Patent

Date

June 22, 2022

Court

Right

Case

2021 (Gyo-Ke) 10115

Intellectual Property High
Court, Fourth Division

number- A case in which the court held that there was an error in the determination in adecision made by the JPO to the effect that an invention relating to osteoporosis could
not have been easily conceived of by a person skilled in the art based on a citedinvention
Case type: Rescission of Trial Decision to Maintain
Result: Granted
References: Article 29, paragraph (2) of the Patent Act
Related rights, etc.: Patent No. 6198346
Decision of the JPO: Invalidation Trial No. 2019-800062
Summary of the Judgment
1. This case is a lawsuit to seek rescission of a decision made by the JPO (the "JPO
Decision") to the effect that a request for a trial for invalidation of a patent relating toan invention titled "PTH-containing therapeutic/prophylactic agent for osteoporosis,
characterized in that PTH is administered once a week in a unit dose of 100 to 200
units" (Patent No. 6198346) is groundless.
The major issue is whether there is a lack of an inventive step (the ease in conceivingof Differences 1 through 3).
In this judgment, the court rescinded the JPO Decision which found that Inventions
1 and 2 involve an inventive step.
2. Claim 1 of the patent in question after the correction ("Invention 1") states as follows.
"An agent for the treatment or prevention of osteoporosis that contains PTH (1-34)
or salt thereof as the active ingredient, characterized in that PTH (1 -34) or salt thereofis administered once a week in a unit dose of 200 units over a duration exceeding 48
weeks to 72 weeks or longer, which is for the inhibition of bone fractures to treat
osteoporosis patients who satisfy all of the following conditions (1) through (3) below:(1) Age 65 years or older(2) Prevalent bone fractures(3) Bone density less than 80% of the young adult mean and/or degree of bone atrophyof I or higher."
3. Differences 1 through 3 between Invention 1 and Exhibit Ko 1 Invention , which isthe primary prior art, are as follows.
i(Difference 1)
In the case of Invention 1, the "specified osteoporosis patients" are "osteoporosis
patients who satisfy all of the following conditions (1) through (3) below:(1) Age 65 years or older(2) Prevalent bone fractures(3) Bone density less than 80% of the young adult mean and/or degree of bone atrophyof I or higher," whereas in the case of Exhibit Ko 1 Invention, they are "subjects
between the ages of 45 and 95 years who were defined as osteoporosis based on the
diagnostic criteria proposed by a Committee supported by the Ministry of Health andWelfare, with a total score higher than 4 as a result of defining osteoporosis in terms of
multiple factors weighted in the form of scores."(Difference 2)
The "therapeutic or prophylactic agent for osteoporosis" is specified to be one "forthe inhibition of bone fractures" in Invention 1, whereas there is no such specificationin Exhibit Ko 1 Invention.
(Difference 3)
The agent is specified to be "administered ... over a duration exceeding 48 weeks to
72 weeks or longer" in Invention 1, whereas there is no such specification in Exhibit
Ko 1 Invention.
4. In this judgment, the court held that, because the composition of Invention 1 relating
to Differences 1 through 3 could have been easily conceived of by a person skilled in
the art, there was an error in the determination in the JPO Decisi on which found that
Invention 1 involves an inventive step. The court further ruled that there was also anerror in the determination in the JPO Decision which found that Invention 2 involves
an inventive step on the basis that Invention 1 involves an inventive step.
5. The outline of the court's determinations relating to Differences 1 through 3 in thisjudgment is as follows.
(1) Regarding Difference 1
The following can be said as a result of examining the conditions of Invention 1,
which are "(1) Age 65 years or older" (Condition (1)), "(2) Prevalent bone fractures"(Condition (2)), and "(3) Bone density less than 80% of the young adult mean and/or
degree of bone atrophy of I or higher" (Condition (3)) (the "Three Conditions"). As
Condition (2) and Condition (3) are the same as conditions applied for the diagnosis ofosteoporosis under the diagnostic criteria of Exhibit Ko 5, it is not difficult at all for a
person skilled in the art to apply Condition (2) and Condition (3) for screening
osteoporosis patients to whom the therapeutic agent for osteoporosis is to beii

administered once a week in a unit dose of 200 units as referred to in Exhibit Ko 1
Invention.
In addition, as there is common general technical knowledge that the incidence o fosteoporosis increases with age, it is only a natural choice and not difficult at all for a
person skilled in the art to apply, in addition to Condition (2) and Condition (3), a
condition similar to Condition (1) specifying that the osteoporosis patients to beadministered the agent are those aged 65 or older, by focusing on the fact that age iscited, along with low bone density and prevalent bone fractures, as the multiple risk
factors for bone fractures caused by osteoporosis.
It follows that it is not particularly difficult for a person skilled in the art who comes
across Exhibit Ko 1 Invention to specify the subject patients for administration of theosteoporosis therapeutic agent to be patients who satisfy all of the Three Conditions.
(2) Regarding Difference 2
The following common general technical knowledge existed at the time:
osteoporosis is a bone disease characterized by decreased bone strength and involving
increased risk for bone fractures, and the purpose of the treatment of osteoporosis is toprevent bone fractures; and "bone strength" consists of two factors—bone density andbone quality—and bone density accounts for almost 70% of bone strength. Therefore,
it should be said that a person skilled in the art would understand the fact tha t anincrease in bone density contributes to prevention of bone fractures.
It follows that a person skilled in the art could have easily conceived of using theosteoporosis therapeutic agent referred to in Exhibit Ko 1 Invention for the inhibitionof bone fractures.
(3) Regarding Difference 3
When examining the condition in Invention 1 to "make the administration period 'aduration exceeding 48 weeks to 72 weeks or longer,'" according to the statements in the
Description, it is difficult to find the significance of a critical range in "48 weeks" and"72 weeks or longer," and no particular technical meaning can be found in the limitationin the Invention which defines the start and the end of a period by stating a specificperiod, that is, "a duration exceeding 48 weeks to 72 weeks or longer." It is reasonable
to regard that the specific period merely indicates that the bone fracture incidence
declined as the PTH administration was continued over a discretionary period.
As of the base date for determining the patentability of Invention 1, it was known
that bone density increases and the occurrence of bone fractures decreases through dailyadministration of a PTH preparation over a duration exceeding 48 weeks.
In the case of Exhibit Ko 1 Invention, on the other hand, when PTH wasiii

administered once a week in a unit dose of 200 units, the lumbar spine bone mineraldensity (BMD) continuously increased over the duration up to 48 weeks, significantly
increasing by 8.1% after 48 weeks, and in Group H, which was administered PTH in aunit dose of 200 units, vertebral bone fractures did not occur during the administration
period of 48 weeks. While a person skilled in the art would understand, according tocommon general technical knowledge, that such increase in bone density contributes topreventing bone fractures, the test in Exhibit Ko 1 Document, which involves
administration over a duration up to 48 weeks, shows a continuous increase in the
lumbar spine BMD although the increase rate has a tendency to gradually decline, anddoes not provide any basis for finding that the lumbar spine BMD turns to a decrease
after 48 weeks.
According to the above, it can be said that, based on the report that had been madeconcerning daily administration of PTH over a duration exceeding 48 weeks and theresulting increase in bone density and decrease in the occurrence of bone fractures, aperson skilled in the art could have easily conceived of also administering thetherapeutic agent for osteoporosis referred to in Exhibit Ko 1 Invention over a duration
exceeding 48 weeks for increasing bone density and preventing bone fractures, andcould have arrived at Invention 1 as a result.
(4) The unpredicted and outstanding effects of the Invention as asserted by the plaintiff
are as follows: [i] an outstanding inhibitory effect on bone fractures, indicating a 79%
relative risk reduction (RRR) in comparison to the placebo, after 72 weeks (Effect [i]);[ii] an effect that the inhibitory effect on bone fractures is intensified throughcontinuous administration of the agent (Effect [ii]); and [iii] an effect of completely
inhibiting bone fractures in practice after 48 weeks (Effect [iii]).
When examining Effect [i], while a person skilled in the art has an understandingthat an increase in bone density contributes to prevention of bone fractures, thedisclosed fact that Exhibit Ko 1 Invention increased bone density by 8.1% in 48 weeks
makes it easy for a person skilled in the art to understand that the osteoporosis
therapeutic agent in Exhibit Ko 1 Invention exhibits an effect of inhibiting bone
fractures. Then, in order to confirm Effect [i], there is a need to compare between theinhibitory effect on bone fractures in high-risk patients (patients who satisfy all of theThree Conditions) and that in low-risk patients (patients who do not satisfy all or partof the Three Conditions). However, it cannot be concluded from the statements in the
Description that the degree to which bone fracture occurrence is inhibited among highrisk patients is higher compared to such degree among low-risk patients. According to
the above, it should be said that Effect [i] is not based on the statements in theivDescription.
When examining Effect [ii], the Description merely compares between patients towhom the osteoporosis therapeutic agent referred to in the Invention was administeredand patients to whom a placebo was administered, and does not indicate that the
inhibitory effect on bone fractures is higher in patients who satisfy all of the Three
Conditions than in patients who do not. In addition, Exhibit Ko 2 Document states that,when 20 or 40 μg of PTH was administered daily for an average of 17 or 18 months,
the rate of inhibition of bone fractures by PTH administration became higher as theadministration period became longer. Therefore, it was within the scope of expectation
for a person skilled in the art that the inhibitory effect on bone fractures would be
intensified through continuous administration of the agent.
Effect [iii] only refers to a fact indicating a test result that no new vertebral fractures
were found when administration went beyond 48 weeks, which can hardly be found tomean that the osteoporosis therapeutic agent referred to in the Invention is a therapeutic
agent that completely inhibits bone fractures in practice after 48 weeks ofadministration (a complete wonder drug). The defendant also does not allege that theosteoporosis therapeutic agent referred to in the Invention has such effect. While it isnatural to consider that the inhibitory effect on bone fractures will continue to a certain
extent even after 48 weeks in Exhibit Ko 1 Invention, given that no vertebral fractures
were found during 48-week administration also in Exhibit Ko 1 Invention, even though
it is merely a fact indicating a test result, it can be understood that the bone fracture
incidence was originally low. Accordingly, even if the number of bone fractures during
the period exceeding 48 weeks to 72 weeks was zero in the Invention, one cannot go so
far as to say that this fact itself was surprising for a person skilled in the art . Rather, it
can be said that this fact was within the scope of expectation for a person skilled in theart.

v

Judgment rendered on June 22, 2022
2021 (Gyo-Ke) 10115 Case of seeking rescission of the JPO decision
Date of conclusion of oral argument: May 11, 2022
Judgment
Plaintiff: Nichi-Iko Pharmaceutical Co., Ltd.

Defendant: Asahi Kasei Pharma Corporation

Main text
1. The decision made by the Japan Patent Office (the "JPO") on August 11, 2021, forthe case of Invalidation Trial No. 2019-800062 shall be rescinded.
2. The Defendant shall bear the court costs.
Facts and reasonsNo. 1 Claim
Same as the main text.
No. 2 Outline of the caseThis case is a lawsuit to seek rescission of a decision made by the JPO (the "JPO
Decision") to the effect that a request for a trial for invalidation of a patent is groundless.
1. History of procedures at the JPO (The facts are not disputed between the parties .)(1) On May 25, 2015, the Defendant filed a patent application for an invention titled"PTH-containing therapeutic/prophylactic agent for osteoporosis, characterized in that
PTH is administered once a week in a unit dose of 100 to 200 units" (Patent Application
No. 2015-105266; a part of Patent Application No. 2011-530844 of which theinternational filing date is September 8, 2010 [priority claim: September 9, 2009; Patent
Application No. 2009-208039] filed as a new application; hereinafter referred to as the"Application"), and obtained registration of a patent right for that application on
September 1, 2017 (Patent No. 6198346; number of claims: 2) (the patent relating tothis registration is hereinafter referred to as the "Patent").
(2) On August 29, 2019, the Plaintiff filed a request for a trial for invalidation withregard to Claims 1 and 2 of the Patent (Invalidation Trial No. 2019-800062).
On November 26, 2020, the JPO gave an advance notice of a trial decision toinvalidate the patent with regard to the inventions pertaining to Claims 1 and 2 of the1

Patent. In response, the Defendant made a request for correction to correct Claim 2 of
the Patent on January 29, 2021 (this correction is hereinafter referred to as the"Correction").
On August 11, 2021, the JPO rendered a trial decision (hereinafter referred to as the"JPO Decision") stating as follows: "Correction is allowed for Claim [2] according to
the correction of claims of Patent No. 6198346 as stated in the attached written request
for correction. The request for a trial for invalidation of the inventions pertaining to
Claims 1 and 2 of Patent No. 6198346 is groundless." A certified copy of the JPO
Decision was served on the Plaintiff on August 18, 2021.
(3) On September 16, 2021, the Plaintiff filed the present action seeking rescission of
the JPO Decision.
2. Statement of the claims
The statement of the claims for the inventions pertaining to Claims 1 and 2 of the
Patent after the Correction (hereinafter referred to as "Invention 1" and the like in theorder of the claim number, and Inventions 1 and 2 are collectively referred to as the"Invention" in some cases) is as follows. The description of the Invention, including thedrawings, is referred to as the "Description."(1) Invention 1"An agent for the treatment or prevention of osteoporosis that contains PTH (1 -34)
or salt thereof as the active ingredient, characterized in that PTH (1-34) or salt thereofis administered once a week in a unit dose of 200 units over a duration exceeding 48
weeks to 72 weeks or longer, which is for the inhibition of bone fractures to treat
osteoporosis patients who satisfy all of the following conditions (1) through (3) below:(1) Age 65 years or older(2) Prevalent bone fractures(3) Bone density less than 80% of the young adult mean and/or degree of bone
atrophy of I or higher."(2) Invention 2"An agent for the treatment or prevention of osteoporosis that contains PTH (1 -34)
or salt thereof as the active ingredient, characterized in that PTH (1 -34) or salt thereofis administered once a week in a unit dose of 200 units over a duration exceedi ng 48
weeks to 72 weeks or longer, which is for the inhibition of bone fractures to treat
osteoporosis patients who satisfy all of the following conditions (1) through (3) below,
wherein said PTH (1-34) or salt thereof is human PTH (1-34) acetate and said inhibitionof bone fractures is for reducing the incidence of new vertebral fractures to 0% when
the agent is administered over a duration exceeding 48 weeks and up to 72 week:2(1) Age 65 years or older(2) Prevalent bone fractures(3) Bone density less than 80% of the young adult mean and/or degree of bone
atrophy of I or higher."
3. Summary of the JPO Decision
In the JPO Decision, the JPO stated that the Correction satisfies all of therequirements for correction, and determined as follows: [i] it cannot be said that
Inventions 1 and 2 could have been easily made by a person skilled in the art even basedon the invention described in Exhibit Ko 1"Effect of an Intermittent Weekly Dose of
Human Parathyroid Hormone (1-34) on Osteoporosis: A Randomized Double-Masked
Prospective Study Using Three Dose Levels" (Osteoporosis International, vol. 9, no.4,
p.296–306, 1999) (the document is hereinafter referred to as "Exhibit Ko 1 Document"
and the invention is hereinafter referred to as "Exhibit Ko 1 Invention") and the common
general technical knowledge as of the international filing date of the original application,
which is found to be the base date for determining the patentability of the Patent(September 8, 2010; hereinafter referred to as the "the Base Date"); [ii] it cannot be said
that Inventions 1 and 2 could have been easily made by a person skilled in the art evenbased on the publicly known invention identified from a lecture of which content was
published in Exhibit Ko 14-1 "Teriparachido sakusan'en [PTH (1-34)] no shū 1 kai
kanketsu hika tōyo ni okeru shinki tsuitai kossetsu yokusei kōka" (The inhibitory effecton new vertebral fractures of intermittent weekly subcutaneous administration of
teriparatide acetate [PTH (1-34)]) (Osteoporosis Japan, vol. 17, extra issue no. 1, p.
189, September 11, 2009) and from a broadcast program of which content was recorded
in Exhibit Ko 14-2 "Kotsusoshōshō chiryōyō hito fukukōjōsen horumon seizai
teriparachido sakusan'en" (Teriparatide acetate—a human parathyroid hormone
preparation for the treatment of osteoporosis) (hereinafter referred to as "Exhibit Ko 14
Invention") and the common general technical knowledge as of the Base Date; [iii]Inventions 1 and 2 do not violate the support requirement (Article 36, paragrap h (6),item (i) of the Patent Act), as they are stated in the detailed explanation of the invention
in the description of the Patent (the description, including the drawings, is hereinafterreferred to as the "Description"), and are within the extent of inventions for which aperson skilled in the art is able to recognize that the problems to be solved by theinventions may be solved based on the statement of the detailed explanation of theinvention or on matters suggested thereby; [iv] the statement of the detailed explanationof the invention for the Invention does not violate the enablement requirement (Article
36, paragraph (4), item (i) of the Patent Act), as a person skilled in the art is able to3

work the Invention based on the statement of the Description and the common generaltechnical knowledge as of the filing date; and [v] it cannot be said that Inventions 1 and
2 constitute the invention described in Exhibit Ko 12 "International Publication No.
2011/030774" (hereinafter the document is referred to as "Exhibit Ko 12 Document"
and the invention is referred to as "Exhibit Ko 12 Invention"), because, while theApplication satisfies the requirements for division of an application, Exhibit Ko 12
Document was published on March 17, 2011, after September 8, 2010, which is thefiling date of the original application.
The summary of the JPO Decision regarding each issue is as follows.
(1) Regarding whether there is a lack of novelty based on Exhibit Ko 1 Invention(Grounds for Invalidation 3)
A. Finding of Exhibit Ko 1 Invention
An agent for the treatment of osteoporosis that contains hPTH (1-34) as the active
ingredient, wherein 200 units of hPTH (1-34) are subcutaneously injected every week
to treat subjects between the ages of 45 and 95 years who were defined as osteoporotic
based on the diagnostic criteria proposed by a Committee supported by the Ministry of
Health and Welfare, with a total score higher than 4 as a result of defining osteoporosis
in terms of multiple factors weighted in the form of scores.
B. Common features between Invention 1 and Exhibit Ko 1 Invention
An agent for the treatment or prevention of osteoporosis that contains hPTH (1 -34)
as the active ingredient, wherein 200 units of hPTH (1-34) are administered once a week
to treat osteoporosis patients.
C. Differences between Invention 1 and Exhibit Ko 1 Invention(A) Difference 1
In the case of Invention 1, the "specified osteoporosis patients" are "osteoporosis
patients who satisfy all of the following conditions (1) through (3) below:(1) Age 65 years or older(2) Prevalent bone fractures(3) Bone density less than 80% of the young adult mean and/or degree of bone
atrophy of I or higher,"
whereas in the case of Exhibit Ko 1 Invention, they are "subjects between the ages of
45 and 95 years who were defined as osteoporotic based on the diagnostic criteria
proposed by a Committee supported by the Ministry of Health and Welfare, with a total
score higher than 4 as a result of defining osteoporosis in terms of multiple factors
weighted in the form of scores."(B) Difference 2
4

The "agent for the treatment or prevention of osteoporosis" is specified to be one"for the inhibition of bone fractures" in Invention 1, whereas there is no suchspecification in Exhibit Ko 1 Invention.
(C) Difference 3
The agent is specified to be "administered ... over a duration exceeding 48 weeks to
72 weeks or longer" in Invention 1, whereas there is no such specification in Exhibit
Ko 1 Invention.
(Hereinafter, "(1) Age 65 years or older" is referred to as "Condition (1)," "(2)Prevalent bone fractures" is referred to as "Condition (2))," "(3) Bone density less than
80% of the young adult mean and/or degree of bone atrophy of I or higher" is referred
to as "Condition (3)," and Conditions (1) through (3) are collectively referred to as the"Three Conditions." In addition, osteoporosis patients who satisfy all of the Three
Conditions are referred to as "patients satisfying the Three Conditions" or "high -riskpatients," and osteoporosis patients who do not satisfy all or part of the Three
Conditions are referred to as "patients not satisfying the Three Conditions" or "low -riskpatients.")
D. Ease in conceiving of the Differences(A) Difference 1
The presence or absence of bone fractures, bone density, and age are importantfactors for diagnosing the progression of osteoporosis, but they are irrelevant to theprocess in Exhibit Ko 1 Invention of selecting osteoporosis patients who satisfy all of
the Three Conditions as the patients to whom PTH is to be applied. In addition, the priorart documents have no description or suggestion that motivates the selection of
osteoporosis patients who satisfy all of the Three Conditions.
Therefore, a person skilled in the art could not have easily conceived of the mattersthat define Invention 1 relating to Difference 1.
(B) Difference 2
Although patients with a high risk of bone fractures cannot be judged based on bonedensity measurements alone, factors such as the bone strength are not checked in
Exhibit Ko 1 Document, and even based on statements in the prior art documents, itcannot be determined that the "agent for the treatment or prevention of osteoporosis"
of Exhibit Ko 1 Invention is "for the inhibition of bone fractures."(C) Difference 3
Exhibit Ko 1 Document indicates that, if the agent is administered over a duration
exceeding 48 weeks in a clinical trial including administration of 200 units, aconsiderable number of patients are expected to drop out, and therefore 48 weeks were5

thought to be the limit of duration of administration in the test planning phase. As aresult of the trial, as many as 22% of the patients (more than half the patients
experiencing side effects) dropped out without being able to withstand the trial in thecase of administration of 200 units, which means that an excessively high dropout rate
was observed even with a duration of 48 weeks.
In the experiment in Exhibit Ko 3 "SAITO Mitsuru et al., 'Teriparachido (hPTH1 34) no shū ikkai tōyo wa kotsuryō/kotsushitsu wo kaizenshi kotsu kyōdo wo zōkyō
suru: ransō tekitshutsu saru ni taisuru 18 kagetsu tōyo no kentō" (Weekly administrationof teriparatide (hPTH1-34) improves the bone mass/bone quality and enhances the bonestrength: a study on 18-month administration to ovariectomized monkeys' (The Journalof the Japanese Orthopaedic Association, vol. 82, no. 8, S1159, 2-8-23, 2008)"(hereinafter referred to as "Exhibit Ko 3 Document"), PTH is subcutaneously injectedonce a week over a duration of 18 months to ovariectomized (OVX) monkey models.
As humans and monkeys are different animal species, it cannot be said that the agent
has a similar effect on both monkeys and humans, and its inhibitory effect on bone
fractures is also unknown. Therefore, it cannot be said that the statements in Exhibit Ko
3 Document serve as a motivation for continuing treatment for a duration of 18 months
in Exhibit Ko 1 Invention. Exhibit Ko 2 "EFFECT OF PARATHYROID HORMONE(1-34) ON FRACTURES AND BONE MINERAL DENSITY IN POSTMENOPAUSALWOMEN WITH OSTEOPOROSIS (J Med, vol. 344, no.19, p.1434–1441, 2001)"(hereinafter referred to as "Exhibit Ko 2 Document") relates to a clinical trial in which
20 μg or 40 μg of PTH is administered subcutaneously daily over a period of 17 to 18
months (about 74 to 78 weeks) on average for the treatment of osteoporosis in
postmenopausal women. As the dropout rate due to side effects is less than half of 22%,
which is the dropout rate at 48 weeks (about 12 months) in the case of Exhibit Ko 1
Invention, it cannot be said that the statements in Exhibit Ko 2 Document serve as amotivation for continuing treatment for a duration exceeding 48 weeks in Exhibit Ko 1
Invention.
E. Effect of Invention 1
When the relative risk reduction (hereinafter referred to as the "RRR") of bone
fractures in comparison to the placebo (control) is calculated based on the Description[Table 35], the RRR between 0 to 24 weeks in the case of administering the agent topatients who satisfy all of the Three Conditions for a duration of 24 weeks was about
54%, the RRR between 24 to 48 weeks in the case of administering the agent to patients
who satisfy all of the Three Conditions for a duration of 48 weeks was about 82%, andthe RRR between 48 to 72 weeks in the case of administering the agent to patients who
6satisfy all of the Three Conditions for a duration of 72 weeks was about 100%.
Therefore, it is found that the rate of reducing the risk of bone fractures in comparison
to the placebo group rises by continuing weekly administration of 200 units of PTH topatients satisfying the Three Conditions in the long term.
In addition, Experiment Result Certificate I (Exhibit Ko 64; hereinafter referred toas "Exhibit Ko 64 Certificate") in Attachment 3 indicates the following RRR for thecase of administering the test drug (200 units of PTH once a week) to patients satisfying
the Three Conditions and patients not satisfying the Three Conditions who satisfy
Condition (1) but do not satisfy at least one of Condition (2) or Condition (3), over aduration exceeding 48 weeks to 72 weeks or longer, and the case of administering thecontrol (placebo) to these patients over a duration exceeding 48 weeks to 72 weeks orlonger:[i] Administration over a duration Patients satisfying the Three About 51%
exceeding 48 weeks (Table 2)

Conditions
Patients not satisfying the About 43%
Three Conditions[ii] Administration over a duration Patients satisfying the Three About 59%
of 72 weeks or longer (Table 3)

Conditions
Patients not satisfying the About 36%
Three Conditions

According to this, when administering the agent for a duration of 72 weeks or longer,
the RRR for patients satisfying the Three Conditions was as much as about 23% (59minus 36) larger than that for patients not satisfying the Three Conditions, meaning thatthe agent demonstrated an extremely high inhibitory effect on bone fractures in patientssatisfying the Three Conditions when administered for 72 weeks or longer. In addition,
when administering the agent for a duration exceeding 48 weeks, the difference between
the RRR for patients satisfying the Three Conditions and that for patients not satisfying
the Three Conditions remained at about 8% (51 minus 43). Considering these results,
patients satisfying the Three Conditions are found to be a patient group that isparticularly suitable for long-term administration of 72 weeks or longer. Furthermore,
Experiment Result Certificate J (Exhibit Ko 68; hereinafter referred to as "Exhibit Ko
68 Certificate") in Attachment 4 confirms the validity of Exhibit Ko 64 Certificate.
Due to the above, Invention 1, which specified the usage of "administering the agent
over a duration exceeding 48 weeks to 72 weeks or longer" and selected patients
7

satisfying the Three Conditions as the subject patients for administration, is aninvention for which the patient group and usage are specially limited to those for whicha conspicuous pharmacological effect is demonstrated, and this effect cannot be
predicted from the prior art documents.
F. Summary on Invention 1
Given the above, Invention 1 could not have been easily made by a person skilledin the art based on Exhibit Ko 1 Invention.
G. Regarding Invention 2
Invention 2 limits "PTH (1-34) or salt thereof" of Invention 1 to "human PTH (134) acetate," and limits the purpose, "for the inhibition of bone fractures," of Invention
1 by stating that "said inhibition of bone fractures is for reducing the incidence of new
vertebral fractures to 0% when the agent is administered over a duration exceeding 48
weeks and up to 72 week." Therefore, Invention 2 also could not have been easily madeby a person skilled in the art based on Exhibit Ko 1 Invention based on the same grounds
as those for Invention 1.
(2) Regarding whether there is a lack of an inventive step based on Exhibit Ko 14
Invention (Grounds for Invalidation 4)
A. Finding of Exhibit Ko 14 Invention
An agent for the treatment of osteoporosis that contains teriparatide acetate as theactive ingredient, characterized in that 100 units of teriparatide acetate are administeredonce a week over a duration up to 78 weeks, which is for the inhibition of new vertebral
fractures to treat patients who are diagnosed to have osteoporosis based on the
diagnostic criteria for primary osteoporosis and have one to five prevalent vertebral
fractures and whose average age is 71.6 years.
B. Common features between Invention 1 and Exhibit Ko 14 Invention
An agent for the treatment or prevention of osteoporosis that contains PTH (1-34)
or salt thereof as the active ingredient, characterized in that PTH (1 -34) or salt thereofis administered once a week over a duration exceeding 48 weeks to 72 weeks or longer,
which is for the inhibition of bone fractures to treat osteoporosis patients who satisfy
all of the following conditions (2) and (3) below:(2) Prevalent bone fractures(3) Bone density less than 80% of the young adult mean and/or degree of bone
atrophy of I or higher.
C. Differences between Invention 1 and Exhibit Ko 14 Invention(A) Difference 4
With regard to "osteoporosis patients," the condition "(1) Age 65 years or older" is8

added in Invention 1.
(B) Difference 5
The dose of "PTH (1-34) or salt thereof" is "a unit dose of 200 units" in Invention
1, whereas it is "a unit dose of 100 units" in Exhibit Ko 14 Invention.
D. Ease in conceiving of the Differences(A) Difference 4
The presence or absence of bone fractures, bone density, and age are importantfactors for diagnosing the progression of osteoporosis, but they are irrelevant to theprocess in Exhibit Ko 14 Invention of selecting osteoporosis patients who satisfy all of
the Three Conditions as the patients to whom PTH is to be applied. In addition, the priorart documents have no description or suggestion that motivates the selection of
osteoporosis patients who satisfy all of the Three Conditions.
Therefore, a person skilled in the art could not have easily conceived of the mattersthat define Invention 1 relating to Difference 4.
(B) Difference 5
Exhibit Ko 1 Document indicates that, if the agent is administered over a duration
exceeding 48 weeks in a clinical trial including administration of 200 units, aconsiderable number of patients are expected to drop out, and therefore 48 weeks were
thought to be the limit of duration of administration in the test planning phase. As aresult of the trial, as many as 22% of the patients (more than half the patients
experiencing side effects) dropped out without being able to withstand the trial in thecase of administration of 200 units, which means that an excessively high dropout rate
was observed even with a duration of 48 weeks.
Considering the need to reduce the burden on patients, the document does notsuggest that the dose of 200 units, which causes many side effects, is appropriate, andit neither clearly indicates nor suggests a motivation for trying a dose of 200 units.
Therefore, a person skilled in the art could not have easily conceived of the matters thatdefine Invention 1 relating to Difference 5.
E. Summary on Invention 1
The effect of Invention 1 is as mentioned in (1) E. above, and Invention 1
demonstrates a conspicuous pharmacological effect that cannot be predicted. Therefore,
Invention 1 could not have been easily made by a person skilled in the art based on
Exhibit Ko 14 Invention.
F. Regarding Invention 2
As Invention 2 is an invention that has added limitations as mentioned in (1) G.
above, Invention 2 also could not have been easily made by a person skilled in the art
9based on Exhibit Ko 14 Invention based on the same grounds as those for Invention 1.
(3) Regarding whether there is a violation of the support requirement (Grounds forInvalidation 1)
In Working Example 2 of the Description, a calcium agent and a vitamin agent areboth used for the PTH 200 unit group as well as for the placebo group, and the RRR is
calculated from the ratio between the incidence of bone fractures in the PTH 200 unitgroup and the incidence of bone fractures in the placebo group. Therefore, even if thecalcium agent were to have some influence, the inhibitory effect on bone fractures isregarded as being evaluated while excluding such influence. Accordingly, it cannot be
said that the detailed explanation of the invention of the Description fails to disclose
Inventions 1 and 2 in such a manner that the problems to be solved by the inventions
may be solved, on a basis that the Description does not contain an example of using 200
units of PTH alone without using a calcium agent or data of such example.
Moreover, the pharmacological actions of Teribone in Exhibit Ko 11 "Review report
dated March 31, 2017" (hereinafter referred to as "Exhibit Ko 11 Document") and
Exhibit Ko 30 "Re-examination report dated November 8, 2018" (hereinafter referred
to as "Exhibit Ko 30 Document") indicate the same trend, and Exhibit Ko 11 Document
states that "the incidences of new vertebral fractures in the respective evaluation periodsof the period extension test did not show a sharply increasing trend after administrationfor 72 weeks" (lines 3 to 4 on page 8) with regard to Tables 7 and 8 on page 8.
Considering these matters, even if Exhibit Ko 11 Document and Exhibit Ko 30
Document state that bone fractures occurred in the PTH group after 49 weeks or later,
the results in the two documents do not deny the credibility of the results in [Table 35]of the Description (reducing the incidence of bone fractures to 0% in comparison to theplacebo associated with continued incidence of bone fractures) or the "effect ofcompletely inhibiting bone fractures in practice."
Due to the above, Inventions 1 and 2 are described in the detailed explanation of
the invention in such a manner that a person skilled in the art is able to recognize thatthe problems to be solved by the inventions may be solved.
(4) Regarding whether there is a violation of the enablement requirement (Grounds forInvalidation 2)
Working Example 2 of the Description states that the agent showed an inhibitory
effect on bone fractures in patients satisfying the Three Conditions to which 200 unitsof PTH were administered once a week ([Table 34], [Table 35], paragraphs [0132] and[0133]), and in light of the statement of the claims, Inventions 1 and 2 do not exclude
combined use of calcium. Accordingly, even if the Description does not contain an
10example of using 200 units of PTH alone without using a calcium agent or data of such
example, it cannot be said that the detailed explanation of the invention is not stated ina manner that is clear enough and sufficient to enable a person skilled in the art to work
the inventions.
Furthermore, similar to (3) above, the results in Exhibit Ko 11 Document andExhibit Ko 30 Document do not deny the credibility of the results in [Table 35] of the
Description (reducing the incidence of bone fractures to 0% in comparison to theplacebo associated with continued incidence of bone fractures) or the "effect ofcompletely inhibiting bone fractures in practice," and the contents of the two documents
do not affect the abovementioned determination.
(5) Regarding a lack of novelty based on Exhibit Ko 12 Invention (Grounds forInvalidation 5)
In light of the statements in [14] and [15] in paragraph [0014], paragraphs [0032],[0034], [0131] through [0133], [Table 34], and [Table 35] of the initial description,
claims, or drawings at the time of the filing (hereinafter referred to as the "initialdescription, etc. of the original application") of Patent Application No. 2011-530844,
which is the original application of the Application (Exhibit Ko 12; hereinafter referred
to as the "original application"), it can be said that a mode that does not require
combined use of a calcium agent is also sufficiently described in the original application.
It follows that, as the Application is deemed to have been filed on September 8,
2010, which is the filing date of the original application, and Exhibit Ko 12 Document
was published after that on March 17, 2011, it cannot be said that Inventions 1 and 2
lack novelty based on Exhibit Ko 12 Invention.
4. Grounds for rescission(1) Error in the determination on an inventive step based on Exhibit Ko 1 Invention(Grounds for Rescission 1)(2) Error in the determination on an inventive step based on Exhibit Ko 14 Invention(Grounds for Rescission 2)(3) Error in the determination concerning the support requirement (Grounds for
Rescission 3)(4) Error in the determination concerning the enablement requirement (Grounds for
Rescission 4)(5) Error in the determination on novelty based on Exhibit Ko 12 Invention (Grounds
for Rescission 5)(omitted)
11

