T 2036/21 - Preventing dementia and credible effects

Key points

• The patent was granted in 2011. Decision OD in 2016, appeal decision in 2019 to remit, next decision in 2021 to maintain the patent in amended form. The appeal of the opponent is dismissed, so after 12 years, the opposition procedure now comes to an end.
• The Board, after an extensive analysis, considers the following objective technical problem to be solved by the second medical use claim at issue: "how to provide a personalized treatment and prevent or delay the onset of dementia in the prodromal dementia group who benefit the most from intervention"
• "prodromal (dementia) patients" are subjects who, although not yet suffering from clinical dementia, are on the way towards developing it."
• "The appellant [opponent] argued that D31 and D47, filed after that remittal, provided evidence that the claimed composition neither prevented nor delayed the onset of dementia at the prodromal stage. No therapeutic effect was achieved in prodromal patients. In its opinion, this was relevant to formulating the technical problem underlying the invention and for assessing inventive step."
• "Article 111(2) EPC, does not preclude the opposition division from taking into account facts which were not at the disposal of the board remitting a case for further prosecution."'
• "D31 and D47 relate to the clinical trial "LipiDiDiet". The trial investigated the effects of Fortasyn Connect (Souvenaid), a composition according to claim 1, on patients affected by prodromal Alzheimer's disease expressing the biomarkers of claim 1."
• The Board concludes that: "D31 and D47 do not convey to the skilled person the message that "the tested composition is unsuitable for preventing or delaying the onset of dementia in a prodromal patient", but rather that "this effect was not detected, possibly because the clinical trial was not designed and adequately powered to do so".'
• "The results presented in D47 and the conclusions drawn by its authors leave no doubt that Fortasyn Connect, a composition according to the invention, induces a beneficial and unprecedented effect in prodromal Alzheimer's disease patients."
• D47: " significant benefits were observed on cognition, function, and brain atrophy, with clinically relevant effect sizes demonstrated."
• "Alzheimer's disease, the most common form of dementia, is induced by progressive degeneration of the brain cells causing a gradual decrease in cognitive functions. Therefore, it is credible that, as argued by the respondent, by slowing down this progressive degeneration, the onset of dementia will be delayed or even prevented in prodromal dementia patients as defined in claim 1."
• Let's hope it is not only credible but also true. 
• As a comment, it's not clear to me why the objective technical problem was not formulated in terms of providing "significant benefits ... on cognition, function, and brain atrophy, with clinically relevant effect sizes demonstrated", as that is what the evidence seems to demonstrate. 
• The Board: "In proceedings before the EPO it is not a prerequisite to perform a statistical analysis of the results and to determine a specific confidence interval, as is most often required in biomedical research and by health authorities granting marketing authorisations for medicinal products. As held in G 3/97, Reasons 5 "the principle of free evaluation would be contradicted by laying down firm rules of evidence defining the extent to which certain types of evidence were, or were not, convincing" (see also decision T 2717/17, Reasons 4.3.5)."

EPO 

The link to the decision is provided after the jump, as well as (an extract of) the decision text.

https://www.epo.org/en/boards-of-appeal/decisions/t212036eu1

Standard rendering a technical effect credible

3.25 The crucial point which has to be decided is whether further evidence is available which makes it credible that the claimed composition is suitable for preventing or delaying the onset of dementia in a prodromal patient.

3.26 It is observed that, even if the tests aimed at assessing an endpoint of a clinical trial do not yield a statistically significant outcome, other results may still be taken into account to evaluate the efficacy of a treatment. In some cases, these may provide valuable information in relation to the endpoint for which no significant results were observed.

3.27 In this context, attention is drawn to the fact that proceedings before the EPO are conducted with application of the principle of free evaluation of evidence. According to this principle, the competent EPO body decides in the light of its conviction arrived at freely, taking into account the evidence available in the proceedings and on the footing that one set of facts is more likely to be true than the other (Case Law of the Boards of Appeal, 10**(th)edition, 2022, sections III.G.4.1 and III.G.4.3 and decisions G 3/97, Reasons 5, G 1/12, Reasons 31 and G 2/21, Reasons 55).

3.28 There are no reasons not to apply this principle when deciding whether it is credible that a compound or composition induces a therapeutic effect.

3.29 It is also noted that this approach does not correspond to that applied in other contexts, where conclusions are only drawn if there is a high degree of statistical confidence. In proceedings before the EPO it is not a prerequisite to perform a statistical analysis of the results and to determine a specific confidence interval, as is most often required in biomedical research and by health authorities granting marketing authorisations for medicinal products. As held in G 3/97, Reasons 5 "the principle of free evaluation would be contradicted by laying down firm rules of evidence defining the extent to which certain types of evidence were, or were not, convincing" (see also decision T 2717/17, Reasons 4.3.5).

Technical effects evidenced by D31 and D47

3.30 D47 teaches that the LipiDiDiet trial was primarily designed for the analysis of changes on continuous scales, such as NTB and CDR-SB and on brain atrophy, which reflect cognitive deterioration, disease status and trajectory, rather than discrete outcomes, such as the onset of dementia (D47 page 9, right-hand column last paragraph and page 8 right-hand column).

