T 1403/19 (Method for detecting acquired drug resistance/MEMORIAL SLOAN-KETTERING CANCER CENTER) 14-01-2022

Main request

Claim construction - claim 1

1. Claim 1 of the main request is directed to an in vitro method for detection of an acquired resistance to the therapeutic effects of gefitinib or erlotinib in a subject that is suffering from non-small cell lung cancer ("NSCLC").

1.1 Thus, claim 1 defines a purpose-limited in vitro method aiming at the detection of a property ("acquired resistance") to certain therapeutic agents ("gefitinib" or "erlotinib") in individuals of a specified patient group (suffering from NSCLC).

1.2 The term "acquired" in connection with "resistance" as cited in claim 1 inherently implies that the patients are initially responsive to the treatment, but become resistant against the drugs gefitinib or erlotinib at an unknown time point during the therapy. Acquired drug resistance relates thus to a new property that describes a status.

1.3 The purpose of claim 1 is achieved by process steps (a) to (c). In particular, as set out in step (b), by probing a sample with any means for selectively detecting a mutation in the cDNA sequence (SEQ ID NO: 1) of the epidermal growth factor receptor (EGFR) at a particular position (2369 C -> T, "C2369T"). This nucleotide exchange substitutes the wild-type amino acid threonine (T) by methionine (M) at position 790 ("T790M") in the corresponding protein sequence of EGFR (see patent application, page 2, lines 11 to 14).

1.4 The term "sample" in steps a) and b) of claim 1 is not defined. Accordingly, the steps encompass the use of NSCLC patient-derived samples of any size and origin, including cancerous and non-cancerous material. A single cancer cell, however, is excluded from the "sample" of claim 1 since a single cell has an acquired drug resistance or not by either carrying the mutation or not, respectively. Consequently, a single tumour cell cannot develop drug resistance as mentioned in claim 1, since this requires a sample comprising more than one tumour cell. The appellant argued that the term "sample" in claim 1 did not encompass non-cancerous material, since this was not a technical sensible interpretation of the claim. The board does not agree. The term "sample" in the absence of any further definition encompasses any material obtained from a patient, including for example, cell-free blood plasma samples that contain DNA. Although such a cell-free sample is non-cancerous, the DNA that it contains might carry a C2369T mutation indicative of an acquired drug resistance, which makes it suitable for the claimed method.

1.5 The samples are obtained from a NSCLC patient group that is defined by (i) a treatment scheme (all pretreated with the drugs), and (ii) response characteristics (all initially drug responsive). The time point of sampling and probing is not defined in claim 1, except that the drug treatment of the patients must have started. Accordingly, the method of claim 1 encompasses sampling and probing at any time during the treatment, i.e. early or late, while the cancer in the patients is still drug responsive.

1.6 Likewise the term "means" in step b) of claim 1 is not further defined. Accordingly, the step comprises the use of any suitable means for probing a nucleotide sequence for the presence of the C2369T mutation. The nucleotide sequence analysed comprises DNA and RNA.

1.7 Claim 1 further states that the finding of the mutation C2369T "indicates that the non-small cell lung cancer is developing acquired resistance to the therapeutic effects of gefitinib or erlotinib" (emphasis added), and specifies that the method is performed on samples obtained from gefitinib or erlotinib-treated patients, that were initially responsive to these drugs.

1.8 According to the appellant, an acquired drug resistance of a cancer was a continuous process that started when in a sample in at least one cancer cell the C2369T mutation emerged. The persistent selection pressure on the cancer by the administered drugs had the effect that drug sensitive cells within a tumour died, while drug resistant tumour cells continuously propagated. At the end of this process the whole tumour was drug resistant, i.e. all tumour cells propagated in the drug's presence. Thus, the claimed method provided information on whether the tumour comprised cells that "have developed acquired resistance", which inherently indicated that the overall tumour was "developing acquired resistance". This development of a steadily increasing drug resistance was diagnosed which was accompanied by a tumour size that initially shrunk until it started to grow again. Accordingly the feature that the cancer "is developing acquired resistance" in claim 1 indicated that the method had diagnostic and predictive aspects.

1.9 The board does not agree. The feature the "cancer is developing acquired resistance" in claim 1 is a functional feature that relates to and further specifies the method's purpose set out above in point 1.1. Thus, this feature limits the purpose of the claimed method to the detection of a developing acquired drug resistance in a sample obtained from a NSCLC patient. The detection of a tumour with a developing drug resistance implies that the tumour's acquired drug resistance is not yet established, and hence, that the tumour is still responsive to the therapeutic agents indicated in claim 1. The detection of a tumour with such a drug resistance is different from the detection of a tumour characterised by an acquired, i.e. established drug resistance, where the tumour, i.e. not only a single cell thereof, is no longer drug responsive.

