Transcript Enablement

Experimental Data –
Biological Pharmaceuticals
/JP
Takashi FUJITA
Hiraki & Associates
HIRAKI & ASSOCIATES
Experimental Data

Why experimental data is required?
-To meet Enablement requirements/Industrial Applicability
-To meet Support requirements
-To show Inventive Step: superior effects

Note:
- Pharmaceutical use claims/Pharmaceutical composition claims:
Pharmacological data is required. (Examination guidelines: medicinal
inventions)
- Composition claims comprising too many species lack utility.
Pharmacological Test
Enablement
Examination Guideline (Medicine)
(Enablement/Pharmacological test)

(1) Description of the Result of the Pharmacological Test

Since results of pharmacological tests are to confirm the pharmacological
effect of the claimed medicinal invention, the following should be made
sufficiently clear:
 (i) which compound,
 (ii) is applied to what sort of pharmacological test system,
 (iii) what result is obtained, and
 (iv) what is the relationship between the pharmacological test system and
the medicinal use of the claimed medicinal invention.

Note that results of pharmacological tests should be described with numerical
data. When results cannot be described with numerical data due to the nature
of the pharmacological test system, an acceptable objective description
equivalent to numerical data may be provided, for example, a description of
objective observation results by a doctor is acceptable. The Guideline lists the
following as pharmacological test systems that can be employed: clinical tests,
animal experiments, and in-vitro tests.
Examination Guideline (Medicine)
(Enablements/Pharmacological test)




(2) Example of a Case where Reasons for Refusal are Notified
(a) Where the result of the pharmacological test is not
described
Generally, since it is difficult to predict whether a compound can
actually be used for a specific medicinal use from only the name and
chemical structure of the compound, it remains difficult for a person
skilled in the art to predict whether the compound can actually be
used for the specific medicinal use where an effective quantity,
dosing method, and formulation method are described in the
detailed description, but results of a pharmacological test are not
described. Accordingly, in such a case, in principle, reasons for
refusal are notified.
Note that the reasons for refusal will not be overcome by later
submission of the results of the pharmacological test.
Enablement
(Tokyo High Court 1996 (Gyoke) No. 201 (10 Oct 1998)
(Ginko)
Claims: Medicament against nausea or emesis comprising
pharmacological ginger roots (Rhizoma Zingiberis) and
bilobed and half-folded dried ginkgo (Extr.Ginkgo bilobae
e fol.sicc.)
Specification:
It is described that the medicament is effective against sea
sickness, nausea during pregnancy, and migraine.
It is also disclosed that one dosage of the powdered
medicine may contain 500mg ginger roots and 30mmg
bilobed and half-folded dried ginko, and this is to be
taken three times a day.
Enablement
(Tokyo High Court 1996 (Gyo ke) No. 201 (10 Oct. 1998)
(Ginko)
Tokyo High Court:
(1) In the specification, given its character as a technical publication,
there is a requirement that the purpose, construction and particular
effect is to be specifically described to an extent sufficient for a
skilled person to easily carry out the invention (Art 36 (3)). Thus, in a
use invention concerning a pharmaceutical, since it is generally
difficult to predict its efficacy from only the name of the substance
and the chemical formula, even where the effective amount, method
of administration and formulation thereof has been described to
some extent in the specification, it is not possible for a skilled person
with only this information to know whether the pharmaceutical has
efficacy in respect of this use or not. Consequently, it is necessary
to provide support for the efficacy of this use with a description in the
specification of pharmacological data or equivalent. Detailed
descriptions of the invention which do not contain such descriptions
must be said to contravene Article 36(3) of the Patent Law.
 DE3626128, FR2602144
Enablement
Tokyo High Court 2001 (Gyoke) 99
(Equivalent to pharmacological test)

