Friday, 4 August 2017

T 488/16 - Not plausible at the filing date

Is it plausible that the compound had the effect?

In this opposition appeal the effect (inhibiting PTK activity) of the claimed compound (dasatinib) was supported with post-published documents: documents (9) and (10) filed during the Examination procedure and documents (36) and (37) filed with the statement of the grounds. 

The application as filed contains a large number of compounds of which one is selected in the claim under appeal. The decision does not contest that the post-published documents show that this compound works, indeed works very well. The question is, whether this was plausible at the filing date. The board maintains the revocation of the patent. 




Reasons for the Decision
1. The appeal is admissible.
2. As communicated in advance to the board (see point IX above), respondent 2, who did not submit any comments or observations with regard to the substantive issues, did not attend the oral proceedings before the board, to which it had been duly summoned. The board decided to continue the proceedings pursuant to Rule 115(2) EPC and Article 15(3) RPBA.
3. Admission of documents (36), (37) and (38)
3.1 Documents (36) and (37) were filed with the statement of grounds of appeal in direct response to the opposition division's decision revoking the patent. In the decision under appeal, the opposition division was of the opinion that the technical effect relied on by the appellant had not been plausibly demonstrated at the filing date. Furthermore, it criticised the lack of an identifiable pharmacophore. As a consequence, contrary to the opposition division's initial indication in its preliminary opinion, the post-published evidence was not taken into account and inventive step was not acknowledged.
The appellant challenged the opposition division's findings and addressed these key issues in its statement of grounds of appeal, in particular the concern as to the lack of an identifiable pharmacophore. Documents (36) and (37), dealing with the question of what the application conveyed to the skilled reader, were filed in support of the appellant's position that the opposition division erred in its assessment of what was plausibly disclosed in the application, and consequently in its assessment of inventive step. In these circumstances, the board is of the opinion that the submission of these documents with the statement of grounds of appeal is an appropriate and legitimate attempt by the appellant to address the objections raised in the decision under appeal and to further support its position with respect to plausibility and inventive step.
The argument of respondent 1 that these declarations might have been considered much earlier and could therefore have been filed at a much earlier state is not convincing. The title page of both documents makes reference to such data as the patent, application and appeal number. It identifies the patentee and the opponents and, in this context, also mentions third party observations. In the board's opinion this reference is not an indication that the present declarations were a late reaction to these third party observations, which for some unknown reasons were not filed before.
3.2 Hence, the board decided to admit documents (36) and (37) into the proceedings.
3.3 Document (38) was filed about one month before the oral proceedings took place. None of the respondents raised an objection to its introduction into the proceedings. Nor did the board see any reason to reject this document. Consequently, document (38) was admitted into the proceedings.
4. Post-published documents
4.1 Documents (9) and (10), in particular document (9), on which the appellant relied as evidence that the presently claimed compound dasatinib showed protein tyrosine kinase (PTK) inhibitory activity and was therefore suitable in the treatment of disorders associated therewith, particularly cancer, were filed more than three years after the filing date of the patent in suit (document (9) in December 2004 (on the Internet in July 2004); document (10) in November 2003). In the decision under appeal, the opposition division decided not to take these documents into account on the grounds that the alleged activity had not been made plausible at the effective date of the patent in suit and that the post-published documents were the first disclosure going beyond speculation. This decision was challenged by the appellant, who continued to rely on these documents as confirmation for a plausible disclosure of dasatinib as PTK inhibitor.
4.2 It is established jurisprudence of the boards of appeal that the assessment of inventive step is to be made at the effective date of the patent on the basis of the information in the patent together with the common general knowledge then available to the skilled person. Post-published evidence in support that the claimed subject-matter solves the technical problem the patent in suit purports to solve may be taken into consideration, if it is already plausible from the disclosure of the patent that the problem is indeed solved (see Case Law of the Boards of Appeal, 8th edition, I.D.4.6; T 1329/04, point 12 of the Reasons; T 1043/10, point 12 or the Reasons).
Thus, for post-published evidence to be taken into account, it is necessary to establish whether or not the asserted activity has been made sufficiently plausible for dasatinib at the effective date of the patent in suit. Basis for this assessment is the application as filed and the common general knowledge of the person skilled in the art at the filing date.
