T 0910/21 (Executive function / NUTRICIA) 08-12-2023

Patent as granted (main request)

1. Admittance reference to T 1491/14 and document D29

1.1 The objection that the claimed subject-matter does not involve a new patient group had been maintained in the opponent's reply to the appeal (see section 4.1). The additional reference to T 1491/14 in the opponent's letter of 15 September 2022 merely further developed this argument and is therefore not disregarded as an amendment to the respondent's case under Article 13(1) RPBA.

1.2 Document D29 represents new evidence, which was filed by the opponent after its reply to the appeal. The filing of document D29 thus corresponds to an amendment to the opponent's appeal case under Article 13(1) RPBA.

The opponent argued that document D29 confirmed that IADL are strongly correlated to EXEC and that MEM does not have such effect on IADL. According to the opponent document D29 was filed in response to the allegation in the proprietor's letter of 16 June 2022 that a change in IADL did not necessarily reflect a change in EXEC.

The Board observes that the proprietor already relied in its statement of grounds of appeal (see for instance pages 6-7) on the argument that IADL can be affected by MEM, EXEC or both. Moreover, whilst document D29 reports that IADL are associated with cognitive functions and mentions that EXEC may be more important than MEM for performing ADL functions (see D29, abstract under "Conclusions"; see also page 2, right column), the document does not exclude that a change in IADL may be linked to a change in MEM.

Accordingly, the Board has not admitted document D29 into the appeal proceedings under Article 13(1) RPBA, because the reason for filing of document D29 at the late stage of the appeal proceedings is not convincing and because the filing of document D29 is not suitable to resolve the issue raised by the proprietor.

2. Novelty

2.1 Documents D6 and D28 describe compositions comprising uridine or an equivalent thereof, EPA and/or DHA for improving activities in which the operational and the executive brain functions play an important role, i.e. the instrumental and/or basic activities of daily living (IADL/BADL), and for supporting and enabling those complex activities where initiation, planning and effective operation performances play a role (see D6, page 1, line 30 to page 2, line 16 and page 3, lines 6-12; see D28, pages 2-3; pages 4-5). The compositions are described to be in particular useful for patients with early or mild Alzheimer's disease, preferably with a MMSE score of 20-26 (see D6, page 12, lines 5-13; see D28, page 13). Document D28, which refers to document D6 as priority document, additionally reports in example 5 the results from a clinical study. An improved ADCS-ADL score was observed in AD patients following treatment with a relevant composition for the duration of twelve weeks. These improvements resulted mainly from an improvement in instrumental activities (see D28, pages 20-21).

2.2 The Board observes that documents D6 and D28 describe the beneficial effect of a formulation with the same components as defined in claim 1 as granted on activities which are influenced by EXEC, in particular the IADL, but do thereby not explicitly disclose the beneficial effect on EXEC itself as defined in claim 1 as granted.

The opponent argued in line with the findings in the decision under appeal that any improvement in the activities as described in documents D6 and D28 is nevertheless inevitably associated with a positive effect on EXEC.

However, document D26 explains that changes in MEM and EXEC are independently associated with the rate of change in IADL (see D26, abstract and page 5, lines 13-17). The benefit of treatment with respect to IADL as described in documents D6 and D28 does therefore not necessarily imply an improvement in EXEC, because the reported benefit may well have resulted from an improvement in MEM.

2.3 The opponent further argued that EXEC was generally affected in patients with AD and could not be improved in isolation. The purpose of improving EXEC as defined in claim 1 as granted did therefore anyway not qualify as a new therapeutic indication with respect to the teaching in documents D6 and D28, which already described the same compositions for treatment of the same patients.

However, document D22 indicates that in patients with dementia there is no parallel decline in EXEC and MEM. In particular, document D22 shows in the column charts of Figure 2 (see D22, page 11), that in different forms of dementia , namely Alzheimer type, primary progressive aphasia and frontotemporal dementia (FTD), different levels in the decline in EXEC and MEM are observed. The presented column charts furthermore demonstrate that in each different form of dementia the decline in EXEC and MEM develops differently over time. The presented data indicate for the initial stages of dementia in primary progressive aphasia and FTD a more prominent impairment of EXEC over MEM, whereas for the initial stage of Alzheimer type dementia a strikingly more prominent decline in MEM over EXEC is reported.

It is evident from document D22 that a decline in EXEC, and thus also the need for treatment intended to improve EXEC, can be specifically diagnosed in patients who develop dementia and that the change in EXEC over time, and thus also the response to treatment, can be specifically monitored. As confirmed in for instance document D3 (see page 555) the Trail Making Test B (TMT-B) described in the patent (see paragraphs [0033]-[0035] and [0105]) is commonly known as suitable for this purpose. The Board therefore considers that the purpose of improving EXEC defines a specific clinical situation which characterizes the therapeutic use as defined in claim 1 as granted.