No. 4 Summary of the court decision
1. Regarding the Invention(1) Matters stated in the Description
The Description (Exhibit Ko 69) contains statements as described in Attachment 1"Matters stated in the Description (extract)." According to these statements, thefollowing matters are found to be disclosed with regard to the Invention.
A. Technical Field
The Invention relates to a therapeutic or prophylactic agent for osteoporosis that
contains PTH (parathyroid hormone) as the active ingredient, and also relates to anagent to inhibit or prevent bone fractures that contains PTH as the active ingredient(paragraphs [0001] and [0018]).
B. Background Art
Osteoporosis is a disease characterized by a decrease in bone strength that poses anincreased risk of bone fractures, and PTH preparations are known as one agent for thetreatment of osteoporosis (paragraph [0002]).
A prior art reference discloses a method of treating osteoporosis by subcutaneousadministration of a unit dose of 100 or 200 units of PTH to the osteoporosis patient
once a week over a period of 26 weeks, but it does not demonstrate whether or not thetreatment method is capable of increasing the bone strength of the osteoporosis patientor decreasing the risk of bone fractures (paragraphs [0004] and [0005]).
There are also prior art references disclosing methods of treatment through dailyadministration of PTH, but as there were reports of instances of hypercalcemia as anadverse drug reaction and the like, and the treatment methods cannot be called adequate
in terms of safety, a highly safe and effective method of treating osteoporosis by PTH
was desired (paragraphs [0006] through [0009]).
C. Problems to be Solved by the Invention
The Invention provides a highly safe and effective method for treating or preventing
osteoporosis by PTH, and furthermore, provides a highly safe method for inhibiting or
preventing bone fractures by PTH (paragraph [0012]).
D. Means to Solve the Problems, etc.
In order to solve the above problems, it was discovered that a highly safe andeffective method of treating or preventing osteoporosis and a highly safe method of
inhibiting/preventing bone fractures can be achieved by limiting the PTH dose andadministration interval, specifically, by administering PTH once a week in a unit doseof 100 to 200 units, and that these methods are especially effective in patients having a12high risk of bone fractures (paragraphs [0013], [0015], [0018], [0034], and [00 35]).
While risk factors for bone fractures in osteoporosis include age, gender, low bonedensity, prevalent bone fractures, smoking, alcohol consumption, steroid use, family
history of bone fractures, exercise, factors related to falls, bone metabolism markers,
weight, calcium intake, and the like, osteoporosis patients who satisfy the following
three conditions are defined as "high-risk patients" in the Invention: (1) age 65 years orolder; (2) prevalent bone fractures; and (3) bone density less than 80% of the young
adult mean and/or degree of bone atrophy of I or higher (paragraph [0068]).
E. Working Example 1
Male and female patients diagnosed with primary osteoporosis, of which examples
includeinvolutional

osteoporosis(postmenopausal

osteoporosis

andsenileosteoporosis) and idiopathic osteoporosis (postpregnancy osteoporosis, juvenile
osteoporosis, and the like), were classified into high-risk patients and low-risk patients(patients other than high-risk patients), and were subcutaneously administered 5 or 100
units of teriparatide acetate, which is a PTH preparation, once a week, intermittently(paragraphs [0037], [0077], and [0079]).
In the high-risk patients, a significant increase in the bone density, a significantly
lower occurrence of new vertebral fractures, and a significantly lower occurrence of
fractures at sites other than the vertebrae were found among the 100 unit group incomparison to the 5 unit group, and administration of 100 units of teriparatide acetateonce a week was confirmed to provide a useful osteoporosis therapeutic agent and agent
to inhibit or prevent bone fractures in high-risk patients; however, no significant
difference could be found between the 100 unit group and the 5 unit group in the low risk patients in terms of the bone density, the occurrence of new vertebral fractures, andthe occurrence of fractures at sites other than the vertebrae (paragraphs [0083] through[0094], and [Table 4] through [Table 11]).
The administration also did not cause hypercalcemia at either dose during theadministration period (paragraph [0095] and [Figure 1]).
F. Working Example 2
Teriparatide acetate "200 units" (test drug) and placebo (control) were eachadministered subcutaneously at a frequency of once a week over a span o f 72 weeks tomale and female high-risk patients diagnosed with primary osteoporosis (paragraph[0098]).
When the incidence of multiple vertebral fractures (two or more new vertebral
fractures) (number of cases) was compared in the test drug group and control group
after 72 weeks of administration, it was 2.1% (6 cases) in the control group and 0.8%
13

(2 cases) in the test drug group, and the test drug demonstrated an inhibitory or
preventative effect against multiple vertebral fractures (paragraph [0109] and [Table12]). In addition, the test drug was shown to be effective on worsening bone fractures(paragraph [0118] and [Table 20]).
The incidence of new vertebral fractures every six months was basically steady atapproximately 5% in all divisions of the placebo group, but in contrast, the incidenceof each division dropped as the administration period lengthened in the PTH200 unitgroup, and no new vertebral fractures occurred after 48 weeks; the incidence of new
vertebral fractures was also lower than that of the placebo group in all divisions
consisting of within 24 weeks, 24 to 48 weeks, and 48 to 72 weeks, and the relative risk
reduction (RRR) in comparison to the placebo increased as administration continued;
thus, weekly administration of 200 units of PTH inhibited the occurrence of new
vertebral fractures from an early stage, and the risk of fractures had already dropped
53.9% versus the placebo after 24 weeks, and the inhibitory effect of this drug on bone
fractures also tended to intensify as administration continued (paragraphs [0131] and[0132], [Table 34], and [Table 35]).
The incidence of vertebral fractures (new + worsening) after 72 weeks by Kaplan Meier estimation in the FAS (Full Analysis Set) of the fracture study was 3.5% in the
PTH200 unit group and 16.3% in the placebo group, and the incidence in the PTH 200
unit group was thus lower than that in the placebo group (log rank test, p < 0.0001);
200 units of this drug also lowered the risk of vertebral fractures (new + worsening)
78.6% in comparison to the placebo after 72 weeks; and when the six-month vertebral
fracture (new + worsening) incidence was compared between groups, the incidence of
the PTH200 group was lower than that of the placebo group in all divisions consistingof within 24 weeks, 24 to 48 weeks, and 48 to 72 weeks (paragraph [0133]).
(2) Regarding the statement of the Description
According to the contents of a reply (undisputed fact; Exhibit Ko 76) made by the
Plaintiff that owns the Patent to the trial panel at the time of the trial of the present case,the following points are found in the contents disclosed by the Description.
A. While Working Example 1 relates to patients who were diagnosed with osteoporosis
based on Exhibit Ko 5 Diagnostic Criteria ([Non-patent Reference 12] in paragraph[0011], and paragraph [0077]), they are all patients who have one or more vertebral
fractures and were diagnosed with osteoporosis due to falling under the category of "I.
With vertebral fracture on X-ray film" under the diagnostic criteria. They do not include
patients who were diagnosed with osteoporosis due to falling under the category of "II.
Without vertebral fracture on X-ray film" and "Degree of bone atrophy of II or higher
14

on spinal X-ray images or a bone density value of less than 70% of YAM" under the
diagnostic criteria.
B. As tests relating to the Invention did not make bone density measurement a
requirement, patients without no data of the lumbar spine bone mineral density areincluded. Therefore, the young adult mean value (YAM value) of the lumbar spine bonemineral density indicated is the mean value for patients for whom such data was
obtained.
The number of patients for whom the YAM value data of the lumbar spine bonemineral density was obtained was as follows: in [Table 2] (paragraph [0081]), 35 out of
the total 64 cases in the 5 unit group, and 35 out of the total 52 cases in the 100 unitgroup; and in [Table 3] (paragraph [0081]), 8 out of the total 10 cases in the 5 unit group,and 2 out of the total 11 cases in the 100 unit group.
Of the total numbers of cases mentioned above, those for whom the bone density
was measured with regard to the changes in the lumbar spine bone mineral density
situation in high-risk patients (paragraph [0084] and [Table 4]) was 33 cases in the 5unit group and 30 cases in the 100 unit group. Those for whom the bone density wasmeasured with regard to the changes in the lumbar spine bone mineral density situation
in low-risk patients (paragraph [0085] and [Table 5]) was 7 cases in the 5 unit groupand 1 case in the 100 unit group. The numbers are even smaller than the numbers ofpatients for whom the YAM value data of the lumbar spine bone mineral density was
obtained, due to such reasons as that the lumbar spine bone mineral density at eachpoint of time after the start of administration could not be measured for the relevant
patients' own reasons, etc. and therefore the change rate of the lumbar spine bonemineral density could not be evaluated.
C. With regard to the situation of new vertebral fractures in high-risk patients(paragraph [0087] and [Table 6]), the number of cases evaluated was 64 cases in the 5unit group and 52 cases in the 100 unit group. With regard to the situation of new
vertebral fractures in low-risk patients (paragraph [0088] and [Table 7]), the number ofcases made subject to evaluation was 10 cases in the 5 unit group and 11 cases in the
100 unit group. The respective total numbers of cases are the same as those in [Table 2]and [Table 3].
D. In [Table 2] (paragraph [0081]), the number of cases of high-risk patients was 64 in
the 5 unit group and 52 cases in the 100 unit group, whereas in the situation of new
vertebral fractures every 26 weeks in high-risk patients shown in [Table 8] (paragraph[0091]), the number was 63 cases in the 5 unit group and 51 cases in the 100 unit group.
This was due to erroneous entry of the number of cases evaluated in [Table 8], the cause15

of which is unknown. Even if [Table 8] is re-analyzed and the significant difference is
examined, the incidence of bone fractures in the 100 unit group is significantly lower
than that in the 5 unit group.
Meanwhile, in the situation of new vertebral fractures in high-risk patients shownin [Table 6] (paragraph [0087]), the number of cases of bone fractures in the 5 unitgroup is 13 cases, whereas in the situation of new vertebral fractures every 26 weeks inhigh-risk patients shown in [Table 8], the number is 18 cases in the 5 unit group. Thisis because, in [Table 8], the number of cases with bone fractures is aggregated for each
evaluation division in the 5 unit group, whereas in [Table 6], the number of cases thatexperienced bone fractures throughout the entire period is aggregated (a patient thatexperienced fractures in multiple divisions is counted as one case).
E. In [Table 3] (paragraph [0081]), the number of cases of low-risk patients was 10
cases in the 5 unit group and 11 cases in the 100 unit group, whereas in the situation of
new vertebral fractures every 26 weeks in low-risk patients shown in [Table 9](paragraph [0091]), the number was 21 cases in the 5 unit group and 12 cases in the 100
unit group. This was due to erroneous entry of the number of cases evaluated in [Table9], the cause of which is unknown. Even if [Table 9] is re-analyzed (shown below) andthe significant difference is examined, no significant difference is found between thegroups.
5 unit group
After
26 W
After
52 W
After
78 W
After
104 W
After
130 W

100 unit groupNo.
evaluated

No. with
fractures

Incidence(%)

No. offracturesNo.
evaluated

No. with
fractures

Incidence(%)

No. offractures

10

0

0.0

0

11

1

9.1

2

10

1

10.0

1

11

0

0.0

0

7

0

0.0

0

11

0

0.0

0

2

0

0.0

0

6

0

0.0

0

1

0

0.0

0

3

0

0.0

0

F. In the situation of fractures of sites other than the vertebrae in high-risk patients(paragraph [0093] and [Table 10]), the number of cases evaluated is 64 cases in the 5unit group and 52 cases in the 100 unit group, which are the same as the total numbersof patients in [Table 2].
2. Regarding whether there are Grounds for Rescission 1 (error in the determination on
an inventive step based on Exhibit Ko 1 Invention)(1) Regarding Exhibit Ko 1 Invention

16

Exhibit Ko 1 Document contains statements as described in Attachment 2 "Mattersstated in Exhibit Ko 1 Document (extract)" (the Japanese translation of this document
is based on Exhibit Otsu 2). According to these statements, Exhibit Ko 1 Invention canbe found in the same manner as it was in the JPO Decision, and there is no dispute
between the parties regarding this point.
Meanwhile, "the diagnostic criteria proposed by a Committee supported by the
Ministry of Health and Welfare" in Exhibit Ko 1 Invention is found to be Exhibit Ko 6
Diagnostic Criteria.
(2) Regarding the common general technical knowledge as of the Base Date (September
8, 2010)In this case, there is a dispute between the parties regarding the base time fordetermining the requirements for patentability of the Patent (there are explicit
allegations in Grounds for Rescission 5), but this point is set aside for the moment, andan examination is first made based on the earlier date, September 8, 2010, alleged by
the Defendant (the Base Date).
A. Regarding the common general technical knowledge concerning osteoporosis as of
the Base Date(A) The following documents contain the statements respectively cited below.
a. "Kotsusoshōshō no byōtai to chiryō: Kotsusoshōshō no atarashii shindan kijun tomondaiten" (Disease states and treatment of osteoporosis: a new diagnostic criteria forosteoporosis and issues) (1999; Exhibit Ko 6)[i] "In Japan, the Ministry of Health and Welfare Silver Science Osteoporosis ResearchGroup (Leader [A]) proposed diagnostic criteria based on a scoring system in 1988,
from a standpoint that importance should be placed on both decreased bone mass andclinical conditions (Table 1)." (Line 18 of the left column to line 2 of the right column
on page 38)[ii] "Table 1. Diagnostic criteria for involutional osteoporosis
Score
1) With low bone mass
2) With bone fracture3
1 at the spine1

Determined

2 or more at the spine

2

Certain5 points or moreAt the femoral neck3

Almost certain

4 points

At the radius

1

Possible

3 points-1

Denied2 points or less

3) Premenopausal woman

174) With low back pain

15) Serum calcium, phosphorus, and AL-P values
Normal1

1 item abnormal

0

2 items abnormal-1" (page 38; This "Table 1. Diagnostic criteria for involutional osteoporosis" is Exhibit
Ko 6 Diagnostic Criteria.)b. "Kotsusoshōshō" (Osteoporosis) (1989; Exhibit Ko 7)[i] "Introduction
In recent years, osteoporosis has drawn substantial interest in line with the adventof an aging society ... the Ministry of Health and Welfare Silver Science'Comprehensive Research Group for Prevention and Treatment of Senile Osteoporosis'(Leader [A]) has proposed draft criteria for allowing anyone to easily diagnose
osteoporosis, that is, a method to weigh subjective and objective findings in the formof scores, and make a diagnosis according to those scores." (Lines 1 to 13 of the uppercolumn on page 27)[ii] "(3) Age
Looking at the incidence of osteoporosis by age and by gender, the incidence isoverwhelmingly high in women of age 60 years or older, whereas it rises sharply at age
80 years or older in men. This means that, in women, osteoporosis associated withclinical symptoms begins to develop 10 to 15 years after menopause." (Lines 6 to 11 of
the upper column on page 30)[iii] "This disease does not develop within a short term, but begins to develop over thecourse of a long term based on aging ..." (Lines 14 to 16 of the lower column on page31)c. "Diagnostic criteria for primary osteoporosis (year 1996 revision)" (1997; Exhibit
Ko 5)"Table 4. Diagnostic criteria for primary osteoporosis (year 1996 revision)
I. With vertebral fracture on X-ray film
A case with a low bone mass (degree of bone atrophy of I or higher, or bonedensity less than 80% of the young adult mean (YAM)) and non-traumatic
vertebral fracture is determined to have osteoporosis.
II. Without vertebral fracture on X-ray film

18

Spinal X-ray images
NormalDecreased bonemass
Osteoporosis

Bone density value

Without bone atrophy
Grade I bone atrophy

80 to 70% of YAM

Grade II bone atrophy or
higherLess than 70% of YAM

YAM: young adult mean (age 20 to 44 years)(Note) The bone density value is that of the lumbar spine, in principle. Only whenevaluation of the lumbar spine bone mineral density value is difficult, the bone density
value of the radius, second metacarpal, femoral neck, or calcaneus is used.
Bone atrophy corresponds to radiographic osteopenia.
..." (page 223; This "Table 4. Diagnostic criteria for primary osteoporosis (year 1996
revision)" is Exhibit Ko 5 Diagnostic Criteria.)d. "Diagnostic criteria for primary osteoporosis (year 2000 revision)" (2001; Exhibit
Ko 9)[i] "In 1995, the Japanese Society for Bone and Mineral Metabolism (now the JapaneseSociety for Bone and Mineral Research) established The Osteoporosis Diagnostic
Criteria Review Committee, which consisted of representatives from the fields oforthopedics, internal medicine (geriatrics), gynecology, radiology, and sports medicine
who were involved in clinical research or the medical care of patients with osteoporosis.
After obtaining the consensus of its members and following discussions held at the 13th
scientific meeting of the Society, the Committee created diagnostic criteria for primaryosteoporosis. ... Further, the Committee reviewed the diagnostic criteria in 1996, andcreated the year 1996 revision of the criteria. ... This time, the Committee created theyear 2000 revision by incorporating the results of osteoporosis research achieved from1996 onward." (Lines 2 to 13 of the left column on page 76)[ii] "Table 3. Diagnostic criteria for primary osteoporosis (draft year 2000 revision)Primary osteoporosis is diagnosed when no disease causing low bone mineraldensity other than osteoporosis and no secondary osteoporosis are observed, and theresults of bone assessment meet the following requirements.
I. With fragility fracture (Note 1)
III. Without fragility fracture
Bone mineral density (BMD) (Note 2)

19

Radiographic osteopenia of thespine(Note 3)

NormalDecreasedbone mass
Osteoporosis

80% of YAM or higher

Absent70%–80% of YAM

PossibleLess than 70% of YAM

Present

YAM: young adult mean (age 20–44 years)
Note 1: Fragility fracture is a non-traumatic bone fracture that is caused by slightexternal force to a bone with low BMD (BMD less than 80% of YAM or presenceof radiographic osteopenia of the spine). Sites of fracture include the spine, fem oral
neck, and the distant end of the radius.
Note 2: Bone mineral density usually refers to lumbar BMD. ...
Note 3: In the evaluation of radiographic osteopenia of the spine, existing criteria for
determining the degree of bone atrophy are to be referenced.

Radiographic osteopenia of the spine

Existing criteria for determining thedegree of bone atrophy

AbsentWithout bone atrophy

Possible

Grade I bone atrophy

Present

Grade II bone atrophy or higher"(page 78; the word "draft year 2000 revision" in the title is found to be a misdescriptionof "year 2000 revision"; this "Table 3. Diagnostic criteria for primary osteoporosis(draft year 2000 revision)" is Exhibit Ko 9 Diagnostic Criteria.)e. "Kotsusoshōshō no yobō to chiryō gaidorain 2006 nenban" (Guidelines on prevention
and treatment of osteoporosis 2006) (2006; Exhibit Ko 23)[i] "At the National Institutes of Health (NIH) Consensus Development Conference, thedefinition of osteoporosis was revised to "a skeletal disorder characterized bycompromised bone strength predisposing to an increased risk of fracture." The
conference also stated that "bone strength" consists of two features, bone density andbone quality, and that BMD accounts for approximately 70% of bone strength. It
consolidated the explanatory factor for the remaining 30% into the term "bone quality,"
stating that bone quality refers to architecture, turnover, damage accumulation (e.g.,
microfractures) and mineralization ..." (Lines 27 to 36 of the right column on page 2)[ii] "Osteoporosis is a disease that is frequently seen in elderly people..." (Line 3 of theright column on page 30)[iii] "Against a background of progress and diffusion of bone mass measurement

20

methods, at the International Conference on Osteoporosis in 1991, osteoporo sis was
defined to be a disease characterized by low bone mass and the microarchitectural
deterioration of bone tissue, with a consequent increase in the fragility of bone andsusceptibility to fracture. Diagnostic criteria compliant with this definition w ere
developed also in Japan, and based on the diagnostic criteria created by the JapaneseSociety for Bone and Mineral Research in 1996, a revised version was created in 2000,
which has been used to date (Table 21)." (Lines 3 to 10 of the left column on pa ge 31)[iv] "III. Risk factors of bone fracture associated with osteoporosis...
The risk factors for bone fractures are factors that affect "a decrease in bonedensity," "a decrease in bone quality," and "external force (such as a fall)." In order todetermine patients with a high risk of bone fractures, it is necessary to evaluate risk
factors related to "bone quality" and "external force," in addition to measuring the bonedensity. The key is an understanding of what are risk factors for bone fractures that are
independent of bone density.
Age and gender... Being a woman and advanced age are important risk factors for bone fracturesassociated with osteoporosis. Age is a fracture risk factor that is independent of bonedensity, and even if the bone density is the same, the fracture risk will be higher if theage is higher...
Low bone density
Low bone density strongly predicts bone fractures. ...
Prevalent bone fractures
Presence of prevalent bone fractures approximately doubles the future fracture risk,
irrespective of gender and site. ...
Smoking...
Alcohol consumption...
..." (Page 34)[5] "Table 22. Risk factors for bone fractures (only indicating the results of a metaanalysis or systematic review [Evidence Level I])
Risk factor

Document

Low bone density

...

21

Results...

Risk factors
independent of bonedensity...

Prevalent bone

...

...

Smoking*...

...

Alcohol consumption*

...

...

...

...

...

...

...

...

fractures*..." (Page 35)[vi] "Summary
At present, osteoporosis treatment is started according to the bone density. However,even if the bone density is the same, the fracture risk will be higher if the age is higher
and a larger number of risk factors* shown in Table 22 are present. By comprehensively
considering the bone density, age, and risk factors, it is possible to screen people witha higher fracture risk more effectively." (Lines 1 to 7 of the right column on page 35)[vii] "The purpose of osteoporosis treatment is to reduce the risk of bone fractures andto maintain and improve the quality of life (QOL)." (Lines 1 to 2 of the left column on
page 50)[viii] "Bone strength is defined by bone density and bone quality, and about 70% ofbone strength depends on bone density. Therefore, decreased bone density is the central
factor that increases the risk for bone fractures in osteoporosis. Moreover, it has become
clear in recent years that there are many factors other than decreased bone density that
increase the risk of bone fractures. The risk factor items mentioned by the U.S. National
Osteoporosis Foundation (NOF), the WHO group, Canada guidelines, and the likeslightly differ from each other. However, the commonly mentioned factors are being awoman, estrogen deficiency (menopause), age (65 years or older), low bodyweight (lessthan 57.8 kg), prevalent bone fracture, maternal history of femur fracture, smoking habit,
excessive alcohol consumption, and hypomotility." (Lines 9 to 20 of the left column on
page 50)[ix] "Apart from low bone density, the WHO confirmed seven factors, namely, prevalentbone fractures, smoking, large alcohol consumption (two units or more per day: nearly
equivalent to 2 go (approx. 360 ml) of Japanese sake), parental history of femoral
neckbone fracture, advanced age, rheumatoid arthritis, and use of steroids, as clinicalrisk factors for bone fractures through a meta-analysis. ...In addition, the WHO
indicated that the six clinical risk factors for bone fractures, other than low bone density
and age, respectively increase the fracture risk by about 1.6 to 2 times independently. ...
It also states that age is a factor that increases the fracture risk from the other seven risk
factors for bone fractures.
22Moreover, the WHO sets the incidence of bone fractures in the general populationof each region or country as a relative fracture risk of 1, and proposes to use the absolute
fracture risk, which is obtained by multiplying said fracture risk by the sum of therelative risks associated with low bone density and the other seven clinical fracture risk
factors, as a criterion for starting drug treatment. ... Indeed, it is considered necessary
also for Japan to introduce the "absolute fracture risk" in determining the start oftreatment in the future. Currently, however, although there is evidence concerning low
bone density, prevalent bone fractures, and age, there is still no sufficient data on
relative risks associated with other clinical fracture risk factors and their relevance toage." (Lines 6 to 31 of the right column on page 51)(B) According to the respective statements in (A) above, the common general technicalknowledge concerning osteoporosis as of the Base Date was as follows.
Specifically, it can be said that the following were known: [i] osteoporosis is askeletal disorder characterized by compromised bone strength predisposing to anincreased risk of fracture, and the purpose of its treatment is to prevent bone fr actures
and to maintain and improve the quality of life (QOL); [ii] the incidence of osteoporosis
increases with age; [iii] in Japan, there is evidence concerning low bone density,
prevalent bone fractures, and age from among the several risk factors for bone fracturesassociated with osteoporosis; [iv] with regard to diagnostic criteria for osteoporosis,
there were diagnostic criteria proposed by the Ministry of Health and Welfare Silver
Science Project "Comprehensive Research Group for Prevention and Treatment ofSenile Osteoporosis " (Exhibit Ko 6 Diagnostic Criteria) as of 1990, but the diagnostic
criteria were revised in 1996 (Exhibit Ko 5 Diagnostic Criteria), and then further
revised in 2000 (Exhibit Ko 9 Diagnostic Criteria); and [v] bone strength co nsists of
two features, bone density and bone quality, and bone density accounts forapproximately 70% of bone strength, while bone quality accounts for the remaining
30%.
B. Regarding the common general technical knowledge concerning the administration
period of a PTH preparation as of the Base Date(A) The following documents contain the statements respectively cited below.
a. "Kotsusoshōshō no yobō to chiryō gaidorain 2006 nenban" (Guidelines on prevention
and treatment of osteoporosis 2006) (2006; Exhibit Ko 23)" ■ Parathyroid hormone (PTH)
Human PTH (1-34) (teriparatide) subcutaneous injection agent
PTH, which is expected to demonstrate effects as an osteogenesis promoter, has
undergone large-scale clinical trials overseas, and has already been approved in many23

countries including the United States. In a large-scale clinical trial targeting
osteoporosis patients with vertebral fracture who were five or more years pastmenopause, 20 μg of human PTH (1-34) was self-administered subcutaneously daily
over an average period of 18 months. As a result, the incidence of new vertebral
fractures was reduced to 5%, nearly one-third of the incidence of 14% for the control
group. In addition, the incidence of new non-vertebral fractures was also reduced to 3%,
half of the incidence of 6% for the control group. The bone density in the lumbar spine
and the femoral neck increased by 9% and 3%, respectively, as a result of administrationof 20 μg of human PTH (1-34), showing notable bone density increases in both sites.
These results show that a notable decrease in the fracture rate can be achieved in the
short term of 18 months through daily subcutaneous administration of human PTH (1 34), and clinically prove that, due to promotion of bone formation, bone density
increases even if the bone turnover is enhanced. Based on these results, clinical trialsof daily subcutaneous administration of human PTH (1-34) targeting osteoporosis
patients are also under way in Japan. On the other hand, the effects of a subcutaneous
injection preparation for weekly administration have also been studied in the past, andthe results of its phase II clinical trial showed that weekly administration of 200 units(equivalent to approx. 60 μg) for one year increases the vertebral bone density by 8.1%."(Lines 1 to 25 of the right column on page 99)
b. "Kotsu keisei sokushin'yaku / fukukōkōsen horumon (PTH) / PTH (1-34)"(Osteogenesis promoter / parathyroid hormone (PTH) / PTH (1-34)) (2007; Exhibit Ko34)"3. Clinical trial: daily subcutaneous administration of PTH (1-34)
a. Effects to improve bone density and inhibit bone fractures
In a recent large-scale clinical study, PTH (1-34) was administered daily to 1,637
postmenopausal women with prevalent vertebral fracture for an average of 19 m onths.
As a result, in the 20 μg group, the bone density increased by 9.7% at the lumbar spineand by 2.8% at the femoral neck, while the frequency of new vertebral fractures
decreased by 65%, and the frequency of non-vertebral fractures was also inhibited by
53%." (Lines 11 to 23 of the left column on page 444)
c. "Review report dated April 6, 2010" attached to "Report on the deliberation results
dated May 6, 2010" (April 2010; Exhibit Ko 45)[i] "[Dosage and Administration] The usual adult dosage of Teriparatide (Genetical
Recombination) is 20 μg once daily, administered by subcutaneous injection.
The maximum duration of treatment with Forteo should be 18 months." (Page 2)[ii] "2) Foreign phase III study (...)
24

... A placebo-controlled, randomized, double-blind, parallel-group study was
conducted in foreign postmenopausal patients with osteoporosis (the target sample sizeof 1,476 subjects, 492 patients per group). The primary objective of the study was tocompare the proportion of subjects with new vertebral fracture among the teriparatide
20 μg or 40 μg and placebo groups.
... The median treatment duration [the 25th percentile, the 75th percentile] was
576.0 [534, 624] days for the placebo group, 576.0 [532, 625] days for the teriparatide
20 μg group, and was 570.0 [517, 626] days for the teriparatide 40 μg group.
The primary efficacy endpoint was the proportion of subjects with new vertebral
fracture, and the primary analysis compared the proportion of subjects with newvertebral fracture in the combined teriparatide group (teriparatide 20 μg and 40 μg) withthat in the placebo group. The results of comparison were as shown in Table 17. There
was a significant difference in the proportion of subjects with new vertebral fracture
between the placebo and combined teriparatide groups (teriparatide 20 μg and 40 μg)(P < 0.001, two-sided level of significance of 5%, Pearson's χ2 test).
The secondary endpoint of the proportion of subjects with new nonvertebral fracture
and the ratio of the proportions of the teriparatide group to the placebo group were asshown in Table 18, and the percent changes in BMD was as shown in Table 19." (Pages
53 to 54)[iii] Tables 17, 18, and 19"
Table 17. Proportion of subjects with new vertebral fracture
Treatment group
Placebo
Combined
teriparatide
Teriparatide 20 μg
Teriparatide 40 μg

Proportion of subjects
with new vertebral
Fracture a)
14.3 (64/448 c))

P-value b)

Ratio of proportions d) [95% CI]-

P<0.001c)

4.7 (41/878 )
5.0 (22/444 c))
4.4 (19/434 c))-

0.327 [0.225, 0.476]
0.347 [0.218, 0.553]
0.306 [0.187, 0.503]a) Proportion % (No. of subjects with fracture/No. of evaluable subjects)b) Pearson's χ2 testc) Subjects without evaluable baseline or the last observation X -ray film were excluded.
d) The ratio of proportions of each teriparatide group to the placebo group
Table 18. Proportion of subjects with new nonvertebral fracture
Treatment group
Placebo
Teriparatide 20 μg
Teriparatide 40 μg

Proportion of subjects withnew nonvertebral
Fracture a)
9.7 (53/544)
6.3 (34/541)
5.8 (32/552)

25

Ratio of proportions b) [95% CI]
0.645 [0.426, 0.976]
0.595 [0.390, 0.908]

Combined
6.0 (66/1093)
0.620 [0.438, 0.877]
teriparatidea) Proportion % (No. of subjects with fracture/No. of evaluable subjects)b) Ratio of proportions of each teriparatide group to the placebo group
Table 19. Percent changes in BMD from baseline to the time of last observation
Treatment group
Lumbar spine (L1-L4)
Femoral neckTotal hipPlacebo1.13±5.47 (n=504)-0.69±5.39 (n=479)-1.01±4.25 (n=230)
Teriparatide 20 μg
9.70±7.41 (n=498)
2.79±5.72 (n=479)
2.58±4.88 (n=222)
Teriparatide 40 μg
13.73±9.69 (n=497)
5.06±6.73 (n=482)
3.60±5.42 (n=232)
Mean ± SD %Subjects without baseline or postbaseline BMD measurement were excluded. " (Page 54)[iv] "3) Maximum duration of treatment... it was decided to establish the maximum treatment duration based on the durationof treatment used in the past clinical studies. Teriparatide has been approved for a
maximum treatment period of 24 months in the US and Europe. In Japan, on the premisethat safety would be confirmed by 18-month data from Study GHDB, an application for
approval of teriparatide with the maximum treatment duration of 18 months was filed
and 18-month data were submitted later. Japanese Study GHDB was completed in
September 2009 after an extension of treatment duration to 24 months to gain
experience with 24 months of treatment with teriparatide." (Page 96)
d. Exhibit Ko 2 Document[i] "Abstract...
Methods: We randomly assigned 1,637 postmenopausal women with prior vertebral
fractures to receive 20 or 40 μg of parathyroid hormone (1-34) or placebo, administeredsubcutaneously by the women daily. ...
Results: New vertebral fractures occurred in 14 percent of the women in the placebogroup and in 5 percent and 4 percent, respectively, of the women in the 20-μg and 40μg parathyroid hormone groups; the respective relative risks of fracture in the 20-μg
and 40-μg groups, as compared with the placebo group, were 0.35 and 0.31 (95 percent
confidence intervals, 0.22 to 0.55 and 0.19 to 0.50). New nonvertebral fragility factures
occurred in 6 percent of the women in the placebo group and in 3 percent of those ineach parathyroid hormone group (relative risk, 0.47 and 0.46, respectively [95 percent
confidence intervals, 0.25 to 0.88 and 0.25 to 0.86]). As compared with placebo, the20-μg and 40-μg doses of parathyroid hormone increased bone mineral density by 9 and13 more percentage points in the lumbar spine and by 3 and 6 more percentage points
in the femoral neck; ... Parathyroid hormone had only minor side effects (occasional
nausea and headache).
Conclusions: Treatment of postmenopausal osteoporosis with parathyroid hormone26

(1-34) decreases the risk of vertebral and nonvertebral fractures; increases vertebral,
femoral, and total-body bone mineral density; and is well tolerated." (Lines 1 to 42 of
the left column on page 1434)[ii] "The cumulative duration of the study treatment in the group that received placebo,
the group that received 20 μg of parathyroid hormone (1-34) per day, and the group thatreceived 40 μg per day was 798, 779, and 774 patient-years, respectively, and the mean(±SD) duration of treatment in the three groups was 18±5, 18±6, and 17±6 months,
respectively." (Lines 46 to 53 of the right column on page 1435)[iii] "Figure 1. Cumulative Proportion of Women Assigned to Receive Placebo or
Parathyroid Hormone (1-34) (PTH) at a Daily Dose of 20 μg or 40 μg Who Had One orMore Nonvertebral Fractures (Panel A) and the Cumulative Proportion Who Had One
or More Nonvertebral Fragility Fractures (Panel B) during the Study.
For both panels, the respective numbers of women in the placebo group and in the
20-μg and 40-μg PTH groups were 544, 541, and 552 at base line; 497, 492, and 486 at
6 months; 477, 465, and 456 at 12 months; and 404, 400, and 390 at 18 months. P≤0.05
for all pairwise comparisons with placebo, by the log-rank test." (Figure 1)[iv] "Figure 1.