Claim: Dietary supplement for treatment of an individual exhibiting
insulin-resistance, or prevention of a clinical symptom in an
individual predisposed to the development of a clinical symptom of
insulin-resistant diabetes, comprising D-chiro-inositol in an amount
sufficient to provide a treatment level to the individual exhibiting
insulin-resistance…
Tokyo High Court:
“Equivalent to pharmacological test data” means a description that
enables a person in the art to understand what pharmacological
effect is provided by the chemical compound allegedly having a
medicinal use, and how to use the compound to produce the
desired pharmacological effect.
A person skilled in the art may utilize the general common
knowledge in the art at the time of filing to understand the
specification.
Enablement
Tokyo High Court 2001 (Gyoke) 99
(Equivalent to pharmacological test)

Specification: (Type II diabetes and inability of synthesis of DCI)
(1)
(1) As disclosed in co-pending U.S. Patent application ----, successful
purification, to essential homogeneity, of at least two substances appearing
to mediate the activity of insulin, particularly in terms of activation of PDH
and the inhibition of other enzyme systems,
(2) Structural analysis of the insulin mediator possessing the biological
activity of activating (PDH) has identified this mediator to be comprised of -D-chiro-inositol.
(3) Further research as disclosed in U.S. Patent application --, inventors --have demonstrated that D-chiro-inositol is either absent, or present in
extremely low levels, in type II, insulin-resistant diabetics, in contrast to the
levels observed in non-diabetic control individuals.
(4) Further research has indicated that insulin-resistant diabetes may in fact
be due to a genetic inability to synthesize, in vivo, D-chiro-inositol, an
essential carbohydrate of the insulin mediator responsible for activation of
PDH.
(5) This inability prevents the formation of an insulin mediator responsible
for the activation of PDH. Thus, individuals exhibiting diabetic symptoms as
a result of this deficiency, will not respond to treatment with insulin.
Exhibit 4-8 relating to insulin mediator. (To show common general knowledge)
(2)
(3)
(4)
(5)

Enablement
Tokyo High Court 2001 (Gyoke) 99
(Equivalent to pharmacological test)
Tokyo High Court:
- In points (1)-(3) above, there is no concrete description on isolation
method or details of analysis results regarding insulin mediator, and
as to point (4), there is no data supporting the hypothesis.
-
- Earlier US application may not be relied on because they are not
laid open to the public at the time of filing.
-
- Exhibit 4-8 does not indicate the insulin mediator has PHD
activation ability.
- Thus, a person in the art may not be able to scientifically
understand how DCI produces therapeutic or preventive effects
against diabetes.
Enablement
Tokyo High Court 2001 (Gyoke) 99
(Equivalent to pharmacological test)
Specification (administration of DCI and solving the
problem of lack of synthesis of DCI):
(1) D-chiro-inositol, related to myoinositol, is available from nondietary sources, in forms not readily assimilated by the body.
The methylester of D-chiro-inositol (DCI) is found---in pines,
and legumes. --But the assimilable sugar itself does not
appear, in sufficient quantities, in normal dietary foods, to
make up for a lack of the ability to synthesize the sugar.
(2) When administered as a vitamin, in appropriate therapeutic
amounts, the carbohydrate is absorbed directly through the
lining of the gastrointestinal system, and available for
utilization in the preparation of the insulin mediator.
Enablement
Tokyo High Court 2001 (Gyoke) 99
(Equivalent to pharmacological test)
Tokyo High Court:
- Regarding points (1)-(2), there is no experimental data.

- Exhibits 9 and 10 indicate myo-inositol and DCI show
different activity because a diabetic’s urine contains more
myo-inositol than a non-diabetic’s.

- Exhibit 11-12 is a rapid communication or research report
and is thus not considered as reflecting general common
knowledge as of filing.

