T 0966/18 (Synucleinopathic disease/PROTHENA BIOSCIENCES) 10-11-2020

Parties to the appeal proceedings

1. The opponent withdrew their opposition during the appeal proceedings (see section V. above) and thus ceased to be a party to these proceedings. Hence, the appellants/patent proprietors are the sole party.

Issues considered in the present decision

2. The opposition division decided the issue of sufficiency of disclosure in favour of the opponent. Before withdrawing its opposition, the opponent had replied to the statement of grounds of appeal. Thus, the reasoning in the present decision deals with the opponent's arguments reflected in the reasoning of the decision under appeal and reiterated in their reply to the statement of grounds of appeal.

3. In the decision under appeal, the opposition division found all claims of the main request, except for claim 3, to comply with Article 123(2) EPC. Auxiliary request 1 (identical to the present main request) differed from the main request in that the objected term "comprises" in dependent claim 3 had been replaced with "is". Consequently, the opposition division found auxiliary request 1 to comply with Article 123(2) EPC.

4. In view of the opponent having ceased to be a party to the proceedings, the board only deals with the reasons for revocation in the decision under appeal with regard to auxiliary request 1 (now the main request) and sees no need to consider ex officio any further arguments submitted by the opponent with the reply.

Admission of documents (Articles 12(4) and 13(1) RPBA)

5. The board holds that documents D88, D89 (by the appellants) and document D90 (by the former opponent) were filed in relation to issues in the decision under appeal and that they could not have been filed earlier. The filing of document D91 is considered a reaction to an argument in the opponent's reply. Consequently, the board sees no reason to hold documents D88 to D90 inadmissible or to not admit document D91.

Main request

Sufficiency of disclosure

6. In the decision under appeal, claim 1 of the set of claims of auxiliary request 1 - which are the claims of the present main request - was found not to disclose the claimed invention in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art.

7. Claim 1 is drafted as a second medical use claim pursuant to Article 54(5) EPC and is directed to a pharmaceutical composition comprising either

(i) alpha-synuclein or an immunogenic fragment thereof or

(ii) an antibody to alpha-synuclein or an immunogenic fragment thereof

for use in the prophylaxis or treatment of a disease characterized by Lewy bodies or alpha-synuclein aggregation in the brain.

8. In this decision, solely the embodiment of claim 1 relating to "treatment" is dealt with, absent of any arguments by the opponent regarding the "prophylaxis" aspect of the claim. The treatment with composition (i) above is referred to in the decision under appeal as "active immunisation" and that with composition (ii) above as "passive immunisation", wording which will also be used in the present decision. The feature "treatment of a disease characterized by Lewy bodies or alpha-synuclein aggregation in the brain" will be referred to here as "treatment of Lewy body disease(s)".

9. It is established case law of the boards of appeal that, in a claim pertaining to a second medical use, the therapeutic effect referred to in the claim - here the treatment of a disease characterized by Lewy bodies or alpha-synuclein aggregation in the brain - is a functional technical feature of that claim (see decision T 609/02 and Case Law of the Boards of Appeal of the EPO, 9th edition 2019, I.C.7.2.).

10. At the heart of the present case lies the question whether or not the skilled person, having regard to the disclosure of the patent and the common general knowledge at the relevant date of the application, would have considered that the compounds referred to in the claim were suitable to achieve the therapeutical effect (see decision T 609/02, point 9). Or, in other words, whether it was plausible (or, in yet other words, whether it was credible) that the therapeutic effect could be achieved by the claimed composition.

11. The opposition division found that it was not plausible that the treatment of a Lewy body disease could be achieved by the claimed composition, because:

(i) "[N]o causative link is demonstrated in the original application or is derivable from the common general knowledge establishing that a reduction of alpha-synuclein aggregation will likely lead to Lewy body disease treatment";

(ii) Examples I and II, and the tables and figures related to them, did not show that active or passive immunisation led to a reduction of alpha-synuclein aggregations, and hence the patent did not plausibly establish the link between reduction of alpha-synuclein aggregates and treatment of Lewy body disease either.

Prior art

12. A number of documents have been cited to illustrate the knowledge of the skilled person working in the field of amyloid diseases at the priority date. The board summarises this body of knowledge as follows.

Referred to by the appellants

13. Document D84 states "the intracytoplasmic Lewy body is therefore central to the neurodegenerative process, and both Parkinson's disease and DLB may be alpha-synuclein diseases".

