T 1437/21 - Clinical trial protocols and inventive step

Key points

• In the case at hand, D22 is a press release of the results of Phase III clinical trials.
• However, there is also the general issue of the mandatory publication of clinical trial protocols before the clinical trial is even carried out.
• The Board, obiter it seems: "The prior disclosure that an investigational product for use in the treatment of a particular condition is undergoing clinical trials may in accordance with established jurisprudence preclude that a subsequently claimed invention involving this product for use in the treatment of that specific condition is considered to involve an inventive step, even where the results of the trial have not been made available to the public (see T 2506/12, reasons 3.10 and 3.15; T 239/16, reasons 6.5 and 6.6; T 1123/16, reasons 11; T 2963/19, reasons 4.3.1)."
• " as explained in T 2963/19, the approval of a clinical study depends on the assessment of the foreseeable risks to the participants in relation to the anticipated benefit in terms of the relevance of the findings. The approval of a clinical trial does therefore not, by way of a heuristic, imply an expected positive outcome of the treatment. Furthermore, as underlined in point 4.3.1 of T 2963/19 by reference to the "Communication from the Commission 2010/c 82/01", the authorisation of a clinical trial does not represent a scientific advice on the development programme of the investigational product tested. The considerations in T 2506/12, T 239/16 and T 1123/16 regarding the expectation of success in view of the disclosure of clinical trials are, as in T 2963/19, evidently linked to the further circumstances of the cases decided therein, in particular the nature of the investigational product and of the condition to be treated and the absence of information suggestive of failure of the trial."
• Turning to the case at hand: "The crucial issue in the assessment of inventive step starting from the teaching in documents D22/D29, in particular the reported results from Study 1245.36, thus remains whether in view of the available information in the prior art, including the information in documents D22/D29, the skilled person had a reasonable expectation that empagliflozin would be effective in treatment of diabetic patients having moderate renal impairment."
• The claim is a second medical use claim specifying a sub-population of the patient population used in the clinical trial of D22, and a different sub-population than one of the sub-populations that was specified in D22.
• "The skilled person would furthermore not have expected the efficacy of the 25 mg dose of empagliflozin in patients with moderate renal impairment on the basis of the efficacy of the 10 mg dose in patients with mild renal impairment reported in documents D22/D29 due to the distinctive status of patients with moderate renal impairment which directly affects the mechanism of action of empaglifolozin. Precisely because the efficacy of SGLT-2 inhibitors was known to decrease progressively with decreasing renal function (see D8, page 235, left column), the skilled person could not reasonably expect that any significant efficacy of empagliflozin as still observed according to documents D22/D29 within the group of patients with mild renal impairment would even be retained in the distinctive group of patients with moderate renal impairment."
• "In the absence of a reasonable expectation of significant efficacy of empagliflozin in the treatment of diabetic patients with moderate renal impairment the Board concludes that the subject-matter of claim 1 as granted was not obvious to the skilled person in view of the prior art and thus involves an inventive step."

EPO 

You can find the link to the decision and an extract of it after the jump.

https://www.epo.org/en/boards-of-appeal/decisions/t211437eu1

4.3 Assessment of the solution

4.3.1 The prior disclosure that an investigational product for use in the treatment of a particular condition is undergoing clinical trials may in accordance with established jurisprudence preclude that a subsequently claimed invention involving this product for use in the treatment of that specific condition is considered to involve an inventive step, even where the results of the trial have not been made available to the public (see T 2506/12, reasons 3.10 and 3.15; T 239/16, reasons 6.5 and 6.6; T 1123/16, reasons 11; T 2963/19, reasons 4.3.1).

However, as explained in T 2963/19, the approval of a clinical study depends on the assessment of the foreseeable risks to the participants in relation to the anticipated benefit in terms of the relevance of the findings. The approval of a clinical trial does therefore not, by way of a heuristic, imply an expected positive outcome of the treatment. Furthermore, as underlined in point 4.3.1 of T 2963/19 by reference to the "Communication from the Commission 2010/c 82/01", the authorisation of a clinical trial does not represent a scientific advice on the development programme of the investigational product tested. The considerations in T 2506/12, T 239/16 and T 1123/16 regarding the expectation of success in view of the disclosure of clinical trials are, as in T 2963/19, evidently linked to the further circumstances of the cases decided therein, in particular the nature of the investigational product and of the condition to be treated and the absence of information suggestive of failure of the trial.

