL-4943A had a verybroad range of concentrations as compared to ketotifen in achieving the maximum
10inhibition rate of histamine release on "human conjunctival mast cells", even thoughketotifen and KW-4679 were both treated equally as "ineffective" in inhibiting
histamine release from the conjunctiva in guinea pigs in Exhibit Ko 1.
Further, the present description states that "the eye drops produced by theabove method typically need only be applied to the eyes a few times a day in an
amount of one to several drops at a time.

However, in more severe cases, the eye

drops may be applied several times a day.

A typical amount applied to the eyes isabout 30 μl."

The above statement means that the present compound, when applied

to eye drops, not only has an effective effect with a small number of application s oftwice a day, but also has an effective human conjunctival mast cell stabilizing effectwithout any particular difficulty even when a higher dose is administered by applying
the eye drops several times a day if necessary.

That is, the above statement meansthat the present compound has "high efficacy as a pharmaceutical."Thus, it can be deemed that the experimental results shown in Exhibit Ko 39;
i.e., "AL-4943A had a very broad range of concentrations in achieving the maximum
inhibition rate of histamine release", are consistent with the fact that the present
compound has "high efficacy as a pharmaceutical" as stated in the present description.
In addition, it can be deemed that such experimental results are a particularly
remarkable effect which could not have been predicted by a person ordinarily skilledin the art.
As mentioned above, the fact that the present compound has an excellent
stabilizing effect (a high inhibition rate of histamine release) on "human conjunctival
mast cells", and the fact that AL-4943A had a very broad range of concentrations inachieving the maximum inhibition rate of histamine release are both particularly
remarkable effects which could not have been predicted by a person ordinarily skilledin the art from Exhibit Ko 1, Exhibit Ko 4, and the common general technicalknowledge at the time of the priority date of the present case.

Such particularly

remarkable effects should be taken into consideration in determining an inventive step
as advantageous effects as compared to the Invention of Exhibit Ko 1.
B. Present Invention 2
Present Invention 2 adds to Present Invention 1 the matter "inhibits histamine
release from a human conjunctival mast cell by 66.7% or more" for defining theinvention.

However, from Exhibit Ko 1, Exhibit Ko 4, and the common generaltechnical knowledge at the time of the priority date of the present case, it would havebeen very difficult for a person ordinarily skilled in the art to predict that the present
compound "inhibits histamine release from a human conjunctival mast cell by 66.7%
11

or more".

Thus, it cannot be deemed that Present Invention 2 would have been

easily conceivable.
Further, as well as Present Invention 1, it can be acknowledged that an effectachieved by Present Invention 2 is a particularly remarkable effect which could nothave been predicted by a person ordinarily skilled in the art from Exhibit Ko 1,
Exhibit Ko 4, and the common general technical knowledge at the time of the priority
date of the present case.
C. According to the above, it cannot be deemed that it would have been
easily conceivable to obtain the configuration of Present Invention 2 from Exhibit Ko
1, Exhibit Ko 4, and the common general technical knowledge at the time of thepriority date of the present case.

In addition, each of the Present Inventions achieves

advantageous effects as compared to the Invention of Exhibit Ko 1.
Therefore, it cannot be deemed that each of the Present Inventions could havebeen easily made by a person ordinarily skilled in the art on the basis of Exhibit Ko 1,
Exhibit Ko 4, and the common general technical knowledge at the time of the priority
date of the present case.
(3) Reason 3 for Invalidation (Lack of Inventive Step Based on Exhibit Ko 3
as Primary Cited Document)
A. The Plaintiff asserts that Present Invention 1 and the Invention of Exhibit
Ko 3 are common in that "a topically administrable ophthalmic composition (agent)
for the treatment of allergic eye diseases (conjunctivitis) in humans, comprising atherapeutically effective amount of a specific oxepin derivative", and are different in
Different Features 5 to 7 as follows.
(A) Different Feature 5
In Present Invention 1, an oxepin derivative is limited to "11-(3dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic

acid."

In

contrast, in the Invention of Exhibit Ko 3, the oxepin derivative is expressed as a
generic

concept

includingdihydrodibenz[b,e]oxepin-2-acetic acid".

"11-(3-dimethylaminopropylidene)-6,11In Examples of Invention of Exhibit Ko 3,"11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid"is exemplified.
(B) Different Feature 6
Present Invention 1 is specified as "a human conjunctival mast cell stabilizing
agent for ophthalmic use".

In contrast, the Invention of Exhibit Ko 3 is not specified

as such.
(C) Different Feature 7
12

Present Invention 1 is specified as "prepared as an eye drop".

In contrast, theInvention of Exhibit Ko 3 is merely specified as "an ophthalmic solution".
B. Different Feature 7
An eye drop is a dosage form commonly used as a topically administrable
formulation in the field of ophthalmology.

Therefore, the matter specified as"prepared as an eye drop" in Present Invention 1 is merely a design matter.
C. Different Feature 5
Exhibit Ko 3 discloses a compound represented by formula (I) in Markush form
or a salt thereof, and further discloses that in formula (I), R 1 includes CH2-O-, R2 andR3 each include C 1 alkyl, and R4 includes a C 1 bivalent aliphatic hydrocarbon groupwhich is bonded to the aromatic ring system at the 2-position.

In addition, Exhibit

Ko 3 discloses that the compound represented by formula (I) is believed to have antiallergic activity and to inhibit the release of autacoids (histamine, serotonin, and thelike) from mast cells and may be used for the symptomatic control of allergic
conditions including allergic conjunctivitis, and that a formulation includes those
suitable for ophthalmic administration.
Further, Exhibit Ko 3 discloses that (E)/(Z)11-(3-dimethylamino)propylidene)6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid was used as the specific compoundto test an "anaphylactoid activity"; i.e., whether or not symptoms of respiratory
distress were inhibited by challenge of an anaphylactoid inducing agent, compound48/80, in rats.

Furthermore, Exhibit Ko 3 discloses formulation examples including

an ophthalmic solution.
However, Exhibit Ko 3 does not disclose a result of an experiment using thepresent compound of the present patent; i.e., 11-(3-dimethylaminopropylidene)-6,11dihydrodibenz[b,e]oxepin-2-acetic acid.

Thus, it cannot be deemed that Exhibit Ko

3 discloses motivation to select "the present compound" of Different Feature 5 fromthe compounds represented by formula (I) in Markush form or salts thereof, and use"the present compound".
In addition, the system for testing an "anaphylactoid activity" disclosed in
Exhibit Ko 3 evaluates inhibition of respiratory distress induced by an anaphylactoid
inducing agent in rats, and does not evaluate an effect of inhibiting release of
autacoids such as histamine from human conjunctival mast cells; i.e., an effect ofstabilizing human conjunctival mast cells.
Further, Exhibit Ko 3 discloses that "The present compound is believed toinhibit the release of autacoids (i.e., histamine, serotonin, and the like) from mast
cells and to inhibit directly the antigen-induced production of histamine."
13

However,Exhibit Ko 3 does not show the results of the experiments specifically confirming theeffect of inhibiting autacoid release from mast cells.

Thus, the above disclosure of

Exhibit Ko 3 merely indicates an assumption, and the effect of stabilizing mast cells is
not specifically disclosed in Exhibit Ko 3.