14. Document D86 finds that "the formation of alpha-synuclein aggregates could be a critical step in PD pathogenesis, which is accelerated by the PD-linked mutations" (see Abstract), and that "[s]uch inhibitors [i.e. compounds that block alpha-synuclein aggregation] could be useful as PD therapeutics if aggregation of alpha-synuclein is a critical step in all forms of PD" (see page 9846, right column).

15. Document D49 states on page 711, right column: "Interestingly, preliminary observations suggest that transgenic mice overexpressing alpha-synuclein develop inclusion bodies and dopaminergic deficits (Figure 3), supporting the contention that abnormal aggregation of alpha-synuclein might play a central role in LBD." Based on this finding the authors put forward a model in which "intracellular NACP/alpha syn aggregation" plays a central role for the pathology of the disease (see Figure 4, reproduced below).

FORMULA/TABLE/GRAPHIC

16. The preliminary results referred to in the review D49 were published in document D58. In its final sentence the authors state: "increased expression or intracellular accumulation of wild-type alpha-synuclein may play a key role in the pathogenesis of these conditions".

17. Document D2 states in paragraph [0008] that "[r]ecent studies on transgenic animals [D58] also suggest that aggregation of alpha-synuclein is harmful to neurons" and in paragraph [0024] that "decrease in the amount of aggregation indicates that the agent is capable of inhibiting the aggregation of alpha-synuclein, and thus that the agent would be useful in the treatment of the disease".

18. Document D3 shows that beta-synuclein overexpression in alpha-synuclein transgenic mice resulted in a reduction of neuronal inclusions, that this was accompanied by a reduction in neuronal loss, and that this was indicative of potential as an anti-Parkinsonian therapeutic.

19. In document D4 it is stated that "inhibition of alpha-synuclein aggregation may represent a feasible therapeutic strategy in LBD and related disorders" (see page 213, final paragraph).

20. In document D5 it is noted with reference to document D4 that "[t]here is a clear correlation between decrease in alpha-synuclein inclusion bodies and an improvement in motor function, which has been described elsewhere" (see page 66, right column).

21. The patent illustrates why alpha-synuclein was likely to be a causative agent for Lewy body diseases as follows:

"(1) this protein accumulates in LBs (Spillantini et al., Nature (1997) 388:839-40 [D84]; Takeda et al., AM. J. Pathol. (1998) 152:367-72; Wakabayashi et al., Neurosci. Lett. (1997) do239:45-8), (2) mutations in the alpha-SN gene co-segregate with rare familial forms of parkinsonism (Kruger et al., Nature Gen. (1998) 18:106-8; Polymeropoulos MH, et al., Science (1997) 276: 2045-7 [D85]) and, (3) its overexpression in transgenic mice (Masliah et al., Science (2000) 287:1265-9 [D58]) and Drosophila (Feany et al., Nature (2000) 404:394-8) mimics several pathological aspects of PD" (see paragraph [0005]).

22. From this collection of scientific and patent literature alone, the board is convinced that, at the priority date, there was agreement that the intracytoplasmic Lewy body potentially caused neurodegeneration. The development of a mouse model in which human alpha-synuclein was overexpressed, and which not only showed intracellular accumulation of alpha-synuclein but also some of the pathological symptoms associated with Parkinson's disease, was considered in the field to be a confirmation of this hypothesis. Compounds that block alpha-synuclein aggregation were already suggested as therapeutics for Parkinson's disease (see document D86).

Referred to in the decision under appeal and by the former opponent

23. The former opponent cited a number of documents (D7, D30 and D50 to D53) which were also relied upon by the opposition division (see point 19.3.6 of the decision). However, in the board's view, these documents rather strengthen the view that alpha-synuclein is a causative agent for Lewy body diseases.

24. In document D7 it is said that "the results obtained in both model systems strongly suggest that the accumulation of wild-type and/or mutant alpha-synuclein in neurons plays a causal role in PD" (page 388, top of third column).

25. Document D50 summarises that "[a] series of evidences indicate that abnormal accumulation and aggregation of alpha-synuclein, a presynaptic protein, play a primary role in PD pathogenesis. Lewy's bodies, the round intracellular inclusions that form in degenerating neurons, are composed by polymers of full-length alpha-synuclein [13]; point mutations of alpha-synuclein gene are associated with early-onset familial PD [9,11,12]; mutant alpha-synuclein proteins show an increased tendency to form detergent insoluble filaments as well as a higher toxicity than wild type peptide in cultured neurons [4]" (see page 65, left column).