Figure 1. Cumulative Proportion of Women Assigned to Receive Placebo or Parathyroid Hormone (134) (PTH) at a Daily Dose of 20 μg or 40 μg Who Had One or More Nonvertebral Fractures (Panel A)
and the Cumulative Proportion Who Had One or More Nonvertebral Fragility Fractures (Panel B) during
the Study.
For both panels, the respective numbers of women in the placebo group and in the 20-μg and 40-μg PTH
groups were 544, 541, and 552 at base line; 497, 492, and 486 at 6 months; 477, 465, and 456 at 12
months; and 404, 400, and 390 at 18 months. P≤0.05 for all pairwise comparisons with placebo, by the
log-rank test. " (Page 1438)(B) According to the respective statements in (A) above, the common general technicalknowledge concerning the administration period of the PTH preparation as of the Base
Date was as follows.
Specifically, it is found that the following were known as the common general27

technical knowledge: [i] a preparation for daily administration of 20 μg of PTH was
already approved overseas for a maximum administration period of 24 months; and [ii]an increase in bone density and inhibition of new vertebral fractures can be achieved
through daily administration of 20 μg or 40 μg of PTH for 18 months or longer.
(3) Regarding the ease in conceiving of Difference 1
A. Examination(A) Exhibit Ko 1 Invention and Invention 1 are the same in terms of the dose, as they
are both "characterized in that PTH (1-34) or salt thereof is administered once a week
in a unit dose of 200 units," but they differ in terms of the scope of osteoporosis patientsto which they are administered.
(B) As mentioned in (1) above, those selected as the subject patients for administrationin Exhibit Ko 1 Invention are patients who were diagnosed with osteoporosis based on
Exhibit Ko 6 Diagnostic Criteria. However, as it is a common practice for a person
skilled in the art to select patients by referring to newer criteria, it can be said that if aperson skilled in the art who comes across Exhibit Ko 1 Invention is to select the
subjects for administration of the agent for the treatment of osteoporosis for weekly
administration of 200 units of PTH in Exhibit Ko 1 Invention, the person would refer
to not only Exhibit Ko 6 Diagnostic Criteria, but also to newer Exhibit Ko 5 Diagnostic
Criteria or Exhibit Ko 9 Diagnostic Criteria.
As mentioned in A. (A) c. and d. above, those diagnosed with osteoporosis basedon Exhibit Ko 5 Diagnostic Criteria are [i] those with a low bone mass (degree of bone
atrophy of I or higher or bone density less than 80% of YAM) and non -traumatic
vertebral fracture, or [ii] those without vertebral fracture on X-ray film, but with thedegree of bone atrophy of II or higher or a bone density value of less than 70% of YAM.
Meanwhile, those diagnosed with osteoporosis based on Exhibit Ko 9 Diagnostic
Criteria are [iii] those with a non-traumatic bone fracture, etc. that is caused by slightexternal force to a bone with low bone density (degree of bone atrophy of II or higher
or bone density less than 80% of YAM) (fragility fracture), or [iv] those without
fragility fracture, but with the degree of bone atrophy of II or higher or a bone density
value of less than 70% of YAM.
As Conditions (2) and (3) are the same as [i] above ("prevalent bone fractures"
include "non-traumatic vertebral fractures"), it is not at all difficult for a person skilledin the art to select osteoporosis patients for administration of the agent for the treatmentof osteoporosis for weekly administration of 200 units in Exhibit Ko 7 Invention basedon Conditions (2) and (3).
In addition, as mentioned in (2) A. (B) above, there was the common general28technical knowledge that the incidence of osteoporosis increases with age. As it is clearthat elderly people are people of advanced age, it is a commonsense practice to selectthose of age 65 years or older as elderly people. Also, as mentioned in (2) A. (A) e. [ix]above, the age of 65 years or older is a commonly mentioned factor from among therisk factor items mentioned by the U.S. NOF, the WHO group, Canada guidelines, andthe like, and Article 32 of the Act on Assurance of Medical Care for Elderly People also
defines elderly people to be those of age 65 years or older. Accordingly, it is a natural
choice and not difficult at all to consider these points and to set a conditi on like
Condition (1), in addition to Conditions (2) and (3), by selecting those of age 65 years
or older as osteoporosis patients subject to administration, focusing on the fact that age
is mentioned, along with low bone density and prevalent bone fractures, as multiple
risk factors for bone fractures associated with osteoporosis.
Therefore, it would not have been particularly difficult for a person skilled in theart who came across Exhibit Ko 1 Invention to specify the subject patients foradministration to be patients who satisfy all of the Three Conditions, even as of theBase Date.
B. Regarding the Defendant's allegations
As mentioned in No. 3, 1. (2) B. above, the Defendant alleges the following: [i]there is no reason to apply Exhibit Ko 5 Diagnostic Criteria as of the priority date of
the Patent, and even if patients were diagnosed with osteoporosis based on Exhibit Ko
5 Diagnostic Criteria, there is no motivation to select those who satisfy Conditions (2)and (3) from among them; [ii] as special circumstances are needed for using 200 unitsof PTH that have the risk of side effects on elderly people of age 65 years or older, who
generally have poor physical strength, there is no motivation to select those who satisfy
Condition (1); and [iii] Exhibit Ko 1 Document states that no differences were observedin the effects even when the subjects were divided into subgroups based on viewpoints
including "age" and "prevalent bone fractures," and does not motivate the combinationof the Three Conditions.
As mentioned in (2) A. (A) e. above, Exhibit Ko 5 Diagnostic Criteria divide
patients into those with or without bone fracture, and change the degree of bone atrophy
and the bone density value. However, given that osteoporosis is a skeletal disorder withan increased risk of fracture as mentioned in (2) A. (B) above, a person skilled in theart may select, as appropriate, the diagnostic criteria for a case with prevalent bone
fractures from among those criteria. Whichever diagnostic criteria are used, a person
who satisfies the diagnostic criteria will be diagnosed with osteoporosis. Therefore,
which diagnostic criteria to select is merely an arbitrary choice of a person skilled in29the art. Also, merely because elderly people generally have poor physical strengthcompared to young people, it is unlikely for a person skilled in the art to give up
application of the agent for the treatment of osteoporosis, which elderly people
particularly need, as the incidence increases with age as mentioned in (2) A. (B) above.
Indeed, it is found that Exhibit Ko 1 Document contains a statement that "Responses
were similar among subgroups of subjects who were 64 years or younger and 65 years
or older, weighed 49 kg or less and 50 kg or more, were less than 10 years, be tween 10
and 20 years and more than 20 years after the postmenopause, and had 0, 1 and 2 ormore vertebral fractures" (line 11 of the left column to line 6 of the right column on
page 300) as described in Attachment 2. However, this statement merely compar es the
drug effect between the subgroups that were divided based on the conditions statedabove, and it cannot be said that this statement impedes the overall act of dividing the
subject patients for administration in Exhibit Ko 1 Invention into subgroups.
Accordingly, all of the Defendant's allegations above are unacceptable.
(4) Regarding the ease in conceiving of Difference 2
A. Examination
As mentioned in (2) A. (B) above, there was the common general technicalknowledge that osteoporosis is a skeletal disorder characterized by compromised bonestrength predisposing to an increased risk of fracture, the purpose of its treatment is toprevent bone fractures, "bone strength" consists of two features, bone density and bonequality, and bone density accounts for approximately 70% of bone strength. Therefore,
it should be said that a person skilled in the art would have understood that an incre ase
in bone density contributes to prevention of bone fractures.
It follows that, as Exhibit Ko 1 Document states that "considerable advances havebeen made in the prevention of fractures through increases in bone mineral density(BMD) by using these agents" (line 10 of the right column on page 296 to line 25 of theleft column on page 297), indicating that an increase in bone density contributes toprevention of bone fractures, and also discloses that bone density increased by 8.1%
after 48 weeks of administration (line 11 of the left column to line 6 of the right column
on page 300), a person skilled in the art could have easily conceived of using the agent
for the treatment of osteoporosis in Exhibit Ko 1 Invention for the purpose of inhibitingbone fractures, even as of the Base Date.
B. Regarding the Defendant's allegations(A) As mentioned in No. 3, 1. (2) C. (A) above, the Defendant alleges that the inhibitory
effect on bone fractures cannot be completely substituted by the bone density value
alone, and therefore even if the lumbar spine BMD increased due to administration of30

the agent for the treatment of osteoporosis in Exhibit Ko 1 Invention, it is not possible
to predict the inhibitory effect on bone fractures from Exhibit Ko 1 Invention, for which
comparison tests with a placebo, etc. has not been conducted.
With regard to this point, PFSB/ELD Notification No. 742 dated April 15, 1999 by
the Director of Evaluation and Licensing Division, Pharmaceutical and Food Safety
Bureau, Ministry of Health, Labour and Welfare "Kotsusoshōshō-yō-yaku no rinshō
hyōka hōhō ni kansuru gaidorain ni tsuite" (Regarding guidelines for clinical evaluation
methods for osteoporosis drugs) (Exhibit Ko 41-2) contains statements on the three
items below. [i] Clinical trials are divided into the following: a phase I trial conductedbased on information obtained in non-clinical trials, targeting a relatively limited
number of healthy volunteers, with focus on confirmation of the safety of the test drugon humans; a phase IIa trial, targeting osteoporosis patients, conducted for making an
exploratory study on the efficacy, relative safety, and dosage/dose response of the test
drug, as well as differences in its effects by osteoporosis type or disease; a phase IIb
trial, targeting osteoporosis patients, conducted for clarifying the dose-response
relationship and determining the dosage/administration for the phase III trial ; and a
phase

III

trial

conducted

forconfirming

theefficacy

andsafety,thedosage/administration for the indications, and side-effects, and for investigating thestate of recovery, to study the effects produced when the test drug is actually put toclinical use. [ii] In the phase III controlled trial, the clinical efficacy and safety of thetest drug are evaluated by comparing the test drug with a standard drug or a placebo by
a randomized, double-blind method (page 2260). [iii] For evaluating the efficacy of an
osteoporosis drug, it is desirable to track changes in bone strength as the endpoint, but
as it is difficult to measure bone strength in humans at present, it is necessary to indicate
the effect against bone fractures associated with osteoporosis as a surrogate endpoint;
and to evaluate drug efficacy by the current evaluation means, one year of observation
is insufficient, and at least three years are expected to be normally required (pages 2259
to 2260). Exhibit Ko 1 Invention reports the results of the phase IIb trial.
However, "Daitai endo pointo no hyōka" (Evaluation of surrogate endpoints) (June2009; Exhibit Otsu 14) states as follows: "The FDA changed the policy to approve drugs
based on test results using bone density as a surrogate endpoint, and has come to requirea clinical trial using the true endpoint, bone fracture, as the endpoint in a phase III trial(...). However, bone density has been approved as a surrogate endpoint by Japanese,
U.S., and European regulatory authorities, and when filing a new-drug application, it is
a common practice to use bone density as a surrogate endpoint in the phase II trial to
study the dose response, and use bone fracture, the true endpoint, in the phase III trial31

to conduct a placebo- or active-control trial." (Page 16) The abovementioned"Kotsusoshōshō-yō-yaku no rinshō hyōka hōhō ni kansuru gaidorain ni tsuite"(Regarding guidelines for clinical evaluation methods for osteoporosis drugs) also
states as follows with regard to the endpoint for a phase IIb trial: "as proof of efficacy,
it is primarily desirable to see changes in bone strength or the fracture rate, but as thisrequires a long period of time, it can be substituted by seeing changes in bone mass"(page 2258).
In light of these points, it is found to have been merely required, when intending toobtain approval of a drug, to confirm its inhibitory effect on bone fractures in a placebocontrol trial, while taking it for granted that an increase in bone density contributes toinhibition of bone fractures, and it cannot be said that it is impossible to predict anagent's inhibitory effect on bone fractures from an increase in bone density unless theinhibitory effect is confirmed by a placebo-control trial.
Accordingly, the Defendant's allegation above is unacceptable.
(B) In addition, as mentioned in No. 3, 1. (2) C. (B) above, the Defendant all eges that
Exhibit Ko 1 Document contains a statement that, with regard to the number of vertebral
fractures in groups with different increases in bone density, "the difference between thegroups was not significant."
However, although there are some cases in which an increase in bone density is not
linked with an inhibitory effect on bone fractures, it can be said, as mentioned in A.
above, that as long as a person skilled in the art understands that an increase in bonedensity contributes to prevention of bone fractures, the person would understand that if
bone density increases, it will have an inhibitory effect on bone fractures. In addition,
while Exhibit Ko 1 Document states that there was no significant difference between
group L (50 unit group), group M (100 unit group), and group H (200 unit group) withregard to the number of vertebral fractures, it merely means that there was no significant
difference between each group, and it does not suggest that the 200 unit administration
has no prospect of having an inhibitory effect on bone fractures.
Accordingly, the Defendant's allegation above is unacceptable.
(C) As mentioned in No. 3, 1. (2) A. (C) above, the Defendant alleges that the 200 unitgroup in Exhibit Ko 1 Invention experienced many cases of side effects, and therefore,
a dose level of 200 units is recognized to be associated with a high side-effect-related
dropout rate, whereas the Three Conditions are based on a novel finding achieved forthe first time through a stratified analysis that PTH's inhibitory effect on bone fractures
is high when Conditions (1) through Condition (3) are combined, and this has made it
possible for the first time to enjoy a benefit worth the risk.
32

Indeed, as described in Attachment 2, Exhibit Ko 1 Document contains informationthat side effects occurred in 42% of group H which received weekly administration of
200 units of PTH, with 16 out of 72 subjects (about 22%) dropping out due to side
effects, and that the rate of side effects and that of dropout due to side effects in thisgroup are higher than those in both group L to which 50 units were administered (therate of side effects: 19%) and group M to which 100 units were administered (the rateof side effects: 19%) (Table 6). As treatment of osteoporosis takes a long time, and it isundesirable for the agent to cause side effects that directly affect the patient's symptoms
or intention to continue to receive treatment when it is put to clinical use (Exhibits Ko
48, 50-1 and 2, and Exhibit Otsu 50), a person skilled in the art who comes across theabovementioned information in Exhibit Ko 1 Document may recognize that it is more
appropriate to administer the agent in 100 units than in 200 units, when considering this
aspect alone.
On the other hand, however, Exhibit Ko 1 Document also states that no serious
adverse phenomena were noted. (Line 1 of the left column to line 4 of the right column
on page 301) Furthermore, it states that administration of 200 units caused the lumbar
spine bone mineral density to increase by 8.1% after 48 weeks, showing a larger
increase than 3.6% for administration of 100 units and 0.6% for administration of 50
units, and evaluates that a significant dose-dependent increase in lumber BMD in a
relatively short period of 48 weeks makes PTH quite promising. (Line 11 of the left
column to line 6 of the right column on page 300, and line 5 of the right column on
page 301 to line 23 of the right column on page 303; It would be hard to understandthat administration of 200 units alone is excluded from the promising object doses.) In
addition, as mentioned in (2) A. (B) above, while the purpose of osteoporosis treatment
is to prevent bone fractures, there is the common general technical knowledge that low
bone density is one of the fracture risk factors for which there is evidence in Japan,
along with prevalent bone fractures and age, and that bone density accounts forapproximately 70% of bone strength.
According to the above, when a person skilled in the art who comes across Exhibit
Ko 1 Document compares weekly administration of 200 units and weekly
administration of 100 units, the person is likely to determine which to choose bycomprehensively considering the aspect of side effects and the aspect of the effect of
the agent. On such basis, the person skilled in the art would not likely consider weekly
administration of 200 units to be so inferior that it would be excluded from the choice;rather, it should be said that there is also sufficient motivation for the person to choose
this dose level.
33

Furthermore, as indicated in (3) A. (B) above, in light of the common generaltechnical knowledge as of the Base Date, it would not have been particularly difficult
for a person skilled in the art who comes across Exhibit Ko 1 Invention to speci fy the
subject patients for administration to be patients who satisfy all of the Three Conditions.
In addition, there is no sufficient evidence to find that the combination of the Three
Conditions is a special choice from an objective viewpoint, or that combining the Three
Conditions has a special meaning in itself, while various combinations including otherfracture risk factors as well can be assumed (as mentioned later, the stratified analysis
alleged by the Defendant merely made a comparison between a group of patients who
satisfy all of the Three Conditions (high-risk patients) and only a part of a group ofpatients who do not satisfy all or part of the Three Conditions (low-risk patients), andits result itself cannot be immediately judged to serve as a basis for finding aconspicuous effect as alleged by the Defendant).
It follows that, even by making examination anew from the viewpoints of the side
effects associated with the agent for the treatment of osteoporosis in Exhibit Ko 1
Invention and the inhibitory effect on bone fractures achieved by choosing the Three
Conditions, as alleged by the Defendant, the determination mentioned in A. above is
not affected.
Accordingly, the Defendant's allegation above is unacceptable.
(D) Other allegations made by the Defendant also do not affect the determination
mentioned in A. above.
(5) Regarding the ease in conceiving of Difference 3
A. Examination(A) Technical meaning of administration "over a duration exceeding 48 weeks to 72
weeks or longer"
While the structure of Invention 1 relating to Difference 3 specifies theadministration period as "over a duration exceeding 48 weeks to 72 weeks or longer,"
this can be understood as defining administration within a specific range of period bystating "over a duration," and specifying the start of that range (the administration itself
starts from week 0) as "exceeding 48 weeks" and the end of that range as "72 weeks orlonger."
The Description states that, in a double-blind comparative clinical trial with theoccurrence of bone fractures as the primary endpoint, the effect of the agent appeared
early at after 24 or 26 weeks, and that no new vertebral fractures were found whenadministration went beyond 48 weeks, and presents 24 weeks or longer, 26 weeks orlonger, 48 weeks or longer, 52 weeks or longer, 72 weeks or longer, and 78 weeks or
34

longer as examples of administration periods, with 78 weeks or longer being the mostfavorable (paragraph [0032]).
In addition, the Description states, as Working Example 2, that when patients who
satisfy all of the Three Conditions (high-risk patients) were subcutaneously
administered the test drug (PTH 200 units) or the control (placebo) once a week,
intermittently, for a duration of 72 weeks (paragraph [0098]), the incid ence of new
vertebral fractures every six months was basically steady at approximately 5% in alldivisions, consisting of within 24 weeks, 24 to 48 weeks, and 48 to 72 weeks, in thecontrol group, but in contrast, the incidence of each division dropped as theadministration period lengthened in the test drug group, and that no new vertebral
fractures occurred after 48 weeks (paragraphs [0131] and [0132], [Table 34], and [Table35]). It also states that the incidence of vertebral fractures (new + worsening) after 72
weeks by Kaplan-Meier estimation was 3.5% in the test drug group and 16.3% in thecontrol group (paragraph [0133]).
According to these statements, it is understood that the Invention specified"exceeding 48 weeks" as the start of the range of the administration period in
consideration that no new vertebral fractures occurred after 48 weeks at the latest, andspecified "72 weeks or longer" (including week 72) as the end of that range inconsideration that the test period lasted for 72 weeks and therefore that administrationneeds to be continued for at least 72 weeks.
Meanwhile, while the Description has no statements other than the above
concerning the technical meaning of the numerical value "48 weeks," administration
exceeding 48 weeks is premised on administration of the agent up to 48 weeks. The factthat no new bone fractures occurred after 48 weeks until 72 weeks in [Table 34] meansthat no further bone fracture occurred after the last bone fracture that occurred after 24
weeks until 48 weeks, and although the time of the occurrence of that last fracture is
unknown, given that only two cases of bone fractures occurred during the considerably
long period of 24 weeks ([Table 35] of the Description), if focus is to be simply placedon whether or not new vertebral fractures occurred, it can also be evaluated that theeffect was already demonstrated in the division of 24 to 48 weeks. Furthermore, 72
weeks was indicated only because the test period was 72 weeks, and although the
Description states 72 weeks "or longer," the incidence of bone fractures for the period
exceeding 72 weeks is unknown from the Description.
According to the above, "48 weeks" and "72 weeks or longer" are not defined tohave technical meaning in themselves, and no particular technical meaning can be foundin the limitation of the Invention specifying the specific range of period of "over a35

duration exceeding 48 weeks to 72 weeks or longer" to indicate the start and the end of
the range. It is reasonable to regard that, in showing that the incidence of bone fractures
dropped through continuous administration of PTH for the discretionary divisions of
the test period that were divided for convenience, this period was merely adopted byfocusing on the fact that no new vertebral fractures occurred in that period, as a factindicating the test result.
(B) Regarding the ease of conceiving of the difference
As mentioned in (2) B. (B) above, it was known as of the Base Date that bonedensity increases and the occurrence of bone fractures decreases through dailyadministration of a PTH preparation over a duration exceeding 48 weeks.
Meanwhile, in Exhibit Ko 1 Invention, as a result of weekly administration of 200
units of PTH, the lumbar spine BMD continuously increased up to 48 weeks,significantly increasing by 8.1% after 48 weeks (line 1 of the left column to line 7 of
the right column on page 296 of Exhibit Ko 1 Document), and further, no vertebral
fractures occurred in group H, which is the PTH 200 unit group, during theadministration period of 48 weeks (line 11 of the left column to line 6 of the rightcolumn on page 300 of Exhibit Ko 1 Document).
While it can be said that a person skilled in the art would have understood that anincrease in bone density contributes to prevention of bone fractures based on thecommon general technical knowledge mentioned in (2) A. above, the test in Exhibit Ko
1 Document, conducted for administration for up to 48 weeks, shows a continuous
increase in the lumbar spine BMD, although there is a diminishing trend in the increase
rate (Figure 1 of Exhibit Ko 1 Document), and no grounds are found to indicate that theincrease turns to a decrease when administration exceeds 48 weeks.
According to the above, it can be said that, even as of the Base Date, a person skilledin the art could have easily conceived of also administering the agent for the treatmentof osteoporosis in Exhibit Ko 1 Invention over a duration exceeding 48 weeks in order
to increase bone density and prevent bone fractures, based on the report that dailyadministration of PTH was conducted over a duration exceeding 48 weeks, and thatbone density increased and the occurrence of bone fractures decreased as a result. As aconsequence, it should be said that a person skilled in the art could have arrived at
Invention 1.
B. Regarding the Defendant's allegations(A) As mentioned in No. 3, 1. (2) D. (A) above, the Defendant alleges as follows: [i]given the high rate of side effects and dropout rate for the weekly administration of 200
units of PTH in Exhibit Ko 1 Invention, there is no motivation to attempt long -term
36

administration of the agent with this dosage and administration; and [ii] in the test in
Exhibit Ko 1 Invention, a duration of 48 weeks was considered to be the limit ofcontinuous administration, and therefore, there is an obstructive factor for attempting
long-term administration of the agent in Exhibit Ko 1 Invention.
However, the allegation mentioned in [i] above is unacceptable due to the following
reasons: although it cannot be confirmed from the matters disclosed (Figure 1) in
Exhibit Ko 1 Document that the increase rate of the lumbar spine BMD rose due toadministration over a period exceeding 48 weeks, it can be confirmed that the net
lumbar spine BMD increased while the increase rate diminished; thus, even if there isnaturally a limit to the increase in the lumbar spine BMD due to the limits of the human
body, there are no particular grounds indicating that the increase in the lumbar spine
BMD immediately disappears after 48 weeks of administration; also, even if there is no
significant statement concerning the inhibitory effect on bone fractures itself, the factthat an increase in bone density contributes to prevention of bone fractures was common
general technical knowledge, as mentioned above; therefore, it cannot be said that aperson skilled in the art would be obstructed from applying the agent to clinical use dueto the high rate of side effects and dropout rate for the weekly administration of 200
units of PTH in Exhibit Ko 1 Invention, and it can be regarded that there is sufficientmotivation to adopt long-term administration when making such application, in light ofthe effect of the agent to increase the BMD.
Moreover, Exhibit Ko 1 Document states as follows: "... the period of the study wasset at 48 weeks. This was also thought to be the limit of duration for an adequatel ycontrolled multicenter study with regular bone measurement and blood and urine
sampling without suffering an excessive dropout rate, in a population of osteoporotics
at constant risk and anxiety for fracture." (Line 48 of the right column on page 297 toline 24 of the left column on page 298) Therefore, it is clear in Exhibit Ko 1 Documentthat the direct reason for setting the test period at 48 weeks was for concerns about the
problem in management of the clinical trial. Also considering that the test period wasto be set before knowing the results of the test in Exhibit Ko 1 Document, it should besaid that when a person skilled in the art who saw the results of the test in Exhibit Ko
1 Document uses the agent for the treatment of osteoporosis in Exhibit Ko 1 Invention
in practical treatment, the person cannot be regarded to be obstructed fromadministering the agent for a period exceeding 48 weeks. Therefore, the allegation
mentioned in [ii] above is also unacceptable.
(B) As mentioned in No. 3,1. (2) D. (B) above, the Defendant alleges that, as Exhibit
Ko 2 Document is about a test with different dosage and administration from those of37

Exhibit Ko 1 Invention, the matters stated in Exhibit Ko 2 Document would not serve
as a motivation for administering the agent for the treatment of osteoporosis in Exhibit
Ko 1 Invention over a duration exceeding 48 weeks.
However, although the dosage and administration in the clinical trial in Exhibit Ko
2 Document differ from those in Exhibit Ko 1 Invention, and therefore it cannot be
regarded that a continuation period that is completely the same can immediately be
adopted, it is natural and reasonable for a person who came across information on an
agent, which is also a PTH preparation, and which is also found to have an effect ofincreasing bone density, to conceive of administering an agent for the treatment of
osteoporosis with weekly administration of 200 units of PTH, which is expected toincrease bone density, over a duration exceeding 48 weeks. Accordingly, it at leastcannot be said that Exhibit Ko 2 Document would not serve as a motivation.
(C) The Defendant has also made other allegations, but none of them affect thedetermination mentioned in A. (B) above.
(6) Regarding the effect of the invention
A. Regarding an unpredictable and outstanding effect
Whether or not the effect of an invention is unpredictable and outstanding needs tobe examined from the perspectives of whether the effect is one that a person skilled in
the art could not have predicted as an effect produced by the structure of the invention
as of the base date for determining the patentability of the invention and whether theeffect is an outstanding one that goes beyond the scope of effect that a person skil led in
the art could have predicted based on that structure (see the judgment of the Third Petty
Bench of the Supreme Court, 2018 (Gyo-Hi) 69, rendered on August 27, 2019, Shumin,
No. 262, at 51). Indeed, as it is difficult to determine whether or the invention is foundto have an unpredictable and outstanding effect solely from the structure of theinvention, it is regarded to be permissible to take into consideration the effect produced
by prior art that was selected as having a structure similar to that of the invention or asimilar type of effect that had been achieved by the state of the art at the time.
Meanwhile, the burden of proof regarding the unpredictable and outstanding effect lieson the patentee. Therefore, even if the effect produced by the structure of the invention
is unknown, it cannot be immediately concluded that the invention has an unpredictableand outstanding effect.
B. Regarding the effect of the Invention(A) Regarding the unpredictable and outstanding effects alleged by the Defendant
As mentioned above, the structure of Invention 1 could have been easily conceivedof by a person skilled in the art. In contrast, however, as mentioned in No. 3, 1. (2) E.
38