Furthermore, in view of the common

general technical knowledge on mast cell heterogeneity at the time of the priority dateof the present case (the above (2)A(D)b), it cannot be deemed that a stabilizing effecton "human conjunctival mast cells" is disclosed in Exhibit Ko 3 on the basis of theresults of the experiments based on the test system for the "anaphylactoid activity"
using rats as disclosed in Exhibit Ko 3.
Thus, taking the disclosure of Exhibit Ko 4 into consideration, even if it would
have been easily conceivable to replace the active compound disclosed in Formulation
Examples of Exhibit Ko 3 (Compound No. 3 in Exhibit Ko 4) with "the present
compound (Compound No. 20 in Exhibit Ko 4)" of Different Feature 5 on the basis of
the fact that "Compound No. 20 (the present compound)" of Exhibit Ko 4 has thesame or a slightly superior anti-allergic action to "Compound No. 3 (the active
compound disclosed in Formulation Examples of Exhibit Ko 3)" of Exhibit Ko 4, itcannot be deemed that it would have been easy to make the invention of Exhibit Ko 3
to be "a human conjunctival mast cell stabilizing agent for ophthalmologic use" ofDifferent Feature 6, since the stabilizing effect on "human conjunctival mast cells" isnot disclosed in Exhibit Ko 3.
D. Different Feature 6
As mentioned in the above C, a person ordinarily skilled in the art who hadread the disclosure of Exhibit Ko 4 could not have predicted that the compound of"Compound No. 20" of Exhibit Ko 4 (the present compound) has a stabilizing action
on human conjunctival mast cells.

Thus, it cannot be deemed that it would havebeen easy to make the invention of Exhibit Ko 3 to be "a human conjunctival mastcell stabilizing agent for ophthalmologic use" of Different Feature 6 on the basis of
the disclosure of Exhibit Ko 4.
In addition, a person ordinarily skilled in the art who had read the disclosure of
Exhibit Ko 1 could not have predicted that KW-4679 of Exhibit Ko 1 (the cis isomerof the present compound) has a stabilizing action on human conjunctival mast cells.
Thus, it cannot be deemed that it would have been easy to make the invention of
Exhibit Ko 3 to be "a human conjunctival mast cell stabilizing agent for
ophthalmologic use" of Different Feature 6 on the basis of the disclosure of Exhibit
Ko 1.
Even if the motivation to select the present compound from the compounds
14

shown in Formula (I) in Markush form in Exhibit Ko 3 or salts thereof, and to apply
the present compound to the use of "a human conjunctival mast cell stabilizing agent"is not denied in view of the descriptions in Exhibit Ko 4 and Exhibit Ko 1, the effects
achieved by each of the Present Inventions are particularly remarkable effects which
could not have been predicted by a person ordinarily skilled in the art from Exhibit
Ko 3, Exhibit Ko 1, Exhibit Ko 4, and the common general technical knowledge at thetime of the priority date of the present case.

Such particularly remarkable effect s

should be taken into consideration as advantageous effects as compared to theInvention of Exhibit Ko 3 in determining an inventive step.
E. As mentioned above, it cannot be deemed that it would have been easily
conceivable to obtain each of the Present Inventions from Exhibit Ko 3, Exhibit Ko 1,
Exhibit Ko 4, and the common general technical knowledge at the time of the priority
date of the present case.

Even if it would have been easily conceivable, each of the

Present Inventions achieves advantageous effects as compared to the Invention of
Exhibit Ko 3.
Therefore, it cannot be deemed that each of the Present Inventions could havebeen easily made by a person ordinarily skilled in the art on the basis of Exhibit Ko 3,
Exhibit Ko 1, Exhibit Ko 4, and the common general technical knowledge at the timeof the priority date of the present case.
(omitted)

No. 5 Judgment of This Court
1. Each of the Present Inventions(1) Claims 1 and 5 in the Scope of Claims after the Second Correction
concerning each of the Present Inventions is as mentioned in the above No. 2, 2.

Thestatement of the present description is as follows (Exhibit Ko 205).
A. Field of the Invention
The present invention relates to topical ophthalmic formulations used fortreating allergic eye diseases, such as allergic conjunctivitis, vernal conjunctivitis,
vernal keratoconjunctivitis, and giant papillary conjunctivitis.

More particularly, thepresent invention relates to therapeutic and prophylactic topical use of 11-(3dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid for treating
and/or preventing allergic eye diseases.
(Page 3, lines 3 to 9)
15

B. Description of the Related Art
As taught in U.S. Patent No. 4,871,865 and No. 4,923,892 ... ("Burroughs
Wellcome Patents"), certain carboxylic acid derivatives of doxepin, including 11 -(3dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid and 11(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepine-2(E)-acrylic
have antihistaminic and antiasthmatic activity.

acid,

These two patents classify the

carboxylic acid derivatives of doxepin as mast cell stabilizers with antihistaminic
action. ...
Although both of the Burroughs Wellcome Patents claim that the variety ofpharmaceutical formulations disclosed are effective for both veterinary and human
medical use, neither patent contains an example demonstrating that the carboxylic
acid derivatives of doxepin have activity in humans.
However, it is now well established that the types of mast cells which exist inrodents are different from those in humans. ... Moreover, mast cell populations exist
within the same species that differ in phenotype, biochemical properties, functional
and pharmacological responses, and ontogeny.

These recognized differences in mast

cells both between and within species are referred to as mast cell heterogeneity. ...
Because different mast cells exhibit different responses to pharmacological agents, it
is not obvious that compounds claimed to be anti-allergic agents ("mast cellstabilizing agents") will have clinical utility in specific mast cell populations.

The

assumption that mast cells are a homogeneous population and that therefore theeffects of anti-allergic drugs observed in experiments in rat mast cells would havebeen predictive of those in human cells is known to be incorrect.
(Page 3, line 10 to page 4, line 18)
Topical ophthalmic formulations which contain drugs having conjunctival mastcell activity may only need to be applied once every 12 to 24 hours instead of once
every 2 to 4 hours.

One disadvantage to the ophthalmic use of reported anti -allergic

drugs which in fact have no human conjunctival mast cell stabilizing activity is anincreased dosage frequency.

Because the effectiveness of ophthalmic formulations

containing drugs which do not have conjunctival mast cell activity stems primarily
from a placebo effect, more frequent doses are typically required than for drugs which
do exhibit conjunctival mast cell activity. ...
What is needed are topically administrable drug compounds that havedemonstrated stabilizing activity on mast cells obtained from human conjunctiva, thetarget cells for treating allergic eye diseases.
(Page 5, lines 10 to page 6, line 5)16

C. Summary of the Invention
The present invention provides a method for treating an allergic eye diseasecharacterized by administering to the eye a topical ophthalmic formulation.

This

topical ophthalmic formulation contains a therapeutically effective amount of 11 -(3dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid (hereinafterreferred to as Compound A) or a pharmaceutically acceptable salt thereof.
formulation

maycontainthecisisomerofCompound

A

The(Z-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid), the transisomerofCompoundA(E-11-(3-dimethylaminopropylidene)-6,11-

dihydrodibenz[b,e]oxepin-2-acetic acid), or a combination of both the cis and thetransisomersofCompoundA,

andunlessspecifiedotherwise,

dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic"11-(3-acid"or"Compound A" means the cis isomer, the trans isomer, or a mixture of the two. …
Compound A has human conjunctival mast cell stabilizing activity, and may be
applied as infrequently as once or twice a day in some cases.

In addition to its mastcell stabilizing activity, Compound A also possesses significant antihistaminic
activity.

Thus, in addition to a prophylactic effect, Compound A will also have atherapeutic effect.
(Page 6, lines 7 to 29)
D. Detailed Description of the Invention
Compound A is a known compound and both the cis and the trans isomers ofCompound A can be obtained by the methods disclosed in U.S. Patent No.
5,116,863 ... . ...
The inhibitory effects of reported anti-allergic, mast cell stabilizing drugs onmast cells obtained from human conjunctiva (the target cells for topical ophthalmic
drug preparations claimed useful in treating allergic conjunctivitis) were tested
according to the following experimental method.