1.10 It is likely that a tumour with a developing acquired drug resistance becomes drug resistant in the future. Therefore, since the method according to claim 1 is directed to the detection of a new situation which was not present ab initio, the board agrees with the opposition division's finding in the decision under appeal that the overall purpose of the claimed method is a predictive one.

1.11 The appellant submitted that the claimed method has a diagnostic as well as a predictive character.

1.12 The board does not agree. It is uncontested that a diagnostic test is generally used for identifying a disease/condition or its underlying cause, while a prognostic method is generally directed to a prediction of a likely development of a disease/condition, and of a treatment's outcome. For the reasons outlined above the method of claim 1 is not directed to the detection of NSCLC with an acquired drug resistance by screening samples for the presence of the C2369T mutation as a molecular marker, but to the detection of NSCLC with a developing acquired drug resistance based on the detection of this molecular marker. Since claim 1 explicitly defines that an acquired drug resistance is developing in NSCLC, the molecular marker C2369T in the claimed method is not used for identifying the underlying cause of the acquired drug resistance in NSCLC, but to predict a likely development/outcome.

1.13 In summary, the claimed method is directed to the detection of a developing (i.e. not yet established) acquired drug resistance (to the therapeutic agents gefitinib or erlotinib) of NSCLC in samples obtained from a specific patient group (as defined in the claim) through the screening for a marker mutation (C2369T) in the gene encoding EGFR.

Substantive entitlement to priority

2. It is contested between the parties whether or not the invention as defined in claim 1 as a whole (see point 1.13 above) is the same invention as that disclosed in the priority document (US 60/652488) within the meaning of Article 87(1) EPC. It was particularly contested whether the detection of a developing acquired drug resistance is disclosed in the priority document.

3. In opinion G 02/98 (OJ 2001, 413) it was established that the "requirement for claiming priority of "the same invention", referred to in Article 87(1) EPC, means that priority of a previous application in respect of a claim in a European patent application in accordance with Article 88 EPC is to be acknowledged only if the skilled person can derive the subject-matter of the claim directly and unambiguously, using common general knowledge, from the previous application as a whole" (see headnote). Furthermore, with the aim to apply a uniform concept, the disclosure as the basis for the right of priority and as the basis for amendments in an application have to be interpreted in the same way (as also confirmed in decisions G 2/10, point 4.6 of the reasons, in OJ EPO 2012, 376 and G 1/16, point 17. of the reasons, in OJ EPO 2018, A70).

4. The appellant submitted that the priority document disclosed the predictive character of the claimed invention already in the title which states "CANCER RELAPSE PROGNOSIS BY DETECTION OF AN EGFR MUTANT RESISTANT TO CERTAIN THERAPIES AND METHODS FOR DESIGNING NEW THERAPIES", in combination with the summary of the invention (see page 1, last paragraph). A further indication that the patent and the priority document related to the same invention was that the objective problem and its solution were identical in both documents. Further support that a finding of the C2369T mutation indicated that the cancer was developing acquired resistance was derivable from the patients' case reports disclosed on pages 16 to 18 (see Example 5) of the priority document.

4.1 The board does not agree. Although the title of the priority document mentions "CANCER RELAPSE PROGNOSIS" that is based on the "DETECTION OF AN EGFR MUTANT RESISTANT TO CERTAIN THERAPIES", there is no functional link between this title, and the remaining disclosure of the priority document, which instead focuses on the detection of an EGFR mutant "to determine the cause for resistance to the treatment with certain EGFR inhibitors" (see e.g. page 1, first paragraph, and page 2, line 1). In other words, the priority document relates to the provision of a diagnostic method (see e.g. page 1, fourth paragraph, page 4, last paragraph, page 7, second paragraph of the priority document). There is also no link to the specific method of claim 1. The priority document, except for the title, does not mention the term prognosis, or another related term that directly and unambiguously implies a prognostic/predictive purpose.

4.2 Nor is a predictive/prognostic purpose of the claimed invention derivable from page 1, last paragraph of the priority document which states: "In patients with tumors bearing gefitinib- or erlotinib-sensitive EGFR mutations, resistant subclones containing an additional EGFR mutation emerge in the presence of drug", and from "the T790M mutation confers resistance to EGFR mutants usually sensitive to either gefitinib or erlotinib. This new mutant guides the search for a more effective therapy against a specific subset of lung cancers or any other cancers where the T790M mutation in EGFR confers resistance to therapy".

