Key points
- Claim 1 reads: "1. A compound having FGFR inhibitory activity or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing cancer
- in a patient who has been identified to express a fusion polypeptide comprising an FGFR3 polypeptide and a BAIAP2L1 polypeptide or to carry a polynucleotide encoding the fusion polypeptide, [wherein the polypeptide expressed in the patient has a certain sequence]
- wherein the compound or a pharmaceutically acceptable salt thereof is capable of inhibiting a growth of a cancer cell expressing the fusion polypeptide or having a nucleotide encoding the fusion polypeptide." - The compound is hence only defined in functional terms.
- The Board: "Claim 1 (see section I.) is a purpose-restricted product claim directed to a compound having "FGFR inhibitory activity" for use in a method of treating or preventing cancer in a patient who has been identified as expressing a particular biomarker or as carrying a polynucleotide encoding it. This biomarker is a fusion polypeptide comprising an FGFR3 polypeptide and a BAIAP2L1 polypeptide, each polypeptide being defined by particular sequences. The claim further specifies that the claimed compound is capable of inhibiting the growth of a cancer cell expressing this fusion polypeptide or having a nucleotide encoding it."
- The Board, under sufficiency: "[the question is] (1) whether the skilled person would have been able, based on the disclosure in the application as filed and/or on their common general knowledge, to obtain compounds as defined in claim 1 without undue burden. These compounds are defined by two functional features, namely that (i) they have FGFR inhibitory activity and that (ii) they are capable of inhibiting the growth of a cancer cell expressing the fusion polypeptide comprising an FGFR3 polypeptide and a BAIAP2L1 polypeptide."
- "in addressing issue (1), [the opponent] referred to the approach developed in particular in decision T 1063/06 (OJ EPO 2009, 516) in the context of so-called "reach-through" claims. The appellant [opponent] argued that the patent did not enable the skilled person to identify all compounds falling within the broad dual-function definition of the claim without undue burden and, accordingly, such alternatives were not available to the skilled person.
" The board is of the opinion that the situation underlying decision T 1063/06 is not the same as that in the case at hand. The invention at stake in T 1063/06 was based on the discovery that a known illness (in this case cardiovascular disease) could be treated by compounds having the capability of stimulating the soluble guanylate cyclase enzyme independently of the heme group in the enzyme, i.e. the compounds stimulated both the heme-containing soluble guanylate cyclase enzyme and the heme-free soluble guanylate cyclase enzyme. No compounds having this capability were known in the art and such compounds could only be identified by means of a newly disclosed screening method as a new research tool. The claim under consideration in that decision was thus for the use of (hitherto unidentified and thus unknown) compounds, which were defined solely in terms of the specific new capability (function), for the manufacture of a medicament to treat a known illness.
" By contrast, the invention underlying the case at hand relates to the identification of a subgroup of cancer patients which is susceptible to treatment with FGFR inhibitors. The inventors found that a known human cancer cell line (SW780), which was known to be susceptible to the antiproliferative effect of known FGFR inhibitors, expresses a fusion polypeptide of the FGFR3 polypeptide and the BAIAP2L1 polypeptide which was also identified in various other types of human-derived cancer cells. The claim under consideration is for FGFR inhibitors which have the capability of inhibiting the growth of cancer cells expressing a FGFR3-BAIAP2L1 fusion polypeptide for use in a method of treating cancer in patients who express a FGFR3-BAIAP2L1 fusion polypeptide. This is not the same situation as in T 1063/06, in which any kind of compound (without guidance in terms of chemical structure or other selection rules) would have to be screened for the desired enzyme-stimulating activity."
"Numerous FGFR inhibitors were known from and made available in the art, and are also identified by their chemical names or structures in the application as filed. These constitute a large pool of candidates. Together with the general structural and functional requirements mentioned in the application as filed, this information would, moreover, have provided some orientation to the person skilled in the art for identifying further FGFR inhibitors, if required"
"Testing for the second level activity against cancer cells (as described in the application as filed) would not have had to be carried out by trial and error on randomly selected compounds, but only on a limited selection of compounds, i.e. compounds chosen from the class of FGFR inhibitors. No evidence was provided to show that a large proportion of FGFR inhibitors would fail this test (in which case identifying active compounds would be an undue burden on the skilled person). "
Regarding another decision:" In the case underlying T 1959/15, the invention resided in providing a further class of compounds for treating the disease; in the present case, the invention resides in the identification of the specific genetic make-up of a subgroup of patients who are particularly susceptible to treatment with a known class of compounds. For this reason alone, the findings in decision T 1959/15 do not directly apply to the facts and circumstances of the case at hand."