Human conjunctival tissues ...

were weighed and transferred to petri dishes containing culture medium... andequilibrated ... Test compounds were administered to the mast cell cultures either 1 or
15 minutes before stimulation with anti-human IgE.

Inhibition of histamine releaseresulting from challenge of drug treated mast cells was determined by directcomparison with histamine release from vehicle treated, anti-IgE challenged mast
cells ... .

The results are reported in Table 1 below.

As Table 1 clearly shows, the anti-allergic drugs disodium cromoglycate andnedocromil failed to significantly inhibit human conjunctival mast cell degranulation.
In contrast, Compound A (cis isomer) produced concentration-dependent inhibition of17

mast cell degranulation.
(Page 7, line 1 to page 9, line 7)18

Table 1
Effect of Compound on Histamine Release from Human
Conjunctival Tissue Mast Cells upon anti-Human IgE Challenge
Compound

Dose Treatment Inhibition(min)

Cromolyn sodium

Cromolyn sodium

Nedocromil sodium

Nedocromil sodium

Compound*p<0.05, Dunnett's t-test

Compound A may be administered to the eye by means of conventional topicalophthalmic formulations, such as solutions, suspensions, or gels.

The preferred

formulation for topical ophthalmic administration of Compound A is a solution.
solution is administered as eye drops.

The

The preferred form of Compound A in the

topical ophthalmic formulations of the present invention is the cis isomer.

A general

method of preparing the eye drops of the present invention is stated below.
Compound A and an isotonic agent are added to sterilized purified water, and if
19required, a preservative, a buffering agent, a stabilizing agent, a viscous vehicle, andthe like are added to the solution and dissolved therein.

The concentration ofCompound A is 0.0001 to 5 w/v%, preferably 0.001 to 0.2 w/v%, and most preferably
about 0.1 w/v%, based on the sterilized purified water.

After dissolution, the pH isadjusted with a pH controller to be within a range which allows use as an
ophthalmologic medicine, preferably within the range of 4.5 to 8. ...
The eye drops produced by the above method typically need only be applied tothe eyes a few times a day in an amount of one to several drops at a time.

However,in more severe cases, the eye drops may be applied several times a day.

A typical

amount applied to the eyes is about 30 μl.
(Page 13, line 1 (except for Table part) to page 14, line 13)(2) According to the above (1), it can be acknowledged that each of the
Present Inventions is as follows.
A. Each of the Present Inventions relates to therapeutic and prophylactic
topical use of the present compound for treating and/or preventing allergic eyediseases (the above (1)A).
B. The present compound has human conjunctival mast cell stabilizing
activity, and may be applied as infrequently as once or twice a day in some cases.

In

addition to its mast cell stabilizing activity, the present compound also possesses
significant antihistaminic activity.

Therefore, the present compound has atherapeutic effect in addition to a preventive effect. (the above (1)C)
C. The inhibitory effects of anti-allergic, mast cell stabilizing drugs on mast
cells obtained from human conjunctiva were tested.

As a result, the anti-allergic

drugs disodium cromoglycate and sodium nedocromil (it can be acknowledged that "ネドクロシルナトリウム" stated in the present description is a clerical error of "ネドクロミルナトリウム" (sodium nedocromil)) failed to significantly inhibit human
conjunctival mast cell degranulation.

In contrast, the present compound (cis isomer)

produced concentration-dependent inhibition of mast cell degranulation (Table 1) (theabove (1)D).
D. A general method of preparing the eye drops of each of the Present
Inventions is as follows: the present compound and an isotonic agent are added tosterilized purified water, and if required, a preservative, a buffering agent, astabilizing agent, a viscous vehicle, and the like are added to the solution anddissolved therein.

The concentration of the present compound is 0.0001 to 5 w/v%,

preferably 0.001 to 0.2 w/v%, and most preferably about 0.1 w/v%, based on thesterilized purified water. After dissolution, the pH is adjusted with a pH controller to20

be within a range which allows use as an ophthalmologic medicine, preferably within
the range of 4.5 to 8.

(the above (1)D)

E. The eye drops produced by the above method typically need only beapplied to the eyes a few times a day in an amount of one to several drops at a time .
However, in more severe cases, the eye drops may be applied several times a day.

A

typical amount applied to the eyes is about 30 μl. (the above (1)D)
2. Reason 1 for Rescission (Reason 2 forInvalidation:

Erroneous

Determinations of Inventive Step Based on Invention of Exhibit Ko 1)(1) Invention of Exhibit Ko 1
A. Exhibit Ko 1 discloses as follows.
(A) Title
Effects of Anti-allergic Drugs on Experimental Allergic Conjunctivitis in
Guinea Pigs
(B) Abstract
Effects of various anti-allergic drugs on antigen-induced and histamine-induced
conjunctivitis were studied using guinea pigs.

As a result, eye drops ofchlorpheniramine, ketotifen, and KW-4679 showed a more potent inhibitory effect on
histamine-induced conjunctivitis than on antigen-induced conjunctivitis.
(Abstract part, lines 1 to 3)(C) Introduction
Drugs with antihistaminic action, such as chlorpheniramine and ketotifen, arewidely used in the treatment of allergic conjunctivitis.

Previously, the authors foundthat prominent conjunctivitis was induced in guinea pigs by applying antigen andhistamine to the eye.
(Page 603, left column, lines 1 to 6)(D) I. Experimental Method
1. Induction of Conjunctivitis
In the experiment, ... guinea pigs ... five individuals in one group were used. ...
2. Quantification of Conjunctivitis Symptoms
The degree of conjunctivitis was defined as follows.
Score 1: Mild hyperemia is shown.
Score 2: Severe hyperemia is shown.
Score 3: Mild to moderate edema in addition to hyperemia is shown.
Score 4: Prominent edema is shown.
3. Histamine Release from Conjunctiva
Fifteen minutes after applying an antigen to the eye, the conjunctiva was21

excised, weighed, and washed with saline solution.

Then, it was homogenized ...,

centrifuged ..., and the supernatant was cryopreserved.

Thereafter, ... the supernatant

was thawed and centrifuged, and a histamine content of the supernatant wasdetermined by HPLC (High Performance Liquid Chromatography).
4. Measurement of Histamine Content in Tear Fluid
Fifteen minutes after applying an antigen to the eye, saline solution was applied
to the eye, and then collected and ... centrifuged, and a histamine content of thesupernatant was determined by HPLC.
(Page 603, right column, line 1 to page 604, right column, line 2)(E) II. Experimental Results
1. Effects on Antigen-induced Conjunctivitis
Effects of various anti-allergic drugs on allergic conjunctivitis induced byapplying an antigen solution (20 mg/ml) to the conjunctiva in sensitized guinea pigs
are shown in Figure 1.

Chlorpheniramine showed a concentration-dependent

inhibitory action with eye drops of 10 to 100 ng/μl, and a significant difference wasobserved at concentrations of 50 and 100 ng/μl.

Ketotifen, ... and KW-4679 showedsignificant inhibitory actions at concentrations of 10 and 100 ng/μl.

Amelexanox

also showed significant differences at concentrations of 2500 and 5000 ng/μl.
2. Effects on Antigen-induced and Histamine-induced Conjunctivitis
Table 1 shows the effects of various anti-allergic drugs on antigen-induced andhistamine-induced conjunctivitis, with IC 50 values.

Chlorpheniramine, ketotifen, andKW-4679 inhibited histamine-induced conjunctivitis more potently than they
inhibited antigen-induced conjunctivitis. ... Amelexanox inhibited antigen-induced
conjunctivitis but was ineffective in histamine-induced conjunctivitis.
3. Actions on Histamine Release from Conjunctiva
The results showed that ... amelexanox (2500 ng/ml) significantly inhibited
histamine release from the conjunctiva, as shown in Figure 2.