(B) above, the Defendant alleges that the following are unpredictable and outs tanding
effects of the Invention: [i] a remarkable inhibitory effect on bone fractures, indicating
a 79% RRR in comparison to the placebo, after 72 weeks (Effect [i]); [ii] an effect thatthe inhibitory effect on bone fractures is intensified through continuous administrationof the agent (Effect [ii]); and [iii] an effect of completely inhibiting bone fractures inpractice after 48 weeks (Effect [iii]). Therefore, these effects are examined below.
(B) Regarding unpredictable and outstanding effects of the Invention
First, the Defendant alleges that, if the question of whether or not the effect of an
invention is unpredictable and outstanding should be determined based on the structureof the invention, in this case, it would be sufficient to examine the inhibitory effect onbone fractures in patients not satisfying the Three Conditions, which is a structure ofInvention 1, and there is no need to compare the inhibitory effect on bone fractures inpatients satisfying the Three Conditions to that in patients not satisfying the Three
Conditions, and also, there is no need for such comparison to be stated in the
Description.
However, Invention 1 is an invention that has discovered an inventive step in
administering PTH to a group of patients from among a group administered with PTH
for which an extremely high effect can be achieved, based on a premise that PTH was
well-known as an agent for the treatment of osteoporosis as of the base time of this case.
Therefore, in order to confirm the agent's inhibitory effect on bone fractures in patients
who satisfy all of the Three Conditions, it is necessary to compare the inhibitory effecton bone fractures in high-risk patients and that in low-risk patients (patients other thanhigh-risk patients). Merely comparing high-risk patients administered with the agent
for the treatment of osteoporosis in the Invention and patients administered with theplacebo and showing that the agent has an inhibitory effect on bone fractures in thosehigh-risk patients means only showing that the agent has an extremely high inhibitory
effect on bone fractures in a group of patients in the PTH group in comparison to theplacebo group. It does not mean clarifying that the high-risk patient group is a patientgroup from among the PTH group in which the agent has a particularly high effect incomparison to other patient groups, and it merely means confirming the agent's
inhibitory effect on bone fractures in the PTH group.
Accordingly, the Defendant's allegation above is unacceptable.
C. Regarding Effect [i](A) As mentioned in (2) A. (B) above, there was the common general technicalknowledge that osteoporosis is a skeletal disorder characterized by compromised bonestrength predisposing to an increased risk of fracture, the purpose of its treatment is to39

prevent bone fractures, "bone strength" consists of two features, bone density and bonequality, and bone density accounts for approximately 70% of bone strength. Therefore,
a person skilled in the art would have understood that an increase in bone density
contributes to prevention of bone fractures. On such basis, Exhibit Ko 1 Document
states that "considerable advances have been made in the prevention of fractures
through increases in bone mineral density (BMD) by using these agents" (line 10 of theright column on page 296 to line 25 of the left column on page 297), indicating that anincrease in bone density contributes to prevention of bone fractures, and discloses thatbone density increased by 8.1% after 48 weeks of administration (line 11 of the left
column to line 6 of the right column on page 300). It follows that a person skilled in theart would have easily understood that the agent for the treatment of osteoporosis in
Exhibit Ko 1 Invention has an effect of inhibiting bone fractures.
(B) The endpoint for the inhibitory effect on bone fractures, mentioned as Effect [i], is
not regarded to refer to a mere decrease in the incidence of bone fractures, but to therate of decrease in the incidence of bone fractures in comparison to that in the placebogroup. However, as mentioned in B. above, in order to confirm Effect [i], there is a needto compare the inhibitory effect on bone fractures in high-risk patients and that in lowrisk patients, and merely comparing high-risk patients and the placebo patients andshowing that the agent has an inhibitory effect on bone fractures in high-risk patients
does not mean clarifying that the high-risk patient group is a patient group from among
the PTH group in which the agent has a particularly high effect. Given these points, itcannot be understood from the statement of the Description that the agent's inhibitory
effect on bone fractures in high-risk patients, who are defined as patients who satisfy
all of the Three Conditions, is higher than that in low-risk patients, who are defined as
patients who do not satisfy all or part of the Three Conditions.
(C) In other words, the Description only states in Working Example 1 that, among highrisk patients, a significant difference could be found between the incidence of new
vertebral fractures in the group with weekly administration of 100 units and that in thegroup with weekly administration of 5 units, which is practically the placebo group, in
all comparisons, whereas in low-risk patients, no significant difference could be foundbetween the new vertebral fractures in the group with weekly administration of 100
units and that in the group with weekly administration of 5 units in all comparisons(paragraphs [0086] through [0096], [Table 6] through [Table 11]). Even based on thevalues re-analyzed after correcting erroneous entries (1. (2) E. above), with regard to
new vertebral fractures in low-risk patients, there was only one case of bone fractureout of the 11 patients in the group with weekly administration of 100 units and one out
40

of the 10 patients in the group with weekly administration of 5 units. It is clear that,
under such a small number of cases, the abovementioned rate of decrease in theincidence of bone fractures in comparison to that in the placebo group (RRR) willfluctuate substantially by a mere increase or decrease in the number of cases of bone
fractures by one. In the case of administration to low-risk patients, the number of casesof bone fracture is small even in the group with weekly administration of 5 units, andtherefore it is natural that the value of RRR, which is the rate of decrease of theincidence of bone fractures in the group with weekly administration of 100 units incomparison to that in the group with weekly administration of 5 units, is smaller thanthe value for the high-risk patients.
In this regard, the Defendant alleges that, if there is a significant difference between
the inhibitory effect on bone fractures in patients satisfying the Three Conditions andthat in the placebo group, and there is no significant difference between the inhibitory
effect on bone fractures in patients not satisfying the Three Conditions and that in theplacebo group, it can be said immediately that the agent for the treatment of
osteoporosis in Invention 1 has an extremely high effect in patients satisfying the Three
Conditions. However, there being no significant difference merely means that it isunknown whether there is a high effect, and it does not mean immediately that the effectis not high. Also, it cannot be denied that there being no significant difference wascaused by an insufficient number of cases (Exhibit Ko 35). Therefore, it is not
appropriate to derive a conclusion as mentioned above.
Accordingly, it cannot be understood from Working Example 1 that PTH's inhibitory
effect on bone fractures in high-risk patients is higher than that in low-risk patients.
(D) Next, the Description states as follows with regard to Working Example 2:
regarding weekly administration of 200 units of PTH to patients satisfying the Three
Conditions, the incidence of bone fractures in the control (placebo) group was basicallysteady at approximately 5% in all of the periods of ["≤24 weeks," ">24 weeks to ≤48
weeks," and ">48 weeks to ≤72 weeks" after the start of administration, whereas in thegroup with weekly administration of 200 units of PTH, the incidence decreased from
2.3%, 0.9%, to 0%, and the RRR in comparison to the placebo group increased asadministration continued; in the group with weekly administration of 200 units of PTH,
the risk of bone fractures had dropped 53.9% versus that in the placebo group after 24
weeks; and 200 units of the drug also lowered the risk of vertebral fractures (new +worsening) 78.6% in comparison to the placebo after administration for 72 weeks(paragraphs [0131] through [0133], [Table 34], and [Table 35]).
However, these statements merely compare patients to whom the osteoporosis
41therapeutic agent referred to in the Invention was administered and patients to whom aplacebo was administered, among those who satisfy the Three Conditions, and does notindicate that the inhibitory effect on bone fractures is higher in patients who satisfy allof the Three Conditions than in patients who do not in the case where the agent for thetreatment of osteoporosis in the Invention is administered.
(E) In addition, as mentioned in 1. (2) A. above, because all patients in Working
Example 1 have one or more vertebral fractures, they are all patients who satisfy
Condition (2), and because they fall under the category of "I. With vertebral fracture on
X-ray film" under Exhibit Ko 5 Diagnostic Criteria, and therefore have a low bone mass
with "the degree of bone atrophy of I or higher, or bone density less than 80% of theyoung adult mean (YAM))," they are all patients who satisfy Condition (3) (althoughpatients with a bone density value of precisely 80% of YAM do not satisfy Condition(3), that is hard to imagine in reality). In other words, those referred to as high-riskpatients (patients satisfying the Three Conditions) in the Description are, by defin ition,
patients who satisfy Conditions (1) through (3), and even those referred to as low -riskpatients (patients not satisfying the Three Conditions) in the Description satisfy
Conditions (2) and (3) as mentioned above. Therefore, Working Example 1 only
compares the inhibitory effect on bone fractures between those who satisfy Condition(1), which is age 65 years or older, and those who do not. Meanwhile, as mentioned
above, Working Example 2 does not compare the inhibitory effect on bone fractures inpatients not satisfying the Three Conditions with that in patients satisfying the Three
Conditions in the case where the agent for the treatment of osteoporosis in the Invention
is administered. This makes it even more difficult to compare the degree of inhibitionof new vertebral fractures in high-risk patients with that in low-risk patients andconclude that the former effect is higher than the latter effect based on the Description.
(F) Furthermore, when looking at other parts of the Description, they contain statementsthat merely indicate a conclusion to the effect that "the agent has a higher inhibitory
effect on bone fractures in high-risk patients than in low-risk patients." As these are notbased on pharmacological test data, and it cannot be reasonably understood from suchstatements that PTH's inhibitory effect on bone fractures in high-risk patients (patientssatisfying the Three Conditions) is higher than that in low-risk patients (patients notsatisfying the Three Conditions), after all, it should be said that Effect [i] is not basedon the statement of the Description.
(G) The Plaintiff alleges that Effect [i] is clear from Exhibit Ko 64 Certificate andExhibit Ko 68 Certificate.
However, as long as it cannot be understood from the statement of the Description
42

that PTH's inhibitory effect on bone fractures in high-risk patients is higher than that in
low-risk patients and as long as this also cannot be presumed from the statement of the
Description, it is not reasonable to find Effect [i], which is not disclosed to the public,
by adopting the respective Experiment Result Certificates mentioned above.
Even if reference were to be made to the respective Experiment Result Certificatesmentioned above, these certificates, even according to the Defendant's allegations,come down to comparing the number of fracture cases in the PTH groups consisting ofa group of patients who are "age 65 years or older, without prevalent bone fractures,and whose bone density is less than 80% of the young adult mean" and a group ofpatients who are "age 65 years or older, with prevalent bone fractures, and whose bonedensity is less than 80% of the young adult mean," that is, between groups in which
only Condition (2)—the presence or absence of prevalent bone fractures—differs,
against that in the placebo groups (control groups) for the case of administration
exceeding 48 weeks and the case of administration for 72 weeks or longer, and merely
making a comparison between a group of patients who satisfy all of the Three
Conditions (high-risk patients) and only a part of a group of patients who do not satisfy
all or part of the Three Conditions (low-risk patients); therefore, the certificates are notat all suitable for concluding that the degree of inhibition of bone fractures in patients
who satisfy all of the Three Conditions is higher than that in patients who do not satisfy
the Three Conditions. It follows that, even by looking at the respective Experiment
Result Certificates above, it cannot be understood that PTH's inhibitory effect on bone
fractures in patients who satisfy all of the Three Conditions is higher than that inpatients who do not satisfy the Three Conditions.
(H) According to the above, Effect [i] cannot be found in any case. Therefore, without
having to make determinations on other points, there is no room for finding that
Invention 1 has an unpredictable and outstanding effect.
D. Regarding Effect [ii](A) As mentioned in C. above, the Description states as follows with regard to Working
Example 2: regarding weekly administration of 200 units of PTH to patients satisfying
the Three Conditions, the incidence of bone fractures in the control (placebo) group was
basically steady at approximately 5% in all of the periods of "≤24 weeks," ">24 weeks
to ≤48 weeks," and ">48 weeks to ≤72 weeks" after the start of administration, whereas
in the group with weekly administration of 200 units of PTH, the incidence decreased
from 2.3%, 0.9%, to 0% (paragraphs [0131] through [0133], [Table 34], and [Table 35]).
However, these statements merely compare patients to whom the osteoporosis
therapeutic agent referred to in the Invention was administered and patients to whom a43

placebo was administered, among those who satisfy the Three Conditions, and does notindicate that the inhibitory effect on bone fractures is higher in patients who satisfy allof the Three Conditions than in patients who do not in the case where the agent for thetreatment of osteoporosis in the Invention is administered. In addition, while it can beread from Figure 1 of Exhibit Ko 1 Document that the lumbar spine BMD in group H
with weekly administration of 200 units increased by about 5% at 24 weeks from thestart of administration and by 8.1% at 48 weeks from the start of administration, there
are no grounds indicating that the increase in the lumbar spine BMD immediately
disappears after 48 weeks of administration, although the increase rate is expected todiminish, as mentioned in (5) A. (B) above. As long as bone density increases, theinhibitory effect on bone fractures can also be expected to increase. On the other hand,bone density does not increase in the placebo group. Therefore, it is clear that the
inhibitory effect on bone fractures in the group with weekly administration of 200 unitsof PTH will increase in comparison to that in the placebo group as the administration
period progresses. In addition, Exhibit Ko 2 Document contains statements relating todaily administration of 20 μg of PTH or daily administration of 40 μg of PTH that when
20 or 40 μg of PTH was administered daily for an average of 17 or 18 months for thetreatment of osteoporosis in postmenopausal women, the treatment decreased the riskof vertebral and nonvertebral fractures and increased vertebral, femoral, and total -bodybone mineral density (lines 1 to 42 of the left column on 1434, and lines 46 to 53 of theright column on page 1435), and that the rate of inhibition of bone fractures by the PTH
administration became higher as the administration period became longer (Figur e 1).
Therefore, if Effect [ii] simply refers to an effect that the inhibitory effect on bone
fractures achieved by weekly administration of 200 units to patients satisfying the Three
Conditions would be intensified through continuous administration of the agent, it
would have been sufficiently within the scope of expectation for a person skilled in theart.
(B) Furthermore, when looking at other parts of the Description, it cannot be understoodthat PTH's inhibitory effect on bone fractures in high-risk patients (patients satisfying
the Three Conditions) will be intensified more than that in low-risk patients (patientsnot satisfying the Three Conditions) through continuous administration of the agent,and this also cannot be presumed from the statement of the Description; thus, after all,it should be said that Effect [ii] is not based on the statement of the Description.
(C) According to the above, Effect [ii] cannot be found in any case. Therefore, without
having to make determinations on other points, there is no room for finding that Effect[ii] is an unpredictable and outstanding effect.
44

E. Regarding Effect [iii](A) As mentioned in C. (A) above, while it is understood that an increase in bone density
contributes to prevention of bone fractures, Exhibit Ko 1 Invention significantly
increases bone density by 8.1% in 48 weeks, and is expected to continuously increase
the lumbar spine BMD if the administration exceeds 48 weeks. As a fact indicating thetest result, Exhibit Ko 1 Document shows that, in the 200 unit group, no vertebral
fracture occurred during the administration for 48 weeks (line 11 of the left column toline 6 of the right column on page 300). Thus, it is natural to consider that, even if theadministration period exceeds 48 weeks in Exhibit Ko 1 Invention with administrationof 200 units of PTH, an equivalent inhibitory effect on bone fractures as that during theadministration period of 48 weeks will continue to a certain extent.
(B) The inhibitory effect on bone fractures of Effect [iii] is to reduce the incidence ofbone fractures to 0% when 200 units of PTH relating to Invention 1 are administered topatients who satisfy all of the Three Conditions every week for a duration exceeding 48
weeks to at least 72 weeks. However, as mentioned in (5) A. (A) above, no particulartechnical meaning can be found in the numerical values "48 weeks" and "72 weeks"
themselves. It only refers to a fact indicating a test result that no new vertebral fractures
were found when administration went beyond 48 weeks, which can hardly be found tomean that the osteoporosis therapeutic agent referred to in the Invention is a therapeutic
agent that completely inhibits bone fractures in practice after 48 weeks ofadministration (a complete wonder drug). The defendant also does not allege that theosteoporosis therapeutic agent referred to in the Invention has such effect (indeed, thefollowing are found in the case of Teribone, for which there is no dispute between theparties that it is a product embodying Invention 1: the incidence of new vertebral
fractures was 0.7% from 49 to 72 weeks of administration, and the incidence of bone
fractures was 2.2% from 73 to 104 weeks of administration, although these are results
for which the subject patients for administration are not limited to high-risk patients(Exhibit Ko 11); and the incidence of new vertebral fractures by Kaplan-Meierestimation was 1.7% at 24 weeks, 2.5% at 48 weeks, and 3.3% at 72 weeks (Exhibit Ko
30)).
Moreover, as mentioned in (A) above, while it is natural to consider that the
inhibitory effect on bone fractures will continue to a certain extent even after 48 weeks
in Exhibit Ko 1 Invention, given that no vertebral fractures were found during 48 -weekadministration also in Exhibit Ko 1 Invention, even though it is merely a fact indicatinga test result, it can be understood that the bone fracture incidence was originally low.
Accordingly, even if the number of bone fractures during the period exceeding 48 weeks45

to 72 weeks was zero in Invention 1 and thus the incidence of bone fractures was 0%,
one cannot go so far as to say that this fact itself was surprising for a person skilled in
the art. Rather, it can be said that this fact was within the scope of expectation for a
person skilled in the art.
F. Summary
Other allegations made by the Defendant also do not affect the determination
mentioned in C. through E. above. Without the need to add further examination on the
degree of the effect, etc., Invention 1 is not found to have an outstanding effect w hichcould not have been predicted by a person skilled in the art.
(7) Summary on Invention 1
According to the above, it is found to have been easy for a person skilled in the art
to conceive of the structures of Invention 1 relating to Differences 1 through 3, even ona premise of making the determination based on the Base Date, and the effects ofInvention 1 are also not found to be outstanding effects which could not have been
predicted by a person skilled in the art. Therefore, after all, without having to makedeterminations on other points, it should be said that Differences 1 through 3 could havebeen easily conceived of by a person skilled in the art. Thus, there is an error in thedetermination in the JPO Decision which found that a person skilled in the art could nothave easily conceived of Differences 1 through 3. It follows that, the determination in
the JPO Decision which found that Invention 1 involves an inventive step is erroneous.
(8) Regarding Invention 2
As mentioned in (7) above, there is an error in the determination in the JPO Decision
which found that a person skilled in the art could not have easily conceived ofDifferences 1 through 3 in Invention 1. It follows that there is also an error in thedetermination in the JPO Decision which immediately found that Invention 2 involves
an inventive step, for the same reason as for Invention 1, on a basis that Invention 2 isan invention that has limited Invention 1.
3. Conclusion
As described above, Grounds for Rescission 1 are well-founded, and without having
to make determinations on other points, the JPO Decision is rescinded, and thejudgment is rendered as indicated in the main text.
Intellectual Property High Court, Fourth Division
Presiding Judge: KANNO Masayuki
Judge: MOTOYOSHI Hiroyuki
Judge: NAKAMURA Kyo
46

(Attachment 1)
Matters stated in the Description (Abstract)(Tables are posted together at the end of the Attachment.)[Detailed explanation of the invention][Technical field][0001]The present invention relates to a therapeutic or prophylactic agent for osteoporosis
containing PTH as the active ingredient. Further, the present invention relates to an
inhibitor or prophylactic agent for fractures containing PTH as the active ingredient. In
particular, the present invention relates to the aforementioned agents that arecharacterized by administering 100 units to 200 units of PTH per dose per week.
[Background art]
[0002]
Osteoporosis is a "disease characterized by a decrease in bone strength that poses
an increased risk of fractures." Currently, PTH (Parathyroid Hormone) is known as oneof the therapeutic agents for osteoporosis.
[0003]
PTH is a hormone involved in the regulation of blood calcium concentration alongwith calcitonin and vitamin D. For example, it is also known that PTH has the action ofpromoting calcium absorption in the intestinal tract by increasing active vitamin D 3
production in the kidney in vivo (Non-patent Document 1).
[0004]
Patent Document 1 discloses a therapeutic method of osteoporosis where 100 units
or 200 units of PTH per dose are administered by subcutaneous injection to patientswith osteoporosis at the frequency of once a week over a 26-week period so that thebone density of the cancellous bone of the patients with osteoporosis is increased andthe bone density of the cortical bone of the same will not be decreased.
[0005]
Thus, Patent Document 1 discloses that the therapeutic method merely induces anincrease in bone density but does not state whether it is a therapeutic method to increase
the bone strength of patients with osteoporosis or to reduce the risk of fractures. In
addition, PTH alone is used and no calcium agent is used in combination.
[0006]
Non-patent Document 1 discloses that in a clinical trial relating to the osteoporosis
therapy with PTH, when blood was collected after 4 hours to 6 hours afteradministration of PTH (20 μg/day) to patients with osteoporosis, hypercalcemia was47

observed in 11% of the patients, and sustained hypercalcemia was observed in 3%
thereof. In addition, Non-patent Document 1 discloses that, before the following
administration of PTH, serum calcium returned to normal for most of the patients;
however, increases in a sustained serum calcium was observed in one of 541 patients,
and therefore the treatment was discontinued for that patient.
[0007]
With respect to a daily subcutaneous administration of PTH in combination with acalcium agent, Non-patent Document 2 discloses that serum calcium afteradministration of the present agent is clinically not a problem, but also reports that
serum calcium after administration has increased. Non-patent Document 3 is a package
insert of a daily subcutaneous administration formulation disclosed in Non -patent
Document 2. This document reports that transient hypercalcemia after administrationof the formulation was observed in clinical trials while disclosing various adverse
events after administration of the formulation. Further, Non-patent Document 3
discloses that there is a report of adverse reactions of hypercalcemia in the postmarketing surveillance of the formulation.
[0008]As described above, Non-patent Documents 1 through 3 disclose cases of adverse
reactions of hypercalcemia in the treatment of osteoporosis with PTH, and thetherapeutic methods disclosed therein are regarded to be insufficient in terms of safety.
[0009]
Given the aforementioned background, an osteoporosis treatment method using
PTH, which is highly safe and excellent in efficacy and effects, was required.
[Prior art document][Non-patent document][0011][Non-patent Document 12] Hajime Orimo et al, "Diagnostic Criteria for Primary
Osteoporosis (revised version of FY1996)," 1997, Journal of Japanese Society for Boneand Mineral Metabolism Vol. 14, at 219-233[Non-patent Document 13] Diagnostic Criteria for Primary Osteoporosis andPrevention and Treatment Guidelines for Osteoporosis (Hajime Orimo et al,"Prevention and Treatment Guidelines for Osteoporosis 2006," 2006, at 34 -35)
[Outline of the invention][Problems to be solved by the invention][0012]The problem of the present invention is to provide an osteoporosis treatment method48

and prevention method using PTH, which is highly safe and excellent in efficacy andeffects. In addition, the problem of the present invention is to provide an inhibiting andpreventing method of fractures using highly safe PTH.
[Means of solving the problems][0013]In order to solve the above problems, the present inventors have conducted
extensive research and development, and as a result, surprisingly, they found an
osteoporosis treatment and prevention method that is excellent in both efficacy andeffects and safety by limiting the dose and administration interval of PTH. In addition,
they found that specifying the dose and administration interval of PTH results in ahighly safe fracture inhibition and prevention method. Furthermore, they also foundthat the method particularly shows effects for high-risk patients.
[0014]
In other words, the present invention relates to the following:[1] A therapeutic or prophylactic agent for osteoporosis containing PTH as the active
ingredient, which is characterized by administration in combination with a calcium
agent and by 100 units to 200 units of PTH per dose per week.
[2] A therapeutic or prophylactic agent for osteoporosis stated in [1] above, which ischaracterized by the administration in combination with a calcium agent once per weekor more often.
[3] A therapeutic or prophylactic agent for osteoporosis stated in [1] or [2] above, wh ich
is characterized by the administration in combination with a calcium agent of 200 mg
to 800 mg per day as calcium.
[4] Any therapeutic or prophylactic agent for osteoporosis stated in [1] through [3]above, wherein the PTH is human PTH (1-34).
[5] A therapeutic or prophylactic agent for osteoporosis stated in any of [1] through [4]above for administration over a period exceeding 24 weeks or 48 weeks.
[6] Any therapeutic or prophylactic agent for osteoporosis stated in [1] through [5]above for patients with osteoporosis who meet all requirements in (1) through (3)below:(1) Age 65 years or older(2) Prevalent fractures; and(3) Bone density less than 80% of the young adult mean and/or degree of bone atrophyof I or higher.
[7] A therapeutic or prophylactic agent for osteoporosis stated in any one of [1] through[6] above for treatment and prevention of secondary osteoporosis caused by steroid or49

diabetic osteoporosis.
[8] A therapeutic or prophylactic agent for osteoporosis stated in any one of [1] thro ugh[6] above for treatment and prevention of osteoporosis that has a complication with atleast any one of the following diseases in (1) through (8) below:(1) diabetes;(2) hypertension;(3) hyperlipidemia;(4) arthralgia;(5) spondylosis deformans;(6) deformans low back pain;(7) hip osteoarthritis; and(8) temporomandibular joint osteoarthritis.
[9] A therapeutic or prophylactic agent for osteoporosis stated in any one of [1] through[6] above for administering to patients with osteoporosis having medi cation history ofat least any one of therapeutic agents for osteoporosis in the following (1) through (6):(1) L-calcium aspartate;(2) alfacalcidol;(3) elcatonin;(4) raloxifene hydrochloride;(5) menatetrenone; and(6) calcium lactate.
[10] A therapeutic or prophylactic agent for osteoporosis stated in any one of [1]through [6] above for administering to patients with osteoporosis having mild renal
dysfunction or moderate renal dysfunction.
[11] A therapeutic or prophylactic agent for osteoporosis stated in any one of [6] through[10] above, wherein the PTH is human PTH (1-34).
[12] A therapeutic or prophylactic agent for osteoporosis stated in any of [6] through[11] above, wherein the therapeutic agent for osteoporosis containing the
aforementioned PTH as the active ingredient is a subcutaneous injection.
[13] A drug combination or medical kit consisting of a therapeutic or prophylactic agent
for osteoporosis stated in any one of [1] through [12] above and at least any one of thefollowing agents (1) through (6):(1) metoclopramide;(2) domperidone;(3) famotidine;(4) mosapride citrate;50

(5) lansoprazole; and(6) Rokushingan.
[14] A therapeutic or prophylactic agent for osteoporosis containing PTH as the active
ingredient, which is characterized by the administration of 100 units to 200 units of
PTH per dose per week and is used for the treatment of patients with osteoporosis whomeet all requirements in (1) through (3) below:(1) Age 65 years or older;(2) Prevalent fractures; and(3) Bone density less than 80% of the young adult mean and/or degree of bone atrophyof I or higher.
[15] A therapeutic or prophylactic agent for osteoporosis with high risk of fracture,
which contains PTH as the active ingredient and is characterized by the administrationof 100 units to 200 units of PTH per dose per week.
[16] A therapeutic or prophylactic agent for osteoporosis containing PTH as the active
ingredient, which is characterized by the administration of 100 units to 200 units of
PTH per dose per week and is used for treatment and prevention of secondary
osteoporosis caused by steroid or diabetic osteoporosis.
[17] A therapeutic or prophylactic agent for osteoporosis containing PTH as the active
ingredient, which is characterized by the administration of 100 units to 200 units of
PTH per dose per week and is used for administration to patients with osteoporosis
having mild renal dysfunction or moderate renal dysfunction.
[18] An inhibitor or prophylactic agent for fractures containing PTH as the active
ingredient, which is characterized by the administration in combination with a calcium
agent and of 100 units to 200 units of PTH per dose per week.
[19] An inhibitor or prophylactic agent for fractures stated in [18] above, which ischaracterized by administration in combination with a calcium agent once per week ormore often.
[20] An inhibitor or prophylactic agent for fractures stated in [18] or [19] above, which
is characterized by administration in combination with a calcium agent of 200 mg to
800 mg per day as calcium.
[21] Any inhibitor for fractures stated in [18] through [20] above, wherein the PTH ishuman PTH (1-34).
[22] Any inhibitor or prophylactic agent for fractures stated in [18] through [21] abovethat is used for administration to subjects who meet all requirements in (1) through (3)below:(1) Age 65 years or older;51

(2) Prevalent fractures; and(3) Bone density less than 80% of the young adult mean and/or degree of bone atrophyof I or higher.
[23] An inhibitor or prophylactic agent for fractures stated in [22] above, wherein the
PTH is human PTH (1-34).
[24] An inhibitor or prophylactic agent for fractures stated in [22] or [23] above, whichcontains PTH as the active ingredient and is a subcutaneous injection.
[25] An inhibitor or prophylactic agent for fractures stated in any one of [18] through[24] above, which is an inhibitor or prophylactic agent for multiple bone fracture.
[26] An inhibitor or prophylactic agent for fractures stated in any one of [18] through[25] above, which is an inhibitor or prophylactic agent for worsening fractures.
[27] A therapeutic or prophylactic agent for osteoporosis stated in [14] or [15] abovethat is used for treatment and prevention of secondary osteoporosis caused by steroid
or diabetic osteoporosis.
[28] A therapeutic or prophylactic agent for osteoporosis stated in [14] or [15] abovethat is used for administration to patients with osteoporosis having mild renal
dysfunction or moderate renal dysfunction.
[29] A therapeutic or prophylactic agent for osteoporosis stated in [27] above that isused for administration to patients with osteoporosis having mild renal dysfunction ormoderate renal dysfunction.
[30] A therapeutic or prophylactic agent for osteoporosis stated in [16] above that isused for administration to patients with osteoporosis having mild renal dysfunction ormoderate renal dysfunction.
[31] A preventive or therapeutic method using a therapeutic agent, prophylactic agent,
preparation, drug combination or medical kit stated in any of [1] through [30] above.
[Effects of the invention][0015]The therapeutic agent for osteoporosis in the present invention is highly safe andexcellent in efficacy and effect. Also, the inhibitor or prophylactic agent for fracturesin the present invention is highly safe and useful.
[Brief description of the drawings][0016][FIG. 1] FIG. 1 is a graph showing the results of the serum calcium concentration
changes for each administration group (high-risk subjects, low-risk subjects).
[FIG. 2] It shows the impact of administration of the test drug on time-dependentchanges in incidence of new vertebral fractures. The test drug administration group is52

indicated as "PTH 200 group" and the control drug administration group is indicated as"P group."[FIG. 3] It shows the impact of administration of the test drug on time-dependentchanges in incidence of new vertebral fractures. The test drug administration group isindicated as "PTH 200 group" and the control drug administration group is indicated as"P group."[FIG. 4] It shows the results of testing for variations in urinary calcium levels when thetest drug ("PTH 200 group") or the control drug ("P group") is administered to patients
once a week for 72 weeks. The ratio of urinary calcium level / urinary creatine level
was compared before the start of administration and during the observation weeks.
Urinary calcium was measured at the start and after 12 weeks, 24 weeks, 48 weeks, and72 weeks. Standard concomitant drugs (610 mg of calcium, 400 IU of Vitamin D 3, and30 mg of magnesium) were administered once per day after dinner for the period fromwhen informed consent was obtained until the end of the clinical trial.
[FIG. 5] It shows the results of testing for variations in corrected serum calcium levels
when the test drug ("PTH 200 group") or the control drug ("P group") is administeredto patients once a week for 72 weeks. Serum calcium was measured at the start and after
12 weeks, 24 weeks, 48 weeks, and 72 weeks. Standard serum calcium level is 8.4
mg/dL to 10.4 mg/dL. Standard concomitant drugs (610 mg of calcium, 400 IU of
Vitamin D3, and 30 mg of magnesium) were administered once per day after dinner forthe period from when informed consent was obtained until the end of the clinical trial.
[Mode for working the invention][0017]The present invention will be described in detail.
[0018]The present invention provides a treatment or prevention method for osteoporosis
or an inhibition or prevention method for fractures using PTH, which is characterized
by administration of 100 units to 200 units of PTH per dose per week (hereinafter "perweek" may be referred to as "every two weeks"). In addition, the present invention
provides a therapeutic or prophylactic agent for osteoporosis or an inhibitor orprophylactic agent for fractures using PTH as the active ingredient, which ischaracterized by administration of 100 units to 200 units of PTH per dose every two
weeks. Furthermore, the present invention provides the use of PTH for manufacturing
said therapeutic or prophylactic agent for osteoporosis or inhibitor or prophylactic agent
for fractures.
[0019]53

