T 415/11 – No Evidence

Both the patent proprietor and the opponent filed an appeal against the decision of the Opposition Division to maintain the patent in amended form. The patent proprietor withdrew its appeal during the oral proceedings.

The Board found the main request and the first auxiliary request to lack inventive step and then examined the second auxiliary request, claims 4 and 6 of which read:

4. A method for stabilizing one or more saccharides that are meningococcus C (MenC) immunogens upon lyophilization comprising:

(a) dissolving the meningococcus C (MenC) immunogen in a dissolution buffer comprising at least one amorphous excipient and an amorphous organic buffer to form a mixture, wherein the amorphous excipient is sucrose, and

(b) lyophilizing the mixture.

6. A lyophilized composition stabilized according to the method of claim 4 comprising at least one amorphous excipient, at least one amorphous organic buffer, and at least one meningococcus C (MenC) immunogen, wherein the amorphous excipient is sucrose.

The Board fount claim 6 to lack inventive step:

[38] The [opponent] submits that this subject-matter does not involve an inventive step because it cannot be considered to solve the underlying problem. The [opponent’s] approach is based on case law such as decision T 939/92, in which the board held that it followed from the principle that everything falling within a valid claim has to be inventive (see paragraph [2.4.2] of the decision) that it should be credible that the desired technical effect according to the problem to be solved is seen with substantially every embodiment of a claim (see paragraph [2.5.4] of that decision).

[39] The [patent proprietor] submits that decision T 939/92 relates to circumstances where on the one hand the claims cover compounds of a broad structural variety, but where on the other hand there are only data proving an effect for one or very few of the many compounds. These are however not the circumstances here and therefore the reasoning of decision T 939/92 is not applicable to the present case.

[40] The independent claim under consideration in decision T 939/92 related to chemical compounds which were summarized in the form of a Markush formula, i.e. the claims covered in fact a wide variety of compounds. However, in the present board’s understanding, the issue as to whether all compounds covered by the independent claim have the technical effect according to the problem to be solved did not arise because the number of claimed compounds was large, but because the claim was drafted such that it referred to the compounds per se without stating the effect to be achieved according to the problem to be solved.

That this was also the board’s view in decision T 939/92 may be inferred from paragraph 2.2.1 of the decision:

“However, the present independent claim covers certain chemical compounds per se, and not just those compounds having a particular biological activity. Hence the biological activity of these compounds is not an essential technical feature of the claimed subject-matter, and thus not part of the definition of the claimed subject- matter.”

[41] Also the product claims considered here do not recite any effect, let alone the one to be achieved according to the problem to be solved. Hence, therefore, in the board’s view, the reasoning of decision T 939/92 is applicable.

[42] The [patent proprietor] further submits that the examples in the patent show that the use of sucrose and an amorphous organic buffer such as histidine or imidazole reduce the aggregation of MenC immunogen and thus make it credible that the inclusion of sucrose and an amorphous organic buffer improves the stability upon lyophilization of a composition comprising MenC immunogen.

[43] The board notes that the claims under consideration here are directed to compositions containing “pure”, unconjugated, i.e. “protein-free” MenC polysaccharides […]. All the experiments in the patent were carried out with MenC polysaccharides conjugated to a protein carrier – a mutant diphteria toxin denoted as “CRM 197”. In other words, there is not a single result in the patent from an experiment with “pure” MenC polysaccharides.

[44] Moreover, the patent specification consistently discloses that the instability of MenC-protein conjugates upon lyophilization is due to the protein part of the conjugate.

[44.1] It is disclosed in paragraph [0004]:

“Some problems are associated, however, with the use of the conjugate meningococcal polysaccharide vaccine MenC-CRM 197, and, indeed, with protein-containing vaccines in general. To extend the shelf-life of vaccines, formulations are frequently lyophilized. Lyophilization of MenC-CRM 197, however, can lead to protein aggregation during freezing and storage. In the case of MenC-CRM 197, the aggregates represent noncovalently bound, multimers of MenC-CRM 197 which apparently associate through hydrophobic interactions. The use of present dissolution buffer formulations, i.e. containing 10mM sodium phosphate (pH 7.2) as a buffer and 1.5% mannitol as an excipient, can yield aggregation as high as 9.5 to 10%. As aggregation increases, the concentration of available immunogen decreases. Therefore, a need exists for compositions and methods which overcome the problem of aggregation by stabilizing biological molecules against aggregation during lyophilization.

197 vaccine [sic] is composed of two fragments, A and B, covalently bound to one another. Fragment A has been found to be stable and highly resistant to denaturation. Fragment B, however, is highly sensitive to denaturation and is subject to proteolytic breakdown during lyophilization. As proteolytic breakdown increases, the concentration of available functional immunogen decreases. Therefore, a further need exists for compositions and methods of preparation of biological molecules that will minimize breakdown during lyophilization and storage.”

[44.2] Moreover, it is stated in paragraph [0061]:

“Use of histidine or imidazole buffers in the MenC-CRM 197 formulation increased the vaccine stability. Although the inventors do not wish to be bound to this mechanism, it is thought that stabilization maybe due to the interaction of the tryptophan of CRM 197 with the structurally similar imidazole ring.”