- Later filed experimental data
IP High Court 2006 (Gyoke) 10442
Stimulation of fertility
Decided on June 28, 2007 (EP0751782B1)


Claim 1:
An agent for stimulating fertility in mammals by
reducing glycoprotein hormone activity having
luteinizing hormone activity in circulation and
thereby stimulating the production of follicle
stimulating hormone characterized in that
administration to mammals of a non-neutralizing
antibody reduces biological activity of luteinizing
hormone.
IP High Court 2006 (Gyoke) 10442
Stimulation of fertility
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
Description 1:
For example, B105 would reduce the effective
hLH levels by a factor of approximately 4
whereas B110 will reduce the effective hLH
levels by a factor of approximately 2. Reducing
LH levels will permit FSH levels to rise. As FSH
levels rise, they will cause follicular development
and the production of estrogens. When these
levels have reached the physiological
concentrations characteristic of appropriate
follicle development, they will negatively inhibit
the secretion of more FSH.
IP High Court 2006 (Gyoke) 10442
Stimulation of fertility
IP High Court:
 The terms “by a factor of approximately 4”
or “by a factor of approximately 2” found in
Description 1 are not considered to be
pharmacological data obtained through
some experiment in view of nature of the
numeric.

IP High Court 2006 (Gyoke) 10442
Stimulation of fertility
Description 2:
 (Example1)
 Administration of 10g-10 mg of high
affinity antibody (i. e., Ka > 5 x 107M-1)
will be sufficient to induce fertility in
women having polycystic ovarian disease.

IP High Court 2006 (Gyoke) 10442
Stimulation of fertility


IP High Court:
The above description describes that use of a
certain amount (10g-10 mg) of high affinity
antibody (i. e., Ka > 5 x 107M-1) actually causes
stimulation of fertility, but the enhancement is
not quantitatively disclosed, and the subject of
administration is limited to a patient having
polycystic ovarian disease, among mammals
recited in claim 1.
IP High Court 2006 (Gyoke) 10442
Stimulation of fertility

Description 3:

( Example 4)
Administration of 10 yg-10 mg of a non-neutralizing antibody to LH
that causes a transient and self-limiting rise in FSH secretion will
induce ovulation with less risk of hyper-stimulation than treatment
with gonadotropin. The effect is transient because the antibody will
be metabolized or otherwise cleared from the circulation and its
effectiveness will be lost within 1-2 weeks after administration.

The treatment is self-limiting because the negative feedback effect
of estradiol on FSH secretion will not be eliminated. Thus, as FSH
levels rise and stimulate follicle development, estradiol secretion will
rise and inhibit further increases in FSH secretion.
IP High Court 2006 (Gyoke) 10442
Stimulation of fertility
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
IP High Court:
Above description (3) mentions administration
amount quantitatively, but does not mention its
effect quantitatively, namely, to what extent the
danger is reduced and to what extent ovulation
is induced quantitatively. Furthermore, the
specific binding agent (a non-neutralizing
antibody) to be used is not concretely described.
IP High Court 2006 (Gyoke) 10442
Stimulation of fertility

Thus, the above descriptions (1)-(3) are not
considered to disclose concrete data showing
what amount of administration of specific binding
agent reducing LH activity would provide what
extent of reduction of LH activity, and thus what
level of stimulation of fertility would be obtained
thereby.

Thus, the instant description does not enable a
person in the art to work claim 1, which is not
limited by the animal (subject) in which fertility is
to be stimulated.
Pharmacological Test
Support requirements
Examination Guideline Medicine
Support Requirements
Typical examples of violation (1)

An antiemetic drug having an active
ingredient A is claimed, but neither the
pharmacological test method nor
pharmacological data are described in the
detailed description of the invention.
Furthermore, it would not be possible to
presume that the ingredient A was
effective as an antiemetic drug in the light
of the common general technical
knowledge as of the filing.