The effects ofchlorpheniramine, ketotifen, and KW-4679 were not significant.
4. Effects on Histamine Content of Tear Fluid
Before applying an antigen to the eye, a histamine content of the tear fluid inguinea pigs was 1.7 ± 0.4 ng/ml, but after applying the antigen to the eye, thehistamine content increased by a factor of approximately five times (8.6 ± 0.8
ng/ml). ... When amelexanox was applied to the eye 15 minutes before the antigen
was applied, the increase in the histamine content of the tear fluid caused by the
antigen-antibody reaction was significantly reduced.
and KW-4679 did not show significant effects.
22

Chlorpheniramine, ketotifen,

(Page 604, right column, line 3 to page 605, left column, line 19)(F) Figure 1
Figure 1 Effects of Anti-Allergic drugs on Conjunctivitis Caused by AntigenAntibody Reactions(G) Table 1
Table 1 Effects of Anti-Allergic Drugs on Antigen-induced and Histamineinduced Conjunctivitis (IC 50)
Table 1 Effects of Anti-Allergic Drugs on Antigeninduced and Histamine-induced Conjunctivitis (IC 50)(H) Figure 2
Figure 2 Effects of Anti-Allergic Drugs on Increasing Histamine Content ofTear Fluid Caused by Antigen-Antibody Reactions

23

(I) III. Discussion
The results of this study show that chlorpheniramine, ketotifen, and KW -4679
had a more potent effect on histamine-induced conjunctivitis than on antigen-induced
conjunctivitis. ... On the other hand, amlexanox showed a positive effect on anti geninduced conjunctivitis, but was ineffective against histamine-induced conjunctivitis.
These findings suggest that chlorpheniramine, ketotifen, and KW-4679 may havesuppressed conjunctivitis caused by the antigen-antibody reaction, mainly due to theantihistaminic action of these drugs.

On the other hand, levocabastine andamlexanox may inhibit histamine release from the conjunctiva caused by the antigen antibody reaction.

Then, an effect of each drug on histamine release from theconjunctiva caused by the antigen-antibody reaction was investigated, and both drugs
showed significant inhibitory effects.

Chlorpheniramine, ketotifen, and KW -4679

were ineffective.
(Page 605, left column, lines 20 to 34)
B. Invention of Exhibit Ko 1
According to the evidence (Exhibits Ko 2-1 and -2) and the entire import of theoral argument, it can be acknowledged that KW-4679 is hydrochloride of "Z-11-(3dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic

acid"(hydrochloride of the Z form [cis isomer] of the present compound), and KW-4679
corresponds

to"apharmaceutically

acceptablesalt"

dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic

of
acid"

"11-(3(thepresent compound) in Present Invention 1, and KW-4679 corresponds to "(Z)-11-(3dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid" (the cis
24isomer of the present compound) in Present Invention 2.
Further, according to the above A, it can be acknowledged that Exhibit Ko 1
discloses the results of experiments using eye drops containing anti-allergic drugs
such as Amelexanox, Chlorpheniramine, Ketotifen, and KW-4679 (hydrochloride of
the cis isomer of the present compound), and that in the experiments using guinea pigs,
the application of chlorpheniramine, Ketotifen, and KW-4679 to the eye showed morepotent inhibitory effects on histamine-induced conjunctivitis than on antigen-induced
conjunctivitis, but showed no significant effects on histamine release from theconjunctiva.
(2) Invention of Exhibit Ko 4
Exhibit Ko 4 discloses as follows.
A. Scope of Claims
...
(2)

An

anti-allergic

agent

comprising,asanactiveingredient,adibenz[b,e]oxepin derivative represented by the formula(wherein: X represents =N-, =CH-, or -CH2-; n represents 0, 1, 2, 3, or 4; and Z
represents a 4-methylpiperazino group, a 4-methylhomopiperazino group, a piperidinogroup, a pyrrolidino group, a thiomorpholino group, a morpholino group, or -NR6R7(wherein R 6 and R7 are the same or different and represent a hydrogen atom or a lower
alkyl group);

represents a single bond or a double bond; when X is =CH- or -CH2-, -Y'-A" represents -Y-A (wherein: A represents a hydroxymethyl group, a lower
alkoxymethyl group, a triphenylmethyloxymethyl group, a lower alkanoyloxymethylgroup, a lower alkanoyl group, a carboxy group, a lower alkoxycarbonyl group, a
triphenylmethyloxycarbonyl group, -CONR1R2 (wherein R 1 and R2 are the same ordifferent and represent a hydrogen atom or a lower alkyl group), a 4,4-dimethyl-2oxazolin-2-yl group, or -CONHOH; and Y represents -(CH2 )m-, -CHR 3-(CH2 )m-, or CR4=CR5-(CH2)m-, which is substituted at the 2-position or 3-position of the mothernucleus (wherein: R 3 represents a lower alkyl group; R4 and R5 are the same ordifferent and each represent a hydrogen atom or a lower alkyl group; and m represents25

0, 1, 2, 3, or 4), wherein the left side of each formula as defined above is bound to themother nucleus), and when X is =N-, -Y'-A" represents -Y-A wherein Y is bonded to
the 2-position of the mother nucleus (wherein Y and A has the same meanings as
defined above)), or a pharmacologically acceptable salt thereof.
...
B. Detailed Description of the Invention(A) The present invention relates to a novel dibenz[b,e] oxepin derivative
and an anti-allergic agent or an anti-inflammatory agent containing the same as anactive ingredient.
(Page 2, left lower column, lines 3 to 5)(B) Table 1 shows specific examples of the compound (I) or apharmacologically acceptable salt thereof obtained by each producing method andTable 2 shows the structures thereof.
(Page 8, right upper column, line 6 (except for the chemical formula part) to line 8)(C) Table 1
a. Compound No. 3
Cis-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2carboxylic acidTrans-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2carboxylic acidb. Compound No. 20
Cis-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic
acid
Trans-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2acetic acidc. Compound No. 3'
1/2 Fumarate-1/5 hydrate of Compound 3 (trans form 99%)d. Compound No. 20'
Fumarate-3/2 hydrate of Compound 20 (trans form 95%)
(D) Test for anti-allergic action
Anti-allergic action was investigated by a homologous PCA (passive cutaneous
anaphylaxis) test of rats for 48 hours.

As experimental animals, Wistar male rats

having body weights of 180 to 220 g were used for sampling of antiserum, and Wistar
male rats having body weights of 120 to 140 g were used for the PCA test.
A) Preparation of anti EWA rat serum...
26B) Homologous PCA test of rats for 48 hours
Groups each consisting of 3 rats were used, and 0.05 ml of anti-EWA rat serum
diluted 8-fold with a physiological saline solution was incutaneously injected each at
two positions of depilated back to make the animals passively sensiti zed.

After 47

hours, the compound of the present invention, or its solution (physiological saline
solution or CMC solution) was orally administered.

One hour thereafter, 0.5 ml/100

g of 1% Evan's blue physiological saline solution containing 2 mg of the antigen
EWA was administered into the tail vein, and 30 minutes thereafter, the animals weresacrificed by exsanguination.

Then, the skins were stripped and the amount of

leaked pigment at the blue-dyed parts was measured according to the method of
Katayama et al. [Microbiol. Immunol. 22, 89 (1978)].

That is, the blue-dyed parts

were cut out by scissors, and placed in test tubes containing 1 ml of 1 N KOH andincubated at 37°C for 24 hours.

Then, 9 ml of a mixture of 0.6 N phosphoric acidand acetone (5:13) was added thereto, and the mixture was shaken and centrifuged atAbsorbancy of the supernatant at 620 μm was measured,2500 rpm for 10 minutes.

and the amount of leaked pigment was quantitatively determined by the calibration
curve prepared in advance.