4.3 Contrary to the appellant's view, no prediction about a relapse is directly and unambiguously implied by the observation that resistant subclones emerge during the therapy. At best this provides the reason why these patients are drug resistant. The second statement mentioned above refers to a drug research programme (as implied by the term "search for") to find new drugs that are effective against drug resistant tumours due to the presence of the T790M mutation. This, however, is fundamentally different from using this mutation in a method to identify tumours early during the therapy to identify cancers that will develop an acquired drug resistance.

4.4 As mentioned above, a diagnostic test is generally used for identifying a disease/condition or its cause, while a prognostic method is directed to a prediction of a likely development of a disease/condition, and of a treatment's outcome.

4.5 The other parts of the priority document provide ample disclosure for a diagnostic use of the C2369T mutation as molecular marker in determining the underlying cause of progressive, and hence, drug resistant lung cancer. However, the priority document is silent on any predictive use of this marker for the purpose indicated in claim 1. In particular, a direct and unambiguous disclosure is missing in the priority document for a method that identifies NSCLC in samples, for example, early during a patient's therapy, that are "developing acquired resistance" to gefitinib or erlotinib, i.e. a tumour stage that is still drug responsive.

4.6 Rather the priority document mentions consistently, for example, on page 1, fourth paragraph that: "there is a need in the art for new compounds that are able to treat patients that show cancer progression or relapse despite initial response to current EGFR inhibitors. Moreover, there is a need in the art for the determining the underlying causes of such resistance so that a diagnostic test can be developed and more customized treatment can be delivered" (emphasis added). The method disclosed in the priority document therefore determines the cause of an already established acquired drug resistance in a tumour for diagnostic purposes, i.e. the detection of a non-responsive tumour stage usually observed later during the therapy.

4.7 The appellant referred further to Example 5 on pages 16 to 18 of the priority document. However, this working example reports on studies of "identified secondary EGFR mutations in three of six individuals whose disease progressed on either gefitinib or erlotinib (Table 1)" (emphasis added). Accordingly, all patients reported in Example 5 are suffering from progressing tumours, i.e. drug resistant tumours, and not tumours that are developing drug resistance.

4.8 The priority document further mentions in Example 5 on page 18, at the end of the second paragraph "that a subclone of cells harboring these mutations emerged during drug treatment", and on page 18, at the end of the fifth paragraph that "at least in patients 1 and 2, the subclones of tumor cells bearing this mutation probably emerged between the time of initial treatment with a tyrosine kinase inhibitor and the appearance of drug resistance".

4.9 While the emergence of resistant tumour subclones during the treatment in Example 5 of the priority document explains the cause of an acquired drug resistance, a disclosure is missing that necessarily implies a use of this finding in a method for detecting tumours with a not yet established acquired drug resistance.

4.10 Example 5 of the priority document further mentions that a tumour sample obtained from patient 1 having an established acquired drug resistance shows an increased copy number of mutated alleles. However, this observation does not necessarily imply that these alleles are used for identifying tumours characterised by a developing acquired drug resistance.

4.11 Consequently, the claimed method is not entitled to priority rights, and the effective date for assessing novelty is the patent's filing date, i.e. 13 February 2006. As a consequence, document D22 is prior art for the assessment of novelty.

Novelty

5. The appellant has not contested that the method of claim 1 lacked novelty over the disclosure of document D22, if the priority of the claimed method was not valid.

6. In the absence of any arguments of the appellant, the board has no reason to overturn the opposition division's finding that the method of claim 1 lacks novelty over the disclosure of document D22. Thus, the main request contravenes Article 54 EPC.

Auxiliary requests 1 and 2

7. Claim 1 of auxiliary requests 1 and 2 differs from claim 1 of the main request in that the feature "is developing acquired resistance" has been replaced by "has developed acquired resistance" or "has an acquired resistance", respectively.

Claim construction - claim 1

8. The methods of claim 1 of auxiliary requests 1 and 2 are inter alia defined by the functional features "has developed acquired resistance" and "has an acquired resistance", respectively. In essence both of these features have the same meaning, since they refer to the identification of tumours in NSCLC patients characterised by an established acquired drug resistance. Thus, the methods detect tumours that are no longer responsive to the therapeutic effects of gefitinib or erlotinib. Since the finding of the C2369T mutation provides the underlying reason for this drug resistance, both methods have a diagnostic character.

9. For the reasons outlined above, the method of claim 1 of the main request has a predictive character since it detects a developing acquired drug resistance in tumours, i.e. a not yet established drug resistance.

10. The appellant submitted that the process of a developing drug resistance in a tumour as referred to in claim 1 of the main request encompassed the detection of cells in a tumour that were drug resistant due to the emergence of the C2369T mutation in the past, while the tumour as a whole was still drug responsive, until the state when drug resistance of the tumour was established. In other words, the feature "is developing acquired resistance" in claim 1 of the main request encompassed the detection of an acquired drug resistance in a tumour based on using the C2369T mutation as molecular marker from the beginning of the resistance until it was established.

