Enablement in
pharmaceutical claims was central in this Examination appeal. The main request contained the following claims:
1. A pharmaceutical
composition comprising a DNA methylation inhibitor; and an anti-neoplastic agent (...)
20. A combination of a DNA methylation inhibitor and an anti-neoplastic agent (...), for use in a method of treating a disease associated with abnormal cell proliferation.
22. Use of a DNA methylation
inhibitor for the preparation of a pharmaceutical composition for treatment of a disease associated with abnormal cell proliferation (...)
36. A kit for treating a
disease associated with abnormal cell proliferation, comprising (...)
Based on a cited document the Examining division had concluded that it is unlikely that the combination of drugs had a synergistic effect. As the application did not detail how the combination provided an improvement, the application was refused under Art. 83 EPC and Rule 42(1)(e) EPC (Enablement).
The board did not agree with this application of enablement. The board's decision discusses the requirements for enablement for each of the claim categories. The following catchword was provided:
For the purposes of Article 83 EPC, the level of disclosure in the
application which is required for claims directed to pharmaceutical
compositions or kits is not the same as that which is required for
medical-use claims. For claims directed to pharmaceutical compositions
or kits it is in principle sufficient that the application provides
information which allows the skilled person to produce the composition
or kit, and that there are no substantiated doubts that it could indeed
be used in therapy. For second-medical-use claims on the other hand it
is required not only that the composition itself is disclosed in an
enabling way but also that its suitability for the claimed treatment is
plausibly disclosed in the application (Reasons 6).
In the case of a claim directed to a pharmaceutical
composition comprising two classes of compounds which have both already
been used in therapy in the prior art, there is a priori no reason to
doubt that such a pharmaceutical composition can be produced; no
specific functional effect has to be demonstrated (Reasons 6.1.1 and
6.1.2).
In the case of second-medical-use claims, if the claimed
therapeutic effect was already known to the skilled person at the
priority date, it is not necessary to demonstrate it in the application
(Reasons 6.2.2).
This decision is also discussed on
PatLit.
Reasons for the Decision
2. The examining division objected to the description as not meeting the requirements of Article 83 and Rule 42(1)(e) EPC.
3.
Rule 42(1)(e) EPC states that "the description shall describe in detail
at least one way of carrying out the invention claimed, using examples
where appropriate and referring to the drawings, if any".
Article
83 EPC states that the patent application shall disclose the invention
in a manner sufficiently clear and complete for it to be carried out by a
person skilled in the art. In other words, the teaching of the
application as a whole must enable the skilled person to carry out,
without undue burden, the invention which is defined in the claims.
4.
In its decision, the examining division referred to the subject-matter
not of the claims but of the description. For the purposes of Article 83
EPC as well as of Rule 42(1)(e) EPC, it is the invention, as defined by
the claims, which has to be disclosed in the application in an enabling
and detailed way. Examination of whether the description, as part of
the application, provides such enablement and detail has thus to be done
vis-Ã -vis the claimed subject-matter.
5. The present main request
comprises product claims directed to pharmaceutical compositions
(claims 1 to 19), as well as claims directed to medical uses, in the
format of either purpose-restricted product claims (claims 20 and 21,
and dependent claims) or Swiss-type medical-use claims (claims 22 and
23, and dependent claims), and product claims directed to kits (claims
36 to 39).
6.
Clearly the level of disclosure which is required
for these different categories of claims is not the same. For example,
for claims directed to pharmaceutical compositions or kits - which are
product claims, not restricted to any specific therapeutic effect - it
is in principle sufficient that the application provides information
which allows the skilled person to produce the composition or kit, and
that there are no substantiated doubts that it could indeed be used in
therapy. For second medical-use claims on the other hand it is required
not only that the composition itself is disclosed in an enabling way but
also that its suitability for the claimed treatment is plausibly
disclosed in the application.
6.1 Independent claim 1: Pharmaceutical compositions
6.1.1
Claim 1 is directed to a pharmaceutical composition comprising a DNA
methylation inhibitor and an anti-neoplastic agent, wherein the
anti-neoplastic agent is further defined by a functional feature, namely
that its activity is adversely affected by aberrant DNA methylation. As
an example of DNA methylation inhibitors, cytidine analogs are
mentioned and specifically decitabine (e.g. application page 7, lines 9
to 12), a compound whose use in therapy had already been disclosed in
the prior art (e.g. Schwartsmann G. et al., Investigational New Drugs
18: 83-91, 2000, cited in the European search report). The application
also provides a long list of available anti-neoplastic agents (page 1,
line 15 to page 6, line 21), and further indicates which anti-neoplastic
agents are part of the embodiments of the invention (page 7, line 13 to
page 9, line 8); examples of combinations comprising specific groups of
anti-neoplastic agents are also disclosed on page 17, line 26 to page
29, line 28.
There is no reason to doubt that such products could be
formulated as pharmaceutical compositions, since they were indeed
individually available in the prior art as such and had also been used
in combination (Schwartsmann et al., supra). The board thus considers
that the application as filed, and in particular the description,
contains sufficient information to enable the skilled person to produce
the pharmaceutical compositions as claimed.