The crucial issue in the assessment of inventive step starting from the teaching in documents D22/D29, in particular the reported results from Study 1245.36, thus remains whether in view of the available information in the prior art, including the information in documents D22/D29, the skilled person had a reasonable expectation that empagliflozin would be effective in treatment of diabetic patients having moderate renal impairment.

4.3.2 As indicated in the review articles D8 (see page 235, left column) and D70 (see page 473, right column), the mechanism of action of empagliflozin by SGLT-2 inhibition mentioned in documents D22/D29 evidently depends on the GFR of the kidneys, which by definition is reduced in patients with renal impairment. As pointed out by the patent proprietor and confirmed in the post-published document D53 (see page 382, right column) efficacy of treatment was as a matter of fact not expected in patients with severe renal impairment. The Board therefore considers that the mere inclusion of diabetic patients with renal impairment beyond the stage of mild renal impairment in the Phase III clinical trial described in documents D22/D29 could not by itself have provided the skilled person with a reasonable expectation of success of the treatment in these patients with moderate or severe renal impairment.

4.3.3 As observed in section 3.3 above, documents D22/D29 do not provide any specific information on the number of patients in Study 1245.36 having moderate renal impairment. In view of this lack of information the opponents' justification of an expectation of effective treatment of diabetic patients with moderate renal impairment from the reported efficacy in the group of patients with renal impairment as a whole relying on the prevalence of moderate renal impairment within the general population of patients with renal impairment as described in document D5 and the positive comments on the results in documents D22/D29 remains purely speculative and is therefore not considered convincing.

The skilled person would furthermore not have expected the efficacy of the 25 mg dose of empagliflozin in patients with moderate renal impairment on the basis of the efficacy of the 10 mg dose in patients with mild renal impairment reported in documents D22/D29 due to the distinctive status of patients with moderate renal impairment which directly affects the mechanism of action of empaglifolozin. Precisely because the efficacy of SGLT-2 inhibitors was known to decrease progressively with decreasing renal function (see D8, page 235, left column), the skilled person could not reasonably expect that any significant efficacy of empagliflozin as still observed according to documents D22/D29 within the group of patients with mild renal impairment would even be retained in the distinctive group of patients with moderate renal impairment.

Documents D10 and D37, which indicate that the Phase III trial of documents D22/D29 followed the successful conclusion of a Phase I clinical trial involving the administration of empagliflozin to diabetic patients with renal impairment, were not available at the relevant earliest priority date for the patent and do therefore not affect the assessment of inventive step. In this context the Board notes that in view of the mechanism of action of empagliflozin, which requires proper functioning of the kidneys (see 4.3.2 above), the availability of the information regarding the safety of empagliflozin in patients with renal impairment would not affect the skilled person's expectation regarding the efficacy of treatment in diabetic patients with moderate renal impairment.

4.3.4 The opponents further referred to the known effects of other SGLT-2 inhibitors in diabetic patients to argue that the skilled person would expect similar efficacy from empagliflozin. The opponents relied in particular on the effects of ipragliflozin as described in documents D61 and D62, canagliflozin as described in document D32 and luseogliflozin as described in document D63. In this context the opponents dismissed the significance of the lack of efficacy in patients with moderate renal impairement reported in the prior art for dapagliflozin.

Documents D61 (see page 1261, Table 1) and D62 (see Table in the abstract) indicate that a single dose of the SGLT-2 inhibitor ipragliflozin increases the UGE in diabetic patients with moderate renal impairment. However, these documents do not demonstrate that ipragliflozin actually lowers glucose/HbA1c in these patients, which document D61 acknowledges as ultimately determining the clinical utility of the drug (see D61, page 1264, middle column). By contrast, the review in document D8 (see page 235, left column) reports that ipragliflozin did not provide for a clinically significant decrease in FPG and HbA1c in patients with moderate renal impairment.

Document D63 also reports only the effects of a single dose of luseogliflozin in diabetic patients with renal impairement, including specifically patients with moderate renal impairment. Whilst document D63 indicates that such a single dose significantly increases the UGE and decreases the PPG and FPG in patients with moderate renal impairment, document D63 does not report clinically significant efficacy from administration of luseogliflozin in the treatment of diabetes in these patients, for instance by demonstration of a significant effect on the HbA1c. In fact, document D63 itself acknowledges that a long-term clinical trial to assess the efficacy of luseogliflozin in T2DM patients with moderate renal impairment was still in progress.