In a way, we are patenting a diagnostic method, it seems.
"unlike the conclusion in T 1959/15 for the claim at stake therein, for the reasons already set out in point 57. above this board takes the view that under the circumstances of the case at hand, the mere fact that claim 1 also covers compounds beyond those shown to be suitable for the therapeutic use does not automatically equate to an undue burden of screening arbitrary compounds. Moreover, this does not result in the claim being able to be classified as a "reach-through" claim."
There are more interesting issues in the case, e.g. making the claim novel and inventive by adding "wherein said patient is a human patient"
Sufficiency of disclosure (Article 83 EPC)
49. The requirement of sufficiency of disclosure must be satisfied on the effective filing date of the patent, i.e. on the basis of the information provided in the patent application as filed, together with the common general knowledge of the person skilled in the art at that time.
50. Article 83 EPC requires the patent application 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. With respect to the invention as defined in claim 1 of auxiliary request 2, two issues need to be established:
(1) whether the skilled person would have been able, based on the disclosure in the application as filed and/or on their common general knowledge, to obtain compounds as defined in claim 1 without undue burden. These compounds are defined by two functional features, namely that (i) they have FGFR inhibitory activity and that (ii) they are capable of inhibiting the growth of a cancer cell expressing the fusion polypeptide comprising an FGFR3 polypeptide and a BAIAP2L1 polypeptide.
(2) whether, on the basis of the information provided in the patent application as filed, together with the common general knowledge of the person skilled in the art at that time, it was credible that the compound defined in the claim is suitable for the claimed therapeutic application.
51. The board considers that both criteria are met.
52. In the context of sufficiency of disclosure, the board refers to numbered paragraphs of the patent for which equivalent passages are present in the application (see point 49. above).
53. As concerns issue (1) the board agrees with the opposition division (see point 16.1 of the decision under appeal) that FGFR inhibitors, including FGFR3 inhibitors, were well known in the art (see also document D4, page 77, left-hand column, line 36). The patent provides numerous examples of FGFR inhibitors (see, for example, paragraphs [0211] to [0296], Tables 1 and 2, and Example 1) and numerous such inhibitors were also published (see, for example, documents D4 and D6). The skilled person was therefore able to choose from a considerable number of suitable compounds.
Furthermore, the patent and the application as filed disclose in vitro data (Example 3, Figure 7) relating to the assessment of six structurally different compounds which suppress the kinase activity of FGFR (FGFR inhibitors, compounds A to F; Tables 2-1 and 2-2) for their effect on cell proliferation on six types of human bladder cancer-derived cell lines, including cell line SW780 which expressed the fusion polypeptide comprising an FGFR3 polypeptide and a BAIAP2L1 polypeptide. All tested inhibitors demonstrated an antiproliferative effect on SW780 cells in vitro (see Example 3 and Table 3). No evidence was provided to the contrary.
54. Appellant II, in addressing issue (1), referred to the approach developed in particular in decision T 1063/06 (OJ EPO 2009, 516) in the context of so-called "reach-through" claims. The appellant argued that the patent did not enable the skilled person to identify all compounds falling within the broad dual-function definition of the claim without undue burden and, accordingly, such alternatives were not available to the skilled person.
55. The board is of the opinion that the situation underlying decision T 1063/06 is not the same as that in the case at hand. The invention at stake in T 1063/06 was based on the discovery that a known illness (in this case cardiovascular disease) could be treated by compounds having the capability of stimulating the soluble guanylate cyclase enzyme independently of the heme group in the enzyme, i.e. the compounds stimulated both the heme-containing soluble guanylate cyclase enzyme and the heme-free soluble guanylate cyclase enzyme. No compounds having this capability were known in the art and such compounds could only be identified by means of a newly disclosed screening method as a new research tool. The claim under consideration in that decision was thus for the use of (hitherto unidentified and thus unknown) compounds, which were defined solely in terms of the specific new capability (function), for the manufacture of a medicament to treat a known illness.
56. By contrast, the invention underlying the case at hand relates to the identification of a subgroup of cancer patients which is susceptible to treatment with FGFR inhibitors. The inventors found that a known human cancer cell line (SW780), which was known to be susceptible to the antiproliferative effect of known FGFR inhibitors, expresses a fusion polypeptide of the FGFR3 polypeptide and the BAIAP2L1 polypeptide which was also identified in various other types of human-derived cancer cells. The claim under consideration is for FGFR inhibitors which have the capability of inhibiting the growth of cancer cells expressing a FGFR3-BAIAP2L1 fusion polypeptide for use in a method of treating cancer in patients who express a FGFR3-BAIAP2L1 fusion polypeptide. This is not the same situation as in T 1063/06, in which any kind of compound (without guidance in terms of chemical structure or other selection rules) would have to be screened for the desired enzyme-stimulating activity.