3.31 The outcome of this analysis shows that after 36 months the administration of Fortasyn Connect to prodromal dementia patients induces a significant improvement of:

- the NTB 5-item and the NTB memory domain scores, which reflect a slower deterioration in cognitive abilities (D47, discussion, page 7, passage bridging left- and right-hand columns, page 8, right-hand column and figures 2A and 2B)

- the scores of CDR-SB, which is considered to reflect real-life performance, providing a sensitive and meaningful primary clinical outcome assessment in prodromal/early Alzheimer's disease trials and an indication of disease status and trajectory (D47, page 7, passage bridging left- and right-hand columns, page 8, right-hand column, first paragraph, figures 2C and 2D)

- a reduction of brain atrophy (D47, page 7, passage bridging left- and right-hand columns, page 8, right-hand column)

3.32 Furthermore, while acknowledging that the LipiDiDiet trial was not designed to detect changes in the incidence of dementia, the authors of D47 suggest that from the CDR-SB analysis "a stronger effect would be expected in participants at earlier stages of prodromal AD". In their opinion the CDR-SB analysis across the spectrum of MMSE values and the fewer dementia cases during the third year in the active group corroborate this hypothesis (page 9, left-hand column).

3.33 Taking into account the results of the clinical study, the authors of D47 conclude the article stating that:

"In conclusion, the present study provides evidence for potentially altered disease trajectories supporting the positive effects of long-term multinutrient intervention in prodromal AD. Over 3 years, significant benefits were observed on cognition, function, and brain atrophy, with clinically relevant effect sizes demonstrated. Prolonged intervention resulted in a broader range of endpoints showing statistically significant differences than reported before. Such sustainable benefits lasting for 3 or more years have not been reported before for an intervention in prodromal AD. The totality of our results highlights that the benefits might be increased with early and long-term intervention." (page 10, right-hand column, emphasis added by the board)

3.34 The results presented in D47 and the conclusions drawn by its authors leave no doubt that Fortasyn Connect, a composition according to the invention, induces a beneficial and unprecedented effect in prodromal Alzheimer's disease patients.

3.35 As already mentioned above, Alzheimer's disease, the most common form of dementia, is induced by progressive degeneration of the brain cells causing a gradual decrease in cognitive functions. Therefore, it is credible that, as argued by the respondent, by slowing down this progressive degeneration, the onset of dementia will be delayed or even prevented in prodromal dementia patients as defined in claim 1.

3.36 The results shown in figure 2D of D47 which display the variations in the CDR-SB scores across the spectrum of MMSE values make it also credible that, as argued by the respondent, patients at the earliest stage of prodromal disease benefit the most from the treatment. The strongest difference between the treated group and the placebo groups is in fact observed in the patients scoring the highest MMSE values. These are those having the least signs of cognitive impairment. Further support for this is found in figure 1 of D44, which summarises the results of clinical studies conducted in patients suffering from dementia at different stages.

3.37 The appellant drew attention to D43, a short article commenting on the results shown in D31, and drawing negative conclusion on the outcome of the LipiDiDiet trial. However, D43 only relates to the results observed after 24 months of trial and almost two years before the publication of D47. Thus, D43 does not take account of the results of the complete 36 month trial which are discussed above.

3.38 For these reasons, the board concludes that the results described in D47 make it credible that the claimed composition prevents or delays the onset of dementia in the patient identified in claim 1. Furthermore, that patients at the earliest stage of prodromal disease benefit the most from the treatment. These conclusions confirm the earlier finding in decision T 694/16, which was based inter alia on example 4 of the opposed patent and on D29.

Technical effects evidenced by D48

3.39 The board also agrees with the respondent that the tests carried out in the APP/PS1 mouse described in D48 make it credible that omega-3 fatty acids are not, alone, as effective in preventing degenerative processes associated with dementia as the claimed composition. These tests confirm the statement on page 2 of public release D29, that the single ingredients of the claimed composition are not powerful enough to translate into an effective intervention.

3.40 The appellant criticized the tests in D48, arguing that only incremental effects on neurodegeneration were measured, not the onset of dementia. Furthermore, that the mice were sacrificed at six months, although memory deficit typically only appears at ten months.

3.41 These arguments are not convincing. Dementia is a disease induced by a progressive degeneration of the brain cells. Thus, the neurodegenerative process which is already observed in young APP/PS1 mice at six months is suitable for reproducing the processes accompanying the development of dementia in prodromal patients.

3.42 For these reasons, it is credible that a composition combining the specifically claimed ingredients is more suitable for preventing or delaying dementia in the patients defined in claim 1 than a composition comprising only omega-3 fatty acids.

Technical problem

3.43 Starting from D27 as the closest prior art, and taking into account the aforementioned technical effects, the underlying technical problem is formulated, as proposed by the respondent, as "how to provide a personalized treatment and prevent or delay the onset of dementia in the prodromal dementia group who benefit the most from intervention".