I. Active ingredient
PTH, which is the active ingredient in the present invention (hereinafter it may be
simply referred to as "PTH" in some cases) contains human PTH (1-84), which is humanparathyroid hormone, and peptides at a molecular weight of approximately 4,000 to
10,000, which have the same or similar activity as human PTH (1-84).
[0020]
PTH includes any of natural PTH, PTH produced by the genetic engineering
procedure, and PTH synthesized by chemical synthesis. PTH can be produced bygenetic engineering procedures publicly known per se (Non-patent Document 8).
Alternatively, PTH can be synthesized by a peptide synthesis method publicly known
per se (Non-Patent Document 11), and can be synthesized, for example, by solid-phasemethod which extends peptide chains from the C-terminus on an insoluble polymeric
carrier (Non-patented Document 4). In addition, the PTH used in the present invention
may be derived from sources not limited to humans, but also from rats, bovines, pigs,
etc.
[0021]In the description of the present application, when indicating human PTH (n -m), itmeans a peptide shown in the partial amino acid sequence from the n-th to the m-th
amino acid sequence of human PTH (1-84). For example, human PTH (1-34) means apeptide represented by a partial amino acid sequence consisting of the first to the 34th
amino acid sequence of human PTH (1-84).
[0022]
PTH, which is the active ingredient in the present invention, may be a salt formed
with 1, 2 or more kinds of volatile organic acids. As examples of the volatile organicacid, trifluoroacetic acid, formic acid, acetic acid, etc. are cited, among which acetic
acid is preferred. The ratio of PTH in the free form and the volatile organic acid whenforming a salt is not particularly limited as long as it forms salt. For example, sincehuman PTH (1-34) has 9 molecules of basic amino acid residues and 4 molecules ofacidic amino acid residues in its molecule, 5 residues of basic amino acid can be
regarded as the chemical equivalent weight of acetic acid in consideration of salt
formation in these molecules. For example, when the acetic acid content expressed by
the formula "the weight of acetic acid × 100 (%) / the weight of the peptide of human
PTH (1-34)" is used for the volume of acetic acid, as one theory, the chemical equivalentweight of acetic acid to human PTH (1-34) in the free form is approximately 7.3%(wt%). In the description of the present application, PTH (1-34) in the free form issometimes referred to as teriparatide, and an acetate of teriparatide is referred to as54

teriparatide acetate, respectively. The acetic acid content in teriparatide acetate is notparticularly limited so long as the teriparatide and acetate form salt. For example, it
may be 7.3% or more, which is the aforementioned theoretical chemical equivalentweight, or may be 0% to 1%. More specifically, for example, the acetic acid content in
teriparatide acetate may be 1% to 7%, preferably 2% to 6%. These salts can be preparedaccording to methods publicly known per se (Patent Documents 4 and 5).
[0023]As PTH, human PTH (1-84), human PTH (1-34), human PTH (1-38), hPTH (Nonpatent Document 5), human PTH (1-34) NH2, [Nle8,18] human PTH (1-34), [Nle8,18,
Tyr34] human PTH (1-34), [Nle8,18] human PTH (1-34) NH2, [Nle8, 18, Tyr 34] human
PTH (1-34) NH2, rat PTH (1-84), rat PTH (1-34), bovine PTH (1-84), bovine PTH (134), bovine PTH (1-34) NH2, etc. are cited as examples. As preferred PTH, human PTH(1-84), human PTH (1-38), human PTH (1-34), and human PTH (1-34) NH2 are citedas examples (Patent Document 3, etc.). As particularly preferred PTH, human PTH (1 34) is cited. As further preferred PTH, human PTH (1-34) obtained by chemical
synthesis, and as the most preferred PTH, teriparatide acetate (Working Example 1), arecited.
[0024]
II. Combination with other agents
As a result of implementing a double-blind comparative clinical trial using theoccurrence of fractures as the primary endpoint concerning PTH used in combination
with a calcium agent, the present inventors found that the effect was expressed from anearly stage at 24 weeks after or 26 weeks after and hypercalcemia was not confirmed
as an adverse event (Working Examples 1 and 2). Accordingly, one of the features of
the therapeutic agent of osteoporosis or inhibitor or prophylactic agent of fractures
related to the present invention is that it is to be used in combination with other agents.
Here, the expression, "to be used in combination with other agents," refers to the use incombination with another agent (other agents) different from the therapeutic agent of
osteoporosis or inhibitor or prophylactic agent of fractures related to the present
invention.
[0025]As another agent of the present invention, calcium can be cited preferentially as an
example. However, when stating "to be used in combination with other agents" in thepresent invention, it does not exclude cases where it is used in combination with agentsother than said other agents. Therefore, as a use in combination with calciu m, thefollowing can be cited preferentially as examples:55

use in combination with calcium alone; anduse in combination with calcium, vitamin D (including its derivatives) and/or
magnesium alone.
Consequently, a calcium agent may be cited as a specific example of other agents; and,preferentially, the following can be cited as examples:(1) a calcium agent containing calcium as the active ingredient; and(2) a calcium agent containing calcium, vitamin D (including its derivatives), andmagnesium respectively as the active ingredients.
[0026]
The form (administration frequency, administration route, administration site, dose,etc.) of the combination of the therapeutic agent of osteoporosis or inhibitor orprophylactic agent of fractures related to the present invention with other agents is notparticularly limited and can be determined by the prescriptions by physicians, etc. basedon individual patients as necessary.
[0027]For example, when a calcium agent is used in combination as the aforementioned
other agent, the calcium agent may be administered simultaneously (which means oncea week) with the therapeutic agent of osteoporosis or inhibitor or prophylactic agent of
fractures related to the present invention that contains PTH as the active ingredie nt or
may be administered more frequently, or may be administered once or several times aday. Accordingly, said other agent may be a drug combination consisting with thetherapeutic or prophylactic agent of osteoporosis or inhibitor or prophylactic agent of
fractures related to the present invention, or the therapeutic or prophylactic agent of
osteoporosis or inhibitor or prophylactic agent of fractures related to the present
invention and said other agent may be separate agents. As an example of said calc ium
agent, " 新 カ ル シ チ ュ ウ (Shin Karushichu) (trademark) D 3 " (Distributor: Daiichi
Sankyo Healthcare Co., Ltd.; Manufacturer and distributor: Nitto PharmaceuticalIndustries, Ltd.) can be cited.
[0028]
Also, other agents may be administered in conjunction with or sequentially (i.e., atseparate times), by the same or different administration routes with the therapeutic orprophylactic agent of osteoporosis or inhibitor or prophylactic agent of fractur es related
to the present invention. Therefore, the dosage form of other agents are not particularly
limited, and such forms as tablets, capsules, fine granules, etc. can be cited as examples.
In cases where said other agent is a calcium agent, it is preferred to be a calcium agent
containing 100 mg to 400 mg (preferably, 150 mg to 350 mg) of calcium per single
56

dosage form. Thus, if a calcium tablet containing 100 mg to 400 mg of calcium per unit
dosage form, e.g., 2 tablets per day, is administered according to a working example ofthe present invention, 200 mg to 800 mg of calcium will be administered per day, but
not limited thereto.
[0029]As specific examples of the aforementioned other agents, in cases of a calcium agent,
for example, publicly known agents containing such agents as precipitated calcium
carbonate, calcium lactate, calcium carbonate, calcium chloride, calcium gluconate,calcium aspartate, calcium phosphate, calcium hydrogen phosphate, calcium citrate, etc.
as the active ingredients may be cited. Agents containing precipitated calcium carbonate
are preferred. In addition to said other agents, fillers, binders, disintegrants, lubricants,
antacids, etc. may be included as necessary.
[0030]
It is known that gastrointestinal symptoms, such as vomiting, retching, nausea,
heavy stomach, stomach discomfort, pyrosis, etc., are transiently observed at a certain
rate in patients with PTH administration (Patent Document 6).
[0031]As a result of testing of various administration times and efficacies of antiemetic
agents for transient retching and vomiting in association with the administration of thetest drug, the present inventors confirmed that Primperan (generic name of the
medicinal property is metoclopramide), Nauzelin (generic name of the medicinal
property is domperidone), Gaster D (generic name of the medicinal property isfamotidine), Gasmotin (generic name of the medicinal property is mosapride citrate),
Takepron OD (generic name of the medicinal property is lansoprazole), andRokushingan are effective for retching or vomiting in association with theadministration of PTH (Working Example 2). Thus, as additional other agents, theaforementioned antiemetic agents can be cited preferably, and Nauzelin (generic nameof the medicinal property is domperidone), Gasmotin (generic name of the medicinal
property is mosapride citrate), and/or Rokushingan may be cited more preferably. The
dosage and administration of these antiemetic agents can be set by physicians, etc.
based on the symptoms, etc. of individual patients as necessary.
[0032]
III. Administration period
The administration period of the therapeutic or prophylactic agent of osteoporosis
or inhibitor or prophylactic agent of fractures related to the present invention is notparticularly limited but may be determined as necessary by prescriptions, etc. by57physicians, etc. depending on individual patients. The present inventors conducted adouble-blind comparative clinical trial using the occurrence of fractures as the primary
endpoint while setting an administration period to be 156 weeks or 72 weeks. In thepresent trial, a significant inhibitory effect on fractures by the administration was
confirmed and the effects appeared as early as 24 weeks after or 26 weeks after(Working Examples 1 and 2). Furthermore, no new vertebral fracture was observed after
48 weeks from the administration (Working Example 2). Accordingly, as examples of
the administration period, 24 weeks or more, 26 weeks or more, 48 weeks or more, 52
weeks or more, 72 weeks or more, or 78 weeks or more may be cited, and 78 weeks ormore is the most preferable. Also, in the present trial, no hypercalcemia as an adverse
event was found (Working Example 1).
[0033]
IV. Dosage
As a result of a double-blind comparative clinical trial using 100 units or 200 unitsof PTH per dose, the present inventors confirmed a significant inhibitory effect on
fractures by said administration and that the effect appeared as early as 24 weeks afteror 26 weeks after; however, they observed no hypercalcemia as an adverse event(Working Examples 1 and 2).
[0034]
Accordingly, one of the features of the present invention is that the dosage is 100
units to 200 units per dose. Here, one unit amount of PTH can be measured by theactivity measurement method publicly known per se (Non-patented Document 9). As adosage, 100 units or 200 units per dose is cited as an example preferably, and 200 units
per dose is cited as being the most preferable.
[0035]
V. Administration interval
As a result of a double-blind comparative clinical trial wherein PTH is administeredonce a week, the present inventors confirmed a significant inhibitory effect on fracturesby said administration and that the effect appeared as early as 24 weeks after or 26
weeks after; however, they observed no hypercalcemia as an adverse event (Working
Examples 1 and 2). Accordingly, one of the features of the present invention is that theadministration interval is every two weeks.
[0036]
VI. Administration route
The therapeutic or prophylactic agent of osteoporosis or inhibitor or prophylactic
agent of fractures related to the present invention may be administered by an58

appropriate administration route based on its preparation form. For example, when thetherapeutic or prophylactic agent of osteoporosis or inhibitor or prophylactic agent of
fractures related to the present invention is an injection, they may be administeredintravenously, intra-arterially, subcutaneously, intramuscularly, etc. As a result ofsubcutaneous injection of PTH, the present inventors have demonstrated excellent
efficacy and effectiveness and safety (Working Examples 1 to 2). Thus, the present
invention can cite a subcutaneous route as its preferred administration route.
[0037]
VII. Target disease
Osteoporosis related to the present invention is not particularly limited and includes
both primary osteoporosis and secondary osteoporosis. As examples of the primaryosteoporosis, involutional osteoporosis (post-menopausal osteoporosis and senile
osteoporosis), and idiopathic osteoporosis (post-pregnancy osteoporosis, juvenile-onset
osteoporosis, etc.) are cited. Secondary osteoporosis is osteoporosis induced by aspecific disease, specific agents, etc. For example, specific agents, rheumatoid arthritis,
diabetes, hyperthyroidism, sexual dysfunction, immobility, alibility, or other congenital
disorders, etc. are cited as causes. As a specific agent, for example, steroids are cited.
As an example of osteoporosis related to the present invention, osteoporosis with a highrisk of fractures can be cited preferably. The application of the present invention toosteoporosis with a high risk of fractures means the application of the present invention
to the following high-risk patients.
[0038]The present inventors confirmed the effects, efficacy, and safety of the present
invention in the clinical trial targeting patients with primary osteoporosis (Working
Examples 1 and 2). Therefore, as osteoporosis related to the present invention, primaryosteoporosis can be cited preferably, and involutional osteoporosis can be cited most
preferably.
[0039]The present inventors confirmed the effects of the present invention in a clinical
trial targeting patients with primary osteoporosis who take steroids that induce
secondary osteoporosis (Working Example 2). Therefore, as patients with primaryosteoporosis related to the present invention, patients with primary osteoporosis whotake steroids that induce secondary osteoporosis can be cited preferably.
[0040]The present inventors confirmed the effect of the present invention in a clinical trial
targeting patients with primary osteoporosis who have complications (diabetes,
59hypertension, or hyperlipidemia) (Working Example 2). Accordingly, as patients withosteoporosis related to the present invention, patients with osteoporosis who have atleast one of the following complications: diabetes, hypertension, and hyperlipidemia,
can be cited as examples preferably, and patients with primary osteoporosis who haveat least one of the following complications: diabetes, hypertension, and hyperlipidemia,
can be cited as examples more preferably.
[0041]
It is known that diabetes is highly likely to be a risk factor for osteoporotic fracture(Non-patent Document 16).
[0042]
Concerning the relationship between diabetic osteoporosis and PTH, the following
reports are found in animal experiments.
1) It was reported that increases are observed in 'bone mass,' 'trabecular thickness,''osteoid surface,' 'calcified surface,' 'bone mineralization rate,' and 'bone formation rate'in the cancellous envelope by administering hPTH to streptozotocin-administered ratsthat present diabetic osteopenia; and increases in 'osteoid surface,' 'calcified surface,''bone mineralization rate,' and 'cortical bone thickness' in the endocortical envelope(Non-patent Document 21). However, unlike rats with osteopenia due to other causes,
no significant decrease in absorption surface is seen in the present rats.
2) As a result of administration of PTH to streptozotocin-administered rats for 8 weeks,
it was reported that turnover and recovery of cancellous bone mass were observed (Nonpatent Document 22).
3) It was reported in an experiment of cultured cells that when exposed to highconcentration glucose, reaction to hPTH (1-34) decreases (effects of PTH become less)(Non-patent Document 20).
[0043]
Although the present inventors understand that there are many opinions ofphysicians, etc. who expect the effects of PTH administration in patients with diabetic
osteoporosis (e.g., http://ww.richbone.com/kotsusoshosho/basic_shindan/tonyo.htm),
there was no article proving the effects.
[0044]
Therefore, it is important knowledge that the trial in the present invention proved
the fact that the risk of vertebral fractures for patients with primary osteoporosis anddiabetes is reduced by the therapeutic or prophylactic agent of osteoporosis or inhibitor
or prophylactic agent of bone fractures related to the present invention.
[0045]
60

Fractures related to the present invention are not particularly limited and include
both vertebral fractures and non-vertebral fractures (Working Example 1), and include
both pathologic fractures due to osteoporosis, dysostosis, bone tumor, etc., andtraumatic fractures due to traffic accidents, bruises, etc. Preferably, it is possible to cite,
as examples, the application to fractures due to osteoporosis, and more preferably,vertebral fractures due to osteoporosis. The site of fractures is not particularly limited;
however, typically, vertebral compression fractures, femoral neck fractures, femoral
intertrochanteric fractures, femoral shaft fractures, humeral neck fractures, and distal
radius fractures can be cited and, in particular, vertebral compression fractures can b e
cited as examples.
[0046]The number of fractures related to the present invention is not particularly limited
and includes both a single fracture and multiple fractures. The term "a single fracture"means a disease state where a bone is broken or cracked in only one location, and theterm "multiple fractures" means a disease state where a bone is broken or cracked in 2
or more locations. The number of fractures in multiple fractures is not particularly
limited; however, the application to the case where a bone is broken or cracked in 2 to
4 locations is preferred.
[0047]
Vertebral fractures related to the present invention include both new fractures andworsening fractures. For example, the degree of deformation of the entire vertebral
body can be classified by Grade as follows: Grade 0 (normal), Grade 1 (vertebral bodyheight reduced by approximately 20%-25% and vertebral body area reduced by 10%20%), Grade 2 (vertebral body height reduced by approximately 25%-40% and vertebral
body area reduced by 20%-40%), and Grade 3 (vertical body height reduced byapproximately 40% or more and vertebral body area reduced by 40% or more). The
classification of new and worsening can be carried out based on the Grade increase
pattern according to the B]'s criteria. Specifically, when a change from Grade 0 to Grade1, Grade 2, or Grade 3 is observed, it is diagnosed as a new fracture, and when a change
from Grade 1 to Grade 2 or Grade 3, or from Grade 2 to Grade 3 is observed, it can be
regarded as a worsening fracture. Further, in order to accurately determine a change in
Grades, vertebral body height was measured according to the method of [C] et al. (Non patent Document 35) and the method of [D] et al. (Non-patent Document 36).
[0048]The present inventors confirmed the effect of inhibiting worsening fractures in aclinical trial targeting patients with a pre-existing fracture (Working Example 2).
61Accordingly, in the present invention, as application targets, patients with osteoporosis,
preferably patients who have a pre-existing fracture, and more preferably patients witha pre-existing fracture and the possibility of an worsening fracture can be cited.
[0049]
There are many unclear points related to PTH's mechanism of enhancing bonestrength. Bone strength reflects not only bone density but also bone quality conditions.
This means that not only bone density but also bone microstructure, calcification, andother bone quality factors define bone strength (Non-patent Document 17). The present
inventors consider that bone quality may have an impact not only on bone strength but
also on the risk of developing a disease that is different from osteoporosis and theperformance of curing complications thereof. It was suggested that the therapeutic orprophylactic agent of osteoporosis or inhibitor or prophylactic agent of fractures related
to the present invention may be dominant over previous therapeutic agents (Patent
Document 2) in these points.
[0050]
Patent Document 2 discloses that, as a result of administering rhPTH (1-34) topatients with osteoporosis, not only bone mineral content (BMC) and bone mineraldensity (BMD) but also the bone area of the lumbar spine and femur, etc. are increased.
Increases in bone area mean that bones thicken towards the outside.
[0051]
However, as a result of administering the therapeutic or prophylactic agent of
osteoporosis or inhibitor or prophylactic agent of fractures related to the present
invention to patients with osteoporosis, cortical bone thickness increased not toward s
the outside but towards the inside of the bones. That is, there was little change in the
thickness of the bones overall. It is considered that this mechanism, for example, shows
the following important clinical meaning.
[0052](1) There is no joint destruction by long bone hypertrophy.
A femur is one of the long bones (long bones comprising the extremities) and its
epiphysis comes into contact with articular cartilage and forms the knee joint along withthe synovial membrane and meniscus. The contact surface is referred to as an articularsurface covered with cartilage that has a few millimeters in thickness. Knee
osteoarthritis is cited as an example of a disease that causes knee arthralgia.
[0053]On the other hand, it is known that Forteo (PTH for daily administration) showedstronger bone reinforcing efficacy than Fosamax for patients who have the complication62

of prednisone-induced osteoporosis and arthralgia (Non-patent Documents 23 and 24).
[0054]
However, the administration of Forteo is a conventional therapeutic method
substantially the same as PTH administration as stated in Patent Document 2. As
mentioned above, said conventional therapeutic method is to thicken bones towards theoutside of the bone. Hypertrophy of the femur towards the outside means an increasein the area of the articular surface, while the number of chondrocytes does not increase
as compared to the hypertrophy of the bone. Therefore, the hypertrophy of the femur
towards the outside, which is caused by the conventional therapeutic method, may
facilitate joint destruction via damage to chondrocytes that are initiated or worsened by
the increase in the area of the articular surface.
[0055]
However, as in the present invention, the present inventors consider that there is thepossibility that the hypertrophy of the femur towards the inside may cause no increases
in the area of the articular surface and may stabilize cartilage more, and that as a result,burden on cartilage may not increase and joint destruction may not be substantiallypromoted. This suggests that treatment of osteoporosis with the present agent may bekinder to joints than the treatment of osteoporosis by the conventional method.
[0056](2) There is no worsening or onset of spondylosis deformans due to vertebral body
hypertrophy.
When normal vertebral body bone mass decreases due to aging and other causes,
the vertebral body becomes unstable. Destabilization begins with deformation of theendplate. In concrete terms, destabilization of the vertebral body is a thinning of theendplate or the enlargement of endplate holes (Haversian canal). As the destabilization
progresses, the intervertebral disc enters the endplate hole and the disc narrows. If thesymptoms progress further, it will lead to the generation of osteophytes due to collisions
between vertebrae. This degeneration of the spine is a disease called spondylosis
deformans. When spondylosis deformans occurs, the space between vertebrae becomesstable, causing pain due to the invasion of the intervertebral disc and pain due tosurrounding muscle expansion.
[0057]
However, as described in Patent Document 2, when PTH is administered daily tothicken the outside of the bone, there is a possibility that a sufficient inhibitory effecton enlargement of the endplate hole is not observed. Alternatively, an increase in thecontact area between the vertebral body and the intervertebral disc reduces the distance63

between the vertebral bodies, leading to instability of the vertebral body, resulting in an
increased risk of developing or worsening spondylosis deformans.
[0058]On the other hand, the administration of the therapeutic agent of osteoporosis andinhibitor or prophylactic agent of fractures in the present invention increases thecortical bone thickness not to the outside but to the inside of the bone. Therefore, it may
sufficiently suppress the enlargement of the endplate hole and the invasion of theintervertebral disc into the endplate hole.
[0059](3) It does not promote worsening or development of hip osteoarthritis andtemporomandibular joint osteoarthritis.
Hip osteoarthritis is a situation where the articular cartilage on the contact surface
between acetabular, which forms the hip joint, and the femur head suffers wear anddegeneration, and irreversible changes are caused due to poor blood flow to the joint,
extreme weight, or overuse. The femoral cortical bone area of patients with hip
osteoarthritis is significantly larger than that of healthy individuals (Non-patent
Document 18). An increase in femoral cortical bone area means hypertrophy of thefemur to the outside, and this may therefore be involved in the development orworsening of hip osteoarthritis. In the case of thickening towards the inside of the femur
as in the present invention, the femur will not be thickened towards the outside of thebone, and thus there is the possibility that the risk of developing or worsening hip
osteoarthritis is not increased. The main symptom of temporomandibular joint
osteoarthritis is temporomandibular joint deformation, but cortical bone thickening is
also one of the diagnostic findings (Non-patent Document 19). Thus, further outward
hypertrophy of the cortical bone may worsen or develop symptoms. When the bone isthickened towards the inside of the bone as in the present invention, it is presumed that
there is the possibility that the risk of developing or worsening such temporomandibular
joint osteoarthritis is not increased.
[0060]As described above, when (1) to (3) are summarized, patients with osteoporosis
having at least one of the diseases of arthralgia, spondylosis deformans, deformans low
back pain, hip osteoarthritis, or temporomandibular joint osteoarthritis as acomplication (preferably patients with primary osteoporosis) can be preferably cited as
examples of patients suited for the application of the therapeutic or prophylactic agentof osteoporosis and inhibitor or prophylactic agent of bone fractures in the present
invention.
64[0061]The present inventors evaluated the influence of the medication history of othertherapeutic agents for osteoporosis within one year on the efficacy of the present agent.
As a result, higher efficacy of the test drug was revealed for patients with primaryosteoporosis having medication history of other therapeutic agents for osteoporosis thanfor patients with no medication history (Working Example 2). Therefore, in the present
invention, as patients with osteoporosis, the application to patients with os teoporosis
having medication history of other therapeutic agents for osteoporosis can be cited as
an example preferably, and the application to patients with primary osteoporosis who
have a medicinal history of other therapeutic agents for osteoporosis can be more
preferably cited as an example.
[0062]
Further, as other therapeutic agents for osteoporosis, L-aspartate calcium,alphacalcidol, raloxifene hydrochloride, elcatonin, menatetrenone, and calcium lactate
are cited, and preferably, L-aspartate calcium, alphacalcidol, and elcatonin are cited as
examples. Regarding patients with osteoporosis having medication history of othertherapeutic agents for osteoporosis, said other therapeutic agents for osteoporosis areallowed to have been used alone or in combination.
[0063]
It is preferable to administer the therapeutic agent for osteoporosis and inhibitor orprophylactic agent for fractures in the present invention for 24 weeks to 72 weeks orlonger to patients with osteoporosis having medication history of other therapeutic
agents for osteoporosis. In particular, it is preferable to administer the present agent for
24 weeks or longer to patients with a high risk of lumbar spine fracture, and for 72
weeks or longer to patients with a high risk of fractures of the femoral neck or proximal
region of the femur.
[0064]The prevalence of osteoporosis and renal dysfunction increases with age. There isalso a large epidemiological study report that 85% of female patients with osteoporosis
have mild to moderate renal dysfunction (Non-patent Document 32). Therefore, it isimportant to provide an effective and safe agent for patients with osteoporosis that haverenal dysfunction.
[0065]The present inventors presented that the therapeutic or prophylactic agent forosteoporosis and inhibitor or prophylactic agent for fractures in the present invention
are effective to any of patients with osteoporosis having normal renal function, patients65with osteoporosis having mild renal dysfunction, and patients with osteoporosis having
moderate renal dysfunction (Working Example 2). In addition, it has been found that interms of safety related to serum calcium, the therapeutic or prophylactic agent forosteoporosis and inhibitor or prophylactic agent for fractures in the present invention
work equally for all patient groups.
[0066]
Normal renal function and dysfunction, and degree of dysfunction can be classified
based on creatinine clearance. Specifically, when creatinine clearance is 80 mL/min. or
more, renal function can be determined to be normal; when creatinine clearance is 50
mL/min. or more and less than 80 mL/min., it is determined to be mild renal
dysfunction; and when creatinine clearance is 30 ml/min. or more and less than 50
mL/min., it is determined to be moderate renal dysfunction.
[0067]
In general, the normal upper limit of serum calcium concentration is 10.6 mg/mL,
and 11.0 mg/mL, which exceeds the upper limit, is a slightly high value. In theconventional daily administration of PTH, after administration to patients withosteoporosis having moderate renal dysfunction, a slightly high value of serum calcium
exceeding 11.0 mg/mL was observed in 11.76% thereof (Non-patent Document 32).
However, in the present invention, as a result of administration of the therapeutic orprophylactic agent for osteoporosis and inhibitor or prophylactic agent for fractures in
the present invention to patients with osteoporosis having moderate renal dysfunction,no patients with serum calcium exceeding 11.0 mg/L were observed at all occasions of
examinations from the start to the end of administration (Working Example 2). That is,
it is considered that the therapeutic or prophylactic agent for osteoporosis and inhibitor
or prophylactic agent for fractures in the present invention are more excellent not onlyin terms of efficacy but also safety. Therefore, as patients subject to the application of
the present invention, patients with osteoporosis having mild renal dysfunction and/or
patients with osteoporosis having moderate renal dysfunction can be preferably cited as
examples, and more preferably patients with primary osteoporosis having mild renal
dysfunction and/or patients with primary osteoporosis having moderate renal
dysfunction can be cited as examples.
[0068]The race, age, gender, height, weight, etc. of subjects to apply the drug
administration or treatment method related to the present invention are not particularly
limited; however, patients with osteoporosis are cited as examples of the subjects, and
it is preferable to apply the method of the present invention or to administer the66

therapeutic or prophylactic agent for osteoporosis and inhibitor or prophylactic agent
for fractures in the present invention to patients with osteoporosis who have risk factors
of fractures in osteoporosis. Risk factors for fractures in osteoporosis include age,gender, low bone density, prevalent fractures, smoking, alcohol drinking, steroid use,family history of fractures, exercise, factors related to falls, bone metabolism markers,
weight, calcium intake, and the like (Non-patent Document 10). Thus, in the present
invention, patients (or subjects) with osteoporosis who meet all of the requirements (1)to (3) below are defined as "high-risk patients":(1) Age 65 years or older;(2) Having prevalent fractures; and(3) Bone density less than 80% of the young adult mean and/or degree of bone atrophyof I or higher.
[0069]
Bone density as used here typically refers to bone mineral content in the lumbar
spine. However, when it is difficult to evaluate the bone mineral content in the lumbar
spine, the bone density can be indicated by the bone mineral content values of the radius,
second metacarpal bone, femoral neck, and calcaneus. In addition, the young adult mean
refers to the average value of bone density between 20 through 44 years old. The bon edensity can be measured by a method publicly known per se, such as dual-energy X-ray
absorptiometry, photodensitometry, photon absorptiometry, quantitative CT, andquantitative ultrasonography, etc. In the present invention, the degree of bone atrophymeans the degree of bone loss on X-ray. The degree of bone atrophy is classified into
no bone atrophy, bone atrophy degree I, bone atrophy degree II, and bone atrophy
degree III. "No bone atrophy" in the degree of bone atrophy indicates a normal state,and specifically means a state in which the trabecular structure cannot be recognizedbecause the trabeculae in the vertical and horizontal directions are dense. Bone atrophy
degree I means that the vertical trabeculae are conspicuous. Typically, the verticaltrabeculae look thin but are densely arranged, and the vertebral endplates become
conspicuous. Bone atrophy degree II in the degree of bone atrophy means a state inwhich the vertical trabeculae are rough, the vertical trabeculae look thick, thearrangement is rough, and the vertebral endplates look light. Bone atrophy degree III in
the degree of bone atrophy means a state in which the vertical trabeculae are also
unclear, the vertebral body shadow is obscured as a whole, and the difference from theintervertebral disc shadow decreases (Journal of osteoporotic medicine, 5/3, July 2006,"Diagnosis of osteoporosis by simple radiograph"). The degree of bone atrophy can be
determined, for example, from a lumbar lateral X-ray image. The number of vertebral
67fractures in the present invention can be easily measured, for example, by the methodof [B] et al. (Non-patent Document 14). Bone fractures at sites other than the vertebral
body can be easily confirmed, for example, by using an X-ray film.
[0070]In the present invention, it is particularly preferable to apply the method of thepresent invention or administer the therapeutic or prophylactic agent for osteoporosis
and inhibitor or prophylactic agent for fractures in the present invention to high -riskpatients (Working Example 1).
[0071]On the other hand, generally, it is preferable to avoid applying the method in thepresent invention and avoid administrating the therapeutic or prophylactic agent forosteoporosis and inhibitor or prophylactic agent for fractures in the present invention
to patients (subjects) corresponding to at least any of the following (1) to (6):(1) Patients who are prone to hypersensitivity, such as bronchial asthma and rash(erythema, wheals, etc.);(2) Patients with hypercalcemia;(3) Women who are or may be pregnant;(4) Patients with hypothyroidism or hyperparathyroidism;(5) Patients with drug hypersensitivity in the past; and(6) Patients with serious complications, such as heart disease, liver disease, renal
dysfunction.
Therefore, in the present invention, it is preferable to target patients withosteoporosis who are the high-risk patients and who do not correspond to all of (1)through (6) above.
[0072]
VIII. Preparation
The therapeutic or prophylactic agent for osteoporosis or inhibitor or prophylactic
agent for fractures in the present invention (hereinafter simply referred to as the"present agent" in some cases) may be used in various preparation forms. In general,the present agent can be prepared as an injection or the like using PTH alone or with aconventional pharmaceutically acceptable carrier. An injection is preferred as thedosage form of the present agent.
[0073]For example, in cases where the present agent is an injection, it can be prepared by
the following procedures: after PTH is dissolved with an appropriate solvent (sterilewater, buffer solution, saline, etc.), it is filtrated and/or sterilized by other appropriate
68methods, and then filled into an aseptic container. At that time, it is preferred that thenecessary additives (for example, excipients, stabilizers, solubilizers, antioxidants,
soothing agents, tonicity agents, pH adjusters, preservatives, etc.) be added together
with PTH. Examples of such additives include sugars, amino acids, sodium chlor ide,and the like. When sugars are used as additives, it is preferable to add one weight ormore (preferably 50 weight to 1000 weight) of mannitol, glucose, sorbitol, inositol,
sucrose, maltose, lactose, or trehalose as sugars per weight of PTH. When sugar andsodium chloride are used as additives, it is preferable to add 1/1000 weight to 1/5 weight(preferably 1/100 weight to 1/10 weight) of sodium chloride per weight of sugar.
[0074]For example, when the present agent is an injection, it may be solidified by freeze
drying, etc. (freeze-dried preparation or the like) and may be dissolved with anappropriate solvent before use. Alternatively, when the present agent is an injection, it
may be a liquid that is dissolved in advance.
[0075]The present agent is preferably stored in a package on which it is stated that 100
units to 200 units of human PTH (1-34) per dose should be administered every two
weeks as a therapeutic agent for osteoporosis and inhibitor or prophylactic agent for
fractures, or stored in a package along with a package insert stating to that effect.
[0076]The utility of the invention in the present application can be confirmed easily bystatistical processing, etc. of the results of the clinical trials presented in working
examples by the usual methods. In addition, the present invention is explained more
concretely below through working examples, but the scope of the present invention is
not limited thereto.
[Working examples][0077](Working Example 1)
Male and female patients who are diagnosed with primary osteoporosis (Non-patent
Reference 12) were subcutaneously administered 5 units or 100 units of teriparatideacetate, which were prepared using the [E]'s method (Patent Documents 4 and 5; Non patent Document 11), intermittently once a week (each administration group is referred
to as a 5-unit group or a 100-unit group). The activity of the teriparatide acetate wasmeasured according to the article of Marcus et al. (Non-patent Document 9).
[0078]The 5-unit group or the 100-unit group is administered with a full amount of a69

solution in which freeze-dried preparation containing 5 units or 100 units of teriparatideacetate per vial is dissolved with 1 mL saline before use. Both the 5 -unit group and the
100-unit group were administered with two tablets of calcium agent (containing 500 mg
of precipitated calcium carbonate [200 mg as calcium] per tablet) once a day.
[0079]
Comparison was conducted by classifying patients with osteoporosis according to
the conditions as shown in Table 1 based on the fracture risk factors as shown in Nonpatent Document 13. High-risk patients (hereinafter simply referred to as "high-risk
subjects" in some cases) were defined as having all three factors, including age,prevalent vertebral fractures, and bone density or bone atrophy; and low-risk subjects
were defined as other than the above.
[0080][Table 1] (To be presented below.)
Patient backgrounds are as shown in Table 2 and Table 3, and no statisticallysignificant difference was observed between the backgrounds of both groups (p <0.05).
[0081][Table 2] (To be presented below.)[Table 3] (To be presented below.)[0082]
During the administration period, combination with calcitonin preparation, active
vitamin D3 preparation, vitamin K preparation, ipriflavone preparation, bisphosphonate
preparation, estrogen preparation, anabolic hormone preparation, calcium preparationaccording to a physician's prescription (however, excluding the aforementioned calcium
agents that are administered as two tablets per day) and other agents that are considered
to have effects on bone metabolism was prohibited. As a bone evaluation, lumbar spinebone density and the occurrence of fractures were checked. The second through thefourth lumbar spine bone densities were measured at the start and every 6 months
thereafter using dual-energy X-ray absorptiometry (DXA method). Regarding thefrequency of bone fractures, in the vertebral body, X-ray imaging of the front and sidefrom the 4th thoracic vertebra to the 5th lumbar spine was performed at the start andevery 6 months thereafter; referring to the method of [B] et al. (Non-patent Document
14), new vertebral fractures were evaluated by comparing X-ray films at the start andat the following times. Parts other than the vertebral body were evaluated by confirmingwith X-ray film. In all cases, blood was collected at the start of administration andduring the administration period, and general laboratory values including calcium
concentration were measured. (DXA and new vertebral fractures were collectively
70determined at the center, and non-vertebral fractures were determined by X-ray film by
the physician in charge.) The administration period with high-risk patients was
85.1±20.8 weeks in the 5-unit group and 83.7 ± 19.8 weeks in the 100-unit group; andthere was no significant difference between the two groups (p <0.05). The
administration period with low-risk subjects was 72.7 ± 19.4 weeks in the 5-unit groupand 88.3 ± 21.3 weeks in the 100-unit group; and there was no significant difference
between the two groups (p < 0.05).
[0083]
Table 4 and Table 5 show changes in lumbar spine density by administration groupand by high-risk and low-risk subjects. In high-risk subjects, concerning the bonedensity in the 100-unit group, a significantly higher increase of bone density than at thestart of administration was observed, and significantly higher values than the 5 -unitgroup were shown (p<0.05). On the other hand, in the low-risk subjects, no significant
difference was observed in comparison with the value at the start of administration andbetween the groups (p> 0.05).
[0084][Table 4] (To be presented below.)[0085][Table 5] (To be presented below.)[0086]
Table 6 and Table 7 show the results of occurrence of new vertebral fractures byadministration group and by high-risk and low-risk subjects. In high-risk subjects, the100-unit group showed significantly lower occurrence of fractures than the 5-unit group(p <0.05). On the other hand, there was no significant difference between groups in
low-risk subjects (p> 0.05).
[0087][Table 6] (To be presented below.)[0088][Table 7] (To be presented below.)[0089]
Table 8 and Table 9 show the results of occurrence of new vertebral fractures every
26 weeks by administration group and by high-risk and low-risk subjects. In high-risk
subjects, the occurrence of fractures was suppressed at 26 weeks after in the 100 -unitgroup, compared to the 5-unit group. On the other hand, there was no difference
between groups in low-risk subjects.
[0090]
71

