|European Case Law Identifier:||ECLI:EP:BA:2020:T096618.20201110|
|Date of decision:||10 November 2020|
|Case number:||T 0966/18|
|IPC class:||A61K 38/17
|Language of proceedings:||EN|
|Download and more information:||
|Title of application:||Prevention and treatment of synucleinopathic disease|
|Applicant name:||Prothena Biosciences Limited
The Regents of the University of California
|Opponent name:||H. Lundbeck A/S|
|Relevant legal provisions:||
|Keywords:||Sufficiency of disclosure - (yes)
Appeal decision - remittal to the department of first instance (yes)
Summary of Facts and Submissions
I. The appeal of the patent proprietors ("appellants") lies from the opposition division's decision to revoke European patent No. 1 578 253 ("the patent"). The patent is entitled "Prevention and treatment of synucleinopathic disease".
II. An opposition was filed against the patent. The patent was opposed under Article 100(a) EPC on the grounds of lack of novelty (Article 54 EPC) and lack of inventive step (Article 56 EPC), and under Article 100(b) and 100(c) EPC.
III. The opposition division decided that claim 3 of the main request (claims as granted) infringed the requirements of Article 123(2) EPC, and that the invention to which the set of claims of auxiliary request 1 (filed during the oral proceedings) related was not disclosed in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art (Article 83 EPC).
IV. With the statement of grounds of appeal, the appellants filed documents D88 and D89 and a set of claims of a main request (corresponding to auxiliary request 1 on which the decision under appeal was based) and conditionally requested oral proceedings.
Claim 1 of the main request reads:
"1. A pharmaceutical composition comprising an agent that induces an immunogenic response against alpha-synuclein, for use in prophylaxis or treatment of a disease characterized by Lewy bodies or alpha-synuclein aggregation in the brain, wherein the agent is alpha-synuclein or an immunogenic fragment thereof or an antibody to alpha-synuclein or an immunogenic fragment thereof, and wherein the disease is Parkinson's disease, dementia with Lewy bodies, diffuse Lewy body disease, pure autonomic failure, Lewy body dysphagia, incidental Lewy body disease, inherited Lewy body disease or multiple system atrophy."
V. The opponent filed a reply to the statement of grounds of appeal and document D90 and subsequently withdrew their opposition with a letter dated 2 May 2019.
VI. The appellants replied to the opponent's reply. With a further submission the appellants filed document D91.
VII. The board summoned the appellants to oral proceedings as requested and informed them of its preliminary opinion in a communication pursuant to Article 15(1) RPBA.
In point 11 of this communication, the board indicated that it considered the claims of the main request to comply with the requirements of Article 123(2) EPC.
In points 12 and 13, the board drew attention to issues relating to sufficiency of disclosure and its intention to hear the appellants on these issues at the oral proceedings.
VIII. Oral proceedings before the board took place on 10 November 2020 in the form of a videoconference as requested by the appellants. At the end of these proceedings, the chair announced the board's decision.
IX. The following documents are cited in the present decision:
D2 |US 2002/151464 |
D3 |WO 01/60794 |
D4 |Hashimoto, M. et al., Neuron, 2001, vol. 32(2), 213-223 |
D5 |Windisch, M. et al., Journal of Molecular Neuroscience, 2002, vol. 19(1-2), 63-69 |
D7 |Wanker, E. E., Molecular Medicine Today, 2000, vol. 6, 387-391 |
D17|Solomon, B., Current Medicinal Chemistry, 2002, vol. 9, 1737-1749 |
D26|WO 99/27944 |
D30|Cao, C. et al., Neuroscience, 2002, Abstract with proof of publication (published online on 27 August 2002) |
D43|Decision dated 24 July 2013 in the opposition proceedings against EP 1 994 937 |
D44|Bae, E.-J. et al., The Journal of Neuroscience, 2012, vol. 32(39), 13454-13469 |
D49|Hashimoto, M. et al., Brain Pathology, 1999, vol. 9, 707-720 |
D50|Borghi, R. et al., Neuroscience Letters, 2000, vol. 287, 65-67 |
D51|Forloni, G. et al., Ann. Neurol., 2000, vol. 47, 632-640 |
D52|Lansbury, P., Proc. Natl. Acad. Sci. USA, 1999, vol. 96(7), 3342-3344 |
D53|Volles, M. J. et al., Biochemistry, 2001, vol. 40, 7812-7819 |
D54|Bard, F. et al., Proc. Natl. Acad. Sci. USA, 2003, vol. 100(4), 2023-2028 |
D55|Bergström, A.-L. et al., Movement Disorders, 2016, vol. 31(2), 203-213 |
D56|Schneeberger, A. et al., Movement Disorders, 2016, vol. 31(2), 214-224 |
D58|Masliah et al., Science, 2000, vol. 287(5456), 1266-1269 |