57. In the case at hand, the functional definition has two levels, the first one being the required FGFR inhibitory activity and the second being the compound's ability to inhibit the growth of cancer cells having the relevant biomarker. Numerous FGFR inhibitors were known from and made available in the art, and are also identified by their chemical names or structures in the application as filed. These constitute a large pool of candidates. Together with the general structural and functional requirements mentioned in the application as filed, this information would, moreover, have provided some orientation to the person skilled in the art for identifying further FGFR inhibitors, if required (see paragraphs [0208] to [0297] of the patent). Testing for the second level activity against cancer cells (as described in the application as filed) would not have had to be carried out by trial and error on randomly selected compounds, but only on a limited selection of compounds, i.e. compounds chosen from the class of FGFR inhibitors. No evidence was provided to show that a large proportion of FGFR inhibitors would fail this test (in which case identifying active compounds would be an undue burden on the skilled person). While document D11, as mentioned by appellant II, used tests for the biological evaluation of compounds, this does not amount to evidence of undue burden. The argument of appellant II that the compounds tested in the application as filed cover only a limited range of FGFR inhibitors is by itself not sufficient to raise serious doubts about other subgroups of FGFR inhibitors.
58. Appellant II also considered decision T 1959/15 to be relevant to the case at hand. The claim at issue in the case underlying decision T 1959/15 was directed to the further medical use of an inhibitor of soluble epoxide hydrolase (sEH), as such known in the art, for inhibiting cardiomyopathy. Again, the therapeutic agent was defined only functionally. The patent provided a list of known sEH inhibitors and data for two of them tested in an animal model for cardiomyopathy. The competent board held that although the patent provided a list of known compounds allegedly meeting the required functional definition, and assays for providing more compounds that exhibited this function, the requirements of Article 83 EPC were not met because the skilled person would have to resort to trial-and-error experimentation in order to identify further (unknown) compounds that met the functional definition. This represented an invitation to perform a research project and was thus an undue burden on the skilled person (see Reasons 4.3 to 4.5, 4.7 and 4.8).
59. In T 1959/15, the invention was based on the discovery that inhibitors of sEH could treat cardiomyopathy. The claim at issue was thus for inhibitors of sEH for use in inhibiting myocardiopathy. By contrast, the invention underlying the case at hand is based on the discovery that a known human cancer cell line (SW780), already known to be susceptible to the antiproliferative effect of known FGFR inhibitors, expresses a specific fusion polypeptide of the FGFR3 polypeptide and the BAIAP2L1 polypeptide. This fusion was also identified in various types of human-derived cancer cells. The claim under consideration is thus for FGFR inhibitors which have the capability of inhibiting the growth of cancer cells expressing a FGFR3-BAIAP2L1 fusion polypeptide for use in a method of treating cancer in patients who express a FGFR3-BAIAP2L1 fusion polypeptide.
60. In the case underlying T 1959/15, the invention resided in providing a further class of compounds for treating the disease; in the present case, the invention resides in the identification of the specific genetic make-up of a subgroup of patients who are particularly susceptible to treatment with a known class of compounds. For this reason alone, the findings in decision T 1959/15 do not directly apply to the facts and circumstances of the case at hand.
61. Additionally, unlike the conclusion in T 1959/15 for the claim at stake therein, for the reasons already set out in point 57. above this board takes the view that under the circumstances of the case at hand, the mere fact that claim 1 also covers compounds beyond those shown to be suitable for the therapeutic use does not automatically equate to an undue burden of screening arbitrary compounds. Moreover, this does not result in the claim being able to be classified as a "reach-through" claim.
62. In view of these considerations, the board is of the opinion that the findings in decision T 1959/15 do not directly apply to the facts and circumstances of the case at hand.
63. Based on the above facts and considerations, the board concludes that the skilled person would have been enabled to identify, without undue burden, the claimed compounds defined by the two functional features, namely FGFR inhibitory activity and the ability to inhibit the growth of a cancer cell expressing the fusion polypeptide comprising an FGFR3 polypeptide and a BAIAP2L1 polypeptide (see point 50., issue (1)).