An average of measurements at the two position wasmade a value for one individual, and an inhibition rate for each individual was
calculated by the following formula:
Inhibition rate (%) =Average leaked amount ofsolvent-administered group

Leaked amount of test compoundadministered group

Average leaked amount of solvent-administered group

Note that the cases where the inhibition rate is 50% or more were regarded as apositive PCA inhibitory action, and a minimum administered dosage where a positive
case was observed in at least one of three individuals was regarded as a minimum
effective dosage (MED).

The results are shown in Table 5.

(Page 13, left lower column, line 3 from the bottom to page 14, left upper column,
line 7 from the bottom)(E) Table 5

27

Acute Toxicity
CompoundNo.

Anti-allergic Action
Number of Positive Individuals in
DosageOne Group of Three Individuals(Cis)(Trans)(Trans)(Trans)(Cis)(F) ... Compound (I) and a pharmacologically acceptable salt thereof havea PCA inhibitory action and/or carageenin paw edema inhibitory action.

The PCA

inhibitory action is considered to be based on an action inhibiting release of achemical mediator such as histamine from skin mast cell.

Therefore, Compound (I)and a pharmacologically acceptable salt thereof are considered to be useful fortreating an allergic disease such as bronchus asthma which is caused by a trachea
contractile action of the chemical mediator such as histamine.
(Page 15, right upper column, line 1 (except for Table part) to line 10)(3) Common General Technical Knowledge at the Time of the Priority Dateof the Present Case
A. Common General Technical Knowledge on Research and Developmentof Drugs for Inhibiting Human Allergic Conjunctivitis(A) Anti-allergic drugs can be broadly classified into two categories
according to their mechanism of action: drugs which have an antagonistic action
against various chemical mediators such as histamine which is produced and released
from mast cells; and drugs which have an inhibitory action on the release of thesechemical mediators from mast cells (Exhibits Ko 12, 30, and 31).

In research anddevelopment of drugs for inhibiting human allergic conjunctivitis, these two actions
were also generally confirmed (Exhibits Ko 7, 10, 12, 20, 23, 30 to 32, 41, and 42).
(B) In the research and development of drugs for inhibiting human allergic
28

conjunctivitis, animal models of conjunctivitis in rats and guinea pigs, which aresimilar to human allergic conjunctivitis, have been developed and used to evaluate
effects of drugs such as eye drops (Exhibits Ko 13 to 18, 41, and 42).
The package insert of the human anti-allergic ophthalmic eye drop which wasmarketed at the time of the priority date of the present case stated in the column of"Drug

EffectsandPharmacology"

that

each

activeingredient

suppressed

conjunctivitis in a rat and guinea pig model of animal conjunctivitis and inhibited therelease of chemical mediators, such as histamine, from rat abdominal cavity mast cells ,etc. (Exhibits Ko 7, 10, and 23).
(with regard to the above (A) and (B), page 83, line 18 to page 84, line 15 of thePrevious Lawsuit Judgment [Exhibit Ko 84])
B. Mast Cell Heterogeneity(A) At the time of the priority date of the present case, it was common
general technical knowledge that a histamine release inhibitory action of drugs onmast cells may be different for different mast cell species or tissues, and that fromresults of experiments on mast cells in one tissue of one animal species, it is notnecessarily possible to predict results of experiments on mast cells in other tissues ofother animal species (Exhibits Ko 101 to 103 and 127 to 129).
(B) However, according to the facts in the above A(B), it cannot be denied
that results of experiments on drug responses in animal conjunctivitis models of rats
and guinea pigs and on drug responses in human conjunctivitis may show similar
trends, or that results of experiments on mast cells in one tissue of rats and guinea
pigs and on mast cells in human conjunctiva may show similar trends.

Thus, withregard to mast cell heterogeneity, it can only be deemed that results of experiments on
mast cells in one tissue of one animal species cannot necessarily predict experimental
results of mast cells in other tissues of other animal species.
(with regard to the above (A) and (B), page 84, line 16 to page 86, line 3 and page 87,
lines 5 to 12 of the Previous Lawsuit Judgment [Exhibit Ko 84])
(4) The Previous Lawsuit Judgment determined that, based on the common
general technical knowledge as mentioned in the above (3), it should be deemed that aperson ordinarily skilled in the art who had read Exhibits Ko 1 and 4 would have been
motivated to attempt to apply an eye drop containing KW-4679 (hydrochloride of thecis isomer of the present compound) for inhibiting allergic conjunctivitis as disclosed
in Exhibit Ko 1 to an eye drop for allergic eye diseases in humans.

The Previous

Lawsuit Judgment further determined that in attempting to apply KW-4679 as
mentioned above, the person ordinarily skilled in the art would have been motivated29

to confirm that KW-4679 has an antagonistic action on histamine, etc. which is
produced and released from human conjunctival mast cells, as well as to confirm that
KW-4679 has an inhibitory action on the release of histamine from human
conjunctival mast cells.

For such reasons, the Previous Lawsuit Judgment

determined that it can be acknowledged that it would have been easily conceivable toconfirm that KW-4679 has an inhibitory action on the release of histamine fromhuman conjunctival mast cells (an "human conjunctival mast cell stabilizing" action)and to apply KW-4679 to the use of a "human conjunctival mast cell stabilizing
agent."

Then, based on that determination, the Previous Lawsuit Judgment

determined that the Second Trial Decision erred in determining that "it cannot be
deemed that the matter 'human conjunctival mast cell stabilizing' for defining theinvention in each of the Present Inventions would have been motivated from thedisclosures of Exhibits Ko 1 and 4, and that therefore, the reason for invalidation
asserted by the Plaintiff; i.e., lack of an inventive step based on Exhibit Ko 1 as theprimary cited document, is unfounded."
As mentioned above, the Previous Lawsuit Judgment determined that withregard to each of the Present Inventions, there would have been a motivation to arriveat the configuration of the invention.

In this regard, even when there would havebeen a motivation to arrive at the configuration of the invention, in the case where aneffect of the invention is remarkable to the extent that the effect of the invention
exceeds the effect that a person ordinarily skilled in the art could have predicted as
being achieved by the configuration of the invention at the time of the priority date, itcannot be acknowledged that such invention could have been easily made by a person
ordinarily skilled in the art.

The Previous Lawsuit Judgment did not determine tothe extent of whether or not each of the Present Inventions has such an unpredictable
and remarkable effect, and therefore, it is construed that the binding effect of thePrevious Lawsuit Judgment (Article 33, paragraph (1) of the Administrative Case
Litigation Act) does not extend to this issue.
Accordingly, it will be determined whether or not each of the Present
Inventions has such an unpredictable and remarkable effect.
(5) Present Invention 1
A. According to the present description, in the experiment stated in thepresent description (the experiment to measure an inhibition rate of histamine releasefrom human conjunctival mast cells by administering a drug to a cultured cell
population), it can be acknowledged that: the present compound showed an inhibition
rate of histamine release from human conjunctival mast cells of 29.6% at 300 μM,
30