D61|Games, D. et al., The Journal of Neuroscience, 2014, vol. 34(28), 9441-9454 |
D62|Declaration of Eliezar Masliah, undated |
D70|Decision of Opposition Division on EP 2 305 282 |
D76|Additional data on antibody seeding assay |
D77|Dufty, B. et al., American Journal of Pathology, 2007, vol. 170, 1725-1738 |
D78|Doucet, M. et al., PLOS ONE, 2017, 1-25 |
D79|Brody, D. et al., Annual Review of Neuroscience, 2008, vol. 31, 175-193 |
D80|Kohyama, K. et al., ImmunoTargets and Therapy 2015, vol. 4, 27-34 |
D82|Declaration of Patrik Brundin, 30 November 2017 |
D84|Spillantini M., et al., Nature, 1997, vol. 388, 839-840 |
D85|Polymeropoulos, M. et al., Science, 1997, vol. 276, 2045-2047 |
D86|Narhi, L. et al., Journal of Biological Chemistry, 1999, vol. 274, 9843-9846 |
D88|Declaration of Wagner Zago, 2 August 2018 |
D89|New Alzheimer's and Parkinson's Immunotherapy Data at AAN (4th May 2018) - https://www.alzforum.org/news/conference-coverage/new-alzheimers-and-parkinsons-immunotherapy-data-aan |
D90|Declaration by Anne Messer (including CV), 16 December 2018 |
D91|Prothena press release, September 2020|
X. The reasoning in the decision under appeal regarding lack of sufficiency of disclosure is summarised as follows.
According to the relevant case law, see for example T 609/02, it is not always necessary that results of applying the claimed composition in clinical trials, or at least to animals are reported. Yet, this does not mean that a simple verbal statement in a patent specification is enough to ensure sufficiency of disclosure in relation to a claim to a pharmaceutical.
In that decision the board also stated that the patent has to provide some information, for example in the form of experimental tests, to the avail that the claimed compound has a direct effect on a metabolic mechanism specifically involved in the disease, this mechanism being either known from the prior art or demonstrated in the patent.
Showing a pharmaceutical effect in vitro might be sufficient if for the skilled person this effect directly and unambiguously reflects such a therapeutic application, or if there is a clear and accepted relationship between the shown physiological activities and the disease.
In the present case, the most important question was whether, for the skilled person, the effect of a reduction of alpha-synuclein aggregates reflected directly and unambiguously the therapeutic application referred to in the claim, i.e. a treatment of a Lewy body disease.
In the prior art, reduction of alpha-synuclein aggregation had been achieved by alpha-synuclein-binding peptides and antibodies (documents D1 and D2, respectively).
Document D30 disclosed that, by vaccination with alpha-synuclein, considerable antibody titers were created, but an effect on aggregates was not measured.
It was not contested that alpha-synuclein aggregation was known to be linked to Lewy body diseases. However, at the filing date, there was a lack of understanding about what the role of these aggregates was in the pathology of Lewy body diseases.
In view of documents D50 to D53, the skilled person would not come to the conclusion that targeting the aggregations was the first choice for a treatment; other mechanisms could be useful targets.
Thus, a clear and accepted relationship between alpha-synuclein aggregates as the cause of the disease was not known from the prior art.
Disclosure in the patent
Example I described active immunisation with human alpha-synuclein by injecting peripherally human alpha-synuclein in a mouse model of Lewy body disease. Injected mice were divided into three groups of four animals according to their antibody titer (low, high, none).
Injected alpha-synuclein elicited a decrease in alpha-synuclein inclusion formation in the brain tissue of the mice, as disclosed on page 27, line 43 and lines 48 to 49, and shown in Figure 2 (and the reproduction of it - document D57).
Table 1 indicated that the number of animals in each group was only four, i.e. very small, and the statistical significance of the results was not disclosed.
Moreover, the number of synuclein-positive inclusions per mm**(2) brain tissue as shown in Table 1 largely overlapped in the three groups. A trend towards a dose-dependent reduction of inclusions by vaccination could not be identified from Table 1.
Therefore, and because the skilled person knew about the biological variability of in vivo animal models, the data of Table 1 did not credibly demonstrate successful active immunisation, i.e. neither a reduction of aggregations nor that it was linked to anti-alpha-synuclein titers.