Examination Guideline Medicine
Support Requirements
Typical examples of violation (2)
Therapeutic agents for a specified purpose
whose active ingredients are compounds
defined by desired properties are
comprehensibly claimed, but usefulness as
therapeutic agents for the specified purpose can
only be verified from the detailed description of
the invention in respect of only a small fraction of
the compounds included in the claim. A person
skilled in the art could not generally presume the
usefulness as therapeutic agents of chemical
substances included in the claim in the light of
the common general technical knowledge as of
the filing .
Support Requirements
IP High Court 2009 (Gyoke)10033
flibanserin

The Board found that the instant specification does not
contain any pharmacological data supporting the efficacy
of flibanserin as a medicament for treatment of disorders
of sexual desire. Furthermore, the board found that the
descriptions in the detailed description could not be
deemed equivalent to pharmacological data. Therefore,
the detailed description of the invention does not include
any pharmacological data or equivalent, and thus it fails
to meet the requirement set forth in section 36(6)1.
Support Requirements
IP High Court 2009 (Gyoke)10033
flibanserin


IP High Court:
When interpreting the detailed description of the
invention to assess support requirements by
comparing the breadth of claims with detailed
description, it would be sufficient to understand
formally the technical matters described and
disclosed through examples and the like in the
detailed description. In the absence of
extraordinary circumstances, it cannot be said
that a description of pharmacological data or its
equivalent is an indispensable requirement.
Enablement
From Examination Guideline (Enablement)
(Rejection under Enablement Requirements)

Against the notice of reason for refusal, an
applicant may argue or clarify by putting forth
written arguments or experimental results, etc.
Where the applicant's argument is confirmed to
be adequate by examining the submitted
evidence, the reason for refusal shall be
deemed overcome.

However, it must be noted that the evidence,
etc. that has been submitted later cannot be
used to assert matters not described in the
specification.
Examination Guideline (Specification)
(Enablement)

In a technical field where it is difficult to predict
the structure of a product from the function or
characteristic of the product (e.g. chemical
substances), the detailed description of the
invention will be in violation of the enablement
requirement if a person skilled in the art cannot
understand how to make products defined by
the function or characteristic, other than those
for which there is a concrete description of the
manufacturing method (or those which can be
made from these products taking into
consideration common general knowledge)
Examination Guideline (Biology)
(Enablement, how to use)

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
Where genes are claimed in a generic form and
the function is not specified in the
claim (genes specified only by "substituted,
deleted or added," "hybridized" or "having more
than X% identity," etc.), the claim will include
genes which do not have the stated function and
a fraction of the claimed genes will not be able to
be used. Therefore, the invention is not
described in manner enabling a
person skilled in the art to use the product.
TOKYO HIGH COURT 1998 (Gyoke) No. 95
Enablement (22 Feb. 2000)

Claim 1

A part of a mammal T-cell antigen receptor beta subunit which is an
isolated polypeptide or peptide consisting of at least 8 amino acids,
wherein said T-cell receptor beta subunit is characterized by:
(i) being expressed by T-cell specific mRNA,
(ii) being coded by a nucleic acid subject to T cell specific
rearrangement, and
(iii) being coded by a nucleic acid that hybridize with a probe
consisting of a sequence shown below or its complimentary
sequence.
[Formula 1]

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
TOKYO HIGH COURT 1998 (Gyoke) No. 95
Enablement (22 Feb. 2000)

Detailed Description:

- A library of 5000 selected clones was screened and
rescreened by standard procedures-- using the
membrane-bound T-helper cell cDNA probes from the Thybridoma 2B4 from which sequences common to B-cell
messenger from the B-cell L10A had been subtracted
(MBT2B4-BL10A). Thirty-five definite positives resulted-fell into one of the 10 distinct patterns of mRNA size and
expression shown in the following Table.
TOKYO HIGH COURT 1998 (Gyoke) No. 95
Enablement (22 Feb. 2000)

Detailed Description:

- In order to obtain other cDNA clones which arose
independently in different T-lymphocytes, a thymocyte
cDNA library was prepared------ Three thymus-derived clones were obtained
designated 86T1, 86T3 and 86T5. A partial restriction
map is shown in Figure 1.