26. The authors of document D51 state that "[t]he causal role of alpha-synuclein aggregation in PD is supported by the finding that the mutations (A53T and A30P) associated with familial PD influenced the self-aggregation capacity of the protein. ... Although ... alternative explanations have been proposed for the pathogenic mechanism associated with the protein mutations, our data indicate that alpha-synuclein aggregation is a pathological event potentially sufficient to cause dopaminergic cell death" (see page 639, left column, first full paragraph), and finally: "The results of this study show the potential neurotoxic effects of alpha-synuclein aggregation" (see page 639, left column, second full paragraph).

27. Document D52 states on page 3344, right column that both "extreme models" might be correct, namely that "fibrils are an epiphenomenon linked to disease" and that "fibril formation causes disease" (see also Figure 2).

28. Document D53 summarises that "[e]ither the alpha-synuclein fibril itself or a protofibrillar species could be responsible for cell death in PD (18). The identification of the toxic species and characterization of its mechanism of action would provide novel therapeutic targets" (see page 7812, left hand column). It further finds that "[t]he correlation between fibrillar alpha-synuclein (Lewy bodies) and cell death in Parkinson's disease appears to reflect a causal link" (see page 7815, right hand column), and "[c]ompounds that inhibit the conversion of monomer to protofibril could be novel therapeutics against Parkinson's disease" (see page 7818, left column).

29. Finally, document D30, published shortly before the priority date, discloses a vaccine strategy against Parkinson's disease which targets alpha-synuclein. The authors report the administration of recombinant alpha-synuclein to mice and rats resulting in a considerable antibody titer against the synuclein protein.

30. In summary, in contrast to the opposition division, the board is persuaded that the skilled person was made aware by the body of knowledge evidenced above of a link between the reduction of alpha-synuclein aggregation and the treatment of Lewy body disease.

31. Thus, the board also endorses the appellants' summarising statement that "[reduction of] aggregation was an accepted measure of likely therapeutic effects".

Relevant disclosure of the patent

32. The relevant disclosure in the patent referred to in the decision under appeal is found in Examples I and II.

33. The opposition division held that the results of Example I, active immunisation with alpha-synuclein, were not appropriate to demonstrate that a reduction in alpha-synuclein aggregations was linked to the anti-alpha-synuclein titers, because:

(i) The number of animals in each group was small, i.e. it comprised only four animals.

(ii) The results of Example I displayed in Table 1 did not comprise any statistical assessment of their significance.

(iii) The ranges of antibody titers displayed in Table 1 greatly overlapped so that no trend towards a link between titer and reduction could be derived.

34. It is the board's view that the skilled person would have derived from the prior art that reduction of aggregates was "an accepted measure of likely therapeutic effects" on Lewy body diseases (see point 30. above). The experimental set-up of Example I and its results have to be seen against this background.

35. Moreover, the disclosure in paragraph [0157] of the patent and in Figure 2 and Table 1, both relating to Example I, should not be neglected.

36. Paragraph [0157] discloses: "Neuropathological analysis showed that mice producing high titers had a marked decrease in the size of synuclein inclusions. Mice producing moderate titers showed a smaller decrease. ... Fig. 2 shows synuclein inclusions in panel (b) [CFA only] but not panel (a)[non-transgenic]. In panel (c), treated mouse, moderate titers, the inclusions are somewhat reduced in intensity. In panel (d) the inclusions are markedly reduced in intensity."

37. The immuno-stained brain sections shown in Figure 2, and even better in its reproduction in document D57, show a trend inversely correlating antibody titer and alpha-synuclein inclusions. This is reflected qualitatively by the size, number and intensity of the inclusion bodies in the figure.

38. As regards point (iii) above, i.e. the issue that the ranges of alpha-synuclein-positive aggregates per mm**(2) brain tissue in Table 1 overlap, the board agrees that there is a certain overlap: no antibody: 18-29, low antibody titer: 15-29, high antibody titer: 10-22. However, like in Figure 2, a clear trend towards lower numbers of Syn(+) inclusions/mm**(2) in relation to higher antibody titers is also recognisable here. Thus, the data in Table 1 quantitatively support the data from Figure 2.

39. Hence, in view of the combined qualitative and quantitative data in Figure 2 and Table 1, the skilled person would have concluded that Example I of the patent shows that active immunisation with full-length human alpha-synuclein results in the production of high titer anti-alpha-synuclein antibodies that cross the blood-brain barrier and reduce the size, number and intensity of alpha-synuclein inclusions in or attached to neurons in the brain of vaccinated mice.

40. As regards points (i) and (ii) in point 33. above, the board considers that the lack of statistical information and the small number of animals would not have diminished the credibility of the results of Example I, because they build upon what the skilled person would have expected from the prior art, namely that a link existed between the reduction of alpha-synuclein aggregation and the treatment of Lewy body disease.