The review in document D8 reported that the SGLT-2 inhibitor dapagliflozin had, similar to ipragliflozin, failed to significantly decrease FPG and HbA1c in patients with moderate renal impairment (see D8, page 235, left column). This lack of observed significant clinical efficacy of dapagliflozin in patients with moderate renal impairment in terms of a reduction of HbA1c is also reported in the review article of document D70 (see D70, page 474, sentence bridging the columns). Whilst at the earliest priority date the skilled person may, like the authors of document D32 (see D32, penultimate paragraph under "Discussion"), have considered the possibility that the lack of an observed significant clinical efficacy in the study with dapagliflozin could have been due to the design of the study, as later acknowledged in document D58 (see D58, page 968, bridging sentence between the columns), this possibility does not distract from the fact that at the relevant date for the patent the reported efficacy of dapagliflozin in patients with moderate renal impairment was qualified as insignificant in the review articles of documents D8 and D70.

Canagliflozin thus remains the only SGLT-2 inhibitor for which the cited prior art actually indicated efficacy in treatment of diabetic patients with moderate renal impairment (see document D32, Abstract under "Conclusion").

However, as mentioned in the review in document D70, canagliflozin was known as a SGLT-2 inhibitor with only moderate selectivity for SGLT-2 with respect to SGLT-1, whereas empagliflozin was known to be highly selective for SGLT-2 (see D70, page 466, right column). At the same time the skilled person was from the review in document D46 also aware that the reduction in glucose reabsorption in patients treated with SGLT-2 inhibitors may partly be compensated by SGLT-1 and that the lack of a complete blockade by SGLT-2 inhibitors explains the interest in dual SGLT-1/SGLT-2 inhibitors (see D46, page 114, left column and page 115, left column). The skilled person's expectation with regard to the efficacy of empagliflozin on the basis of the known effects of other SGLT-2 inhibitors in patients with moderate renal impairment was therefore affected by the difference in selectivity for SGLT-2 between canagliflozin and empagliflozin.

Accordingly, the skilled person would from the known effects of other SGLT-2 inhibitors in patients with moderate renal impairment not have derived a reasonable expectation of efficacy of empagliflozin in the treatment of diabetes this group of patients because

- ipragliflozin and dapagliflozin had been reported to lack clinically significant efficacy in the treatment of diabetic patients with moderate renal impairment

- the clinical efficacy of luseogliflozin in the treatment of diabetic patients with moderate renal impairment remained to be demonstrated

- the SGLT-1 inhibitory effect of the only moderately selective SGLT-2 inhibitory canagliflozin possibly contributed to its efficacy in the treatment of diabetic patients, whereas empagliflozin was highly selective for SGLT-2.

4.3.5 The review article in document D70 suggested on the basis of the reported known effects of SGLT-2 inhibitors in patients with renal impairment that SGLT-2 inhibitors will confer less benefit for patients with moderate renal impairment than for patients with normal renal function or only mild renal impairment (see page 474, right column). Contrary to the opponents' argument the skilled person would not understand document D70 as suggesting that patients with moderate renal impairment will benefit at least to some extent from SGLT-2 inhibitors, be it less than the other mentioned patients, because such understanding is contradicted by the report in document D70 (see page 474, right column) that the SGLT-2 inhibitor dapagliflozin provides no significant difference in reduction of HbA1c with respect to placebo. In the light of the reported known effects of SGLT-2 inhibitors the skilled person would rather understand the "less benefit" of the suggestion in document D70 as including "no benefit" in case of a SGLT-2 inhibitor such as dapagliflozin and "some benefit" in the case of a SGLT-2 inhibitor such as canagliflozin.

The Board therefore considers that from the mentioned suggestion in document D70 the skilled person would not have derived any reasonable expectation of efficacy of empagliflozin in the treatment of diabetic patients with moderate renal impairment either.

4.3.6 In the absence of a reasonable expectation of significant efficacy of empagliflozin in the treatment of diabetic patients with moderate renal impairment the Board concludes that the subject-matter of claim 1 as granted was not obvious to the skilled person in view of the prior art and thus involves an inventive step.