4.3 The application is directed to an extremely broadly defined group of compounds of the following generic formula I:
FORMULA/TABLE/GRAPHIC
Q is an aryl ring or a 5- or 6-membered heteroaryl ring (see page 3, lines 5 to 14); the variables are defined on page 3, line 10 to page 8, line 7. Furthermore, a subgroup is defined having the following general formula II:
FORMULA/TABLE/GRAPHIC
were A is carbon or nitrogen, B is nitrogen, oxygen and sulfur, X is oxygen and sulfur and the other variables are defined as for formula I (see page 8, lines 8 to 18).
Preferred compounds of formula I are defined on page 13, line 16 to page 14, line 2, where Q is thiazole, Z is a single bond and R2 and R4 are hydrogen. Taking into account, the more preferred definitions of the variables R1, X1, X2, R3 and R5, the information on pages 13 and 14 translates into the following formula
FORMULA/TABLE/GRAPHIC
The application also discloses 580 compounds falling within the scope of general formula I, including dasatinib (see example 455).
4.4 On page 39, line 10 to page 43, line 25, the application describes a number of PTKs, which are potential targets of the claimed compounds, and the diseases or disorders associated therewith. Particular types of kinases, which are listed in this context are the non-receptor kinases Lck, Fyn, Lyn, Src, Yes, Hck, Fgr and Blk, which belong to the Src-family (page 39, lines 10 to 15) or the receptor kinases HER1 and HER2, which belong to the epidermal growth family (see page 42, line 30 to page 43, line 3 and page 1, lines 20 to 21). Other types of receptor and non-receptor tyrosine kinase families are mentioned on page 1, lines 18 to 24. As is apparent from pages 39 to 43, inhibition of specific protein tyrosine kinases are associated with specific disorders, for example Lck inhibitors are of value in the treatment of T-cell mediated diseases, such as arthritis, multiple sclerosis, lupus, transplant rejection delayed-type of hypersensitivity, certain types of cancer, etc; Hck and Fgr are important in the Fc gamma receptor response and are considered valuable in the treatment of inflammatory bowel disease or autoimmune glomerulonephritis; Lyn and Src are important in the Fc epsilon response and are of value in the treatment of asthma or allergic disorders; HER1 and HER2 can be used in the treatment of proliferative treatments, such as psoriasis and certain types of cancer.
4.5 On page 50, line 4 to page 53, line 18, the application refers to assays "which can be employed in ascertaining the degree of activity of a compound ("test compound") as PTK inhibitor" (see page 49, lines 29 to 30). The assays are generically described and refer to the "protein kinase of interest" and the "test compound" or "compounds of interest" to be assayed. No further details are provided in this respect. Nor are any results, for example IC or Ki values, provided. Indeed, there is no evidence at all in the application as filed that shows that any of the compounds falling within the scope of formula I, let alone dasatinib, is active as an inhibitor for any of the specific protein tyrosine kinases, except a mere assertion on page 50, lines 1 to 2 with reads that "Compounds described in the following Examples have been tested in one or more of these assays and have shown activity." No further information is provided. No individual values or range of values are given. No information as to whether the observed "activity" is suitable for the intended use, i. e. the treatment of a number of diseases and disorders, is provided. In the board's judgement, a mere verbal statement that "compounds have been found active" in the absence of any verifiable technical evidence is not sufficient to render it credible that the technical problem the application purports to solve, namely providing PTK inhibitors to treat disorders or diseases associated therewith, is indeed solved, in particular in the present case, where the invention is directed to a very broadly defined class of compounds encompassing millions of structurally rather different candidates with unknown properties, where even the examples show a broad structural variation and where it is inherently unlikely for any skilled person that all of the compounds of the invention or at least a substantial amount of them will exhibit the alleged PTK inhibitory activity.
In the present case, there is also no evidence on file showing that, at the date of filing, the skilled person was in the possession of common general knowledge which, even in the absence of data, made it plausible that the compounds of the invention, in particular dasatinib, could be expected to show PTK inhibitory activity. The appellant's argument that a number of structurally different compounds are known as PTK inhibitors and are in clinical trials or near clinical development (see document (34), point 3 on pages 559 to page 565) is not pertinent in this context, as no conclusion with regard to PTK inhibitory activity of dasatinib can be drawn from this knowledge in the absence of any correlation between structural features and function.