[45] It is stated very generally in the patent, for example in paragraph [0022]:

“The present invention provides buffer compositions, biological molecule compositions, and methods for the preparation and stabilization of biological molecules by reducing aggregation and breakdown of biological molecules upon lyophilization.”

[45.1] However, in the board’s opinion, in the absence of supportive evidence, this general statement is not sufficient to establish in the context of the patent that stability of “pure”, i.e. unconjugated MenC polysaccharides is improved by inclusion of sucrose and an amorphous organic buffer. Both the patent and the prior art, such as for example document D4, explicitly teach only that aggregation during lyophilisation occurs with proteins. In other words, neither the patent nor any of the prior art documents in these proceedings report that polysaccharides, which are composed of hydrophilic sugar residues, aggregate during lyophilization and thus could be stabilized by reducing aggregation. Even if the heat and drying stress during lyophilization had a detrimental effect on polysaccharides, and be it even by aggregation, then, due to their different chemical nature - sugar residues versus amino acids - it is questionable whether polysaccharides could be stabilized by the same means as proteins. Also the [patent proprietor] alleges that proteins and polysaccharides have different stabilisation requirements during lyophilization […].

[46] In view of the circumstances depicted above, the board concludes that neither the patent nor the prior art provides convincing evidence that the claimed lyophilized compositions achieve the desired technical effect to be achieved in accordance with the underlying problem, i.e. the improvement of the stability of an unconjugated MenC polysaccharide-containing composition.

[46.1] When the credibility that a technical effect is achieved by substantially all claimed compounds is at issue and in a situation where, as in the present case, it is prima facie unlikely that this is credible, it is – contrary to the [patent proprietor’s] view – not the opponent […], but the patentee […] who has the burden of proving that the effect is achieved (for example T 939/92 [2.6.1]; T 97/00 [3.1.6]).

[47] The [patent proprietor] submits that the modifications applied by the [opponent] to its own meningococcus vaccine, Mencevax™, confirm that the inclusion of sucrose and an amorphous organic buffer in the formulation enhances not only the stability of conjugated, but also of unconjugated MenC immunogen during lyophilisation. It refers (i) to document D26 published in the year 2000 disclosing that the product Mencevax™, which contains unconjugated MenC polysaccharides and lactose but no buffer, has a shelf life of 2 years; (ii) to documents D37 and D37a published in the year 2008 disclosing that a modified Mencevax™, which includes sucrose and Tris, has a shelf life of 3 years; (iii) to document D38 disclosing that the new Mencevax™ vaccine contains Tris as a “stabilizing agent” and finally, (iv) to document D40, a report published by the Belgian Federal Agency for Medicines and Health Products and published in the year 2008, comparing the old and new Mencevax™ products, and coming on page 51 to the conclusion that the addition of Tris “assures pH stability over the new Mencevax ACWY shelf-life”.

[48] The [opponent] submits that the change in the composition had not been made with the aim of increasing the stability of the composition, but was triggered by completely different considerations.

[49] All documents D26, D37, D37a, D38 and D40 referred to by the [patent proprietor] are published after the priority date of the patent at issue.

[50] Post-published evidence to support that the claimed subject-matter solves the problem to be solved is taken into account if it is already credible from the disclosure in the patent that the problem is indeed solved. In other words, supplementary post-published evidence may not serve as the sole basis to establish that the problem is solved (see for example decision T 1329/04 [12]).

[50.1] Therefore, the board decided in decision T 1329/04 that the post-published evidence could not be regarded as supportive of evidence in the application as filed since there was not any. Therefore, the post-published evidence was considered to be the first disclosure going beyond speculation and was therefore not taken into consideration.

[50.2] In contrast, for example, the board in decision T 1336/04, who was confronted with a different technical situation, namely one where the quality of evidence provided in the respective patent was such that the claimed invention was considered to be a bona fide solution to the problem to be solved, decided to take the disclosure in a post-published document into consideration as a further support (T 1336/04).

[51] The present circumstances are that (i) there are no indications either in the patent or in the prior art that the stability of a MenC polysaccharide-containing formulation is improved by sucrose and an amorphous organic buffer and that (ii) the patent indicates that stability problems are caused by proteins. The board therefore sees the present situation as being closer to that in decision T 1329/04 than to that in decision T 1336/04 because the post-published documents relied on by the [patent proprietor] would, if the disclosures therein were suitable to support the [patent proprietor’s] view, be the first disclosures establishing that the problem was solved by the claimed compositions. The board decides therefore that these documents cannot be taken into consideration.

[52] It follows that no decision is necessary therefore as to whether or not the disclosures in documents D26, D37, D37a, D38 and D40 demonstrate at all that the inclusion of sucrose and Tris in the formulation enhances the stability of a composition comprising unconjugated MenC immunogen during and after lyophilisation.

[53] Hence, the board comes to the conclusion that not substantially all (in fact: none) of the claimed compositions can be considered as being improved unconjugated MenC-polysaccharide-containing lyophilized compositions and therefore cannot acknowledge that the problem is solved by the claimed subject-matter.

[54] Besides the argument that the technical problem is not solved, no further arguments were submitted by the parties, for example as to the reformulation of the technical problem or as to whether or not a reformulated, solved problem could be considered as obvious in view of the prior art.

[55] Consequently, auxiliary request 2 [… is] refused for failure to comply with the requirements of A 56.

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