Since the methods of auxiliary requests 1 and 2 detected an established acquired drug resistance only, the amendment in fact limited the methods compared to claim 1 of the main request.

11. The board does not agree. According to the claim construction set out above for the main request, the functional feature "the non-small cell lung cancer is developing acquired resistance" excludes the detection of an established acquired resistance in NSCLC, because it defines that this property is still developing. Thus, this functional feature does not encompass the whole development of a tumour's acquired drug resistance from the emergence of a C2369T mutation in at least a single cell until the tumour is no longer drug responsive.

Extent of protection

12. The appellant submitted that the functional feature "has developed acquired resistance" in claim 1 of auxiliary request 1 did not extend the protection conferred but rather limited it.

12.1 The board does not agree. Article 123(3) EPC requires that the claims of a patent as granted may not be amended during opposition/appeal proceedings in such a way as to extend the protection conferred. In order to assess whether an amendment of the patent satisfies that requirement, it is necessary to compare the protection conferred by the claims as granted, with that of the claims after amendment. A very rigorous standard, namely that of "beyond reasonable doubt" is to be applied when checking the allowability of amendments under Article 123(3) EPC (see e.g. T 307/05, points 3.3 and 3.4 of the reasons and T 2285/09, point 3.1 of the reasons), such that the slightest doubt that the scope of the patent as amended could cover embodiments not covered by the unamended patent would preclude the allowability of the amendment.

12.2 In the present case, in view of the construction of claim 1 of auxiliary request 1 (which equally applies to claim 1 of auxiliary request 2) for the reasons indicated above, the claimed method defines a purpose (the detection of an established acquired drug resistance in NSCLC), which is excluded from the detection of a "developing acquired resistance" in NSCLC.

12.3 The method of claim 1 as granted likewise mentions that the finding of the C2369T mutation in a sample obtained from a subject having lung cancer "indicates that the cancer is developing acquired resistance". In other words, the method of claim 1 as granted (like that of the main request) is directed to the detection of a developing acquired drug resistance in cancer.

13. Therefore, the methods of claims 1 of auxiliary requests 1 and 2 encompass subject-matter (detection of an established acquired drug resistance) that is excluded from the method of claim 1 as granted.

14. Consequently, in applying the rigorous standards mentioned above, the board concludes that the amendments in claims 1 of auxiliary requests 1 and 2 shift, and thereby extend, the scope of protection conferred, contrary to the requirements of Article 123(3) EPC.

Auxiliary request 3

15. Claim 1 of auxiliary request 3 differs from claim 1 of the main request solely in that the feature "wherein the non-small cell lung cancer harbors a somatic gain-of-function mutation in the tyrosine kinase domain of EGFR that renders the non-small cell lung cancer sensitive to gefitinib or erlotinib" has been added.

16. The amendment in claim 1 only limits the method of claim 1 of the main request to the extent that the tumour of the NSCLC-type comprises explicitly a somatic gain-of-function mutation in the EGFR which renders the tumour sensitive to gefitinib or erlotinib. However, this limitation is considered implicit in the method of claim 1 of the main request since without that gain-of-function mutation patients affected by NSCLC are non-responsive to a treatment with gefitinib or erlotinib (see patent, paragraph [0002]). Therefore, the methods of claim 1 of auxiliary request 3 and of claim 1 of the main request are in fact identical.

17. Consequently, the objections under lack of priority entitlement (Article 87(1) EPC) set out above for the method of claim 1 of the main request equally apply to the method of claim 1 of auxiliary request 3.

18. Since, moreover, the appellant has not contested that the claimed method lacks novelty over the disclosure of document D22, if the priority of the claimed method is not valid, auxiliary request 3 contravenes Article 54 EPC.

Auxiliary requests 4 to 7

19. As set out above under sections XIII to XVI, the method of claim 1 of auxiliary requests 4 to 7 is inter alia defined by the functional features "has an acquired resistance" (see auxiliary request 4, 6 and 7), or "has acquired resistance" (see auxiliary request 5). In other words, an established acquired drug resistance.

Extent of protection

20. Since for the reasons outlined above under auxiliary requests 1 and 2, the detection of an established acquired drug resistance is excluded from the method of claim 1 as granted, the methods of claims 1 of auxiliary requests 4 to 7 likewise shift, and thereby extent the scope of protection conferred by the patent as granted, contrary to the requirements of Article 123(3) EPC.

21. In the absence of an allowable set of claims, the appeal has to be dismissed.