47.5% at 600 μM, 66.7% at 1000 μM, and 92.6% at 2000 μM; that is, the inhibition
rate increased as the concentration increased in the range from 30 μM to 2000 μM,
and the present compound showed a high inhibition rate of histamine release of 66.7%
at 1000 μM and maintained a high inhibition rate of 92.6% at 2000 μM, which is
twice as high as 1000 μM; and that in contrast, disodium cromoglycate (cromolyn
sodium), which is an anti-allergic drug, showed an inhibitory effect on histamine
release of 10.6% at 10 μM and 1.8% at 30 μM at the same treatment time, but it could
not significantly inhibit histamine release at 100 μM, 300 μM, and 1000 μM; and that
nedocromil sodium, which is another anti-allergic drug, showed no concentrationdependent change in the range up to 1000 μM at the same treatment time, and only
showed a maximum inhibition rate of histamine release of 28.2% at 100 μM.
According to these, as an effect of the present compound in Present Invention 1,
it can be acknowledged that an inhibition rate of histamine release from human
conjunctival mast cells increased in a concentration-dependent manner between 30
μM and 2000 μM, to a maximum value of 92.6%, and between these concentrations,unlike cromolyn sodium and nedocromil sodium, a phenomenon of decreasing theinhibition rate did not occur with higher doses (concentrations) than the dose(concentration) at which the maximum inhibition rate was reached.
B.(A) First of all, with regard to the present compound, there is no evidence
that it can be acknowledged that it was clear at the time of the priority date of thepresent case that the inhibition rate of histamine release from human conjunctival
mast cells increased in a concentration-dependent manner between 30 μM and 2000
μM, to a maximum value of 92.6%, and between these concentrations, a phenomenonof decreasing the inhibition rate did not occur with higher doses (concentrations) thanthe dose (concentration) at which the maximum inhibition rate was reached.
(B) Next, it will be determined whether or not the effects of the present
compound could have been predicted from the effects of ketotifen.
a. According to Exhibit Ko 1, both Ketotifen (ketotifen) and KW-4679(hydrochloride of the cis isomer of the present compound) have been evaluated as nothaving a significant inhibitory effect on histamine release from the conjunctiva inguinea pigs.

However, Exhibit Ko 32 discloses that effects of Ketotifen (HC)(ketotifen) eye drop solution on histamine release were studied in the eyes of patientswith cedar pollen allergy, and that amounts of histamine in tear fluids at 5 and 10
minutes after the induction of an allergic reaction showed significant inhibitory
effects on histamine release as compared to those in the control eye, and that the
inhibition rates of histamine release were 67.5% at 5 minutes after the induction and31

67.2% at 10 minutes after the induction.
Accordingly, it can be acknowledged that ketotifen has application as a human
conjunctival mast cell stabilizing agent in humans, in contrast to the results ofexperiments in guinea pigs (Exhibit Ko 1), where the inhibition rate of histamine
release was 67.5% at 5 minutes after the induction and 67.2% at 10 minutes after the
induction.

However, there is no evidence that it can be acknowledged that, at thetime of the priority date of the present case, it was clear whether or not ketotifen has aconcentration-dependent effect on an inhibition rate of histamine release from human
conjunctival mast cells between 30 μM and 2000 μM.
Note that Exhibit Ko 39 is a publication which was published after the priority
date of the present case, and thus, by taking the disclosure of Exhibit Ko 39 into
consideration, it cannot be acknowledged that ketotifen has an effect beyond what has
been found above.
b. There is no evidence that it can be acknowledged that it was known toa person ordinarily skilled in the art at the time of the priority date of the present casethat Chlorpheniramine (chlorpheniramine), which is stated in Exhibit Ko 1 as nothaving an inhibitory effect on histamine release in the conjunctiva in guinea pigs aswell as Ketotifen (ketotifen) and the present compound, has a stabilizing effect onhuman conjunctival mast cells.
In addition, anti-allergic drugs with a tricyclic skeleton include amelexanox(Amelexanox in Exhibit Ko 1) and nedocromil sodium as well as the present
compound and ketotifen (Exhibits Ko 1, 11, 19, and 31, and the entire import of theoral argument).

In this regard, amelexanox has a significant inhibitory effect on

histamine release from the conjunctiva in guinea pigs (Exhibit Ko 1).

However, thepresent compound does not show a significant effect (Exhibit Ko 1).

Further,

nedocromil sodium hardly stabilized human conjunctival mast cells in the experimenton cell populations in which human conjunctival mast cells were cultured (Table 1 ofthe present description).

However, the present compound showed a significant

stabilizing action on human conjunctival mast cells in the same experiment.

In viewof the above, only the fact that the compounds are common to the extent that they aretricyclic compounds does not provide a basis for a person ordinarily skilled in the art
to expect the same kind and the same level of efficacy in stabilizing human
conjunctival mast cells.
Furthermore, ketotifen has been used in various experiments for comparison
with the present compound (or the compound of its generic concept) (Exhibits Ko 208
to 210, note that Exhibit Ko 210 is a document after the priority date of the present
32case).

In Exhibit Ko 1, ketotifen and the present compounds are listed together.

However, the ring structure and substituents are different between ketotifen and thepresent compounds.

Therefore, simply because the present compound is used incomparison or listed together with ketotifen as mentioned above, it cannot be deemedthat a person ordinarily skilled in the art would have expected that the present
compound would have the same kind and the same level of inhibitory effect on
histamine release on the basis of the inhibitory effect of ketotifen on histamine release.
The Plaintiff asserts that it would have been possible to deduce the degree ofeffects of KW-4679 (the present compound) from the degree of effects of ketotifen,
since ketotifen is common to the present compound in terms of an anti-allergic drug
having a tricyclic skeleton, and ketotifen has been compared in terms of the effects ofthe generic concept compounds of the present compound and KW-4679, etc. (Exhibits
Ko 208 to 210).

However, the assertion by the Plaintiff is not acceptable.

Therefore, it cannot be deemed that a person ordinarily skilled in the art, who
had read the disclosure of Exhibit Ko 1, could have predicted from the effect of
ketotifen that the present compound would have the effect on human conjunctival
mast cells as mentioned in the above A.
(C) Further, based on the fact that there were documents of Exhibits Ko 20,
34, and 37 at the time of the priority date of the present case, it will be determined
whether or not the stabilizing effect of the present compound on human conjunctival
mast cells could have been predicted from these documents.
a. Exhibit Ko 20 discloses that in an experiment of administration ofprocaterol hydrochloride eye drop solution to the eyeballs of patients with cedarpollen allergy, average inhibition rates of histamine release 5 minutes after the
induction were 81.7% for 0.003% eye drop solution, 81.6% for 0.001% eye drop
solution, and 79.0% for 0.0003% eye drop solution, and average inhibition rates ofhistamine release 10 minutes after the induction were 90.7% for 0.003% eye drop
solution, 89.5% for 0.001% eye drop solution, and 82.5% for 0.0003% eye drop
solution.
In addition, Exhibit Ko 34 discloses that in an experiment of administration of
DSCG (disodium cromoglycate) 2% eye drop solution to the eyeballs of patients withcedar pollen allergy, average inhibition rates of histamine release 5 minutes after the
induction and 10 minutes after the induction were 73.8% and 67.5%, respectively.
Further, Exhibit Ko 37 discloses that in an experiment of administration of
pemirolast potassium eye drop solution to the eyeballs of patients with cedar pollen
allergy, average inhibition rates of histamine release 5 minutes after the induction
33

were 71.8% for 0.25% eye drop solution and 69.6% for 0.1% eye drop solution, andaverage inhibition rates of histamine release 10 minutes after the induction were
61.3% for 0.25% eye drop solution and 69% for 0.1% eye drop solution.
b. However, the chemical structure of the present compound isremarkably different from those of procaterol hydrochloride (Exhibit Ko 20),
disodium cromoglycate (Exhibit Ko 34), and pemirolast potassium (Exhibit Ko 37).
In addition, as mentioned in the above (B)b, the present compound and amelexanox,
both of which have a tricyclic skeleton, differ in inhibitory effect on histamine releasefrom the conjunctiva in guinea pigs.

Further, nedocromil sodium and the present

compound have different stabilizing effects on human conjunctival mast cells.

Thus,

it could have been known to a person ordinarily skilled in the art that the stabilizing
effect on human conjunctival mast cells also varies depending on chemical structureof the compound.