Even if the board were to accept the assertion on page 50 of the application as filed as an indication that some tests had been carried out, no information is provided as to which of the structurally rather different compounds had been tested and in which assay, in particular whether any of the tests included dasatinib. In this context, the board would like to emphasise that it does not accept the appellant's contention that the passage on page 50 is to be read in the sense that all compounds of the examples had been tested. As pointed out by the respondents, such a reading also appears to be in conflict with the appellant's post-published evidence according to which certain compounds of the examples were inactive at a specific concentration. In this context, the board notes that in document (38), Mr Barrish, one of the inventors, refers to a review of the results of the assays performed before the patent was filed, which showed that these specific compounds were tested and found active in "one or more PTK assays" (see points 20 and 21). Irrespective of fact that document (38) can not be relied on for the purpose of what has been made plausible by the application (see point 4.7 below), no evidence was provided in support of this assertion. Nor are any results concerning the performance of dasatinib provided in document (38).
4.6 In support of its position that the claimed effect had been made plausible for the skilled reader, the appellant relied on the declarations of Professor Alessi and Professor Parang (documents (36) and (37)).
4.6.1 As a preliminary remark, the board would like to point out that the opinion of highly skilled experts on how a disclosure of a document is to be understood does not reflect the view of the notional skilled addressee, who is a person of ordinary skills aware of what is common general knowledge in the art at the relevant date. Experts give evidence based on their professional experience and expertise which is not common general and will have an influence on their way of reading the disclosure of a document. Since the assessment of the disclosure from the point of view of the skilled person does not normally call for special technical knowledge or experience, expert evidence on this matter will not be pertinent. Such evidence is only necessary when the board does not consider itself in a position to decide upon a matter without technical assistance. As the board includes two technically qualified members such cases will be rare and will only occur in special circumstances. Finally, opinions by party experts are subject to the free evaluation by the board. It is therefore the adequate substantiation and persuasiveness of the experts' propositions that matter rather than the mere fact that they are presented as an expert opinion which is a means of evidence within the meaning of Article 117(1) EPC.
4.6.2 In his declaration, Professor Alessi mainly comments on the suitability and reliability of the assays referred to in the application for measuring the effectiveness of kinase inhibition (see paragraphs 13 to 27 of document (36)). This is not contested by the board. However, the board fails to see the significance of Professor Alessi's observations, in particular since they do not provide an explanation as to why the skilled reader would simply accept the assertion on page 50 of the application without question. In the board's opinion, the skilled reader can be expected to react in a way common to all persons skilled in the art, which means that any acceptance as to whether or not a particular assertion is correct must be based on verifiable facts, be it information provided in the patent application or available to the skilled person as common general knowledge. In the present case, no such verifiable facts exist. The situation is further aggravated taking into account that, contrary to the appellant's view, the skilled person is not in a position to readily verify the assertion on page 50 in the absence of any detailed information as to the conditions under which the assays are to be carried out. As is apparent from point 4.5 above (see last paragraph), whether or not a compound is "active" apparently also depends on its concentration.
4.6.3 In his declaration, Professor Parang mainly reviewed the examples in the application, which in his opinion indicated to the skilled person a progression through a research program. Starting from early hit compounds, such as example 1, successive variants were synthesised to improve those compounds. Professor Parang identified in the first 129 examples three groups of thiazole compounds (see document (37), page 5, Figures 1, 2 and 3). From example 376 onwards, he identified a further common core structure with a 2-chloro 6-methyl-phenyl group at the carboxamide in position 5 of the thiazole ring (see Figure 4 on page 6 of document (37)). According to Professor Parang, the continued re-use of this common structure meant that a useful pharmacophore had been identified and the additional work embodied in the subsequent examples was to fine tune and optimise the physicochemical properties, particularly the solubility of the compounds. Dasatinib was one of the compounds that re-use the aforementioned common structure. It also fell into the preferred group of compounds as described on page 13 to 14 of the application which lent additional support to it being a PTK inhibitor.