TOKYO HIGH COURT 1998 (Gyoke) No. 95
Enablement (22 Feb. 2000)

Detailed Description:

- In conclusion, the structure of 86T1 is that of a 19
amino acid leader polypeptide, a 98 amino acid variable
region, a 16 amino acid J region and a single globular
constant region domain followed by transmembrane and
cytoplasmic portions. By analogy to immunoglobulins,
the two outermost cysteines in each globular domain
would be linked and the last cysteine at position 260
would be bound to the other chain of the receptor
heterodimer.
.
TOKYO HIGH COURT 1998 (Gyoke) No. 95
Enablement (22 Feb. 2000)

Detailed Description:

- It was further found that antisera raised against
synthetic peptide fragments of 86T1 can significantly
inhibit the antigen-dependent release of IL-2 by T-helper
hybridomas. It is therefore concluded that the locus
described above represents a type of immunoglobulin
gene specifically rearranged and expressed in at least
some subsets of T-lymphocytes and that it plays a role in
the recognition of antigen by T-cells
TOKYO HIGH COURT 1998 (Gyoke) No. 95
Enablement (22 Feb. 2000)
Tokyo High Court:
As described above, the present invention relates to a chemical
substance being a “peptide or polypeptide”. Further, as each of
the peptides encompassed in claim 1 are independent chemical
substance inventions, and since the essence of a chemical
substance invention is the creation of a useful chemical
substance, it is a requirement that all of the numerous peptides
to which the application relates, be useful.


Therefore, regarding utility, for the present application to fulfill
the requirement of Art 36(3) of the patent law, the utility of all the
peptides encompassed in the scope of the claim must either be
described in the specification, or clear to a skilled person from
common technical knowledge.
TOKYO HIGH COURT 1998 (Gyoke) No. 95
Enablement (22 Feb. 2000)


Consequently, cases where the present application
would contravene Article 36(3) of the Patent Law are
cases (1) where it cannot be said that the utility of all of
the peptides etc., within the scope of the claims are
described in the specification; nor that this utility would
be clear to a skilled person on the basis of common
technical knowledge; and (2) where there is no
description in the specification allowing a skilled person
to easily select from among the peptides, etc. included
in the scope of the claims, only those having utility.
(EP174366, EP0570027)
2008 (Gyoke) 10274
Decided on September 2, 2009
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Claim 1
A polypeptide comprising a sequence of at least 8 consecutive
amino acids, and having following characteristics:
(1) the said sequence of at least 8 consecutive amino acids contains
a part wherein the said part in the said sequence of at least 8
consecutive amino acids or in the said polypeptide (a) can combine
with antibody against HCV, and
(2) the said sequence of at least 8 consecutive amino acids is
obtained from a sequence having one or several deletions,
insertions or substitutions to the following amino acid sequence
(Omitted: an amino acid sequence of 1-2436 ), provided that the
polypeptide does not contain a sequence of at least 8 consecutive
amino acids obtained from the following amino acid sequence
(Omitted: same amino acid sequence of 1-2436 as above )
2008 (Gyoke) 10274
Decided on September 2, 2009



Court:
- Indeed in the field of biotechnology，there are cases where it is
allowed that a claim may be written to include a sequence having
one or several deletions, insertions, or substitutions to a specifically
recited sequence.
- In technical fields relating to a novel gene having a useful activity,
from the viewpoint of promoting invention, and the viewpoint of
preventing the imitation by third parties and inability to preserve a
monopoly that would result from not allowing such claims, there
should be cases where a claim may be written to include a
sequence having one or several deletions, insertions, or
substitutions to a specifically recited sequence.
2008 (Gyoke) 10274
Decided on September 2, 2009



Court:
- In other words, regarding a case where an amino acid sequence
constituting a novel polypetide having a useful activity may be
generically described in a claim (in a way allowing a variation in a
part of the sequence), it may be considered that enablement
requirement is met when it is considered that a modified polypetide
having same active as original polypetide may be easily obtained.
- However, the enablement requirement is not met when it would
require excessive trial-and-error or an innovation beyond that which
can be expected from person skilled in the art.
2008 (Gyoke) 10274
Decided on September 2, 2009