[Table 8] (To be presented below.)[0091][Table 9] (To be presented below.)[0092]
Table 10 and Table 11 show the results of occurrence of fractures at sites other thanthe vertebral body by administration group and by high-risk and low-risk subjects. In
high-risk subjects, the 100-unit group showed significantly lower occurrence of
fractures than the 5-unit group. On the other hand, there was no significant difference
between groups in low-risk subjects.
[0093][Table 10] (To be presented below.)[0094][Table 11] (To be presented below.)[0095]
FIG. 1 shows the results of changes in serum calcium concentration byadministration group and by high-risk and low-risk subjects. Among the clinicallaboratory test results using the collected blood samples, hypercalcemia was notobserved in all cases except for one case where the value was higher than that before
the start of drug administration in a low-risk subject in the 5-unit administration group.
The tendency of increases in serum calcium was not observed.
[0096]
As can be seen from the above tables, in patients with primary osteoporosis who
have risk factors for new fractures, significant increases in bone density of the lumbar
spines and suppression of new vertebral fractures were observed as a result ofsubcutaneously administering teriparatide acetate once a week for 100 unitsintermittently. In other words, it was confirmed that 100 units of teriparatide acetate
administered once a week to high-risk patients for new fractures in the present invention
can be a useful therapeutic agent for osteoporosis and inhibitor or prophylactic agent
for fractures.
[0097]In addition, during the administration period, under the weekly administration of
teriparatide acetate in the present invention, there was no onset of hypercalcemia withany dosage, and it is considered to be useful compared to a daily administration of
teriparatide acetate, which has already been known.
[0098](Working Example 2)
72

The test drug (1 vial; injectable freeze-dried preparation containing 200 units ofteriparatide acetate per vial), which is prepared by the [E]'s method (Patent Documents
4 and 5, Non-patent Document 11) or the control drug (1 vial; placebo preparation that
substantially does not contain teriparatide acetate per vial) is dissolved with 1 mL ofsaline respectively before use and administered once a week intermittently for 72 weeks
to male and female high-risk patients who were diagnosed to have primary osteoporosis.
[0099]
The aforementioned patients took two tablets of calcium agents daily after dinner
in combination. The calcium agent is a soft chewable preparation containing 610 mg
calcium, 3400 IU of Vitamin D 3 and 30 mg of magnesium in two tablets; it contains, as
ingredients, precipitated calcium carbonate, magnesium carbonate, cholecalciferol(vitamin D3), etc.; and it is marketed under the commercial name of "新カルシチュウ(Shin Karushichu) (trademark) D 3 " (Distributor: Daiichi Sankyo Healthcare Co., Ltd.;
Manufacturer and distributor: Nitto Pharmaceutical Industries, Ltd.).
[0100]
The aforementioned patients are all outpatients capable of walking independently
and do not fall under any of the following criteria (1) to (19).
(1) A patient diagnosed with secondary osteoporosis due to predetermined causes. Here,the predetermined causes refer to endocrine (hyperthyroidism, gonadal dysfunction,
Cushing syndrome), alibility (scurvy, other (protein deficiency, vitamin A or D excess)),
drug (corticosteroid, Methotrexate (MTX), heparin, aromatase inhibitor, GnRH agonist),
immobility (systemic (bed rest, paraplegia, space flight), local (after fracture, etc.)),congenital (osteogenesis imperfecta, Marfan's syndrome, etc.), and other (rheumatoid
arthritis, diabetes, liver disease, gastrointestinal disease (gastrectomy), etc.).
(2) A patient having a predetermined disease that shows bone mass loss other thanosteoporosis. Here, the predetermined diseases include various types of osteomalacia,
primary, secondary hyperparathyroidism, bone metastasis of malignant tumors,
multiple myeloma, spinal hemangioma, spinal caries, pyogenic spondylitis, etc.
(3) A patient with predetermined X-ray findings that are considered to affect vertebral
body strength. Here, the term "predetermined X-ray findings" refers to the state where
6 or more consecutive vertebral bodies form cross-links; where significant ossification
is observed in the ligaments around the vertebral bodies; where the spine has asignificant spinal deformity; and where surgery has been performed on a vertebral body.
(4) A patient wearing a corset that covers the entire thoracolumbar body.
(5) A patient who was administered bisphosphonate preparation within 52 weeks (364days) before obtaining informed consent.
73

(6) A patient who was administered with a therapeutic agent for osteoporosis on thedate of informed consent (however, if drug washout of 8 weeks (56 days) or more ispossible before the start of treatment, the patient can be selected as a subject).
Calcitonin preparation, active vitamin D 3 preparation, vitamin K preparation,
ipriflavone preparation, estrogen preparation, SERM preparation, or anabolic hormone
preparation.
(7) A patient who is prone to hypersensitivity, such as bronchial asthma, rash (erythema,
wheals, etc.), etc.
(8) A patient with a history of hypersensitivity to PTH preparation.
(9) A patient with Paget's disease of bone.
(10) A patient with a history of malignant bone tumor or a history of malignant tumor
within 5 years.
(11) A patient with multiple exostosis.
(12) A patient with a history of radiation external-beam radiotherapy or a history ofradiation brachytherapy.
(13) A patient with 11.0 mg/dL or more of serum calcium value.
(14) A patient with more than twice the standard upper value of alkaline phosphatasevalue.
(15) A patient with serious renal disease, liver disease, or heart disease. The criteria foreach disease are as follows.
Renal disease: Serum creatinine level is 2 mg/dL or higher.
Liver disease: AST (GOT) or ALT (GPT) level is 2.5 times the upper limit of thereference value or 100 IU/L or higher.
Heart disease: To be determined in reference to Grade 2 as shown in "Severity
classification criteria of adverse reactions of pharmaceuticals" (June 29, 1992;
PFSB/SD Notification No. 80).
(16) A patient who was determined to have low reliability in interview (be sure to
exclude at least patients who were diagnosed as having dementia).
(17) A patient who was administered other study drugs within 26 weeks (182 days) prior
to obtaining informed consent.
(18) A patient who was administered a PTH preparation in a clinical trial in the past.
(19) Other patients who were determined to be non-conforming by the investigator (subinvestigator) when implementing the clinical trial.
[0101]In addition, for the aforementioned patients, administration of any of the following
drugs (1) to (6) was prohibited from the time of obtaining informed consent for the74clinical trial until the end of the clinical trial.
(1) Therapeutic agents for osteoporosis other than teriparatide acetate (specifically,bisphosphonate preparation, calcitonin preparation, active vitamin D 3 preparation,
calcium preparation (however, excluding the aforementioned calcium preparation thatis administered once a day after dinner), vitamin K preparation, ipriflavone preparation,
estrogen preparation, SERM preparation, and anabolic hormone preparation)(2) Corticosteroid preparation (however, in cases of intramuscular injection,
intravenous injection, or oral administration in prednisolone conversion, whereadministration exceeds 5 mg/day on average for one week, where the daily dose exceeds
10mg/day, or where the total dose exceeds 450 mg)(3) Aromatase inhibitor(4) GnRH agonist(5) Other study drugs[0102]The numbers of administration cases of the test drug and the control drug are 290
cases (it may be referred to as the "test drug group" in working examples) and 288 cases(it may be referred to as the "control group" in working examples), and the total numberof administration cases was 578 cases. However, the number of examples in eachadministration group may differ depending on the types of tests, and may be expressedby, for example, (n = **) or the number of evaluation examples.
[0103]For bone evaluation, bone density, bone geometry, and bone fracture occurrence
were checked.
[0104]
Concerning lumbar spine bone density, the second spine to the fourth spine density
were measured at the start and every 24 weeks thereafter using dual-energy X-ray
absorptiometry (DXA method).
[0105]
Concerning femur bone density, the proximal region of the femur was rotatedinternally by 20 degrees and only the left side was measured at the start and every 24
weeks thereafter using dual-energy X-ray absorptiometry (DXA method).
[0106]DXA geometry was evaluated with femur bone density data measured by thephysician in charge at the start and every 24 weeks thereafter.
[0107]
CT geometry was performed by using multi-slice CT at the start of measurement of75

the proximal region of the femur, and after 48 weeks and 72 weeks.
[0108]
Regarding the frequency of bone fractures, in the vertebral body, X-ray imaging of
the front and side surfaces from the 4th thoracic vertebra to the 5th lumbar spine was
performed at the start and every 24 weeks thereafter; referring to the method of [B] etal. (Non-patent Document 14), new and worsening vertebral fractures were evaluatedby comparing X-ray films at the start and at the following times. Regarding sites otherthan the vertebral body, evaluation was conducted through checking with X -ray films(DXA, bone geometry, new and worsening vertebral fractures were determinedcollectively at the center, and non-vertebral fractures were determined by the physician
in charge using the X-ray films).
[0109](A) Efficacy of the test drug for multiple vertebral fractures
Here, multiple vertebral fractures are defined as two or more new vertebral fractures.
Comparing the incidence of multiple vertebral fractures between the test drug group(n=261) and the control group (n=281) in 72 weeks after the administration, theincidence was 2.1% for the control group (6 cases) and was 0.8% for the test drug group(2 cases). It shows that the test drug has an inhibitory or preventive effect on multiple
vertebral fractures.
The number of cases by the number of bone fractures is shown in the table below.
[Table 12] (To be presented below.)[0110](B) Efficacy of the test drug in patients with primary osteoporosis who are taking
steroids
The efficacy of the test drug in patients with primary osteoporosis taking steroids
was examined. As a result, as shown in the following tables, the test drug is effectivein patients with primary osteoporosis taking steroids.
[0111][Table 13] (To be presented below.)[Table 14] (To be presented below.)[0112]
Since steroids are agents that cause secondary osteoporosis, the above results
suggest that the test drug may be effective against secondary osteoporosis caused bysteroidal agents that induce secondary osteoporosis.
[0113](C) Efficacy of the test drug in 3 sites of the femur
76

The efficacy of the test drug in 3 sites of the femur (femoral neck, intertrochantericfemur, and femoral shaft) were examined according to the general CT method. As aresult, as shown in the following tables, the test drug is effective for each site of thefemur.
[Table 15] (To be presented below.)[Table 16] (To be presented below.)[Table 17] (To be presented below.)[0114](D) Examination of prescription for retching and vomiting in association with theadministration of the test drug
The administration timing and efficacy of various treatment agents for retching andvomiting in association with the administration of the test drug was examined.
[Table 18] (To be presented below.)[0115]As described above, Purinperan, Nauzerin, Gaster D, Gasmotin, Takepron OD, andRokushingan were effective. In particular, Nauselin, Gasmotin, and Rokushingan werepreferred.
[0116](E) Assessment of the influence of the type of complication and its presence on theefficacy of the test drug
The aforementioned patients contain those with complications. Therefore, theinfluence of the type of complication (diabetes, hypertension, and hyperlipidemia) andits presence on the efficacy of the test drug was assessed. As a result, as shown in thefollowing table, it became clear that the test drug suppressed the occurrence of new
vertebral fractures 24 weeks after the administration, regardless of the type andpresence of these complications.
[Table 19] (To be presented below.)[0117]
Diabetic osteoporosis, for which the primary disease is diabetes, is a secondary
osteoporosis; however, the fact that the effect of the test drug in patients with primaryosteoporosis having diabetes as a complication was found suggests that the test drug
may have a therapeutic effect on diabetic osteoporosis.
[0118](F) Efficacy of the test drug on worsening fractures
The efficacy of the test drug on worsening fractures was tested. As a result, as shownin the following table, the test drug is effective against worsening fractures.
77[Table 20] (To be presented below.)[0119](G) Assessment of the influence of the medication history of other therapeutic agentsfor osteoporosis on the efficacy of the test drug
As described above, it was prohibited to administer any therapeutic agents forosteoporosis other than teriparatide acetate to the aforementioned patients for the period
from when informed consent for the clinical trial was obtained until the end of theclinical trial in principle. However, there were patients who were administered othertherapeutic agents for osteoporosis under the predetermined conditions prior to when
informed consent for the clinical trial was obtained. Therefore, the influence of the
medication history with other therapeutic agents for osteoporosis on the efficacy of thetest drug was assessed from the perspective of the incidence of new vertebral fractures
and the rate of changes in bone density.
[0120]
The assessment results regarding the incidence of new vertebral fractures are shownin the table below. In the table, at the 72nd week after the administration of the test
drug, concerning patients having a medication history with other therapeutic agents forosteoporosis, the bone fracture rate was 2.9% for the test drug group and was 16.1% for
the control group; however, concerning patients without a medication history, the bone
fracture rate was 3.2% for the test drug group and was 12.9% for the control group. In
other words, it was revealed that the efficacy of the test drug is higher in patie nts witha medication history of other therapeutic agents for osteoporosis than patients without
a medication history.
[Table 21] (To be presented below.)[0121]
Next, the evaluation results for the bone density change rate are shown in the tablebelow. In the table, regarding lumbar spine bone density, the increase in the bonedensity was remarkable at the 48th week after the administration of the test drug evenin patients with a medication history with other therapeutic agents for osteoporosis. In
particular, in patients with a medication history with any of L-calcium aspartate,
elcatonin, alfacalcidol, menatetrenone, and calcitriol as other therapeutic agents forosteoporosis in the test drug group, a significant increase in lumbar spine bone density
was observed as early as at the 24th week after the administration. It is further notedthat when other therapeutic agents for osteoporosis are L-calcium aspartate andelcatonin, a distinctive increase in bone density of the femoral neck and proximal regionof the femur was observed at the 72nd week after the administration of the test drug. In
78

particular, it is worthy of note that when the other therapeutic agent for osteoporosis iselcatonin, the bone density in the proximal region of the femur already increased
drastically at the 24th week after the administration of the test drug.
[Table 22] (To be presented below.)[0122]In addition, the following table shows the results of the detailed assessment of theinfluence of the medication history of other therapeutic agents for osteoporosis on theefficacy of the test drug for each of said other therapeutic agents for osteoporosis fromthe perspective of the incidence of new vertebral fractures. As can be seen from thetable, in patients with a medication history with therapeutic agents for osteoporosis
other than calcitriol, significant suppression of new bone fractures by the administrationof the test drug was observed.
[Table 23] (To be presented below.)[0123](H) Efficacy and safety of the test drug in patients with osteoporosis having renal
dysfunction
The efficacy and safety of the test drug were examined in the group of patients withosteoporosis having normal renal function, the group of patients with osteoporosis
having mild renal dysfunction, and the group of patients with osteoporosis having
moderate renal dysfunction.
[0124](H-1) Distribution of background factors in each patient group (detail)The group of patients with osteoporosis having normal renal function is indicatedas "Normal (80≤)," the group of patients with osteoporosis having mild renal
dysfunction as "Mild impairment (50≤ <80)," and the group of patients withosteoporosis having moderate renal dysfunction as "Moderate impairment (<50)." In
addition, the test drug administration group is indicated as "PTH 200 group" and thecontrol drug administration group as "P group." Also, the group of patients withosteoporosis having mild renal dysfunction and the group of patients with osteoporosis
having moderate renal dysfunction are collectively indicated as "Abnormal (<80)" insome cases. Each patient was classified into the above groups based on their creatinine
clearance. Specifically, when creatinine clearance is 80 mL/min. or more, renal function
can be determined to be normal; when creatinine clearance is 50 mL/min. or more andless than 80 mL/min., it is regarded as mild renal dysfunction; and when creatinine
clearance is 30 mL/min. or more and less than 50 mL/min., it is regarded as moderate
renal dysfunction.
79[0125](H-1) Distribution of background factors in each patient group
The distribution of background factors in each patient group is as shown below.
[Table 24] (To be presented below.)[0126](H-2) Efficacy of the test drug in each patient group (fracture suppression)
It was revealed that the test drug has the efficacy to inhibit new vertebral fracturesin all of the groups of patients with osteoporosis having normal renal function and thegroups of patients with osteoporosis with (mild and moderate) renal dysfunction .
[Table 25] (To be presented below.)[0127](H-3) Efficacy of the test drug in each patient group (increases in bone density)
It was revealed that the test drug has the efficacy to increase lumbar spine bonedensity in all of the group of patients with osteoporosis having normal renal function,
the group of patients with osteoporosis having mild renal dysfunction, and the group ofpatients with osteoporosis having moderate renal dysfunction.
[Table 26] (To be presented below.)[0128](H-4) Safety of the test drug in each patient group (corrected serum calcium)
As a result of administering the test drug in the group of patients with osteoporosis
having normal renal function, the group of patients with osteoporosis having mild renal
dysfunction, and the group of patients with osteoporosis having moderate renal
dysfunction, there were no significant differences between the test drug group and thecontrol group. Thus, it was revealed that the test drug works equally for all groups interms of safety related to serum calcium.
[Table 27] (To be presented below.)[0129](H-5) Safety of the test drug in each patient group (incidence of adverse events)
The incidence of adverse events after the administration of the test drug was
examined in the group of patients with osteoporosis having normal renal function, thegroup of patients with osteoporosis having mild renal dysfunction, and the group ofpatients with osteoporosis having moderate renal dysfunction, respectively.
[Table 28] (To be presented below.)[Table 29] (To be presented below.)[Table 30] (To be presented below.)[0130]
80

(H-6) Safety of the test drug in each patient group (incidence of adverse reactions)
As a result of administering the test drug to the group of patients with osteoporosis
having normal renal function, the group of patients with osteoporosis having mild renal
dysfunction, and the group of patients with osteoporosis having moderate renal
dysfunction, the test drug showed approximately a double incidence of adverse
reactions compared to the control drug in all patient groups. Thus, it was revealed thatthe test drug works equally for all groups in terms of safety related to incidence ofadverse reactions.
[Table 31] (To be presented below.)[Table 32] (To be presented below.)[Table 33] (To be presented below.)[0131](I) Effect of the administration of the test drug on time-dependent changes in theincidence of new vertebral fractures
The test drug administration group is indicated as "PTH 200 group" and the control
drug administration group as "P group."[Table 34] (To be presented below.)[Table 35] (To be presented below.)[0132]As shown in the above table, the incidence of new vertebral fractures every six
months was almost constant at about 5% in all sections in the P group. On the other
hand, in the PTH200 group, the incidence of each section decreased as theadministration period became longer, and no new vertebral fractures occurred after the
48th week. The incidence of new vertebral fractures in the PTH200 group was lower
than the P group in all sections of within 24 weeks, 24 weeks to 48 weeks, and 48 weeks
to 72 weeks. Relative risk reduction (RRR) for the placebo increased as administration
was continued. Thus, once-weekly administration of 200 units of the test drug
suppressed the occurrence of new vertebral fractures from an early stage, and, after 24
weeks, the bone fracture risk was already reduced by 53.9% compared to the placebo.
In addition, the effect of suppressing bone fractures by the test drug tended to increase
with administration.
[0133]In addition, in the FAS of the fracture test, the incidence of vertebral fractures (new+ worsening) after 72 weeks by the Kaplan-Meier estimation method was 3.5% for the
PTH200 group and 16.3% for the P group. The incidence in the group administered 200
units of the test drug was lower than in the placebo group (logrank test, p<0.0001). In
81

addition, the administration of 200 units of the test drug reduced the risk of vertebral
fracture (new + worsening) by 78.6% after 72 weeks compared to the administration of
the placebo. Comparing the incidence of vertebral fractures (new + worsening) every 6months between the groups, the incidence in the PTH 200 group was lower than in the
P group in all sections of within 24 weeks, 24 weeks to 48 weeks, and 48 weeks to 72
weeks.
[0134](J) Effect of administration of test drug on urinary calcium and serum calcium ofpatients with osteoporosis
The test drug administration group is indicated as "PTH 200 group" and the control
drug administration group as "P group." The results of tests on changes in urinary
calcium level and corrected serum calcium level when the test drug or the control dr ug
were administered to patients once per week for 72 weeks are shown (FIG. 4 and FIG.
5).
The mean values (and median) of the change rate in urinary calcium were 3.2% ( 14.7%) for the PTH 200 group and 23.6% (1.6%) for the P group after 72 weeks, whencompared with the values at the start. A decreasing tendency was more notable in the
PTH 200 group than in the P group.
The corrected serum calcium level changed in the range of 9.3 mg/dL to 9.6 mg/dL
on average in both groups. The corrected serum calcium after administration in the PTH
200 group was 8.5 mg/dL at a minimum (after 48 weeks and 72 weeks), 11.6 mg/dL at
a maximum (after 4 weeks), and in the P group, it was 8.5 mg/dL at a minimum (after
4 weeks) and 12. 1 mg/dL at a maximum (after 12 weeks). No major changes wereobserved in both groups.
There were no adverse events, such as increases and decreases in serum calcium inthe clinical trial.
In the clinical trial, no onset of hypercalcemia or hypercalciuria was observed in the
PTH 200 group compared to the P group.
[Industrial availability][0135]The therapeutic agent or prophylactic agent for osteoporosis and inhibitor orprophylactic agent for fractures in the present invention have both excellent efficacy
and effects and safety. The fracture suppression method in the present invention ishighly safe. Both of them are innovative medical technologies that greatly contribute to
the treatment of osteoporosis and the suppression and prevention of fractures. Therefore,
the therapeutic or prophylactic agent for osteoporosis and inhibitor or prophylactic
82

agent for fractures for said purpose are very useful in the pharmaceutical industry.

83

(Tables)[Table 1]
Table 1 Classification by fracture risk factors
Risk factor

High-risk subjects

Low-risk subjects

Age

65 or older

Younger than 65

Prevalent vertebral fractures

One or more

None

Evaluation of bone density

Less than 80% of the young

80% of the young adult meanor bone atrophy*

adult mean** or atrophy gradeor higher or normal atrophy

I or higher

grade*Bone density evaluated by x-ray films**Young adult mean: Average bone density of 20 to 44-year-olds[Table 2]
Table 2 Patient background of the 5-unit group and 100-unit group among high-risk subjects
Mean ± standard deviationGroup

No. ofAge (years)

subjects

No. of prevalent

Lumbar spine bonevertebral fracturesmineral density(%*)

5-unit group6473.9±4.6

2.3±1.2

63.4±11.6

100-unit group52

73.9±5.8

2.1±1.2

67.9±15.5*Value taking the young adult mean as 100%

[Table 3]
Table 3 Patient background of the 5-unit group and the 100-unit group among low-risk patients
Mean ± standard deviationGroup

No. ofAge (years)

subjects

No. of prevalent

Lumbar spine bonevertebral fractures

density (%*)

5-unit group1057.9±5.1

1.8±0.968.3±8.8

100-unit group1161.5±2.4

2.4±1.259.9±1.9*Value taking the young adult mean as 100%84

[Table 4]
Table 4 Lumbar spine bone density (% change) among high-risk subjects
Mean ± standard deviation
Group

After 26 W

After 52 W

After 78 W

After 104 W

Final check

5-unit group-0.9±4.4-0.6±4.1

0.4±4.1

0.4±4.0-0.1±4.8

100-unit

3.3±4.5*#

4.3±4.5*#

4.0±4.5*#

4.9±4.2*#

4.5±4.6*#

group* Difference from the start of administration# Difference from the 5-unit groupp<0.05p<0.05[Table 5]
Table 5 Lumbar spine bone density (% change) among low-risk subjects
Mean ± standard deviationGroup
5-unit group
100-unit group$

After 26 W

After 52 W

After 78 W

Final check-0.6±6.4-0.7±6.2

1.9±7.5-0.6±5.7

3.2

6.1

12.0

12.0

$ The bone density was measured for only one patient and the value is shown as a reference.

[Table 6]
Table 6 New vertebral fractures among high-risk subjects
Group

No. with fractures

No. of vertebral(persons)

fractures

5-unit group13

22

100-unit group3

3

Difference between groups

p<0.05[Table 7]
Table 7 New vertebral fractures among low-risk subjects
Group

No. with fractures

No. of vertebral

Difference between(persons)

fracturesgroups5-unit group1

1

p>0.05100-unit group

1

2

85

[Table 8]
Table 8 New vertebral fractures every 26 weeks among high-risk subjects
5-unit group

100-unit group

No.

No. with

Incidence

No. ofNo.

No. with

Incidence

No. ofevaluatedfractures(%)

fractures

evaluatedfractures(%)

fractures

After 26 W

63

6

9.5

8

51

1

2.0

1

After 52 W

63

7

11.1

9

51

1

2.0

1

After 78 W

57

4

7.0

4

45

1

2.2

1

35

1

2.9

1

25

0

－

0

10

0

－

0

5

0

－

0

After

104

W
After

130

W

[Table 9]
Table 9 New vertebral fractures every 26 weeks among low-risk subjects
5-unit group

100-unit group

No.

No. with

Incidence

No. ofNo.

No. with

Incidence

No. ofevaluatedfractures(%)

fractures

evaluatedfractures(%)

fractures

After 26 W

21

0

－

0

12

1

8.3

2

After 52 W

21

1

4.8

1

12

0

－

0

After 78 W

16

0

－

0

12

0

－

0

2

0

－

0

6

0

－

0

2

0

－

0

2

0

－

0

After 104
W
After 130
W

[Table 10]
Table 10 Fractures of sites other than the vertebral body among high -risk subjects
Group5-unit group

No. with fractures(persons)
6

100-unit group1

Site
Right clavicle
Proximal phalanx of the 5th
toe of the right footLeft 5th rib
Right 10th, 11th ribs
Left pubis
Right 6th rib
Neck of proximal phalanx ofthe 2nd toe on the left

86

Difference between
groupsp<0.05

[Table 11]
Table 11 Fractures of sites other than the vertebral body among low-risk subjects
Group

No. with fractures

Site

Difference between(persons)
5-unit group

groups1

5th toe of the rightp>0.05

foot100-unit group0[Table 12]
New vertebral fractures
Test drug group (n = 261)
No. of fractures

No. of Subjects

Control group (n = 281)

Incidence (%)

No. of Subjects

Incidence (%)

None

254

97.3

244

86.8

One

5

1.9

31

11

Two

2

0.8

4

1.4

Three

0

0.0

1

0.4

Four

0

0.0

1

0.4

Five or more

0

0.0

0

0.0

[Table 13]
Change in bone density (%)
Steroid
Time afteradministration

Lumbar spine

Femoral neck

24

48

72

W

W

W

0.00

3.50

5.97

6.82

0.00

0.00

1.26

1.91

1.23

0.00

0W

0W

Proximal femur

24

48

72

W

W

W

2.53

2.79

2.44

-

-

-

2.51

1.52

1.74

0W

24

48

72

W

W

W

2.46

3.39

3.06

-0.8

0.81

Test druggroup (n = 14,

0.00

18, 18)Control group(n = 17, 21,
21)

87

0.00

0.86

[Table 14]
Steroid

Existence of new vertebral fractures
Discontinued

Fracture: Yes

Total

Fracture: No

Test drug group

4

0

29

33

Control group

3

3

24

30

[Table 15](C-1) Effect on the femoral neckFemoral neck
Volume bonemineral density(total)[vBMD total]
Volume bonemineral density(cortical bone)[vBMD
cortical]Buckling ratio

Maximum
sectionmodulus(SM (Z min))(At thestart→48
W→72 W)
Test druggroup (n =30→28→22)
Controlgroup (n =37→33→30)
Test druggroup (n =30→28→22)
Controlgroup (n =37→33→30)
Test druggroup (n =30→28→22)
Controlgroup (n =37→33→30)
Test druggroup (n =30→28→22)
Controlgroup (n =37→33→30)

Baseline

Changefrom thebaseline
after 48
weeks (%)

p value(betweengroups)(*P<0.05)

Changefrom thebaseline
after 72
weeks (%)

p value(betweengroups)(*P<0.05)

221.380.92

0.11550.15

0.1658227.98-0.72

665.02-0.77

676.84

-0.22

14.01

-3.48

13.44

1.27

0.38513.43

0.3793

-0.27

88

-1.23
0.5638-1.14

0.6852-0.82*0.0084-3.40*0.0121.85
0.08191.87
0.62

0.5837

[Table 16](C-2) Effect on the intertrochanteric femur
Intertrochanter
ic femur
Volume bonemineral density(total)[vBMD total]
Volume bonemineral density(cortical bone)[vBMD
cortical]Buckling ratio

Maximum
sectionmodulus(SM (Z min))(At thestart→48
W→72 W)
Test druggroup (n =30→28→22)
Control group(n =36→32→30)
Test druggroup (n =30→28→22)
Control group(n =36→32→30)
Test druggroup (n =30→28→22)
Control group(n =36→32→30)
Test druggroup (n =30→28→22)
Control group(n =36→32→30)

Change fromthe baseline
after 48
weeks (%)

p value(betweengroups)Change fromthe baseline
after 72
weeks (%)

p value(betweengroups)186.451.36*0.0086

0.95

0.0802

196.10-1.50

638.98-0.49

646.03

-0.34

19.64

1.59

19.26

4.26

0.69895.19

0.7295

2.38

Baseline

89-1.47
0.8300-1.49

0.1653-0.61
0.30151.27

0.76812.13
0.43243.20
1.81

0.6567

[Table 17](C-3) Effect on the femoral shaft
Femoral shaft
Volume bonemineral density(total)[vBMD total]
Volume bonemineral density(cortical bone)[vBMD
cortical]Buckling ratio

Maximum
sectionmodulus(SM (Z min))(At thestart→48
W→72 W)
Test druggroup (n =29→28→21)
Control group(n =37→33→30)
Test druggroup (n =30→28→22)
Control group(n =36→32→30)
Test druggroup (n =30→28→22)
Control group(n =36→32→30)
Test druggroup (n =30→28→22)
Control group(n =36→32→30)

BaselineChange fromthe baseline
after 48
weeks (%)

p value(betweengroups)Change fromthe baseline
after 72
weeks (%)

p value(betweengroups)463.591.03

0.35211.25

0.0613482.05-0.22

880.910.59

892.97

0.33

3.64

-0.66

3.39

0.92

0.90151.28

0.9343

-0.78

90

-1.43
0.77960.18

0.2703-0.87
0.3977-3.54*0.0008

1.91
0.14992.69
0.32

0.1604

[Table 19]

Complication(diabetes)

No
Yes

Complication(hypertension)No
Yes

Complication(hyperlipidemia
)

No
Yes

No.
evaluated

No. discontinue
d

No.
with
fracture
s

243
257
18
24
117
150
144
131
156
169
105
112

54
29
4
2
29
16
29
15
34
17
24
14

7
35
0
2
3
26
4
11
4
26
3
11

Test drug group
Control group
Test drug group
Control group
Test drug group
Control group
Test drug group
Control group
Test drug group
Control group
Test drug group
Control group

Incidence of new
vertebrae fractures(%)
Afte Afte Afte
r 24
r 48
r 72
W
W
W
2.8
3.3
3.3
5.8 11.0 15.0
0.0
0.0
0.0
0.0
4.3
8.9
2.1
3.1
3.1
6.3 13.0 19.0
3.1
3.1
3.1
4.0
7.5
9.2
2.2
3.0
3.0
5.6 10.2 16.8
3.2
3.2
3.2
4.8 10.9 10.9

[Table 20]

FAS

Test
drug
group
ControlgroupNo.
evaluated

No. discontinued

No. with
fractures

Incidence ofworsening vertebral
fractures (%)
After
24 W

After
48 W

After
72 W

261

60

1

0.4

0.4

0.4

281

37

6

2.3

2.3

2.3

91

Difference between
investigational productgroup and control group
after 72 W (%)
90%
confidence
Difference
interval

1.8

Lower
limit

Upper
limit

0.2

3.5

log
rank
test

0.0860[Table 21]

Prior therapeutic
agents forosteoporosis(No)

Test drug
group
Controlgroup

Prior therapeutic
agents forosteoporosis(Yes)

Test drug
group
Controlgroup

Incidence of new vertebral
fractures (%)
After
After
After
24 W
48 W
72 W

No.
evaluated

No. discontinued

No. with
fractures

139

31

4

2.4

3.2

3.2

142

13

17

6.7

9.8

12.9

122

27

3

2.9

2.9

2.9

139

18

20

3.8

11.2

16.1

92

[Table 22]
Percentage change in bone density (%)
Calcium Laspartate
Week
PTH 200
group (n =17, 23, 23)
P group (n =20, 24, 24)

Lumbar spine

PTH 200
group (n =41, 51, 51)
P group (n =37, 46, 45)
Raloxifenehydrochloride
Week
PTH 200
group (n =18, 21, 21)
P group (n =22, 24, 24)
Elcatonin
Week
PTH 200
group (n =22, 28, 28)
P group (n =20, 26, 26)