4.6.4 The board agrees with Professor Parang insofar as it is possible to group compounds from the examples together which share a common structural moiety, such as a methyl substituted thiazole ring as illustrated in Figure 2 of the declaration, a 2,4,6 trimethylphenyl groups at the carboxamide in position 5 of the thiazole ring as illustrated in Figure 3, or a 2-chloro 6-methyl phenyl at the carboxamide in position 5 of the thiazole ring as illustrated in Figure 4. Other groups are also apparent, for example, compounds without a thiazole ring (see examples 368 to 375), compounds with a 2-chloro 6-methyl phenyl at the carboxamide in position 5 of the thiazole ring but no aryl or heteroaryl group at the nitrogen in position 2 as in Figure 4 (see examples 322 to 362), compounds without a 2,4,6-trimethylphenyl group or a 2-chloro 6-methyl phenyl group as illustrated in Figures 3 and 4 (see examples 410 to 427 or 521 to 526, 539 to 551). Indeed, no moiety is apparent which is common to all examples.
However, in the complete absence of any data, no conclusion can be drawn as to whether or not the examples reflect a progression in the direction of improved PTK inhibitory activity. Nor is any conclusion possible as to whether or not a suitable pharmacophore reflected by the formula in Figure 4 of Professor Parang's declaration, which includes dasatinib, had indeed been found at the filing date of the application.
4.6.5 In summary, neither Professor Alessi's nor Professor Parang's declaration can support the appellant's view that the alleged activity had been made plausible for dasatinib at the time of filing.
4.7 Document (38), on which the appellant also relied, is not relevant in answering the question whether the application made it plausible for the skilled person that dasatinib showed PTK inhibitory activity, since it refers to knowledge which was not available to the skilled person at the filing date. Furthermore, although this document refers to results, which had been obtained before the filing date of the patent in suit, none of these results were included in this document or were ever provided in the proceedings before the EPO, in particular not for dasatinib.
4.8 The appellant also argued that the EPC does not require experimental proof. A summary statement as provided on page 50, lines 1 to 2 was sufficient to meet the low plausibility threshold, which was satisfied in the absence of any substantiated doubts. No absolute proof was required and there was no legal basis to provide any raw data. As the threshold test had been met, the post-published evidence which merely confirmed the PTK inhibitory activity of dasatinib should be taken into account.
4.9 The board agrees with the appellant insofar as it is not always required to include experimental data or results in an application (see T 578/06, point 13 of the Reasons). It is however a conditio sine qua non that it is shown that the technical problem underlying the invention was at least plausibly solved at the filing date. If, as in the present case, the nature of the invention is such that it relies on a technical effect, which is neither self-evident nor predictable or based on a conclusive theoretical concept, at least some technical evidence is required to show that a technical problem has indeed been solved. In the board's judgement, it is not acceptable to draw up a generic formula, which covers millions of compounds, vaguely indicate an "activity" against PTKs and leave it to the imagination of the skilled reader or to future investigations to establish which compound inhibits which kinase and is therefore suitable to treat the respective diseases associated therewith. In this context, the board notes that it has been acknowledged by the appellant that the skilled person would not expect that each compound would be active against all kinases. The board would also like to emphasise that in the present case the issue is not the absence of any in vivo data or clinical data, but rather the absence of any verifiable data with regard to the asserted technical effect.
Furthermore, contrary to the appellant's assertion, the post-published document (9) - the only document which refers to dasatinib - does not merely confirm the technical effect, but rather discloses a specific PTK profile, which identifies dasatinib as an inhibitor with potent anti-tumour activity (see table 2 on page 6660). No such disclosure is present in the application as filed.
4.10 With regard to the appellant's argument that the burden of proof was on the respondents to show that the application did not solve the technical problem it purports to solve, the board notes the following:
In the present case, no decision is required as to whether there exists, as argued by the appellant, a presumption that a granted patent solves the technical problem it purports to solve. The respondents (opponents), starting from the disclosure in the application as filed, have provided technically sound and persuasive arguments as to why the alleged effect had not been made plausible, which raises doubts as to whether the technical problem had been solved at the filing date, in particular by dasatinib. Thus, even if the burden was on the opponents to raise substantiated doubts, they discharged of it. It then rests on the appellant who continues to rely on the alleged effect to counter-argue and to rebut these doubts.
4.11 In support of its case, the appellant also made extensive reference to the Case Law of the Boards of Appeal. In particular, it relied to a number of decisions in which the boards have taken post-published evidence into account, for example T 428/12, 1677/11, T 715/03 (erroneously referred to as T 517/03), T 1642/07 or T 210/11.
4.12 In the board's judgement these decisions cannot support the appellant's case.
(...)