Example II disclosed the use of mouse neuronal GT1-7 cells having mouse alpha-synuclein-inclusions associated with the cell surface - which includes cell membranes and intracellular membranes (see Figures 3c and 3d and Figure 4) - for screening for alpha-synuclein antibodies able to clear these inclusions from the membranes. One of the tested antibodies showed clearing activity.
Hence, the experimental set-up of Example II was not representative for passive immunisation as no in vivo data were provided, and it thus had not been shown whether injected antibodies would arrive at the brain to exert their effects.
Consequently, in summary, the patent did not plausibly establish the link between reduction of alpha-synuclein aggregates and treatment of Lewy body disease.
XI. The appellants' arguments submitted in writing and during the oral proceedings, as far as relevant to the decision, may be summarised as follows.
Sufficiency of disclosure (Article 83 EPC)
The board explained in decision T 609/02 that:
i) A mere assertion that compound X is suitable for treating disease Y is not sufficient on its own to render the invention plausible (Reasons 9).
ii) The disclosure of the patent specification does not have to be definitely predictive of the efficacy of the invention: in vitro tests which may well not be reproducible in humans or animals may suffice (Reasons 10 and 11).
iii) The patent should provide some information to the avail that the claimed compound has a direct effect on a metabolic mechanism specifically involved in the disease, an example of adequate support being experimental tests (Reasons 9).
iv) Ultimately the purpose of the requirement of sufficiency is to place the reader in possession of the invention without imposing undue burden on them by way of further investigation or research (Reasons 10).
It was widely accepted at the filing date that alpha-synuclein aggregation was at least one of the causative factors of synucleinopathic diseases.
Reducing alpha-synuclein aggregates was regarded as a treatment of the disease because it reduced an abnormal, characteristic disease pathology (see for example D49, D84, D85, D58).
Disclosure in the patent
Example I showed in vivo - for the first time and using an accepted animal model of synucleinopathies (see document D51) - that immunisation with peripherally administered alpha-synuclein (active immunisation) could provide a dose-dependent "marked decrease" in both the size and intensity of synuclein inclusions, which were, as was known from the prior art, the "hallmark pathology" of synucleinopathic diseases.
Table 1 showed the number of synuclein inclusions per mm**(2) in the three different groups of tested mice (no titer, moderate titers and high titers). The highest titers of anti-human alpha-synuclein antibodies correlated with the lowest levels of synuclein inclusions.
The quantitative results in Table 1 (relating to the number of synuclein inclusions) did not contradict the highly encouraging qualitative results (i.e the dose-dependent marked decrease in both the size and intensity of synuclein inclusions). Thus, the pooled results of Table 1 showed a quantitative trend that was consistent with the trend in qualitative results.
The data in Example I demonstrated that peripherally induced antibodies were involved in the in vivo reduction of alpha-synuclein deposits in the brain, thus providing a mechanistic explanation which supported the plausibility of passive immunotherapy according to the invention.
The patent also provided in vitro data showing that antibodies to alpha-synuclein were effective in clearing or preventing the development of alpha-synuclein inclusions in neuronal cells (Example II) and provided this neuronal cell model as an example of a method by which the skilled person could screen for further antibodies which might be used in the claimed treatment.
The experimental evidence and teaching in the patent made it plausible that immunotherapy targeting alpha-synuclein would be a useful therapeutic strategy for the treatment of synucleinopathies.
The experiments disclosed in the patent represented the initial in vivo proof-of-concept work, using an accepted animal model of synucleinopathies, which led to the development of alpha-synuclein-based active and passive immunotherapies for synucleinopathies. The results in the patent prompted the development and publication of various examples of successful alpha-synuclein-related active and passive immunotherapies for synucleinopathies, some of which were now being pursued in phase 2 clinical trials.
The prior art supported the view that, at the filing date, reduced aggregation would have been considered a credible measure of likely therapeutic effects in treating synucleinopathies.
XII. The appellants request that the decision under appeal regarding auxiliary request 1 (the main request in the appeal proceedings) be set aside and the case be remitted to the opposition division for further prosecution of the remaining grounds of opposition.
Furthermore, the appellants request that documents D88, D89 and D91 be admitted into the proceedings.
Reasons for the Decision
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.
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.
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).
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  that "[r]ecent studies on transgenic animals [D58] also suggest that aggregation of alpha-synuclein is harmful to neurons" and in paragraph  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 ).
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 ; 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 " (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  of the patent and in Figure 2 and Table 1, both relating to Example I, should not be neglected.
36. Paragraph  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.
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.
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.
For these reasons it is decided that:
1. The decision under appeal is set aside.
2. The case is remitted to the opposition division for further prosecution.