T 0908/10: Sufficiency of disclosure second medical use claim
This appeal case discusses inventive step and sufficiency of disclosure as grounds for dismissing the appeal. The Board refused most requests because they lack an inventive step. Auxiliary request 8 has been refused because it lacks sufficiency of disclosure for a second medical use claim in this request. This case shows which disclosure the Board expects in the context of a second medical use claim. In the present case the Board concludes that the skilled person has to set up a complete research program to carry out the invention.
The appeal lies against the interlocutory decision of the opposition division and was filed by the proprietor of the patent (the appellant).
Background / Summary of Facts and Submissions
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IV. With its letter dated 6 July 2010 the appellant filed a statement of grounds of appeal, a main request and auxiliary requests 1 to 9. The claim requests were identical to the corresponding requests underlying the decision under appeal. Claims 1, 9, 10, 11 and 12 of the main request read as follows:
"1. Use of a variant of human prolactin having a substitution of the glycin at position 129 for the preparation of a medicament for inhibiting the proliferation of a breast or prostate cancer cell which expresses a prolactin receptor.
9. A fusion protein comprising a variant of human prolactin which is linked to another protein, wherein the variant has a substitution of the glycine at position 129.
10. A fusion protein according to claim 9, wherein the prolactin variant is linked to interleukin 2.
11. A fusion protein according to claims 9 or 10, wherein the variant has a substitution of the glycine at position 129 with arginine.
12. Use of a fusion protein according to any one of claims 9 to 11 for the preparation of a medicament for treating breast or prostate cancer, wherein said breast or prostate cancer expresses a prolactin receptor."
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"1. Use of a variant of human prolactin having a substitution of the glycin at position 129 for the preparation of a medicament for inhibiting the proliferation of a breast or prostate cancer cell which expresses a prolactin receptor.
9. A fusion protein comprising a variant of human prolactin which is linked to another protein, wherein the variant has a substitution of the glycine at position 129.
10. A fusion protein according to claim 9, wherein the prolactin variant is linked to interleukin 2.
11. A fusion protein according to claims 9 or 10, wherein the variant has a substitution of the glycine at position 129 with arginine.
12. Use of a fusion protein according to any one of claims 9 to 11 for the preparation of a medicament for treating breast or prostate cancer, wherein said breast or prostate cancer expresses a prolactin receptor."
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IX. The appellant's arguments submitted in writing and orally may be summarized as follows:
Main request
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Sufficiency of disclosure: claim 12Claim 12 was drawn up as a second medical use claim and was thus limited to fusion proteins that treated breast or prostate cancer. The opposed patent gave one example of a suitable fusion partner, IL-2, and described in detail how to screen fusion proteins for their ability to inhibit proliferation of breast and prostate cancer cells. Although it was not predictable whether or not a fusion protein possessed the therapeutic effect, the skilled person could design and produce suitable fusion proteins and test them using the assays disclosed in the patent in suit.
Auxiliary requests 1 to 8
No further arguments were submitted relating to these requests.
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Main request
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Sufficiency of disclosure: claim 12Claim 12 was drawn up as a second medical use claim and was thus limited to fusion proteins that treated breast or prostate cancer. The opposed patent gave one example of a suitable fusion partner, IL-2, and described in detail how to screen fusion proteins for their ability to inhibit proliferation of breast and prostate cancer cells. Although it was not predictable whether or not a fusion protein possessed the therapeutic effect, the skilled person could design and produce suitable fusion proteins and test them using the assays disclosed in the patent in suit.
Auxiliary requests 1 to 8
No further arguments were submitted relating to these requests.
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Reasons for the Decision
Main request
Introduction
1. The patent in suit relates to the inhibition of the cell proliferation-promoting effects of prolactin (PRL) on its receptor. The prolactin receptor (PRLR) is a member of the cytokine receptor superfamily and binds a group of hormones, including not only PRL but also growth hormone (GH) (see e.g. document D2, abstract). PRL and GH possess two binding sites for the receptor, termed binding site 1 and binding site 2. Binding of PRL or GH to PRLR is sequential. First the hormone, e.g. PRL, interacts with the receptor through its binding site 1, forming an inactive complex. The hormone then binds to a second receptor through its site 2, which leads to receptor homodimerisation and formation of an active complex (see e.g. document D1, page 10, left hand column, first full paragraph; Figure 3A).
2. By replacing small side chain residues with amino acids carrying large side chains, PRL and GH analogs whose binding sites 2 are sterically hindered and unable to interact with their receptor are generated. With these hormone analogs receptor dimerisation cannot occur and the hormone analog is inactive. Moreover, since such mutants maintain the ability to bind through their binding site 1, they block the receptor in the inactive 1:1 stoichiometry and thus act as hormone antagonists (see document D1, page 10, right hand column, first full paragraph; Figures 3B and 3C).