In this context the Board is not convinced by the opponent's argument that in view of the considerations in decisions T 233/96 (see Headnote) and T 1491/14 (see section 2.2) the treatment defined in claim 1 lacked novelty, because it does not define the treatment of a new group of patients. The purpose of improving EXEC as defined in claim 1 as granted relates to a specific clinical situation requiring treatment, namely the situation in which it is desired to target a decline in EXEC. As explained above, this decline can be specifically diagnosed and an improvement of the cognitive funtion EXEC following a therapeuitc treatment can be specifically monitored. Thus, in line with the considerations in T 836/01 (see section 10) the purpose of improving EXEC distinguishes the treatment defined in claim 1 as granted from the treatment of patients with AD as described in documents D6 and D28 even without the explicit definition of a new patient group.

2.4 Documents D5, D7, D8 and D10-D15 were cited by the opponent as further evidence that compositions with the same components as defined in claim 1 as granted were known to have a beneficial effect on the brain function in patients with AD.

These documents do not specifically address the effect of such composition on EXEC.

In this context the Board observes that document D8 reports a beneficial effect of a corresponding composition on the verbal recall scores of patients following twelve weeks of administration (see D8, page 6, Figure 2 and page 7, Table 3; see also Abstract). However, document D8 describes the delayed verbal recall test as a measure of episodic memory (see D8, page 2, right column, lines 3-5) and presents the verbal recall scores as indicators of memory performance, not of EXEC (see D8, page 7, the subscript under Table 3).

Documents D5, D7, D8 and D10-D15 do therefore not provide any more pertinent disclosure than documents D6 and D28 regarding the utility of the compositions for improving EXEC as defined in claim 1 as granted.

2.5 Accordingly, the Board concludes that the patent as granted meets the requirement of novelty.

3. Inventive step

3.1 As explained in section 2.1, documents D6 and D28 describe the utility of a composition as defined in claim 1 of the patent for improving IADL, in particular in patients with early or mild Alzheimer's disease. Document D28 represents more pertinent prior art than document D6 in view of the additional information regarding a clinical study in which an improved ADCS-ADL score was observed in AD patients following twelve weeks of treatment, which resulted mainly from an improvement in instrumental activities.

As further explained in section 2.4, document D8 describes improvements in the verbal recall score of mild AD patients who were treated with a composition as defined in claim 1 of the patent during a period of twelve weeks.

Following the conclusion in section 2.5, the difference between the claimed subject-matter and the teaching in document D28 as well as the teaching in document D8 concerns the definition of the therapeutic indication, namely the utility for improving EXEC.

3.2 The patent demonstrates that the administration of an exemplified composition according to claim 1 as granted to patients with mild AD during a period of twenty-four weeks provided a beneficial effect on EXEC (see the patent, paragraphs [0097]-[0105], "Example 2. Clinical study" and Figure 2).

As explained above in section 2.3, the purpose of improving EXEC relates to a specific clinical situation which distinguishes the defined treatment from the treatment of patients with AD as described in documents D6 and D28. Contrary to the opponent's argument the purpose of improving EXEC does therefore not merely concern a further criterion or reason for providing the otherwise known treatment of this group of patients.

The problem to be solved in view of document D28 or document D8 may therefore be formulated as the provision of a further therapeutic use for the defined compositions.

The question to be answered is whether on the basis of the prior art the skilled person had a reasonable expectation that the defined composition would be useful for improving EXEC in the defined group of patients.

3.3 It was not in dispute that EXEC is compromised in patients with AD and that EXEC plays an important role in IADL. However, as pointed out in section 2.2 above, changes in MEM and EXEC are according to document D26 independently associated with the rate of change in IADL. Without any further specific indication from the prior art the improvement in IADL reported in document D28 does not provide a reasonable expectation of a beneficial effect on EXEC, because the improvement in IADL could well have resulted from an improvement in MEM.

Moreover, the results reported in the patent (see Figure 2) indicate that the effect of administration of the defined composition on EXEC may only become clearly recognizable after twelve weeks from the start of the administration. The skilled person who further investigates the effects on IADL from the twelve week treatment as reported in document D28 may thus not recognize the improvement in EXEC as disclosed in the patent. On the contrary, when investigating the effect on IADL from twelve week administration of the composition as described in document D28 the skilled person would on the basis of the results from the administration of such a composition for the duration of twelve weeks as described in document D8, which concerned improved verbal recall scores (see D8, page 6, Figure 2 and page 7, Table 3; see also Abstract), likely conclude that the reported improvement in IADL was due to an improvement of MEM.