Court:
In the instant case, the claimed polypetide of the present
invention has an amino acid sequence of "at least 8
amino acids", and includes those having one or several
deletions, insertions, or substitutions in the sequence,
but the description of the application does not disclose a
mode to obtain modified polypetides, based on the
polypeptide defined with such a small number of amino
acids, that have a similar activity as the polypetide so as
to enable a person in the art to easily carry out the
invention.
Reference for 2008 (Gyoke) 10274
Decided on September 2, 2009


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
Granted Claim 1 of parent application :
A polypeptide comprising a sequence of at least 8 consecutive
amino acids, and having following characteristics:
(1) the said sequence of at least 8 consecutive amino acids contains
a part wherein the said part in the said sequence of at least 8
consecutive amino acids or in the said polypeptide (a) can combine
with antibody against HCV, and (b) does not combine with antibody
against other Flavi virus, and
(2) the said sequence of at least 8 consecutive amino acids is
obtained from the following amino acid sequence (Omitted: an
amino acid sequence of 1-2436)
Inventive Step
From Examination Guideline (Inventive Step)
(Effects to be considered, asserted in a written argument)


Where advantageous effects compared to cited
inventions are described in a specification, or where
advantageous effects are not explicitly described but can
be inferred from the statements in the specification or the
drawings by a person skilled in the art, effects asserted
or verified (e.g., experimental results) in a written
argument, etc. should be considered.
However, effects asserted in a written argument, which
are not described in the specification and that a person
skilled in the art couldn’t deduce from the description of
the specification or the drawings, should not be taken
into consideration
Soluble TNF-R
2007 (Gyoke) 10105
Claim 1
 Multimer of soluble TNF-R having
capability of blocking the binding of TNF to
its receptor and preventing function of
TNF-R or its salt, wherein the multimer
consists of TBP-I, or mixture of TBP-I and
TBP-II.

Soluble TNF-R (Yeda)
2007 (Gyoke) 10105
Applicant:
 Inventors discovered:
 (1) aggregation of TNF-R is essential for
activation of its function,
 (2) involvement of non-functional TNF-R in
the aggregation efficiently blocks the
function of TNF.

Soluble TNF-R (Yeda)
2007 (Gyoke) 10105

Prior art:

- D1 discloses multimer of soluble TNF-R comprising
TBP-II. D1 also mentions that soluble TNF-R may be
administrated to prevent TNF dependent reaction.

- D5 discloses TBP-I protect cells against TNF’s cell
damaging activity, and made it clear that TBP-I
specifically binds to TNF, and blocks its function.
Soluble TNF-R
2007 (Gyoke) 10105




Applicant argued that the inventors discovered
that:
(1) aggregation of TNF-R1 is essential for
activation of its function,
(2) involvement of non-functional TNF-R1 in the
aggregation efficiently block the function of TNF.
Claimed inventions are based on (2) above.
Soluble TNF-R
2007 (Gyoke) 10105

Applicant:

- Exhibit 18 (later published document) shows that fusion
protein of Ig and dimer of TBP-I(TNF-R1) completely
neutralizes the function of TNF-alpha, while a fusion
protein of Ig and dimer of TBP-II(TNF-R2) cannot.

- D1 discloses binding of TBP-II to TNF, but does not
mention the maintenance of binding capability as a
monomer nor mentions capability to bind as a multimer.
Soluble TNF-R
2007 (Gyoke) 10105

Court:

- Both TBP-I and TBP-II had been known as
having a ability to protect against TNF having an
ability to damage cells before priority date.

- Thus, it would be obvious to a person in the art
to extend knowledge of TBP-II to TBP-I.
Soluble TNF-R
2007 (Gyoke) 10105

Court:

- Exhibit 18 was published after thus priority date, and
thus cannot be considered.

- Furthermore, it does not deny the function of fusion
protein comprising TNF-R1(TBP-I).

- The present specification does not contain any
experimental data supporting the effect of claim 1.