T 0713/08 (Neurotrophins/H. LUNDBECK A/S) 24-10-2012

Reasons for the Decision

1. The appeal is admissible.

Main request - Article 123(2) EPC

2. The main ground for the refusal of the patent application was the finding that the subject-matter of claim 1 of the main request before the examining division did not comply with the requirements of Article 123(2) EPC.

3. Before the examining division the applicant had indicated as a basis for claim 1 of the main request then on file (see section III, above) inter alia the passages on page 27, lines 26 to 31 (in particular: "the agent may be capable of inhibiting the binding of said neurotrophin or said pro-neurotrophin to a Vpsl0p-domain receptor by binding to an extracellular part of the receptor, an intracellular part of the receptor, or a segment of the transmembrane part of the receptor"), taken in combination with the passages on page 32, lines 10 to 12: "Accordingly, agents of the present invention may be utilized in methods for the treatment of a variety of neurological diseases and disorders."

4. The examining division decided however that these two passages taken together failed to provide a direct and unambiguous link between the diseases to be treated and the agent to be used. The agents to be used were disclosed in the application either to inhibit the binding of a neurotrophin or a pro-neurotrophin (which have opposing effects) to the receptor and as a consequence decrease their activity, or to bind to the receptor and increase their activity. Also claim 13 as originally filed, the passage on page 27, lines 1 to 14 and the passage on page 31, line 26 onwards ("capable of interfering with binding between a receptor of the Vpsl0p-domain receptor family and a neurotrophin and/or pro-neurotrophin") left the choice between a neurotrophin and/or pro-neurotrophin inhibitor open. A direct and unambiguous link between the specific inhibition of the binding of a pro-neurotrophin to a Vpsl0p-domain receptor and the specific treatment of neurological diseases and disorders was also not derivable from claim 27 as originally filed as this claim mentioned neural disorders among other diseases. Claim 1 thus related to a new combination of features, which as such was neither disclosed nor directly and unambiguously derivable from the originally filed application.

5. Claim 1 of the main request before the board has been amended as compared to claim 1 of the main request before the examining division essentially by defining the agent which is capable of inhibiting the binding of a pro-neurotrophin (now e.g. proNGF) to a defined Vpsl0p-domain receptor (now sortilin) to be an antibody directed against an extracellular part of sortilin. The antibody is now claimed "for use in treating a neurological disease or disorder in an individual".

6. The board therefore notes that besides the more detailed description of the pro-neurotrophin (now e.g. proNGF) concerned and the Vpsl0p-domain receptor (now sortilin), and the change of the claim format from a second to a first medical use, the amended claim still relates to a specific combination of the inhibition of the binding of a pro-neurotrophin to a Vpsl0p-domain receptor by binding of an agent to the extracellular part of the receptor in the treatment of a neurological disease or disorder. The reasoning of the examining division would therefore still be applicable to this claim.

7. In accordance with established case law of the Boards of Appeal, the relevant question to be decided in assessing whether an amendment adds subject-matter extending beyond the content of the application as filed is whether the proposed amendment is directly and unambiguously derivable from the patent application as filed.

8. In a primary line of argumentation the appellant has referred to a combination of various claims as originally filed which when taken in combination supported claim 1. However, the board notes that when combining the various embodiments of the claims as recited in section II, above, it transpires that the specific subject-matter of claim 1 can only be derived therefrom when making a variety of specific selections from the lists of embodiments which are the subject of these claims. By way of example the board refers to claim 12 as filed in which antibodies are listed among other candidate inhibitory binding compounds; to claim 13 as filed, in which a choice has to be made between pro-neurotrophin and neurotrophin and to claim 27 as filed where neuronal diseases are merely one of the numerous diseases listed to be treated.

9. Accordingly, the claims as originally filed cannot provide a basis for claim 1 to comply with the requirements of Article 123(2) EPC.

10. In a second line of argumentation the appellant has referred to the description of the patent application as a whole to support the insight of the skilled person that the claimed subject-matter was disclosed in a clear and unambiguous manner.

11. The following disclosures in the patent application as originally filed are of relevance for the assessment of this argument.