Proximal femur

0W

24
W

48
W

72
W

0W

24
W

48
W

72
W

0W

24
W

48
W

72
W

0.00

3.78

6.16

5.85

0.00

1.44

1.88

4.17

0.00

1.76

2.28

3.69

0.00

-0.31

-1.01

-1.52

0.00

0.57

0.83

1.61

0.00

0.71

-0.18

-0.17

Lumbar spine
24
48
W
W

72
W

0W

Femoral neck
24
48
W
W

72
W

0W

Proximal femur
24
48
W
W

72
W

0.00

3.11

5.47

6.47

0.00

1.64

0.85

2.19

0.00

2.77

2.31

2.31

0.00

-0.65

-1.01

-0.69

0.00

-0.28

-0.16

-0.96

0.00

0.11

-0.89

-1.05

Alfacalcidol
Week

Femoral neck0W

Lumbar spine

Femoral neck

Proximal femur

0W

24 W

48 W

72 W

0W

24 W

48 W

72 W

0W

24 W

48 W

72 W

0.00

1.77

4.96

4.59

0.00

0.21

1.03

-0.51

0.00

2.44

2.26

3.03

0.00

-0.33

-1.74

-1.89

0.00

-0.61

-0.61

0.58

0.00

0.04

0.45

0.62

0W

Lumbar spine
24 W 48 W

72 W

0W

Femoral neck24 W 48 W

72 W

0W

Proximal femur
24 W 48 W 72 W

0.00

3.95

3.59

5.36

0.00

1.62

0.72

3.15

0.00

3.86

3.44

4.41

0.00

-0.29

0.20

0.95

0.00

-1.35

0.95

0.29

0.00

-0.73

-0.95

0.10

93

Percentage change in bone density (%)
Menatetrenone
Week
PTH 200
group (n = 5,5, 5)
P group (n =4, 6, 6)

Lumbar spine

PTH 200
group (n = 7,5, 5)
P group (n =6, 9, 9)

24
W

48
W

72
W

0W

24
W

48
W

72
W

0W

24
W

48
W

72
W

0.00

2.70

3.04

4.32

0.00

0.72

-3.18

-0.78

0.00

0.60

-0.56

-1.40

0.00

-1.03

2.47

-1.53

0.00

-1.16

1.03

-4.70

0.00

-0.34

-2.43

-3.78

Lumbar spine

PTH 200
group (n = 5,6, 6)
P group (n =11, 13, 13)Femoral neck

Proximal femur

0W

24
W

48
W

72
W

0W

24
W

48
W

72
W

0W

24
W

48
W

72
W

0.00

1.96

3.45

4.93

0.00

0.30

-4.35

-2.53

0.00

1.78

-1.68

-3.20

0.00

-0.88

-0.17

0.43

0.00

-2.19

0.83

-3.00

0.00

0.39

1.15

-1.58

Calcitriol
Week

Proximal femur

0W

Calciumlactate
Week

Femoral neck0W

Lumbar spine
24
48
72 W
W
W

Femoral neck

Proximal femur

0W

24 W

48 W

72 W

0W

24 W

48 W

72 W

0.00

3.50

4.40

6.38

0.00

-0.60

-4.03

-3.53

0.00

-1.40

-1.05

-0.04

0.00

0.70

0.49

-0.72

0.00

-1.26

-1.25

-3.81

0.00

0.55

-0.01

-0.43

94

[Table 23]
Calcium L-aspartate

New vertebral fractures: Yes or No
Discontinued

Yes

Total

No

Test drug group

9

1

28

38

Control group

2

5

27

34

Alfacalcidol

New vertebral fractures: Yes or No
Discontinued

Yes

Total

No

Test drug group

16

1

62

79

Control group

12

11

50

73

Raloxifene hydrochloride

New vertebral fractures: Yes or No
Discontinued

Yes

Total

No

Test drug group

9

0

20

29

Control group

8

5

24

37

Elcatonin

New vertebral fractures: Yes or No
Discontinued

Yes

Total

No

Test drug group

10

2

35

47

Control group

9

5

34

48

Menatetrenone

New vertebral fractures: Yes or No
Discontinued

Yes

Total

No

Test drug group

1

0

6

7

Control group

3

3

4

10

Calcium lactate

New vertebral fractures: Yes or No
Discontinued

Yes

Total

No

Test drug group

1

0

8

9

Control group

1

2

7

10

Calcitriol

New vertebral fractures: Yes or No
Discontinued

Yes

Total

No

Test drug group

2

1

7

10

Control group

1

2

13

16

95

[Table 24]
Ccr at thestart
Normal(80≤)

Safetyanalysis set
Age
Height (cm)Weight (kg)BMI (kg/m 2)
Time after
menopause(years)Mild
impairment(50≤ <80)

Prevalentvertebralfractures atenrollment(no.)
Prevalentvertebralfractures
beforeadministration(no.)
Lumbar spinebone mineraldensity before
administration(YAM
converted)(%)
Femoral neckbone mineraldensity before
administration(YAM
converted)(%)
Proximalfemur totalbone mineraldensity before
administration(YAM
converted)(%)
Age
Height (cm)

No. ofcases

AveragevalueStandard
deviation

Minimum
valueMedianvalue

Maximum
value

49

70.2

3.8

65

70.0

78

49

70.4

3.9

65

70.0

82

49

150.56

5.65

138.5

151.50162.5

49151.11

4.46

140.0

151.20

162.5

49

57.81

5.42

47.5

57.30

70.5

49

57.51

7.73

41.5

56.50

80.1

49

25.57

2.77

20.5

25.70

35.5

49

25.22

3.57

17.7

24.80

37.2

49

19.7

4.8

11

19.0

30

49

20.6

6.0

10

20.0

42

PTH
200

49

2.0

1.2

1

1.0

5

P

49

1.7

0.8

1

1.0

4

PTH
200

49

1.8

1.3

0

1.0

5

P

49

1.3

0.9

0

1.0

4

PTH
200

33

68.9

8.4

51

69.1

82

P

38

70.6

9.0

50

70.4

91

PTH
200

37

73.3

8.7

57

74.4

94

P

37

72.6

9.3

48

73.3

92

PTH
200

37

75.4

11.4

51

76.0

96

P

36

79.5

9.0

57

80.6

97

160

74.3

4.7

65

74.0

85

151

74.5

4.6

65

74.0

90

160

147.57

5.14

136.2

147.35166.0

151147.41

5.15

134.5

147.0

160.4

Group
PTH
200
P
PTH
200
P
PTH
200
P
PTH
200
P
PTH
200
P

PTH
200
P
PTH
200
P

96

Ccr at thestart

Safetyanalysis set
Weight (kg)BMI (kg/m 2)Moderate
impairment(<50)

Time after
menopause(years)Prevalentvertebralfractures atenrollment(no.)
Prevalentvertebralfractures
beforeadministration(no.)
Lumbar spinebone mineraldensity before
administration(YAM
converted)(%)
Femoralneckbonemineraldensity before
administration(YAM
converted)(%)
Proximalfemur totalbone mineraldensity before
administration(YAM
converted)(%)
Age
Height (cm)Weight (kg)BMI (kg/m 2)
Time after
menopause(years)No. ofcases

AveragevalueStandard
deviation

Minimum
valueMedianvalue

Maximum
value

160

50.57

6.19

37.2

50.40

69.0

151

49.73

6.56

34.2

49.80

66.0

160

23.26

2.85

15.9

23.20

31.3

151

22.89

2.82

15.3

22.80

30.1

160

24.9

5.6

11

24.0

39

151

25.2

5.6

12

25.0

43

160

1.9

1.1

1

1.5

5

P

151

2.0

1.2

1

2.0

5

PTH
200

160

1.8

1.4

0

1.0

8

P

151

1.7

1.3

0

1.0

6

PTH
200

91

68.4

9.4

51

67.7

99

P

84

67.2

11.4

42

67.9

98

PTH
200

104

67.3

8.7

46

67.0

96

P

95

65.6

10.0

38

66.1

91

PTH
200

103

72.2

11.3

44

70.5

102

P

95

69.7

11.2

42

70.2

91

68

80.5

5.5

65

80.0

93

78

80.3

5.5

65

81.0

95

68

144.79

6.57

124.3

145.00158.0

78

143.99

6.14

133.0

143.50

159.0

68

44.48

6.65

30.4

43.65

60.5

78

44.59

6.74

31.0

44.25

67.0

68

21.28

3.28

14.5

21.30

29.5

78

21.54

3.21

16.2

21.40

32.7

68

31.0

6.7

12

30.0

46

Group
PTH
200
P
PTH
200
P
PTH
200
P
PTH
200

PTH
200
P
PTH
200
P
PTH
200
P
PTH
200
P
PTH
200

97

98

Ccr at thestart

Safetyanalysis set
Prevalentvertebralfractures atenrollment(no.)
Prevalentvertebralfractures
beforeadministration(no.)
Lumbar spinebone mineraldensity before
administration(YAM
converted)(%)
Femoralneckbonemineraldensity before
administration(YAM
converted)(%)
Proximalfemur totalbone mineraldensity before
administration(YAM
converted)(%)

No. ofcases
78

Averagevalue
30.5

Standard
deviation
6.7

Minimumvalue
12Medianvalue
31.0

Maximum
value
48

68

2.3

1.3

1

2.0

5

P

78

2.1

1.3

1

2.0

5

PTH
200

68

2.3

1.5

0

2.0

6

P

78

1.8

1.3

0

1.5

5

PTH
200

30

65.9

13.5

31

64.3

102

P

39

71.1

11.6

51

72.8

102

PTH
200

40

62.8

12.1

39

62.0

91

P

46

63.5

10.4

42

63.1

88

PTH
200

40

65.6

13.2

33

62.9

90

P

46

67.9

12.7

43

66.8

93

Group
P
PTH
200

[Table 25]
Incidence of newNo.

No. dis-No. with

vertebral fractures (%)

evaluated

continued

fractures

After

After

After

24 W

48 W

72 W

Creatinine

NormalPTH

clearance

(80≤)

200

46

9

0

0.0

0.0

0.0

P

48

5

4

2.2

4.4

9.1

value at thestart

Abnormal

PTH

(<80)

200

202

47

6

2.8

3.4

3.4

P

223

25

31

6.2

12.2

15.3

99

[Table 26]
PTH 200 group
Change in lumbar
spine bone density(%)
Normal(80≤)

Mild
impairment (50≤ <80)

Moderate
impairment (<50)

Afte
r 24
W
Afte
r 48
W
Afte
r 72
W
Fina
l
Afte
r 24
W
Afte
r 48
W
Afte
r 72
W
Fina
l
Afte
r 24
W
Afte
r 48
W
Afte
r 72
W
Fina
l

P group

No.
of
case
s

No.
of
case
s

Mean

SD

Min

Mean

SD

Min Median

28

4.3

4.7

-5.0

5.1

13.7

36

1.2

3.2

-5.3

1.0

8.9

25

5.4

3.7

-1.1

5.6

11.9

30

1.4

3.4

-4.7

0.8

6.7

24

8.1

5.3

-1.0

8.0

20.2

29

1.9

4.8

-4.9

0.8

12.6

29

7.5

5.4

-1.0

5.6

20.2

36

1.4

4.6

-4.9

0.8

12.6

66

3.9

3.8

-4.7

3.7

15.4

73

0.3

2.9

-6.6

0.6

6.8

60

6.0

4.9

-7.0

5.7

18.0

72

0.1

3.5

-8.7

0.7

7.2

56

6.3

5.3

-4.6

6.6

18.3

67

-0.4

4.3

10.2

-0.9

9.3

74

5.8

5.0

-4.6

5.4

18.3

79

-0.2

4.1

10.2

-0.5

9.3

24

3.7

5.8

-8.5

3.5

15.4

33

0.4

3.5

-5.6

0.7

7.5

22

4.9

4.4

-4.5

3.8

14.1

31

0.7

4.2

-8.8

0.7

9.2

21

6.1

5.0

-1.3

6.3

21.5

30

0.2

4.4

-9.1

0.5

8.0

27

5.6

5.3

-2.4

4.9

21.5

36

0.0

4.1

-9.1

0.1

8.0

Median Max

100

Max

[Table 27]
PTH200 group
Corrected serum
calcium (mg/dL)
Normal(80≤)

Mild
impairment (50≤ <80)

Moderate
impairment (<50)

At
the
start
Afte
r4
W
Afte
r 12
W
Afte
r 24
W
Afte
r 48
W
Afte
r 72
W
Fina
l
At
the
start
Afte
r4
W
Afte
r 12
W
Afte
r 24
W
Afte
r 48
W
Afte
r 72
W
Fina
l
At
the
start
Afte
r4
W
Afte
r 12
W
Afte
r 24
W
Afte
r 48
W
Afte
r 72
W

No.
of
case
s

Mea
n

SD

49

9.5

49

P group
Max

No.
of
case
s

Mea
n

SD

Min Median

Max

9.5

10.6

49

9.5

0.4

8.9

9.5

10.4

8.8

9.5

10.6

48

9.6

0.3

8.9

9.6

10.5

0.4

8.6

9.5

10.5

48

9.5

0.3

8.6

9.5

10.3

9.5

0.4

8.9

9.5

10.7

48

9.5

0.4

8.9

9.5

10.9

39

9.3

0.3

8.8

9.2

10.0

44

9.4

0.3

8.8

9.4

10.3

37

9.4

0.3

8.9

9.3

10.1

43

9.3

0.3

8.6

9.3

10.2

49

9.4

0.3

8.9

9.4

10.4

48

9.3

0.3

8.6

9.3

10.2

160

9.5

0.4

8.8

9.5

10.9

151

9.5

0.4

8.8

9.5

10.8

155

9.5

0.4

8.6

9.5

11.6

151

9.6

0.4

8.8

9.6

11.7

137

9.6

0.3

8.8

9.5

10.5

149

9.5

0.4

8.7

9.5

12.1

121

9.5

0.4

8.7

9.5

10.7

143

9.5

0.3

8.7

9.4

11.6

112

9.3

0.3

8.5

9.3

10.8

135

9.3

0.3

8.7

9.3

10.2

107

9.3

0.3

8.5

9.3

10.7

128

9.3

0.3

8.7

9.3

10.2

157

9.4

0.3

8.5

9.4

10.7

151

9.4

0.3

8.5

9.3

10.9

68

9.6

0.4

8.6

9.5

10.6

78

9.6

0.4

8.9

9.5

10.8

66

9.5

0.3

9.0

9.5

10.8

78

9.6

0.4

8.5

9.6

10.7

62

9.5

0.4

8.8

9.5

10.4

75

9.6

0.4

8.9

9.6

10.7

59

9.5

0.4

8.8

9.5

10.5

71

9.6

0.4

8.8

9.5

10.5

51

9.3

0.3

8.7

9.3

10.2

67

9.4

0.4

8.7

9.4

10.5

45

9.4

0.3

8.8

9.4

10.2

63

9.4

0.4

8.7

9.3

10.3

Min

Media
n

0.3

8.8

9.5

0.4

45

9.6

43

101

Fina
l

67

9.4

0.4

8.7

9.4

102

10.4

78

9.4

0.4

8.5

9.3

10.4

[Table 28]
Adverse events

95%
confidence
interval of thedifference

Normal

Total

(80≤)
Yes

No

No. of

PTH 200
group
P groupNo. of95%(asymptote)

confidence

Fisher's

interval of each

exact

Point

continuity

group (exact)

test pestimate

correction)

Lower

Upper

value

of the

Lower

Upper

limit

limit

(2-way)difference

limit

limit

1.0000

2.0

-10.2

14.3

cases

(%)

cases

(%)

46

93.9

3

6.1

49

83.1

98.7

45

91.8

4

8.2

49

80.4

97.7

(with

[Table 29]
Adverse events

95%
confidence
interval of thedifference

Mild

95%

impairment(50≤ <80)
Yes

No

No. of

PTH 200
group
P groupNo. of(asymptote)

confidence

Fisher's(withinterval of each

exact

Point

continuity

group (exact)

test pestimate

correction)

Lower

Upper

value

of the

Lower

Upper

cases

(%)

cases

(%)

Total

limit

limit

(2-way)difference

limit

limit

147

91.9

13

8.1

160

86.5

95.6

0.6689

-1.5

-7.9

4.9

141

93.4

10

6.6

151

88.2

96.8

103

[Table 30]
Adverse events

95%
confidence
interval of thedifference

Moderate

95%

impairment
(<50)
Yes

No

No. of

PTH 200
group
P groupNo. of(asymptote)

confidence

Fisher's(withinterval of each

exact

Point

continuity

group (exact)

test pestimate

correction)

Lower

Upper

value

of the

Lower

Upper

cases

(%)

cases

(%)

Total

limit

limit

(2-way)difference

limit

limit

65

95.6

3

4.4

68

87.6

99.1

0.3385

4.6

-4.8

13.9

71

91.0

7

9.0

78

82.4

96.3

104

[Table 31]
Side effects

95%
confidence
interval of thedifference

Normal95%(80≤)

confidence

Fisher's

interval of each

exact

Point

continuity

group (exact)

test pestimate

correction)

Lower

Upper

value

of the

Lower

Upper

Yes

No

No. ofNo. of(asymptote)
(with

cases

(%)

cases

(%)

Total

limit

limit

(2-way)difference

limit

limit

22

44.9

27

55.1

49

30.7

59.8

0.0318

22.4

2.2

42.7

11

22.4

38

77.6

49

11.8

36.6

PTH 200
group
P group[Table 32]
Side effects

95%
confidence
interval of thedifference

Mild

95%

(asymptote)

impairment

confidence(with(50≤ <80)interval of eachFisher's

group (exact)

exact

Point

test pestimate

Yes

PTH 200
group
P group

No

No.

No.

of

of

continuity
correction)

Lower

Upper

value

of the

Lower

Upper

cases

(%)

cases

(%)

Total

limit

limit

(2-way)difference

limit

limit

72

45.0

88

55.0

160

37.1

53.1

<.00001

29.1

18.8

39.4

24

15.9

127

84.1

151

10.5

22.7

105

[Table 33]
Side effects

95% confidence
interval of theNormal
(<50)

Yes

No

No.

No.

of

of

95%

difference

confidence(asymptote) (withinterval of eachFisher's

Point

continuity

group (exact)

exact

estimate

correction)

test pof the

Lower

Upper

value

differenc

Lower

Upper

e

limit

limit

cases

(%)

cases

(%)

Total

limit

limit

(2-way)

25

36.8

43

63.2

68

25.4

49.3

0.0251

15

19.2

63

80.8

78

11.2

29.7

PTH 200
group
P group

17.5

1.7

33.3

[Table 34]
FAS

Difference between PTH200
group and P group after 72
W (%)
Incidence of new

90%

vertebral fracturesconfidence(%)

interval

After

After

After

No.

No. dis-No. with

24

48

72

evaluated

continued

fractures

W

W

W

261

58

7

2.6

3.1

3.1

281

31

37

5.3

10.4

14.5

log
Lower

Upper

rank

Difference

limit

limit

test

11.4

7.3

15.4

<.00001

PTH
200
group
P
group

106

[Table 35]
New vertebral fractures
PTH 200 groupP group

Incidence

Incidence

Time afterNo.

No. withof

No. ofNo.

No. withof

No. ofadministration

evaluatedfractures

fractures

fractures

evaluatedfractures

fractures

fractures

(%)

(%)

≤24 W

261

6

2.3

7

281

14

5.0

18

24 W< ≤ 48 W

219

2

0.9

2

257

13

5.1

13

48 W< ≤72 W

206

0

0

0

245

13

5.3

15

107

(Figures)[Figure 1]
Figure 1 Changes in serum calcium concentration by risk and group

LOW.RISK SUBJECTS 5-UNIT GROUPSERUM Ca (mg/dL)

SERUM Ca (mg/dL)

HIGH-RISK SUBJECTS 5-UNIT GROUP

TIME (WEEKS)

TIME (WEEKS)LOW-RISK SUBJECTS 100-UNIT GROUPSERUM Ca (mg/dL)

SERUM Ca (mg/dL)

HIGH-RISK SUBJECTS 100-UNIT GROUP

TIME (WEEKS)

TIME (WEEKS)

108

[Figure 2]

Incidence of new vertebral fractures (%)

Group
PTH 200 groupP group

0 weeks

24 weeks

48 weeks

72 weeks

Observation day (weeks after the administration)

109

Incidence of new vertebral fractures (%)[Figure 3]

PTH 200
group

P group≤24 weeks

PTH 200
group

P group

24 weeks < ≤48 weeks

PTH 200
group

P group

48 weeks< ≤72 weeks

110

Dosage group
Evaluation
section[Figure 4]

At thestart

After 12 weeks After 24 weeks

After 48 weeks

PTH200 group111

P group

After 72 weeks

[Figure 5]

At thestart

After 12 weeks After 24 weeks

After 48 weeks
PTH200 group112

P group

After 72 weeks

(Attachment 2)
Matters stated in Exhibit Ko 1 Document (Abstract)(Tables and figures are posted together at the end of the Attachment.)[Page 296, left column, line 1 through right column, line 7]
Abstract
To test the effect of amino-terminal peptide 1-34 of human parathyroid hormone(hPTH (1-34)) as a possible bone anabolic agent in the treatment of osteoporosis,
weekly subcutaneous injection of 50 units (L group), 100 units (M group) or 200 units(H group) of hPTH (1-34) was started with 220 patients with osteoporosis at 71
institutions, who were randomly divided into three groups in a double-blind system.
Lumbar spine bone mineral density (BMD) measured by dual-energy X-ray
absorptiometry (DXA) increased by 0.6%, 3.6% and 8.1% after 48 weeks in groups L,
M and H, respectively. Responses in groups M and H were significantly higher than in
L group (p<0.05, [F]'s U-test). Since the coefficient of variation for lumbar spine
measurement stayed at 1% to 2.5%, increases of 3.6% and 8.1% appeared significant.
Metacarpal BMD and cortical thickness measured by radiogrammetry did not change
significantly. Serum calcium decreased in each group and serum phosphorus decreasedin groups M and H. Urinary calcium/creatinine decreased at the 12th week in group H
and at the 24th and 48th weeks in groups M and L. Serum 25(OH) vitamin D and1.25(OH)2 vitamin D decreased in each group at the 48th week (p<0.05). Serum bonespecific alkaline phosphatase was increased at the fourth week in groups H and M anddecreased at the 48th week in group H. Urinary hydroxyproline, pyridinoline anddeoxypyridinoline declined significantly in each group. Backache improved in 30% to
40% of each group. No serious adverse reactions were found during the test period.
Intermittent weekly injection of hPTH (1-34) increased lumbar spine BMD in patientswith osteoporosis, suggesting usefulness in the treatment of osteoporosis.
[Page 296, right column, line 10 through page 297, left column, line 25]
Introduction
Treatment of postmenopausal and involutional osteoporosis has mainly depended
on antiresorptive agents such as estrogen, bisphosphonates and calcitonins. As
considerable advances have been made in the prevention of fractures through increases
in bone mineral density (BMD) by using these agents, stimulators of bone formation
would supplement the prompt and sometimes transient effect of antiresorbers, and giventhat their bone anabolic effects are of longer duration, they would be expected to be
113

particularly useful in the treatment of involutional osteoporosis, especially in those with
low-turnover disease. Parathyroid hormone (PTH) has been shown to have bone
anabolic effects in animals and humans, especially by intermittent administration.
However, as seen in primary hyperparathyroidism, when bones are exposed to a large
amount of PTH continuously, osteitis fibrosa may develop. According to the result of apreliminary study where 100 units or 200 units of amino-terminal peptide 1-34 ofhuman PTH (hPTH (1-34)) was administered by subcutaneous injection for a single
time, decreases in serum phosphorus, increases in serum cyclic AMP, increases inurinary calcium and cyclic AMP excretion, and other important effects on the metabolic
system were observed. When 100 units or 200 units are administered weekly, lumber
spine BMD significantly increased at the 26th week after the start of the treatment;
however, no effects were seen under administration of 5 units weekly.
Based on these results, in this clinical trial, a randomized, prospective, double -blind,and multicenter study was conducted with 220 patients with osteoporosis in order toobserve the effects when 50 units, 100 units, or 200 units of hPTH (1-34) areadministered weekly. Primary endpoint is an assessment of lumbar spine BMD using adual-energy X-ray absorptiometry (DXA). Secondary endpoints are metacarpal cortex
BMD by radiogrammetry and biochemical marker of bone turnover. The clinical trial
examined whether once-weekly administration of hPTH (1-34) at the concentrations
listed here - meaning an intermittent administration plan at low concentrations that has
never been examined - is beneficial to the treatment of osteoporosis.
[Page 297, left column, line 27 through right column, line 42]
Subject of the clinical trial
A multicenter clinical trial with the participation of 71 institutions was conducted.
The clinical trial was conducted with 220 subjects between the ages of 45 and 95 years
who were diagnosed as having osteoporosis based on the diagnostic criteria proposedby a committee supported by the Ministry of Health and Welfare. This system does not
simply define osteoporosis as the presence of a non-traumatic fracture or the presenceof spine fractures at 2 sites but defines osteoporosis by evaluating multiple factors asscores. The case where patients' total score is more than 4 (defined as osteoporosis) isused as a criterion for enrollment in the clinical trial. In most areas in Japan, the methodthat healthcare personnel can use for diagnosing osteoporosis is still limited to X -ray
imaging of spines. Therefore, X-ray imaging had to be implemented as a diagnostic
criterion of osteoporosis. Bone loss on X-ray film is determined to be found whentrabecular thinning is observed on an X-ray film of the side of the lumbar spine; in other114

words, (1) vertical trabeculae become conspicuous due to horizontal trabeculae defect;(2) vertical trabeculae become rough; and (3) vertical trabeculae loss is observed. Boneloss on X-ray film corresponds to loss by 20% or 2.5 SD in BMD from the young adultmean value. In this clinical trial, for example, the following persons were included in
the subjects: those whose lumbar spine BMD mean value is 0.736 g/cm 2 when measured
using a DPX densitometer manufactured by Luna Innovations Inc.; 0.694 g/cm 2 whenmeasured using a QDR densitometer manufactured by Hologic, Inc.; or 0.624 g/cm 2
when measured using an XR densitometer manufactured by Norland, respectively.
These criteria conform to other criteria that are used at present. When the degree ofbone loss on X-ray film is Grade 1 to Grade 3 or when BMD is less than 2.5 SD fromthe young adult mean, the score is 3. If a vertebral fracture occurred at one site, thescore is 1 and if a vertebral fracture occurred at two or more sites, the score is 2. If there
is a femoral neck fracture, the score is 3 and if there is a distal radius fracture, the scoreis 1. In order to eliminate osteomalacia, primary hyperparathyroidism, and renal
osteodystrophy, etc. that cause decreases in bone mass, as a factor to support thediagnosis of osteoporosis, the score of normal serum calcium, phosphorus, and alkaline
phosphatase value is determined to be 1. However, if there are one or moreabnormalities, the score is reduced by 1. In the same way, if a subject is inpremenopause, the score is reduced by 1.
Subjects whose serum creatinine level is 2 mg/dL or higher, or BUN is 30 mg/dL or
higher and who are suspected of having reduced renal function, subjects who have pre existing hypersensitivity, or subjects for whom the reliability of their self-evaluation ofsubjective symptoms is questionable, were eliminated. Intradermal test with 0.003 unitsof hPTH (1-34) was conducted with each person scheduled to participate in the clinical
trial. Subjects who presented a positive result with a diameter of erythematous area
exceeding 10 mm after 15 minutes were also excluded.
In order to avoid any mixture of the effects of other agents with the effects of hPTH
(1-34), the use of agents that are considered to have impact on bone turnover and theprogress of osteoporosis was withheld voluntarily for three months prior to the start ofthe clinical trial and the administration of these agents was also withheld during theclinical trial period. Such agents include estrogen, calcitonin, active vitamin D, Vitamin
K2, ipriflavone, bisphosphonate, and anabolic steroids.
Analgesics and muscle relaxants were administered when the physician in charge
found it to be necessary. Physical therapies and agents for complications continued to
be provided and administered without making any changes before and after the study
as long as the patient's symptoms allowed it.
115

Prior to the start, the importance of the clinical trial, including the characteristics
and possible adverse reactions of hPTH (1-34), was explained in detail to the persons
scheduled to participate in the clinical trial and the informed consent of the subjects
was obtained orally or in writing. This clinical trial was approved by the institutional
review board of each participating facility.
[Page 297, right column, line 43 through page 298, left column, line 24]
Preparation and administration method of hPTH (1-34) (teriparatide acetate)
The purity and biological effects of hPTH(1-34) synthesized by Asahi Chemical
Industry Co., Ltd. were assessed by using the generation of cyclic AMP of bovine PTH(1-84) by the cortical membrane of rat kidney, which is an international standard, andthe result was 3,300 units/mg. Each vial was determined to contain 50 units, 100 units,
and 200 units of teriparatide acetate. They correspond to approximately 15 μg, 30 μg,
and 60 μg of peptide, respectively. 3 lots were prepared from one batch, and vials
containing 50 units, 100 units, and 200 units were created. Based on the aforementioned
preparation, 5,000 vials containing one type of concentration were always preparedfrom one lot. Preparations were stable at 25°C for 3 years. The content of the vial wasmeasured with randomly extracted samples by a neutral institution. Controllers(physician [G] and physician [H]) confirmed that 3 vials were indistinguishable. The
content of the vial was dissolved with 1 mL of saline immediately before use andsubcutaneously injected once a week for 48 weeks.
102 sets of 50 units, 100 units, and 200 units of samples were prepared as controllers
for the clinical trial. They were assigned randomly within the set (numbers wereassigned, such as 1, 2, and 3), and then each set was sent to participating facilities on afirst-come-first-served basis. Each set was opened at each facility and sample numbers
1, 2, and 3 were administered to patients sequentially over time. In order to ensure thedouble-blind nature of the clinical trial, codes were locked and maintained until the endof the clinical trial.
According to the preliminary study results, when 100 units or 200 units of hPTH
(1-34) were administered once a week for 26 weeks, lumbar spine BMD increased. Then,the clinical trial period was set for 48 weeks. This period was considered to be the upper
limit where even if regular bone measurement and blood and urine sampling are
implemented with patients who always have a risk and concern of fractures, dropouts
will not be excessive and a multicenter test can be implemented under sufficient control.
[I] et al. also reported safety in the administration of 5 μg/kg of PTH (1-84) to humanbeings.
116

[Page 298, left column, line 25 through page 299, left column, line 9]
Accumulated data
Data before the start of the treatment: The following items were recorded: age, gender,
age of menopause, body height, body weight, experience of hospitalization or
ambulatory status, general medical record, intradermal test results of hPTH (1 -34)
antigenicity, score for osteoporosis diagnosis, pre-existing disease(s), treatment of
osteoporosis and complications of osteoporosis before the clinical trial, agents otherthan the test drug that were administered during the clinical trial period, nonprescription
calcium preparations and dairy products.
Subjective symptoms: Pain due to osteoporosis is classified into spontaneous pain atrest and pain on motion and evaluated in accordance with the following grades at the
0th week, 2nd week, 4th week, 12th week, 24th week, and 48th week after the start of
the treatment or at the end of the clinical trial. The pain at rest was shown as thefollowing grades: 1: No pain; 2: Moderate pain; 3: Pain that cannot be ignored but
acceptable; and 4: Serious and severe pain. The pain on motion was shown as thefollowing grades: 1: No pain; 2: Moderate pain; 3: Pain that hinders motion and cannot
be ignored; and 4: Serious disabling pain. Patients voluntarily evaluated degree of theirpain using an analog scale.
Bone findings: (a) Measurement of lumbar spine BMD: Bone mineral content, bone
area of lumbar spines (L2-L4), and BMD were measured using a DXA (QDA (Hologic),
DPX (Lunar), or XR (Norland)) by imaging anteroposteriorly at the 0th week, 12th
week, 24th week, and 48th week after the start of the treatment or at the end of theclinical trial. It was difficult to maintain appropriate accuracy management at many
participating facilities. Each facility measured BMD every day using a phantom on aroutine basis in accordance with the recommendation attached to the device. As a result,the coefficient of variation (CV) was maintained between 1% to 2.5%.
Since the age of patients was high, when anteroposteriorly measuring spine BMD,
degenerative changes of the spine was a major problem in addition to compression
fractures and changes in association thereto. Based on the aforementioned reasons, allsubjects who had degenerative changes of the spine, such as osteophyte in L2, L3, orL4, compression, deformation, etc., were eliminated from the data that serves as thebasis for efficacy of the test drug. For this reason, the dropout rate at spine BMD
measurement before enrollment was high.
117