Inventive step (Article 56 EPC): claim 1
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Introduction
1. The patent in suit relates to the inhibition of the cell proliferation-promoting effects of prolactin (PRL) on its receptor. The prolactin receptor (PRLR) is a member of the cytokine receptor superfamily and binds a group of hormones, including not only PRL but also growth hormone (GH) (see e.g. document D2, abstract). PRL and GH possess two binding sites for the receptor, termed binding site 1 and binding site 2. Binding of PRL or GH to PRLR is sequential. First the hormone, e.g. PRL, interacts with the receptor through its binding site 1, forming an inactive complex. The hormone then binds to a second receptor through its site 2, which leads to receptor homodimerisation and formation of an active complex (see e.g. document D1, page 10, left hand column, first full paragraph; Figure 3A).
2. By replacing small side chain residues with amino acids carrying large side chains, PRL and GH analogs whose binding sites 2 are sterically hindered and unable to interact with their receptor are generated. With these hormone analogs receptor dimerisation cannot occur and the hormone analog is inactive. Moreover, since such mutants maintain the ability to bind through their binding site 1, they block the receptor in the inactive 1:1 stoichiometry and thus act as hormone antagonists (see document D1, page 10, right hand column, first full paragraph; Figures 3B and 3C).
Inventive step (Article 56 EPC): claim 1
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17. In view of the above considerations, the subject-matter of claim 1 of the main request lacks an inventive step and the request is therefore for this reasons alone not allowable.Sufficiency of disclosure (Article 83 EPC): claim 12
18. In view of the fact that the main request is in any event not allowable for lack of inventive step, it is strictly not necessary for the board to say anything about the Article 83 EPC objection against claim 12 of the main request. However, the board's view on this issue has consequences for the auxiliary requests and so it is convenient to deal with the issue here.
19. Claim 12 of the main request concerns the use of a fusion protein comprising a variant of human prolactin which is linked to another protein, wherein the variant has a substitution of the glycine at position 129 for the preparation of a medicament for treating breast or prostate cancer, wherein said breast or prostate cancer expresses a prolactin receptor.
20. Claim 12 is drafted as a second medical use claim and thus attaining the claimed therapeutic effect, namely treating breast or prostate cancer, is a functional technical feature of the claim. The relevant question to be addressed in the context of Article 83 EPC is whether or not the patent in suit provides enough guidance for the skilled person to manufacture fusion proteins which also show the claimed therapeutic effect without undue burden or rather whether the skilled person is faced with a research program for which no guidance is forthcoming.
21. The sole disclosure in the patent as regards fusion proteins is to be found in paragraphs [0017] and [0027]. Paragraph [0017] discloses a fusion protein comprising a PRL variant having a substitution of the glycine at position 129 linked to another protein while [0027] reads as follows:
"In yet other embodiments, a prolactin variant having a substitution of the glycine at position 129 is linked to another protein as part of a fusion protein. As one specific embodiment, the prolactin variant may be linked to interleukin 2. One nonlimiting example of such an embodiment is a G129R variant of human prolactin linked to interleukin 2."
22. These paragraphs thus disclose the linkage of hPRL variants, e.g. of the G129R-hPRL variant, to other proteins, e.g. to interleukin 2, but are silent as regards the type of linker used, the location of the linkage on the prolactin variant, or any other suitable fusion partner of the prolactin variants wherein the resulting fusion protein will have the effect of treating breast or prostate cancer.
23. According to the patent, the treatment of breast or prostate cancer relies on the inhibition of the cell proliferation-promoting effects of PRL on its receptor (see paragraphs [0001], [0018]). The patent is silent as regards the mechanism underlying this inhibition. From the prior art it is however clear that the prolactin variants act as antagonists by binding to the hPRL receptor through their binding site 1 while at the same time not dimerizing it, due to changes in their binding site 2 (see point 2 above). In order to function as an inhibitor of cell proliferation the fusion protein must thus retain the ability of the prolactin variant to bind to the hPRL receptor through binding site 1. The board considers it likely that the size of the fusion partner and the location of the linkage on the prolactin variant have an influence on the binding of the prolactin variant to the hPRL receptor by virtue of, e.g., changes in the three dimensional conformation of the protein and/or steric hindrance.
24. Without any information in the patent as regards the effect of the linker, the fusion partner or the location of linkage on the binding site 1 of the prolactin variant, the skilled person has to produce and test each and every fusion protein by a trial and error in order to determine whether or not the particular choice of linker, fusion partner and location of linkage provides a fusion protein having the claimed therapeutic effect.
25. This was not contested by the appellant, who conceded that without testing a particular fusion protein it was not predictable whether it would possess the claimed therapeutic effect.
26. The board considers that in the present case, in view of the lack of technical guidance and details in the patent, the production and the testing of fusion proteins showing the claimed therapeutic effect amounts to a research program which represents an undue burden for the skilled person.