11.1 The paragraph bridging pages 1 and 2 discloses that according to then current knowledge neurotrophins bind to two discrete receptor types which can be distinguished pharmacologically, i.e. the Trk and p75**(NTR)neurotrophin receptors, and (see page 2, line 30 to page 3, line 4) that they are of clinical interest as they play an important role in neuronal cell survival and differentiation. Trk receptors transmit signals promoting neuronal survival, whereas p75**(NTR) can induce neuronal apoptosis as well as neuronal survival depending on any co-expression of TrkA, i.e. activation of the TrkA receptors can negate the proapoptotic effect of p75**(NTR). By reference to Lee at al. 2001 (Science, Vol. 294, pages 1945-1948) the application further states that it is probable that propeptides of neurotrophins play important biological roles: pro-neurotrophin and its proteolytically processed and mature counterpart product differentially activate pro- and anti-apoptotic cellular responses through preferential activation of p75**(NTR) and Trk receptors, respectively, whereby pro-neurotrophin has an enhanced affinity for p75**(NTR) receptors and a reduced affinity for Trk receptors relative to the mature forms of the neurotrophin. It had been demonstrated that pro-NGF induced p75**(NTR)-dependent apoptosis in cultured neurons with minimal activation of TrkA-mediated differentiation or survival (page 3, lines 5 to 13).

11.2 Concerning the understanding of the role of the Vps10p-domain receptor family members, such as sortilin, the application discloses a possible involvement in Golgi-endosome sorting (page 4, line 25 to page 3, line 2).

11.3 In general terms the application states at page 5, lines 23 to 32, that the invention relates to "a method for modulating the activity of at least one neurotrophin and/or pro-neurotrophin in an animal comprising administering to said animal a sufficient amount of an agent capable of (i) binding to a receptor of the Vps10p-domain receptor family and or (ii) interfering with binding between a receptor of the Vps10p-domain receptor family and a neurotrophin and/or pro-neurotrophin (...)".

11.4 In the Figures and their corresponding legends (page 6, line 9 to page 8, line 17) various experiments are disclosed whereby the in vitro binding of inter alia the neurotrophin NGF, its proneurotrophin proNGF or the propeptide as such to p75, TrkA and sortilin is measured (see Figures 2 to 4 and page 6, lines 12 to page 7, line 12) demonstrating a preferential binding of proNGF to sortilin and a low binding affinity of NGF for sortilin.

11.5 In a section called "Detailed description" on page 24 the application re-iterates that the "inventors have identified that neurotrophins bind to receptors of the Vps10p-domain receptor family. Accordingly, the present invention relates to modulation of the activity of at least one neurotrophin." (page 24, lines 6 to 8). It then continues on page 24, lines 10 to 28:

"Without being bound by theory it is believed that Vps10p-domain receptor family is involved in one or more of the following mechanisms in relation to neurotrophins:

- Retrograde transport, including uptake of proneurotrophin, neurotrophin and p75

- Transport within biosynthetic pathways, including sorting of proneurotrophin and transport from the Golgi network

- Release of neurotrophins

- Signalling, including modulation of cellular transport and signalling by formation of ternary complexes with p75 and neurotrophin or pro-neurotrophin

Thus, one aspect of the present invention is a method for modulating the activity of at least one neurotrophin and/or a pro-neurotrophin in a single cell or an organism, including an animal, comprising administering to said animal a sufficient amount of an agent capable of binding to a receptor of the Vps10p-domain receptor family or capable of interfering with binding between a receptor of the Vps10p-domain receptor family and a neurotrophin and/or proneurotrophin."