Therefore, it cannot be deemed that, based on the results of theexperiments mentioned in the above a, a person ordinarily skilled in the art could havepredicted the stabilizing effect of the present compound on human conjunctival mast
cells to be of the same degree as those of the compounds mentioned in the above a.
In addition, from each disclosure of the above a, it cannot be acknowledgedthat it is clear whether or not procaterol hydrochloride (Exhibit Ko 20), disodium
cromoglycate (Exhibit Ko 34), and pemirolast potassium (Exhibit Ko 37) haveconcentration-dependent effects between 30 μM and 2000 μM on the inhibition rate ofhistamine release from human conjunctival mast cells.

Further, there are no otherevidences that it is clear whether or not these drugs have a concentration-dependent
effect on the inhibition rate of histamine release from human conjunctival mast cells
between 30 μM and 2000 μM.
Therefore, from each disclosure of the above a, it cannot be deemed that it
would have been possible to predict that the present compound would have the effectas mentioned in the above A on inhibiting histamine release from human conjunctival
mast cells.
C. The Plaintiff asserts that in order for a remarkable effect of Present
Invention 1 to be acknowledged, the present compound must have a remarkable effecton inhibition rates of histamine release over the entire range of concentrations from
0.0001 to 5 w/v% and over the entire range of inhibition rates of histamine releasefrom 29.6% to 92.6% as stated in Table 1 of the present description.
However, the effect of Present Invention 1 lies in the fact that the inhibition
rate of histamine release increases in a concentration-dependent manner between 30
μM and 2000 μM, reaching a maximum value of 92.6%, and that between these34

concentrations, a phenomenon of decreasing the inhibition rate does not occur withhigher doses (concentrations) than the dose (concentration) at which the maximum
inhibition rate was reached.

Thus, it is not required that the present compound

exceed the inhibition rates of histamine release of other drugs over the entire range ofconcentrations from 0.0001 to 5 w/v% and over the entire range of inhibition rates ofhistamine release of 29.6% to 92.6% as stated in Table 1 of the present description.
Therefore, the above assertion by the Plaintiff is not acceptable.
D. According to the above, it can be acknowledged that the effect of Present
Invention 1 is remarkable beyond the scope of effects that a person ordinarily skilledin the art could have predicted as being achieved by the configuration of the invention.
Therefore, it cannot be acknowledged that Present Invention 1 could have been easily
made by a person ordinarily skilled in the art.
(6) Present Invention 2
Present Invention 2 is limited to the Z form (cis isomer) of the present
compound of Present Invention 1.

Further, in Present Invention 2, the matter"inhibits histamine release from a human conjunctival mast cell by 66.7% or more"
for defining the invention is added to Present Invention 1.
achieves the same effect as Present Invention 1.

Then, Present Invention 2

With regard to Present Invention 2,

according to the above (5), it can be deemed that the effect of Present Invention 2 isremarkable beyond the scope of effects that a person ordinarily skilled in the art could
have predicted from Exhibits Ko 1 and 4, and the common general technicalknowledge at the time of the priority date of the present case.
Further, it cannot be acknowledged that a person ordinarily skilled in the art
could have predicted the effects of the present compound on the basis of the effect of
ketotifen and Exhibits Ko 20, 34, and 37, as mentioned in the above (1).
Therefore, it cannot be acknowledged that Present Invention 2 could have been
easily made by a person ordinarily skilled in the art.
(7) According to the above, Reason 1 for Rescission is unfounded.
3. Reason 2 for Rescission (Reason 3 forInvalidation:

Erroneous

Determinations of Inventive Step Based on Invention of Exhibit Ko 3)(1) Invention of Exhibit Ko 3
Exhibit Ko 3 discloses as follows.
A. Title of the Invention
TRICYCLIC AROMATIC COMPOUND, METHOD FOR PRODUCING THE
SAME, AND PHARMACEUTICAL COMPOSITION
B. Scope of Claims
35(1) A compound of formula (I)(wherein: R 1 is -CH2-CH2-, -CH2 -O-, or -O-CH2-; R2 and R3 are the same or different
and are each hydrogen, or a C1-4 alkyl, or taken together with the nitrogen atomcomprise a nitrogen-containing heterocyclic ring having four to six ring members; R 4
is a single bond or a C 1-7 bivalent aliphatic hydrocarbon group and is bonded to thearomatic ring system at the 2-, 3-, 8-, or 9- position; and n is 0 to 3), or a salt, ester, or
amide thereof.
C. Detailed Description of the Invention(A) The compound of the present invention having anti-allergic activity
may be used for the same indications as clinically used antiasthmatic compounds, ...
to help control bronchoconstriction or bronchospasm characteristic ... .

The present

compound is believed to inhibit the release of autacoids (i.e. histamine, serotonin, andthe like) from mast cells and to inhibit directly the antigen-induced production ofhistamine.

Thus, they may be classified as mast cell stabilizers with antihistaminic

effect.
The compound of the present invention having antihistaminic activity may be
used for the same indications as clinically used antihistamines; namely, to relieve
detrimental symptoms (caused by histamine release) of nasal stuffiness due to colds
and vasomotor rhinitis and for the symptomatic control of allergic conditions
including nasal allergy, perennial rhinitis, urticaria, angioneurotic edema, allergic
conjunctivitis, food allergy, drug and serum reactions, insect bites and stings , anddesensitizing reactions.
(Page 6, left upper column, line 18 to the same page, right upper column, line 19)(B) The formulations include those suitable for oral, rectal, topical, nasal,
ophthalmic, or parenteral (including subcutaneous, intramuscular and intravenous)
administration.
(Page 7, left upper column, lines 7 to 9. )(C) Example 1(E)/(Z)-11-(3-(dimethylamino)propylidene)-6,11-dihydrodibenz[b,e]oxepin-236

carboxylic acida) ...
b) ...
c)(Z)-11-(3-(dimethylamino)propylidene)-6,11-dihydrodibenz[b,e]oxepin-2-

carboxylic acid (Compound 1)(Page 7, right lower column, line 13 to page 8, left lower column, line 12)(D) Example 7
Antihistamine Activity
A. ...B. In vivo Antihistaminic Activity: Guinea pigs (Hartley, male, 300 to 350 g)
were fasted for 20 hours and then dosed orally or intravenously with the test
compound.

One hour after dosing, on an individual basis, the guinea pigs wereplaced in a clear plastic chamber which was saturated and continually gassed with
0.25% histamine from an aerosol nebulizer.

The guinea pigs were monito red forsigns of histamine anaphylaxis (e.g. cough, sneeze, strong abdominal movements,
cyanoses, or loss of righting).

Under the test conditions, control animals collapsed

on average within 33 seconds.

ED 50 for protection against histamine were calculated

by Probit analysis.

In this test, the ED50 indicates that at that particular dose 50% of

the animals were completely protected against histamine challenge within the time oftesting (1 hour post-dosing).

Complete protection was defined as no histamine

symptoms for six minutes in the aerosol chamber (approximately 10X the collapse
time of the control animals).
Table II
Table II

Results of In Vivo Antihistamine Assays

Compound aED𝑏50 (mg/kg, oral) 4hr post dosing

Doxepina.

The purity of these compounds was 96% or more.

b.

The number of animals was at least 40.

In addition to these results, it was found that Compound 1 could provide
antihistamic activity of very long duration.
37

(Page 15, left lower column, line 2 to page 16, right upper column, line 10 from thebottom)(E) Example G
Anaphylactoid Activity
Non-fasted, Wister rats (180 to 300g) were dosed with the test compound(intraperitoneal or oral) 2 hours before compound 48/80 challenge.

One hour priorto challenge, 5 mg/kg of propranolol was administered intraperitoneally.

The

anaphylactoid inducing agent, compound 48/80, which is well known in the art ofpharmacology, was given intravenously at 2 mg/kg and the animals were monitored
for symptoms of respiratory distress.