For these reasons it is decided that:
1. The appeal is dismissed.
2. The request for referral to the Enlarged Board of Appeal is rejected.

This decision T 0488/16 (pdf) has European Case Law Identifier:ECLI:EP:BA:2017:T048816.20170201. The file wrapper can be found here. Photo by AKuptsova obtained via Pixabay under the Pixabay License (no changes made).

4 comments :

  1. This decision is not without ringing a bell to the famous decision of the UKSC in Actavis vs. Eli Lilly

    https://www.supremecourt.uk/cases/uksc-2015-0181.html#

    There are differences, as in the Eli Lilly patent there was one salt properly identified, but the description contained a very generic statement of the same kind as the present one.

    The link is that in there as well as in the present decision, the question of plausibility of the general statement was at stake.
    The UKSC took pretext to a DoE (Art 2 Protocol on Art 69, which does not define equivalents))to extend the protection to other salts as the one claimed. The uncertainty created by this decision will follow us for quite a while.

    If this patent had been granted, I fear that the same could have happened to competitors.

    ReplyDelete
  2. So plausibility is a YES/NO question to be answered based on the claims and description as filed. Meaning the broadness of the initial markush combined with the absence of data together leads to refusing any post-published evidence, even for just 1 compound belonging to the preferred (i.e. specifically claimed) 80 exemplified compounds. This is unreasonable; the board should have assessed if the application as filed made plausible that the compound(s) NOW claimed would work. Which presumably should have been the case here. It looks like the board has just realized now how excessively broad the initial claims can be. It is entirely justified not to grant applications for a new genus of compounds as long as data has not been given showing activity. It is something else altogether to use the broadness of the initial claim to argue that not even the examples plausibly work and that this cannot be cured.

    ReplyDelete
    Replies
    1. It seems to me that is exactly what the board did: assess if the application as filed made plausible THEN that the single compound NOW claimed would work. See point 4.1 ("the presently claimed compound dasatinib") and point 4.2 (the part marked in red).

      The board found that it did not.

      Delete
  3. Impressive! I really like your blog.
    Thanks for giving the information.
    Documents for IT filing

    ReplyDelete

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