11.6 In the following sections of the description the terms "Receptors of the Vps10p-domain receptor family" (page 24, line 30 to page 25, line 4) and "Neurotrophins" and "Pro-neurotrophins" (page 25 line 6 to 19) are defined. In the subsequent section "Modulation of neutrophin activity" on page 25, line 21 to page 26, line 7, the application defines that the "terms "neurotrophin-mediated" activity, "activity of a neurotrophin" or "neurotrophin activity" refer to a biological activity that is normally promoted, either directly or indirectly, in the presence of a neurotrophin or a proneurotrophin." It is then stated that "Neurotrophin activities include, but are not restricted to, neuronal survival, neuronal differentiation including process formation and neurite outgrowth, biochemical changes such as enzyme induction, involvement in depression and antidepressant action, involvement in accelerating nerve process growth, and involvement in decreasing general cell motility. It has been hypothesized that the lack of neurotrophic factors is responsible for the degeneration of selective neuronal populations as it occurs in Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis." The application then continues that "[t]he activities of pro-neurotrophins include, but are not restricted to, differentially activating both pro- and anti-apoptotic cellular responses, through preferential activation of p75 or TrkA receptors respectively."

11.7 In a following section entitled "Agents capable of modulating activity" starting on page 26, line 15, various "preferred embodiments" of the invention are disclosed such as inter alia (page 26, lines 17 to 23):

"In one preferred embodiment of the present invention, an agent is administered to the animal, said agent being capable of modulating the binding between a receptor of the Vps10p-domain receptor family and a neurotrophin and/or proneurotrophin.

In another, equally preferred embodiment, the agent is capable of binding to a receptor of the Vps10p-domain receptor family or a neurotrophin and/or pro-neurotrophin thereby interfering with the activity of a neurotrophin, either directly or indirectly."

Further on page 26, in line 33, it is then specified that the agent may be a antibody or a polypeptide.

On page 27, lines 1 to 9, it is continued that "(...) the agent administered to the animal is capable of modulating the activity of a sortilin receptor in relation to a neurotrophin, said activity may be, but is not restricted to, one or more of the following:

i) cellular sorting of the receptor

ii) receptor binding directly or indirectly by ligand bridging to other receptors, such as the p75 and Trk receptors

iii) sortilin receptor signalling".

In the following paragraphs (page 27, line 11 to page 28, line 6) it is then stipulated that the agent may be "capable of inhibiting binding of a neurotrophin or pro-neurotrophin to a receptor of the Vps10p-domain receptor family" either by binding to the neurotrophin and/or proneurotrophin or by binding to an extracellular part of a receptor of the Vps10p-domain receptor family, whereby an example is an antibody directed against an extracellular part of the receptor which sterically blocks the binding of the neurotrophin and/or proneurotrophin to the receptor.

11.8 "Methods for treating a disease or disorder" are dealt with on page 31, line 26 to page 34, line 20 and are stated to comprise "administering to said individual, in a pharmaceutically acceptable carrier, a sufficient amount of an agent capable of interfering with binding between a receptor of the Vps10p-domain receptor family and a neurotrophin and/or proneurotrophin" (page 31, lines 30 to 32). In the following paragraph it is stated that the "[a]gents of the present invention are believed to be useful in promoting the development, maintenance, or regeneration of neurons in vitro and in vivo, including central (brain and spinal chord), peripheral (sympathetic, parasympathetic, sensory, and

enteric neurons), and motor neurons. Accordingly, agents of the present invention may be utilized in methods for the treatment of a variety of neurological diseases and disorders." The description subsequently refers to a variety of diseases in which "the agents of the invention" can be used and then concludes on page 34, lines 18 to 20, that "[a]ccordingly, a method of treating a neural disorder in a mammal comprising administering to the mammal a therapeutically effective amount of one or more agents of the present invention is provided."

12. The board concludes that, as far as the function of the binding partners are concerned and as can be taken from points 11.1 and 11.2, above, it was known in the art that pro-neurotrophin and neurotrophin differentially activate pro- and anti-apoptotic cellular responses, respectively. It was furthermore known that relative to neutrophin, pro-neurotrophin had a higher affinity for p75**(NTR) and a reduced affinity for Trk receptors. In addition it was thought that Vps10p-domain receptor family members were possibly involved in Golgi-endosome sorting. The application now demonstrates, see point 11.4, above, that sortilin binds preferentially to proNGF over NGF. The inventors conclude (see point 11.5, above) that accordingly the invention relates to the modulation of the activity of at least one neurotrophin and postulate the involvement of Vps10p-domain receptor family members in a number of activities, which are more refined in relation to neurotrophin in the sections mentioned in point 11.7, above. The passages referred to in points 11.5 to 11.7, above, do not, however, disclose that the binding of any specific (pro-) neurotrophin to Vps10p-domain receptor family members has a direct bearing on a specific medical use let alone a treatment for a disease or disorder. The board considers furthermore that this lack of a disclosure of this link is not remedied by the mere disclosure of a number of possible activities of neurotrophin as referred to in point 11.6, above, because there is no clear and direct link with the binding of the neurotrophin to a Vps10p-domain receptor family member disclosed. Indeed, the passage referred to in point 11.6, above, merely refers to the binding with p75 and Trk receptors and not with sortilin.