The prior art did therefore not provide the skilled person with reasonable expectation that the defined composition would be useful for improving EXEC in the defined group of patients.

3.4 Accordingly, the Board concludes that the patent as granted meets the requirement of inventive step.

4. Sufficiency

4.1 As mentioned above in section 3.2, the patent demonstrates in Example 2 that the administration of an exemplified composition according to claim 1 as granted during a period of twenty-four weeks allows for an improvement of EXEC in patients with mild AD. According to the Board the patent credibly discloses with this example the suitability of the composition for the therapeutic indication as defined in the claims as granted.

4.2 The Board considers that the opponent's objection that the patent does not sufficiently disclose the suitability of the claimed composition for improving EXEC in other patients than those suffering from mild AD remained without substantiation.

The opponent referred to diverse groups of patients as defined in claim 1 and pointed to the results from the study of the effects of the multinutrient combination "Fortasyn Connect" in patients with prodromal AD reported in the post-published document D21. This study did not reveal a significant effect on primary and secondary end points regarding the neuropsychological test battery (NTB) scores, including the scores for the NTB executive domain (see D21, page 970, Table 3 and right column, lines 5-9).

However, the mere fact that no statistically significant effect on EXEC was observed in the study reported in document D21 does in the Board view not raise serious doubts as to the utility of the composition defined in the claims of the patent. In fact, document D21 explicitly recognizes that the study was inadequately powered and recommends further investigation with larger sample sizes (see D21, summary under "Interpretation").

The Board considers that the mere reference to the diverse nature of the disorders defined in claim 1 as granted does not further substantiate the opponent's objection. The claim is specifically directed to the improvement of EXEC, which may be compromised in patients afflicted by the defined disorders and for which the patent exemplarily demonstrates efficacy in patients with mild AD.

4.3 The opponent further objected that the clinical study reported in the patent had only been carried out with a formulation comprising specific amounts of the uridine derivative UMP and the lipids EPA and DHA in combination with a variety of further nutritional components (see the patent, paragraph [0097], Table 1). Taking account of the evidence in documents D21 and D25 the effect on EXEC reported in the patent for this complex composition could not be plausibly extrapolated to the simple combination defined in claim 1 as granted.

Document D21 states that the nutrients in the multinutrient combination "Fortasyn Connect", which includes the components listed in Table 1 of the patent, were selected on the basis of their established neuroprotective properties and combined to enhance their efficacy (see D21, bridging paragraph pages 965-966). Document D25 reports that the effects of the multinutrient combination "Fortasyn Connect" on pheochromocytoma cells in terms of their response to muscarinic receptor agonists could not be attributed to single nutrients (see D25, page 631, Abstract). Document D4 discloses that the administration of uridine or uridine precursors leads to increased levels of cytidine in the human brain and that the potential benefit of an uridine source administration overwhelmingly exceeds the benefit of cytidine administration due to lesser crossing of the blood-brain barrier by cytidine (see D4, page 1, lines 17-26).

The Board observes, however, that document D4 actually confirms that uridine and equivalents thereof, including cytidine, have a beneficial effect on brain function (see D4, page 1, lines 19-21). Moreover, document D5 indicates that the beneficial effects of the omega-3 fatty acid DHA on brain function are enhanced by uridine and can be reproduced with EPA (see D5, abstract). The above discussed documents D6/D28 and D8 further indicate the beneficial effect of the combination of the components defined in claim 1 as granted on the cognitive function in relevant patients. Taking account of the thus already known potential of the defined combination of ingredients to improve compromised brain function, the effects demonstrated in the clinical study reported in the patent may reasonably be attributed to the components defined in claim 1 as granted. In this context the patent provides in paragraphs [0055] and [0069] specific guidance as to the suitable dosages for these active ingredients. The Board therefore considers that the relevance of the additional nutritional components mentioned in documents D21 and D25 does not raise any serious doubts concerning the efficacy of the combination as defined in claim 1 as granted and the skilled person's ability to carry out the claimed invention without undue burden.

4.4 In the clinical study reported in the patent (see Figure 2) the beneficial effect of the administration of the defined composition on EXEC only became clearly recognizable after twelve weeks from the start of the administration. However, this delay for the defined effect to develop does not imply that the initial administration is without consequence. In fact, the clinical study provides the skilled person with guidance towards effective treatment notwithstanding any initial delay before the effect can be observed.

4.5 Accordingly, the Board concludes that the patent as granted sufficiently discloses the claimed invention.