6.1.2 The arguments of
the examining division were based on an alleged lack of evidence in the
application showing that the technical problem as stated in the
application - synergistic improvement of the effectiveness of
anti-neoplastic agents - had indeed been solved, especially in view of
all possible anti-neoplastic agents encompassed in the claims. Since
enablement of claims conferring absolute protection for products does
not require that any specific functional effect be demonstrated, but
rather that the product can be produced, this argument fails. The board
agrees that claim 1 has very broad limits, but these are well defined
and the skilled person would know without undue burden which compounds
were encompassed and which were not: all that is required is to test
whether or not the anti-neoplastic activity of the anti-neoplastic agent
is indeed impaired by aberrant DNA methylation (a phenomenon which is
explained in the application e.g. at pages 12 and 13). The examining
division has not provided any arguments, let alone substantiated by
facts, that such testing would not be possible without undue burden.
6.2 Independent claims 20 to 23: Medical uses
6.2.1
Claims 20 to 23 are directed to medical uses of combinations of a DNA
methylation inhibitor and an anti-neoplastic agent, wherein the medical
use is for treating a disease associated with abnormal cell
proliferation.
By definition, attaining the claimed therapeutic effect
is a functional technical feature of claims directed to medical uses. As
a consequence, under Article 83 EPC, unless this is already known to
the skilled person at the priority date, the application must disclose
the suitability of the product to be manufactured for the claimed
therapeutic application (T 609/02, reasons 9).
6.2.2 As stated
above, the therapeutic application as claimed is treatment of a disease
associated with abnormal cell proliferation. Undisputedly,
anti-neoplastic agents are, by definition, used to treat cancer, which
is an example of a disorder associated with abnormal cell proliferation,
and aim, either directly or indirectly and via different mechanisms, at
controlling such abnormal cell proliferation: this was state of the art
for the present application. Hence,
even in the absence of any data in
the application showing a therapeutic effect of these agents either on
cancer or on other diseases associated with abnormal cell proliferation,
there is no apparent reason to doubt that anti-neoplastic agents would
have a role in controlling abnormal cell proliferation both in cancer
and in other diseases not related to cancer. As such, it can be
considered that said claimed therapeutic effect was already known to the
skilled person at the priority date and that it therefore does not have
to be demonstrated in the application. The fact that the compound to be
used consists of a combination with a further substance, namely a DNA
methylation inhibitor, does not change this conclusion, unless there
were reasons, based on verifiable facts, to believe that this substance
would interfere in a negative way with the activity of the
anti-neoplastic agent. On the contrary, the teaching of the application
is that this further compound may enhance the activity of the
anti-neoplastic agent, and this is further supported by the
post-published evidence submitted by the appellant with the grounds of
appeal (documents D3.1, D3.2, D3.3, D5.10).
6.2.3
The arguments
of the examining division concerning an improvement or synergistic
effect (supra) are also not valid for these claims, as these claims do
not require such an effect. Such an argument could be of relevance in
the discussion of inventive step, but not of sufficiency of disclosure.
6.2.4
As regards D4.1, cited by the examining division as an example that one
of the combinations falling within the limits of the claim (decitabine
plus IFN-gamma) did not have an effect, the board follows the
appellant's arguments that, in fact, this document further supports the
concept underlying the invention. D4.1 discloses (page 5222, last
paragraph and page 5223, first paragraph) that cell lines which are
non-responsive to decitabine do not show a high up-regulation of gene
expression in the same genes which are up-regulated in cells that are
responsive to decitabine. According to D4.1, the cutaneous melanoma cell
lines that are non-responsive to decitabine do not present a high
enough up-regulation of gene expression in comparison to the uveal
melanoma cell lines. Re-expression of silenced genes is an outcome of
the hypomethylating activity of decitabine, and D4.1 regards this
difference in re-expression as the reason behind the sensitisation of
uveal melanoma cell lines, but not of cutaneous melanoma cell lines, to
IFN-gamma by decitabine. Finally, D4.1 does demonstrate that decitabine
and IFN-gamma (and also IFN-alpha) had an effect on uveal melanoma
cells.
6.3 Independent claim 36: Kits
6.3.1 Although claim
36 is directed to a "kit for treating a disease...", thus raising doubts
whether it is directed to a product with no purpose restrictions, or
whether it has the scope of a purpose-restricted product claim (see also
below),
the same considerations as discussed above apply also to this
claim. Hence, for the reasons given above, this claim is also considered
to fulfil the requirements of Article 83 EPC.
Remittal to the first instance
7.
The examining division's decision was based only on Article 83 EPC (in
conjunction with Rule 42(1)(e) EPC). Novelty and inventive step thus
still have to examined and the board notes that a number of documents
have been cited in the search report as X. Moreover, there is no
indication on file that other EPC requirements such as Article 123(2)
EPC or Article 84 EPC have yet been assessed. In particular, it has to
be examined whether all new combinations of features and new
dependencies of claims do have a basis in the application as filed. Also
some issues of lack of clarity are readily apparent, for example as
mentioned above concerning the wording of claim 36, which raises doubts
as to the claim category; a similar lack of clarity is also present in
claim 19.
8. Although there is no absolute right to have an issue
decided upon by two instances, it is also not the function of the board
to consider and decide upon issues which have not been examined at all
by the department of first instance. The board thus decides to exercise
its discretion under Article 111(1) EPC and remit the case to the first
instance for further prosecution.
Order
For these reasons it is decided that:
1. The decision is set aside.
2. The case is remitted to the first instance for further prosecution.
This decision has European Case Law Identifier: ECLI:EP:BA:2014:T161609.20140827. The whole decision can be found here. The file wrapper can be found here. Photo by Lali Masriera obtained via Flickr.