(b) Measurement of metacarpal BMD: In order to implement radiogrammetry of thesecond metacarpal bone of a non-dominant hand, anteroposterior X-rays of the handwere taken along with a phantom at 0th week, 12th week, 24th week, and 48th week
after the start of the treatment or at the end of the clinical trial. At the end of the clinical
trial, all films taken at 71 facilities were measured at Toyo Kensa Center Co., Ltd. using
computerized digital image processing. Concerning the accuracy of digital image
processing when an observer measured metacarpal BMD (ΣGS/D) 10 consecutive times
using the same film, CV was 0.59. When the same process was conducted by 3 observers,
it was 1.47. If the hand of the same subject was filmed 4 times, measurement was
conducted separately and CV was 1.72.
(c) Assessment of vertebral fractures: X-ray films of lateral lumbar spines and thoracic
spines focused on L3 and T8 respectively, and one radiologist assessed compression
fractures and deformations of vertebral bodies. If the anterior border height/posteriorborder height ratio decreased by 25% or more and if the center height/posterior borderheight ratio decreased by 20% or more, it was defined as a significant deformation.
Biochemical parameters: Before the start of the treatment and the 2nd week, 4th week,
12th week, and 48th week after the start of the treatment or at the end of the clinical
trial, the following parameters were measured by the largest laboratory testing company
in Japan, SRL, Inc.: Calcium (Ca), phosphorus (P), 25(OH) vitamin D (measured bycompetitive protein binding analysis), 1.25(OH) 2 vitamin D (measured by radioreceptor assay), osteocalcin, intermediate PTH (measured by radio-receptor assay),total alkaline phosphatase and bone-specific alkaline phosphatase, and albumin inserum, and Ca, P, hydroxyproline, pyridinoline, deoxypyridinoline (measured byHPLC), and creatinine in urine. The following processes were conducted at each facility
at the 0th week, 12th week, 24th week, 36th week, and 48th week after the start of thetreatment or at the end of the clinical trial: cytometry (RBC, WBC and differential
hemocyte count, hematocrit, hemoglobin, and blood platelet), serum biochemical test
(GOT, GPT, A/G, BUN, creatinine, total cholesterol, CPK, Na, K, Cl, and glucose), andurine test (occult blood, protein, sugar, urobilinogen, bilirubin, and pH).
Investigation of adverse reactions and adverse events: Adverse events during theclinical trial period were recorded and examined in detail. Adverse events wereclassified into the following grades based on a comprehensive process assessment, theseverity, treatment, and outcome: (1) adverse event caused by the test drug; (2) adverse
event considered to be caused by the test drug; (3) adverse event for which it is difficult118

to consider that the test drug was the cause; and (4) adverse event for which the test
drug was not the cause. Adverse reactions are determined to include (1) through (3)tentatively.
Statistical analysis
Patient group backgrounds were assessed with a chi-square test with a risk rate of
10% for two-sided tests. Measured values were assayed with U test of [F] and exact testof [J] with a risk rate of 5% for two-sided tests.
[Page 299, left column, line 10 through page 300, left column, line 3]
Results
Table 1 is a summary of the details of the clinical trial enrollment criteria forsubjects who were permitted to participate in the clinical trial.
220 subjects who were originally registered to the clinical trial were assigned
randomly in a double-blind system [73 subjects were assigned to 50-unit group (L), 75
subjects to 100-unit group (M), and 72 subjects to 200-unit group (H)]. 41 subjects fromthem were determined to be non-conforming since they did not conform to the diagnosis
criteria of osteoporosis and the washout period of the drug that was administered before
the clinical trial was insufficient.
When subjects who have degenerative changes and compression changes of thelumbar spine that hinder accurate BMD measurement and patients who were measured
during non-specified times were eliminated, an additional 64 persons were non conforming. Therefore, the analysis of the effects on lumbar spine BMD was conductedwith 115 subjects. The details were 39 subjects in L group, 38 subjects in M group, and38 subjects in H group (Table 2). 61 subjects could not complete the study due to an
adverse reaction, rejection of the clinical trial due to a change of mind halfway through,worsening complications, etc. However, they were determined to be included in theanalysis group if they did not drop out within the first 3 months.
Characteristics of subjects at the start of the clinical trial were compared by thegroup in Table 3. It was confirmed that subjects were distributed evenly in all 3 groups.
[Page 300, left column, lines 4 through 10]
Subjective symptoms
Subjective symptoms mainly comprised of backache were moderately or slightly
improved for 21 subjects out of 52 (40%) in L group, 18 subjects out of 60 (30%) in M
group, and 17 subjects out of 47 (36%) in H group. There was no significant difference119between groups (Table 4).
[Page 300, left column, line 11 through right column, line 6]
Bone measurement
Changes in lumbar spine BMD for 48 weeks during the clinical trial period wereshown in FIG. 1. Lumbar spine BMD increased in a dose-dependent manner at the 24th
week and 48th week after the start of the treatment compared to the start of the clinical
trial, and changes were 0.6%, 3.6%, and 8.1% for L group, M group, and H group,
respectively. The degree of increase in M group and H group was larger than in L groupat the 24th week and 48th week and it was larger in H group than M group at the 48th
week (p<0.05). Responses to drugs were similar among subgroups of subjects who were
64 years or younger and 65 years or older, who weighed 49 kg or less and 50 kg or more,
for whom it was less than 10 years, between 10 years to 20 years, and more than 20
years after the postmenopause, and who had 0, 1 and 2 or more vertebral fractures.
There was no significant difference in the bone density of the second metacarpal bone(consisting of cortical bone) on X-ray film. It showed that cortical bone and the degreeof bone loss on X-ray film in each group did not change and was kept constant. Vertebral
fracture occurred in 3 subjects in L group, 5 subjects in M group, and 0 subjects in H
group; however, there was no significant difference between groups.
[Page 301, left column, line 1 through right column, line 4]
Biochemical parameters
As shown in FIG. 2, serum calcium started to decrease from the 2nd week after thestart of the treatment and it was significantly lower at the 4th week and after than thestandard value before the start of the treatment. Serum P also started to decrease at the
2nd week after the start of the treatment. Urine calcium started to decrease at the 2nd
week and it remained lower than the standard value throughout the clinical trial period.
Urine P also decreased. As shown in FIG. 3, serum 25(OH) vitamin D and 1.25(OH) 2
vitamin D levels slightly decreased in each group at the 48th week from the start of thetreatment. As shown in FIG. 4, bone-specific alkaline phosphatase was higher at the 4th
week after the start of the treatment than the level at the start of the treatment and it
was low only in H group at the 24th week and 48th week. As shown in FIG. 5, excretionsof pyridinoline, deoxypyridinoline, and hydroxyproline into urine decreased in L groupand H group at the 24th week and 48th week from the level at the start of the treatment.
As shown in FIG. 5, abnormal test results appeared in each group during the clinical
trial period; however, not all of them were obvious or were transient and it could not be120

defined that the test drug was the cause. Table 6 is a summary of adverse reactions that
occurred during the treatment. In 29 cases, subjects dropped out due to several
symptoms. The total number of adverse reactions increased in conjunction withincreases in the dose of hPTH (1-34); however, no serious adverse event was observed.
[Page 301, right column, line 5 through page 303, right column, line 23]
Consideration
In primary hyperparathyroidism, an excess amount of PTH is continuously secreted
and it is characterized by significant bone defect, in particular, the cortical bone defect;
however, based on the results of histomorphometry, the cancellous bone is wellpreserved comparatively. PTH probably stimulates both osteoblast activity andosteogenesis and may have an anabolic effect on bone.
In animal testing, the anabolic effect of PTH was often observed and it was reported
that it physically improves bone quality. Since the anabolic effect almost disappears
only by eliminating one amino acid from N terminal, it is considered to depend on the
full-length of amino acid at the N terminal.
It has been constantly reported that cancellous bone increases; however, theresponse of cortical bone was defective. Intermittent administration is considered to be
more effective in the bone anabolism of PTH. In the past, for the treatment of
osteoporosis, an antiresorptive agent, such as estrogen, calcitonin, bisphosphonate, etc.,
was mainly administered and osteogenesis promoters that stimulate bone resorption are
considered to be effective for low-turnover osteoporosis. Despite activity to induceincreases in BMD to an extent far exceeding expectations, fluoride has problems. In
other words, fluoride cannot reduce fracture incident, but causes adverse reactions, suchas bone pain, etc. However, PTH still has a great expectation as a candidate osteogenesis
promoter. If PTH is administered in high doses, increases in BMD were seen also inhuman beings; however, an intermittent administration method, which shows preferable
effects in human beings, is an unsolved problem. [K] et al. implemented a multicentertest with 12 patients with osteoporosis. It was reported that through intermittent
administration, wherein hPTH (1-34) was administered for 7 days and then withdrawn
for 21 days and this cycle was repeated 16 times, whole-body Ca slightly increased, but
no significant increase in BMD at various sites was observed. Daily administration isintermittent when compared to continuous infusion and a preferable impact wasobserved. According to [K] et al., when approximately 250 units of hPTH (1-34) wereadministered daily to 21 patients for 6 months to 24 months, no serious adverse reaction
was observed, while serum alkaline phosphatase increased by 15% and significant
121increases in bones were observed. [L] et al. conducted a 3-year randomized doubleblind controlled study, wherein 25 μg of hPTH (1-34) was subcutaneously injected daily
to 17 women after menopause who were receiving hormone replacement therapy, andthe results were compared with 17 other women to whom hormone replacement therapy
alone was provided as a control. Spine BMD increased by 13.0% in the PTH group;
however, no significant increase was observed in the control group. In other studies,
PTH was effective when it was administered with estrogen.
It is also considered to enhance the effects of PTH by using it in combination withvitamin D derivative. Actually, when 400 units to 500 units of hPTH (1 -34) wereadministered along with 0.25 μg of 1.25(OH)2 vitamin D3, an increase in cancellous
bone was observed. Administration in combination with calcitonin was also conducted.
[M] et al. administered 720 units to 750 units of hPTH (1-34) daily for 8 weeks and,simultaneously, intranasally administered calcitonin on the 2nd day to the 4th day, the
6th day to the 8th day, and the 8th day to the 10th day. This cycle was repeated 4 times.
[N] et al. repeated an administration cycle for 2 years, wherein 800 units of PTH wereadministered daily for one month with an interval of 2 months, and found that lumbar
spine BMD increased by 8% to 10%.
Biological activity per unit weight of hPTH (1-34) seems to have variety between
studies. In the study of [L] et al., for example, 400 units (25 μg) of hPTH (1-34) wereused. Since the preparation method used for the study is different, it is not easy tocompare the results of the clinical trial concerning the dose of hPTH (1 -34) with theresults of other studies. However, when they were compared with many past studies,
the weekly intermittent administration, which was used in the clinical trial, can clearly
reduce the total dose of hPTH (1-34). Since hPTH (1-34) dominantly increased lumbar
spine BMD (mainly consisting of cancellous bone) in a dose-dependent manner over a
relatively short period, such as 48 weeks, etc., without reducing bone density ofmetacarpal bone (consisting mostly of cortical bone), treatment of osteoporosis using
hPTH (1-34) is considered to be very promising.

122

Table 1 Details of enrollment criteria for participants in the clinical trial
Enrollment criteria

L group (50 units)

M group (100H group (200units)

units)

Decreases in bone density
Bone atrophy
Grade 1

31

26

18

Grade 2

19

29

26

Grade 3

21

19

27

Unknown

2

1

1≥0.8315

7

3<0.83117

14

18≥0.71125

17

11<0.711

15

23

27

Unknown

100≥0.7012

4

1<0.701

7

10

12

Unknown

1

0

0

0

32

30

29

1

14

18

15

≥2

27

26

28

Unknown

0

1

0

0

65

72

69

≥1

8

3

3

0

72

71

69

≥1

1

4

3

=<2

0

2

0

3

2

2

1

4

14

13

13

≥5

57

58

58

DXA
DPX

QDR

XR

Number of vertebral fractures

Number of femoral fractures

Number of distal radius
fracture

Total score

123

124

Table 2 Number of cases by endpoint in the clinical trial
Group

Total

Dropouts

Symptom

Lumbar spine

Metacarpal

number of(due to adverse

assessment

BMD

bone BMD

cases

reaction)assessment

assessment

L (50 units)73

12 (3)62

39

60

M (100 units)75

25 (10)

65

38

58

H (200 units)72

24 (16)

56

38

50

Total

220

61 (29)

183

115

168

Table 3 Comparison of backgrounds at the start of treatment by group
L group (50 units)

M

group

(100

units)
Age (years)
Body weight(kg)
Body height(cm)
Years elapsed
after menopause

H

group

(200

x2 testunits)

70.2±9.84 (73)70.1±9.64 (75)71.7±10.78 (72)NS47.7±7.49 (73)49.2±7.54 (75)45.8±8.21 (72)NS

148.2±8.01 (73)148.9±7.77 (75)147.3±6.97 (72)NS

19.0±8.52 (73)18.8±8.35 (75)20.6±9.43 (72)NS

1.86±2.65 (62)1.62±1.89 (61)1.82±2.65 (55)NS

Number ofvertebralfractures
Lumbar spine BMD (g/cm 2 )DPX

0.746±0.123 (13)0.753±0.089 (10)0.711±0.159 (11)

NS

QDR

0.719±0.103 (19)0.723±0.140 (17)0.640±0.132 (19)NS

XR

0.637±0.115 (7)0.680±0.130 (11)0.556±0.064 (8)NS

1.917±0.404 (58)1.850±0.446 (50)NS

Metacarpal BMD (ΣGS/D)

1.875±0.350 (60)

Data is mean value ± standard variation; figures in parentheses are the number of cases.

125

Table 4 Subjective symptoms
Group

Numberof cases

Moderate or
more
improvement

Mild
improvement

Unchanged

Worsening

Utest

's
test;
moderateor higher

L
group
(50

52

21 (40)16 (31)14 (27)1 (2)60

18 (30)28 (47)14 (23)0 (0)47

17 (36)21 (45)9 (19)0 (0)units)
M
group
(100

NS

NS

units)
H
group(200
units)

Changes (%) in BMD of lumbar 2 to lumbar 4

Units for the figures in parentheses are percentages.

Number of weeks

FIG. 1 Number of treatment weeks and change rate of lumbar spine BMD (mean ± standard
variation)□ refers to data of L group (50 units), ● refers to data of M group (100 units), and 〇 refers todata of H group (200 units).
Significant difference of p<0.005 in comparison with the value of a L group; significant differenceof p<0.005 in comparison with the value of bM group; by U-test of126.

* Significant increase with significant difference of p<0.05 in comparison with the start of thetreatment; by U-test of.

127Serum phosphorus(mg/dL)

Serum calcium (mg/dL)

200 units

200 units

100 units

100 units

50 units

50 units

Number of weeks

Number of weeks

FIG. 2 Number of weeks and serum calcium (left) and serum phosphorus (right) (mean ± standard
variation)□ refers to data of PTH 50 units (L group), ● refers to data of PTH 100 units (M group), and 〇refers to data of PTH 200 units (H group).
* Significant difference of p<0.05 in comparison with the start of the treatment; by U -test
of

.

128

200 units

200 units

100 units

100 units

50 units

50 units

Number of weeks

Number of weeks

FIG. 3 Number of weeks and 25(OH) vitamin D (left) and 1.25(OH) 2 vitamin D (right) in the blood(mean ± standard variation)
Symbols refer to the same as FIG. 2.

129

Bone-specific alkaline phosphatase (IU/L)

200 units

100 units

50 units

Number of weeks

FIG. 4 Number of weeks and bone-specific alkaline phosphatase (mean ± standard variation)
Symbols refer to the same as FIG. 2.

130

Table 5 Abnormal laboratory values of subjects during the treatment period
L group

M group

H group(50 units)(100 units)(200 units)

Total number of cases

73

75

72

Number of abnormal laboratory

8

4

12

(11%)

(5%)

(17%)

Number of abnormal data

16

7

22

Decreases in red blood cell count1

1

Increases in segmental karyosphere11Lymphopenia

1values (%)

2

Eosinopenia

1

Basopenia

1

Decreases in hematocrit

2

1

Decreases in hemoglobin

2

1

Decreases in platelet count1

Increases in GOT

1

Increases in GPT

1

Decreases in A/G

1

1

Increases in BUN

2

Increases in total cholesterol

2

1

2

Increases in CPK

1

2

2

Decreases in Na

2

Increases in K

2

Decreases in K

1

Increases in Cl

1

Decreases in Cl

1

Increases in blood glucose

1

Blood in urine

1

Urinary protein

1

Urinary bilirubin

1

131

2

Pyridinoline/creatinine

200 units

100 units

50 units

Number of weeks

Deoxypyridinoline/creatinine

200 units

100 units

50 units

Number of weeks

Hydroxyproline/creatinine

200 units

100 units

50 units

Number of weeks

FIG. 5 Number of weeks and pyridinoline (a), deoxypyridinoline (b), hydroxyproline (c), bloodbone-specific alkaline phosphatase in the urine (mean ± standard variation)
Symbols refer to the same as FIG. 2.

132

Table 6 Adverse reactions of subjects during the treatment period
L group (50 units)

M group (100 units)

H group (200 units)

73

75

72

Number of cases

14 (3 b)14 (10 b)

30 (16 b)

with

(19%)

(19%)

(42%)

Total number ofcases

development ofadversereactions a (%)
Severity andnumber of cases
Subcutaneous
hemorrhage

Mild

Moderate

Total

Mild

Moderate

Total

Mild

Moderate

Total

8

6

14

13

10

23

19

18

37

1

1

Whole-body

1

flush

1

Facial flush
Eczema1

1

Itching11

Lumber pain
Headache1
1

Dizziness
Retching

3

3

4

1

1

1

1

1

2

1

4

5

2

7

9

6

15

1

2

2

4

1

1

1

1

1

1
1

Yawning

1

1

1

1

Anorexia
1

1

1

Fever
Weakness
General malaise

2

1

1

Heat sensation

1

3

Belching

Dry mouth

1

2

1

2

1

1

Vomiting
Stomachache

1

1

1

2

1

1

1

1

3

3

1

1

1

1

1

1
1

1

1

Chill
Sleepiness1

a. Including abnormal laboratory values
b. Number of dropouts due to adverse reactions

133

1

2

3

1

1

134

(Attachment 3)
Exhibit Ko 64 (excluding cover page)<Outline>
Inhibitory effect on bone fractures was compared between patients satisfying conditions andpatients not satisfying conditions using the following data set* (Analysis [i] through Analysis [iii]).
Data analysis was outsourced to CMIC Co., Ltd.
■ Data set (*)- PTH group: Group of patients with primary osteoporosis with whom the following 3 conditions
can be judged and fracture inhibition rate can be calculated, in the post -marketing data for theapplication for re-examination of Teribone® (teriparatide (human PTH 1-34) acetate; dose andadministration of 200 units per week), which is the product of the invention in the application inquestion (1321 cases).
- Control group: Group of patients with primary osteoporosis with whom the following 3 conditions
can be judged and fracture inhibition rate can be calculated, in the data that integrated the placebogroup in clinical trials of our products (Teribone®, Elcitonin®) related to osteoporosis (365 cases).
■ Fractures subject to calculation of fracture incidence
Clinical fractures<Analysis [i]: Comparison of inhibitory effect on bone fractures in patients satisfying the three
conditions and patients not satisfying the three conditions>■ Data analysis date: September 1, 2018 to October 12, 2018
■ Grouping of patients in the data used for analysis
・Patients satisfying the three conditions
Patients who satisfy all of the following 1) through 3)
・Patients not satisfying the three conditions
Patients who satisfy 1) below, but do not satisfy at least one of 2 ) or 3)
3 conditions
1) Age 65 years or older
2) Prevalent bone fractures
3) Bone density less than 80% of the young adult mean
* Bone density was measured at the lumbar spine or femur (neck, proximal region).

135

* Degree of bone atrophy is not yet measured. However, if bone density is YAM 80% or more, thedegree of bone atrophy is usually considered to be less than 1. Therefore, condition 3) is deemed
to be equivalent to "Bone density less than 80% of the young adult mean and/or degree of bone
atrophy of 1 or higher."■ Analysis results(Table 1)
Cases

Cases ofevaluatedfractures (%)

PTH

825

40 (4.8)

Control304

41 (13.5)

PTH

496

18 (3.6)

Control

61

5 (8.2)Group
Patients
satisfying
the threep-valuep-value(x2)(Fisher)8.6

p<0.0001

p<0.0001

4.6

p=0.0906

p=0.0950

Difference*

conditions
Patients notsatisfying
the threeconditions
Fracture incidence was suppressed in the PTH group, even in patients not satisfying the three
conditions, more than the control group; however, fracture incidence was significantly suppressedin patients satisfying the three conditions in the PTH group more than the control group.
<Analysis [ii]: Comparison of inhibitory effect on bone fractures when PTH is administered for theperiod in excess of 48 weeks>■ Data analysis date: August 28, 2019 to October 4, 2019
■ Patients in the data used for analysis
・Patients satisfying the four conditions [i]Patients who satisfy all of the following 1) through 4) among the aforementioned data set (*)
・Patients not satisfying the four conditions [i]Patients who satisfy 1) and 4) below, but do not satisfy at least one of 2) or 3), in the
aforementioned data set (*).
4 conditions

1361) Age 65 years or older
2) Prevalent bone fractures
3) Bone density less than 80% of the young adult mean
4) Administration over a duration in excess of 48 weeks* Bone density was measured at the lumbar spine or femur (neck, proximal region).
* Degree of bone atrophy is not yet measured. However, if bone density is YAM 80% or more, thedegree of bone atrophy is usually considered to be less than 1. Therefore, condition 3) is deemed
to be equivalent to "Bone density less than 80% of the young adult mean and/or degree of bone
atrophy of 1 or higher."■ Analysis results(Table 2) Administration over a duration in excess of 48 weeks
Group
Patients

Cases of

Cases
evaluatedfracturesp-valuep-value(x2)(Fisher)6.3

p=0.0036

p=0.00493.8

p=0.2618

p=0.3370

Difference*

(%)

PTH

428

26 (6.1)

Control

266

33 (12.4)

PTH

261

13 (5.0)

Control

57

5 (8.8)satisfying
the fourconditions[i]Patients notsatisfying
the fourconditions[i]* Difference: Fracture rate (%) in the control group - Fracture rate (%) in the Teribone group
Fracture incidence was suppressed in the PTH group, even in patients not satisfying the four
conditions [i], more than the control group; however, fracture incidence was significantly
suppressed in patients satisfying the four conditions [i] in the PTH group more than the control
group.
<Analysis [iii]: Comparison of inhibitory effect on bone fractures when PTH is administered forthe period in excess of 72 weeks>137

■ Data analysis date: August 28, 2019 to October 4, 2019
■ Patients in the data used for analysis
・Patients satisfying the four conditions [ii]Patients who satisfy all of the following 1) through 5) among the aforementioned data set (*)
・Patients not satisfying the four conditions [ii]Patients who satisfy 1) and 5) below, but do not satisfy at least one of 2) or 3), in the
aforementioned data set (*).
4 conditions
1) Age 65 years or older
2) Prevalent bone fractures
3) Bone density than 80% of the young adult mean
5) Administration over a duration in excess of 72 weeks* Bone density was measured at the lumbar spine or femur (neck, proximal region).
* Degree of bone atrophy is not yet measured. However, if bone density is YAM 80% or more, thedegree of bone atrophy is usually considered to be less than 1. Therefore, condition 3) is dee med
to be equivalent to "Bone density less than 80% of the young adult mean and/or degree of bone
atrophy of 1 or higher."■ Analysis results(Table 3) Administration over a duration in excess of 72 weeks
Group
Patients

Cases of

Cases
evaluatedfracturesp-valuep-value(x2)(Fisher)7.8

p=0.0011

p=0.0017

2.3

p=0.5128

p=0.4554

Difference*

(%)

PTH

348

19 (5.5)

Control218

29 (13.3)

PTH

206

9 (4.4)Control45

3 (6.7)

satisfying
the fourconditions[ii]
Patients notsatisfying
the fourconditions

138

[ii]
* Difference: Fracture rate (%) in the control group - Fracture rate (%) in the Teribone group
Fracture incidence was suppressed in the PTH group, even in patients not satisfying the four
conditions [ii], more than the control group; however, fracture incidence was significantly
suppressed in patients satisfying the four conditions [ii] in the PTH group more than the control
group.

139

(Attachment 4)
Exhibit Ko 68 (excluding cover page)<Outline>
The following Analysis [i] to Analysis [iv] were conducted using the data set* that was used
for the analysis of laboratory performance certificate I (Exhibit Otsu 24) submitted as of January
29, 2021.
Data analysis was outsourced to CMIC Co., Ltd.
■ Data set (*)- PTH group: Group of patients with primary osteoporosis with whom the following 3 conditions
can be judged and fracture inhibition rate can be calculated, in the post-marketing data for theapplication for re-examination of Teribone® (teriparatide (human PTH 1-34) acetate; dose andadministration of 200 units per week), which is the product of the invention in the application inquestion (1321 cases).
- Control group: Group of patients with primary osteoporosis with whom the following 3 conditions
can be judged and fracture inhibition rate can be calculated, in the data that integrated the placebogroup in clinical trials of our products (Teribone®, Elcitonin®) related to osteoporosis (365 cases).
■ Fractures subject to calculation of fracture incidence
Clinical fracture■ Grouping of patients in the data used for analysis
・Patients satisfying the three conditions
Patients who satisfy all of the following 1) through 3)
・Patients not satisfying the three conditions
Patients who satisfy 1) below, but do not satisfy at least one of 2) or 3)
3 conditions
1) Age 65 years or older
2) Prevalent bone fractures
3) Bone density less than 80% of the young adult mean
* Bone density was measured at the lumbar spine or femur (neck, proximal region).
* Degree of bone atrophy is not yet measured. However, if bone density is YAM 80% or more, thedegree of bone atrophy is usually considered to be less than 1. Therefore, condition 3) is deemed
to be equivalent to "Bone density less than 80% of the young adult mean and/or degree of bone140

atrophy of 1 or higher."■ Data analysis date: October 26, 2020 to December 21, 2020
<Analysis [i]: Comparison of patient backgrounds before and after the revision of the Diagnostic
Criteria for Primary Osteoporosis (FY2012 revised version)>
Concerning the PTH group in the aforementioned data set (* above), patients who werediagnosed based on the Diagnostic Criteria for Primary Osteoporosis (FY2000 revised version) or
the Diagnostic criteria for Primary Osteoporosis (FY2012 revised version) were mixed. Then,
whether there were differences in the backgrounds of patients between both diagnostic c riteria wascompared.
The Diagnostic Criteria for Primary Osteoporosis (FY2012 revised version) were estimated tobe published on January 31, 2013. Therefore, patients who started administration of PTH before
January 31, 2013 are defined as patients diagnosed based on the FY2000 revised version and other
patients are defined as patients diagnosed based on the FY2012 revised version.
Analysis results are shown below; however, specific difference in the backgrounds of patients
between both diagnostic criteria was not observed.
(Table 1) Patient backgrounds by diagnosis criteria in Exhibit Otsu 24 Table 1

Age (mean value)
Prevalent

fracturesPatients diagnosed by thePatients diagnosed by the

FY2000 revised version

FY2012 revised version

78.8 years old

78.7 years old

75.3%

71.4%

64.4%

67.7%

(case

rate)
YAM value (mean value)

In addition, the same analysis was conducted for Table 2 and Table 3 in Exhibit Otsu 24 and thesame results were obtained.
(Table 2): Patient backgrounds by the diagnosis criteria in Exhibit Otsu 24 Table 2

Age (mean value)
Prevalent

fracturesPatients diagnosed by thePatients diagnosed by the

FY2000 revised version

FY2012 revised version

78.6 years old

78.3 years old

74.7%

70.8%

(case

rate)

141

YAM value (mean value)

64.5%

142

66.5%

(Table 3): Patient backgrounds by the diagnosis criteria in Exhibit Otsu 24 Table 3
Patients diagnosed by thePatients diagnosed by the

FY2000 revised version

FY2012 revised version

Age (mean value)
Prevalent

fractures

78.6 years old

78.3 years old

73.5%

74.8%

64.2%

66.6%

(case

rate)
YAM value (mean value)<Analysis [ii]: Comparison of satisfaction/non-satisfaction of the three conditions in patients who
were diagnosed by year 2000 revision>
All control groups in the aforementioned data set (* above) were patients diagnosed by the
FY2000 revised version. Concerning the PTH group, the inhibitory effect on bone fractures wascompared between patients satisfying the three conditions and patien ts not satisfying the three
conditions by limiting to patients who were diagnosed by the FY2000 revised version andconditions were arranged to be the same as the control group.
Fracture incidence of the PTH group and control group is shown below.
(Table 4): Fractures in patients who were diagnosed by the FY2000 revised version in Exhibit Otsu
24 Table 1
Group
Patients

PTH

satisfying theControl

three conditions
Patients not

PTH

satisfying theControl

three conditions

Cases

Cases ofevaluate

fractures

d

(%)
484

25 (5.2)

304

41 (13.5)

250

10 (4.0)61

5 (8.2)Difference

p-valuep-value*(x2)(Fisher)8.3

p<0.0001

p<0.00014.2

p=0.1702

p=0.1839

Fracture incidence was suppressed in the PTH group, even in patients not satisfying the three
conditions, more than the control group; however, fracture incidence was significantly suppressedin patients satisfying the three conditions in the PTH group more than the control group.

143

In addition, the same analysis was conducted for Table 2 and Table 3 in Exhibit Otsu 24 and thesame results were obtained.
(Table 5): Fractures in patients who were diagnosed by the FY2000 revised version in Exhibit Otsu
24 Table 2
Group
Patients

PTH

satisfying theControl

four

Cases of

Cases
evaluatedfracturesp-valuep-value2(x )(Fisher)5.7

p=0.0253

p=0.02753.3

p=0.3823

p=0.3589

Difference*

(%)

268

18 (6.7)

266

33 (12.4)

147

8 (5.4)57

5 (8.8)

conditions [i]Patients not

PTH

satisfying theControlfour
conditions [i](Table 6): Fractures in patients who were diagnosed by the FY2000 revised version in Exhibit Otsu
24 Table 3
Group
Patients

PTH

satisfying theControlfour conditions

Cases
evaluated

Cases offracturesp-valuep-value(x2)(Fisher)7.3

p=0.0094

p=0.01412.7

p=0.4619

p=0.4350

Difference*

(%)

218

13 (6.0)218

29 (13.3)

126

5 (4.0)45

3 (6.7)[ii]
Patients not

PTH

satisfying theControlfour conditions
[ii]

144

<Analysis [iii]: Mean administration period>
Mean administration period of each group in the aforementioned data set (*) is shown below.
(Table 7): Mean administration period of each group in Exhibit Otsu 24 Table 1
Mean administration

Group

period (week)

Patients satisfying the

PTH

46

three conditions

Control

69

Patients not satisfying

PTH

46

the three conditions

Control

70

In addition, the mean administration period of each group in Exhibit Otsu 24, Table 2 and Table
3 is shown below.
(Table 8): Mean administration period of each group in Exhibit Otsu 24 Table 2
Mean administration

Group

period (week)

Patients satisfying the

PTH

74

four conditions [i]Control

75

Patients not satisfying

PTH

73

the four conditions [i]Control

74(Table 9): Mean administration period of each group in Exhibit Otsu 24 Table 3
Mean administration

Group

period (week)

Patients satisfying the

PTH

77

four conditions [ii]Control

77

Patients not satisfying

PTH

77

the four conditions [ii]Control75<Analysis [iv]: Analysis excluding cases where administration was discontinued at an early stage>
Concerning the aforementioned data set (*), the inhibitory effect on fractures was compared
between patients satisfying the three conditions and patients not satisfying the three conditions,excluding cases where administration was discontinued at an early stage (cases where145administration was discontinued after less than 12 weeks or less than 24 weeks).
Fracture incidence of the PTH group and control group is shown below.
(Table 10) Excluding cases where administration was discontinued after less than 12 weeks
Group
Patients

PTH

satisfying theControl

three

Cases of

Cases
evaluatedfracturesp-valuep-value(x2)(Fisher)8.7

p<0.0001

p<0.00014.1

p=0.1706

p=0.1892

Difference*

(%)

626

30 (4.8)

297

40 (13.5)

391

17 (4.3)

59

5 (8.5)conditions
Patients not

PTH

satisfying theControlthree
conditions(Table 11) Excluding cases where administration was discontinued after less than 24 weeks
Group
Patients

PTH

satisfying theControl

three conditions
Patients not

PTH

satisfying theControl

three conditions

Cases
evaluated

Cases offracturesp-valuep-value(x2)(Fisher)8.0

p<0.0001

p<0.00013.7

p=0.2411

p=0.2203

Difference*

(%)

547

29 (5.3)

285

38 (13.3)

336

16 (4.8)59

5 (8.5)Fracture incidence was suppressed in the PTH group, even in patients not satisfying the three
conditions, more than the control group; however, fracture incidence was significantly suppressedin patients satisfying the three conditions in the PTH group more than the control group.
In addition, mean administration period of each group in Table 10 and Table 11 is shown below.

146

(Table 12): Mean administration period of each group in Table 10
Mean administration

Group

period (week)

Patients satisfying the

PTH

69

three conditions

Control

70

Patients not satisfying

PTH

58

the three conditions

Control

72(Table 13): Mean administration period of each group in Table 11
Mean administration

Group

period (week)

Patients satisfying the

PTH

65

three conditions

Control

72

Patients not satisfying

PTH

64

the three conditions

Control

72

147