13. In view of the above considerations, the board considers that the skilled person would read the crucial passages in the description of the patent application (see point 11.8, above) rather as a general listing of possible diseases in which agents of the invention could well be applied based on the generally known functions of neurotrophins, rather than a specific disclosure of the use of antibodies, directed against the extracellular part of sortilin for the inhibition of the binding of specifically pro-neurotrophins to a member of the Vps10p-domain receptor family in the treatment of neurological diseases or disorders. Accordingly, the application does not disclose a clear and unambiguous link between the use of any particular antibody and any particular disease group.

14. The appellant has extensively argued that in view of the disclosure of the patent application the skilled person reading the specification would inevitably be lead to conclude that the inhibition of the binding of proNGF to sortilin resulted in an inhibition of the effects of pro-neurotrophin. In this respect the board notes however that, for the assessment of the compliance of a claim with the requirements of Article 123(2) EPC, it is not of relevance which technical teaching is rendered obvious to a skilled person by a disclosure, but rather the subject-matter which the skilled person in fact can derive from this disclosure in a clear and unambiguous manner, be it implicitly or explicitly (see e.g. decision T 329/99 of 5 April 2001, see point 4 of the reasons for the decision).

15. The board concludes therefore that in the light of the above analysis no teaching can be derived from the patent application as filed which in a clear and unambiguous manner links the inhibition of the binding of specifically pro-neurotrophin selected from pro-NGF, pro-BDNF, pro-NT-3 or pro-NT-4/5 to a receptor of the Vps10p-domain receptor family (sortilin) to the treatment of neurological diseases or disorders.

16. Accordingly, claim 1 does not comply with the requirements of Article 123(2) EPC.

First auxiliary request - Article 123(2) EPC

17. The above considerations apply mutatis mutandis to claim 1 of the first auxiliary request. The appellant agreed to this finding. Accordingly, this point needs no more reasoning. Claim 1 therefore does not comply with the requirements of Article 123(2) EPC.

Second auxiliary request - admissibility into the proceedings

18. The second auxiliary request (see section VI, above) was filed by the appellant in response to the board's communication in preparation for the oral proceedings. In this communication the board had indicated its preliminary opinion that the claim requests as filed with the statement of the grounds for appeal did not remedy the deficiencies under Article 123(2) EPC invoked by the examining division in its decision.

19. The subject-matter of claim 1 of this request is, unlike claim 1 of the main and auxiliary requests, substantially different from the former requests in that it concerns the use of antibodies directed against the extracellular part of sortilin for inhibiting the binding of pro-neurotrophins to sortilin. The claim is now devoid of any direct reference to a specific disease to be treated or activity to be impaired by the inhibition of the binding.

20. The board considers that such an attempt by the appellant to overcome the objections under Article 123(2) EPC could have been made during the first instance stage of these proceedings, or upon filing the appeal at the latest. If only for these reasons it would be within the discretion of the board to hold the second auxiliary request inadmissible pursuant to Article 12(4) RPBA.

21. Furthermore, the board doubts the straightforward allowability of the claims of this second auxiliary request as their subject-matter appears to raise questions to be dealt with inter alia under Article 53(c) EPC as well as under Article 57 EPC. Accordingly, and also in view of Article 13 RPBA, the board decides not to admit the second auxiliary request into the proceedings.

22. In view of the above findings, the board decides that the appeal cannot be granted.