41. As regards the use of antibodies against alpha-synuclein for the treatment of Lewy body diseases (see point 7. (ii) above), i.e. the so-called passive immunisation, the opposition division held that the experimental set-up of Example II was not representative for such a treatment.

42. Whether this is the case for Example II or not, the board considers that the results of Example I also support the suitability of the claimed compounds for passive immunisation because endogenous antibodies generated in the peripheral system and detectable in the blood were able to cross the blood-brain barrier and act in the brain (see titers in Table 1 and effect on inclusions in Figure 2). The skilled person would therefore have concluded that antibodies administered peripherally (passive immunisation) would achieve a similar effect. This conclusion is further supported by the data obtained in vitro in Example II which show an effect of polyclonal antibodies on alpha-synuclein inclusion bodies attached to membranes by immuno-staining of cells (Figure 3) and by Western blot of cellular fractions (Figure 4).

43. In conclusion, the data in the patent support the hypothesis developed in the patent that active and passive immunisation targeting alpha-synuclein can reduce synuclein inclusion bodies in the brain. Together with the comprehensive body of knowledge in the prior art (see points 13. to 29. above), the medical use of claim 1 is thus plausible.

Further support by later published evidence

44. The following evidence, published after the relevant date of the application, further supports the appellants' position that the findings in the decision under appeal were not correct.

45. Document D55 summarises a number of clinical trials (see page 205, Table 1) and states: "Immunotherapy using antibodies targeting alpha-synuclein has proven to be an effective strategy for ameliorating pathological and behavioural deficits induced by excess pathogenic alpha-synuclein in various animal and/or cellular models" (see Abstract). The authors conclude: "In summary, these studies provide support for alpha-synuclein antibodies being able to target both extracellular and intracellular alpha-synuclein" (see page 207, left column, end of first full paragraph).

46. Document D56 discusses the utility of vaccination as a potential treatment for synucleinopathies. It summarises a number of preclinical results using full-length or fragments of alpha-synuclein (see Table 2), as well as clinical studies involving short peptides that mimic a region of the alpha-synuclein molecule (see Table 3). Despite stating in the introduction that "[a]ll [synucleinopathies] lack a causal therapy", this document lists a number of vaccination strategies targeting alpha-synuclein and states: "Evidence is mounting for a causative role of alpha-Syn, especially in PD and MSA (Table 1)" (see page 214, right column).

47. Document D91 reports preliminary results of a phase 2 study (clinical trial NCT03100149) using an antibody against an epitope in the C-terminus of alpha-synuclein (PRX002/prasinezumab). Prasinezumab demonstrated "signals of efficacy on multiple pre-specified secondary and exploratory clinical endpoints, including measures of motor function and biomarkers, in patients with early Parkinson's disease" and "[s]ignificantly reduced decline in motor function by 35% vs. placebo at one year and delayed time to clinically meaningful worsening of motor progression over one year".

48. The board concludes that the use of compositions comprising alpha-synuclein or an immunogenic fragment of it, or an antibody to alpha-synuclein or to an immunogenic fragment of it, for therapy of Lewy body diseases is also supported by later published evidence in which such therapies were and still are developed.

Conclusion

49. In view of the observations above, the board concludes that the reasons given in the decision under appeal, for holding that the invention claimed in claim 1 was not disclosed in a manner sufficiently clear and complete for it to be carried out by the skilled person, do not hold. Hence, the decision under appeal is to be set aside.

Remittal

50. Under Article 111(1) EPC, the board of appeal may either decide on the appeal or remit the case to the department which was responsible for the decision appealed.

51. In the present case, the opposition division decided on added subject-matter (Articles 100(c) and 123(2) EPC) and sufficiency of disclosure (Articles 100(b) and 83 EPC) but not on priority (Article 87 EPC), novelty (Article 54 EPC) and inventive step (Article 56 EPC).

52. It is the primary purpose of the appeal proceedings to review the decision under appeal in a judicial manner (see Article 12(2) RPBA 2020). It would run counter to this purpose of appeal proceedings if the boards were required to examine questions regarding the patentability of the claimed subject-matter which have not yet been decided on by the department of first instance. Also, in view of the fact that appeal proceedings are less investigative than first-instance proceedings, it appears more appropriate to remit the case for consideration of undecided issues of patentability unless there are good reasons to depart from this course. However, there were none in the present case. The board therefore allows the appellants' request for remittal of the case to the opposition division.