64. As concerns issue (2) (see point 50.), in Example 3 of the application as filed a number of structurally different FGFR kinase-inhibiting compounds were tested in vitro for their effect on cell proliferation in a total of six types of human bladder cancer-derived cell lines (see Table 3), inter alia cell line SW780 bearing the fusion protein according to the claims. Furthermore, the fusion protein according to the claims was identified in numerous cancer cells obtained from patient samples. Based on the in vitro data on cells in Example 3, which were shown to be relevant in vivo in Example 4, the claimed therapeutic effect is made credible. For the fusion in the claim this was indeed confirmed by the in vivo xenograft example (Example 6).
65. Appellant II argued - in essence based on principles developed in decision T 1063/06 - that there was serious doubt that all of the FGFR inhibitors falling within the definition in claim 1 had a sufficiently potent antiproliferative effect on cells expressing a FGFR3-BAIAP2L1 fusion polypeptide to be effective in the in vivo treatment of cancer in human patients according to claim 1. In particular, the patent did not demonstrate that the results of in vitro cell proliferation assays were predictive of in vivo efficacy, and FGFR inhibitors displayed a broad range of potencies in the SW780 proliferation assay. In addition, the patent contained no evidence that compound A could be used to treat cancer in a human patient identified as expressing an FGFR3-BAIAP2L1 fusion, and merely relied on the assumption that a compound capable of inhibiting tumour growth in a mouse model constructed from the SW780 cell line could be used to treat human patients with any type of cancer who had been identified as carrying any type of FGFR3-BAIAP2L1 fusion polypeptide.
66. According to the case law of the boards of appeal, the mere fact that a claim is broad is not in itself a ground for holding that the application does not comply with the requirement for sufficiency of disclosure under Article 83 EPC. In the case at hand, appellant II expressed doubt that all FGFR inhibitors falling within the dual definition can be used to treat cancer in a human patient identified as expressing an FGFR3-BAIAP2L1 fusion. The experimental data in Examples 3 and 4 render such use credible at least for compound A in bladder cancer expressing the FGFR3-BAIAP2L1 fusion present in cell line SW780 (see point 64.)
67. In such a situation, the onus is on appellant II to demonstrate that there are serious doubts, substantiated by verifiable facts, that the skilled person cannot identify further claimed compounds suitable for the claimed therapeutic application.
68. Appellant II submitted in this context that FGFR inhibitors displayed a broad range of in vitro potencies in the SW780 proliferation assay (see document D4, Table I; Example 3 and Table 3 of the application as filed); although the compounds with the highest in vitro potency had been shown to be capable of suppressing tumour growth in an in vivo SW780 xenograft mouse tumour model (compound PD173074 in the case of document D4 and compound A in the case of Example 6(3) of the application as filed), it was doubtful that less potent and structurally unrelated FGFR inhibitors would also inhibit tumour growth in the in vivo SW780 mouse model. In fact, the patent did not demonstrate that the results of in vitro cell proliferation assays were predictive of efficacy in vivo. According to appellant II, these facts raised serious doubts that all compounds falling within the functional definition of the claim would be therapeutically effective in the treatment of cancer in human patients identified as expressing FGFR3-BAIAP2L1. The in vitro testing (Example 3) and expression study (Example 4) were thus not sufficient to render the therapeutic effect for any FGFR inhibitor plausible for the treatment of human patients expressing an FGFR3-BAIAP2L1 fusion polypeptide.
69. However, appellant II did not provide verifiable facts to show that, under the circumstances of the case at hand, the skilled person is unable to identify, without undue burden, further compounds conforming to the definition in claim 1 that are suitable for the claimed therapeutic application, i.e. the treatment of human patients expressing an FGFR3-BAIAP2L1 fusion polypeptide. The argument questions the capability of the skilled person rather than proving an actual inability. The argument must accordingly fail.
70. Appellant II further submitted that there was no evidence that compound A could be used to treat cancer in a human patient identified as expressing an FGFR3-BAIAP2L1 fusion. It contended that the application merely relied on the assumption that a compound capable of inhibiting tumour growth in a mouse model constructed from the SW780 cell line could be used to treat human patients with any type of cancer who were identified as carrying any type of FGFR3-BAIAP2L1 fusion polypeptide.
71. Also in this case, however, the board considers the argument of appellant II to merely amount to questioning the in vivo applicability of the invention to human patients, without providing supporting evidence. This does not amount to serious reasons on which a finding of a lack of sufficiency of disclosure of the claimed invention can be based.
72. In view of the above considerations, the board concludes that it has not been provided with convincing reasons from appellant II that the decision of the opposition division on sufficiency of disclosure was wrong.
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