Data were analyzed by Probit determinations.

The response was quantitated by determining the dose of test compound which
protected 50% of the animals from death at a given time point.
The above experimental design does not give positive results for selective
antihistamines.

Also, rats do not respond to histamine (intravenous) with symptomsof anaphylaxis.

Agents which block the effects of compound 48/80 are commonlyclassified as inhibitors of anaphylactic mediators or inhibitors of the release ofanaphylactic mediators.
Table III

Table III
Inhibition of Compound 48/80 Induced Anaphylactoid Reaction

CompoundTriprolidine
Doxepina.

Dose of compound (oral) providing 50% protection against death inducedby compound 48/80.
b.

At least 50 animals were used in each assay.

Compound 1 (Example 1) had an LD 50 in rats of approximately 210 mg/kg(intraperitoneal) and 500 mg/kg or more (oral).
(Page 16, right upper column, line 9 from the bottom to page 16, right lower column,
38line 7)(F) Example 8
Formulations
The

activecompoundis(Z)-11-(3-(dimethylamino)propylidene)-6,11-

dihydrodibenz[b,e]oxepin-2-carboxylic acid; i.e., Compound 1.
...
(I) - Ophthalmic Solution
Ingredient

Amount per 100.0 ml

Active Compound

0.1 g

Sodium Chloride

0.8 g

Preservative

0.5 g

Water for Injection

q.s. Total Amount 100.0 ml

This formulation is prepared in a similar way to the nasal spray.
(Page 16, right lower column, line 8 to page 18, left upper column, line 13)(2) Present Invention 1
A. There is no dispute between the parties that the common feature and thedifferent features between Present Invention 1 and Invention of Exhibit Ko 3 are as
mentioned in the above No. 2, 4(3)A.
B. It will be determined whether or not a person ordinarily skilled in the art
would have been motivated to conceive of the configuration of Present Invention 1
concerning Different Feature 5.
As mentioned in the above 2(2)B(C) to (F), it can be acknowledged that
Exhibit Ko 4 discloses that "Compound No. 20 (the present compound)" has the sameor slightly superior anti-allergic action to "Compound No. 3 (the compound disclosed
in Examples of Exhibit Ko 3)".
The compound represented by the formula (I) in Exhibit Ko 3 is a genericconceptofthepresent

compound(11-(3-dimethylamino)propylidene)-6,11-

dihydrodibenz[b,e]oxepin-2-acetic acid).

Exhibit Ko 3 discloses that "The present

compound is believed to inhibit the release of autacoids (i.e., histamine, serotonin,
and the like) from mast cells and to inhibit directly the antigen-induced production ofhistamine" (the above (1)C(A)).

In addition, Exhibit Ko 3 discloses an in vivo

experiment of an antihistaminic action of (E)/(Z) 11-(3-(dimethylamino)propylidene)6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid in guinea pigs (Example 7) and atest of an anaphylactoid activity in rats (Example G) (the above (1)C(D), (E)).
Further, Exhibit Ko 3 discloses formulation examples including an ophthalmic
solution (the above (1)C(F)).
39

However, the present compound is not disclosed explicitly in Exhibit Ko 3, nor
there is any suggestion to select the present compound from the compounds
represented by formula (I).
In addition, Example 7 of Exhibit Ko 3 is an experiment of antihistaminic
action, and Example G of Exhibit Ko 3 is an experiment in which a drug which blocks
an effect of compound 48/80, which is an anaphylactoid activity inducer, wasadministered to rats receiving compound 48/80.

However, Exhibit Ko 3 does notshow experimental results supporting that the compound actually inhibited the releaseof autacoids from mast cells or stabilized human conjunctival mast cells.
On the other hand, in Exhibit Ko 4, in order to test an anti-allergic activity,
PCA (passive cutaneous anaphylaxis) test using rats was performed (the above
2(2)B(E), (F)).

In addition, Exhibit Ko 4 discloses (in the above 2(2)B(F)) that "ThePCA inhibitory action is considered to be based on an action inhibiting release of achemical mediator such as histamine from skin mast cell."

However, these

disclosures relate to rat skin mast cells which in animal species and tissue aredifferent from human conjunctival mast cells.

Moreover, it is merely an assumptionthat the release of histamine, etc. from rat skin mast cells can be inhibited.

In

Exhibit Ko 4, there are no experimental results supporting the fact that the release ofhistamine was actually inhibited.
Thus, even if Exhibit Ko 4 discloses that "Compound No. 20" (the present
compound) has the same or slightly superior anti-allergic action to "Compound No. 3"(the compound disclosed in the Example of Exhibit Ko 3), it cannot be acknowledgedthat a person ordinarily skilled in the art at the time of the priority date of the present
case would have been motivated to derive Compound 20 in Exhibit Ko 4 from thegeneric concept compounds disclosed in Exhibit Ko 3 and at the same time to use thiscompound as "a human conjunctival mast cell stabilizing agent" which is not
explicitly disclosed in Exhibits Ko 3 and 4.

Further, this does not change in light ofthe disclosure of Exhibit Ko 1.
C. As mentioned in the above 2, it can be acknowledged that the effect ofthe present compound on human conjunctival mast cells is remarkable beyond thescope of effects that a person ordinarily skilled in the art could have predicted as
being achieved by the configuration of the invention.
D. Therefore, it cannot be acknowledged that Present Invention 1 could havebeen easily made by a person ordinarily skilled in the art on the basis of Exhibit Ko 3.
(3) Present Invention 2
A. There is no dispute between the parties that the common feature and the40different features between Present Invention 2 and Invention of Exhibit Ko 3 are thefollowing [i] and [ii] in addition to Different Features 6 and 7 as mentioned in theabove (2)A: [i] in Present Invention 2, the oxepin derivative is limited to the Z form
(cis isomer) of the present compound, whereas in Invention of Exhibit Ko 3, theoxepin derivative is expressed in a generic concept that includes the present
compound,andin

Examplesof

InventionofExhibitKo

3,

dimethylaminopropylidene-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic"11-(3-acid"isexemplified; and [ii] Present Invention 2 is specified as inhibiting histamine releasefrom human conjunctival mast cells by 66.7% or more, whereas Invention of Exhibit
Ko 3 is not specified as such.
B. Present Invention 2 is limited to the Z form (cis isomer) of the present
compound of Present Invention 1.

Further, in Present Invention 2, the matter"inhibits histamine release from a human conjunctival mast cell by 66.7% or more"
for defining the invention is added to Present Invention 1.
achieves the same effect as Present Invention 1.

Then, Present Invention 2

As mentioned in the above (2)B, itcannot be acknowledged that a person ordinarily skilled in the art at the time of thepriority date of the present case would have been motivated to derive Compound 20 in
Exhibit Ko 4 from the generic concept compounds described in Exhibit Ko 3 and at
the same time to use this compound as "a human conjunctival mast cell stabilizing
agent" which is not explicitly disclosed in Exhibits Ko 3 and 4.

Further, it can bedeemed that the effect of Present Invention 2 is also remarkable beyond the scope ofeffects that a person ordinarily skilled in the art could have predicted as being
achieved by the configuration of the invention.

Therefore, it cannot be

acknowledged that Present Invention 2 could have been easily made by a person
ordinarily skilled in the art.
(4) According to the above, Reason 2 for Rescission is unfounded.
4. Conclusion
In view of the foregoing, the Plaintiff's claim is unfounded.

Therefore, thePlaintiff's claim shall be dismissed and the judgment is rendered as mentioned in themain text.
Intellectual Property High Court, Second Division

Presiding Judge

MORI Yoshiyuki

Judge MANABE Mihoko
41

Judge SANO Shin42