27. The board concludes from the above that the subject-matter of claim 12 of the main request fails to meet the requirement of Article 83 EPC.
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18. In view of the fact that the main request is in any event not allowable for lack of inventive step, it is strictly not necessary for the board to say anything about the Article 83 EPC objection against claim 12 of the main request. However, the board's view on this issue has consequences for the auxiliary requests and so it is convenient to deal with the issue here.
19. Claim 12 of the main request concerns the use of a fusion protein comprising a variant of human prolactin which is linked to another protein, wherein the variant has a substitution of the glycine at position 129 for the preparation of a medicament for treating breast or prostate cancer, wherein said breast or prostate cancer expresses a prolactin receptor.
20. Claim 12 is drafted as a second medical use claim and thus attaining the claimed therapeutic effect, namely treating breast or prostate cancer, is a functional technical feature of the claim. The relevant question to be addressed in the context of Article 83 EPC is whether or not the patent in suit provides enough guidance for the skilled person to manufacture fusion proteins which also show the claimed therapeutic effect without undue burden or rather whether the skilled person is faced with a research program for which no guidance is forthcoming.
21. The sole disclosure in the patent as regards fusion proteins is to be found in paragraphs [0017] and [0027]. Paragraph [0017] discloses a fusion protein comprising a PRL variant having a substitution of the glycine at position 129 linked to another protein while [0027] reads as follows:
"In yet other embodiments, a prolactin variant having a substitution of the glycine at position 129 is linked to another protein as part of a fusion protein. As one specific embodiment, the prolactin variant may be linked to interleukin 2. One nonlimiting example of such an embodiment is a G129R variant of human prolactin linked to interleukin 2."
22. These paragraphs thus disclose the linkage of hPRL variants, e.g. of the G129R-hPRL variant, to other proteins, e.g. to interleukin 2, but are silent as regards the type of linker used, the location of the linkage on the prolactin variant, or any other suitable fusion partner of the prolactin variants wherein the resulting fusion protein will have the effect of treating breast or prostate cancer.
23. According to the patent, the treatment of breast or prostate cancer relies on the inhibition of the cell proliferation-promoting effects of PRL on its receptor (see paragraphs [0001], [0018]). The patent is silent as regards the mechanism underlying this inhibition. From the prior art it is however clear that the prolactin variants act as antagonists by binding to the hPRL receptor through their binding site 1 while at the same time not dimerizing it, due to changes in their binding site 2 (see point 2 above). In order to function as an inhibitor of cell proliferation the fusion protein must thus retain the ability of the prolactin variant to bind to the hPRL receptor through binding site 1. The board considers it likely that the size of the fusion partner and the location of the linkage on the prolactin variant have an influence on the binding of the prolactin variant to the hPRL receptor by virtue of, e.g., changes in the three dimensional conformation of the protein and/or steric hindrance.
24. Without any information in the patent as regards the effect of the linker, the fusion partner or the location of linkage on the binding site 1 of the prolactin variant, the skilled person has to produce and test each and every fusion protein by a trial and error in order to determine whether or not the particular choice of linker, fusion partner and location of linkage provides a fusion protein having the claimed therapeutic effect.
25. This was not contested by the appellant, who conceded that without testing a particular fusion protein it was not predictable whether it would possess the claimed therapeutic effect.
26. The board considers that in the present case, in view of the lack of technical guidance and details in the patent, the production and the testing of fusion proteins showing the claimed therapeutic effect amounts to a research program which represents an undue burden for the skilled person.
27. The board concludes from the above that the subject-matter of claim 12 of the main request fails to meet the requirement of Article 83 EPC.
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Auxiliary request 8: sufficiency of disclosure (Article 83 EPC)
29. In the board's judgment the board's conclusions under Article 83 EPC for the subject-matter of claim 12 of the main request (see points 18 to 27, above) apply, mutatis mutandis, to the corresponding claim of auxiliary request 8 (and indeed of auxiliary requests 1, 2, 3, 5 and 7), so that auxiliary request 8 is for this reason alone not allowable.
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29. In the board's judgment the board's conclusions under Article 83 EPC for the subject-matter of claim 12 of the main request (see points 18 to 27, above) apply, mutatis mutandis, to the corresponding claim of auxiliary request 8 (and indeed of auxiliary requests 1, 2, 3, 5 and 7), so that auxiliary request 8 is for this reason alone not allowable.
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Order
For these reasons it is decided that:
The appeal is dismissed.
The appeal is dismissed.
This decision has European Case Law Identifier: ECLI:EP:BA:2015:T090810.20150115. The whole decision can be found here. The file wrapper can be found here. Photo "Alien Research lab" by Paul Albertella obtained via Flickr under CC BY 2.0 license (no changes made).
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