Pharmaceutical clinical trials and patentability at the EPO

The novelty of medical use claims (and specifically second medical use claims) has been confirmed by the Boards of Appeal over clinical trial protocols (and similar descriptions of the studies yet to be carried out). For example, the Board in T239/16 (discussed more below) found novelty of the claims because a letter handed out to participating patients with information on the clinical trial study was considered “merely a plan for a clinical study.” As the claims under consideration are medical use claims, the document

“could not be novelty-destroying, since the outcome of the study was not disclosed and therefore no clinical benefit either, similar to the situation in decisions T 158/96, T 1859/08 and T 2506/12.”

However, novelty can be denied in circumstances where the medicament is allowed to leave the hospital with the participating patients and there is no obligation to return unused medicament. As with other inventions, there is a need to keep the invention confidential before the effective filing date of the application.

In T0007/07 the participants had been informed of the ingredients but had not signed a confidentiality agreement, and not all unused drugs had been returned. The EPO’s Board of Appeal concluded that the handing out of the drugs to the participants rendered them publicly available. The logic was that the skilled person could discover the composition or the internal structure of the product used in the clinical trials and reproduce it without undue burden.

However, the Board found that there was no disclosure to the public because the investigators in the trials were instructed to ensure drug accountability and to monitor treatment compliance by taking account of the unused medicament returned by the patients discharged from hospital. In addition, the clinical trials of were carried out in accordance with the EMEA Guidelines for Good Clinical Practice. These guidelines explicitly require adherence to the prescribed protocol and assurance of drug accountability.

As such, the Board concluded that the participating patients who were provided with the tablets under investigation entered into “a special relationship” with the investigators of the trials and were not members of the public that could freely dispose of the tablets. As such, the clinical trials were not considered to destroy the novelty of the claimed invention.

This is a reasonably patentee-friendly approach. However, it is still advised to ensure that participating patients sign a confidentiality agreement and are obliged to return any medicament taken out of the hospital.

However, the Board of Appeal found that the efficacy of treatment with empagliflozin announced in the study may well be understood as relating to the patient population having mild, moderate or severe renal impairment as a whole (having an eGFR between 15‑90 ml/min/1.73m²). As such, the skilled person cannot directly and unambiguously derive the information that the treatment is effective in each of the subgroups of patients defined by the mentioned levels of renal impairment.

In addition, the press release announced a positive result of the trial with respect to the group of diabetic patients with mild, moderate or severe renal impairment as a whole despite the actual lack of glucose-lowering efficacy of the 25 mg dose of empagliflozin in patients with severe renal impairment (as subsequently reported in a post-published document). The Board found this to be further evidence that the press release was not specific enough to be relevant to the novelty of the treatment of patients with the individual patient sub-population with moderate renal impairment, as claimed.

As such, the Board found the claims to be novel over the press releases. This case demonstrates the strict test of novelty and specifically that a claim may be novel over such a press release as long as there is not a specific disclosure of the efficacy of a treatment in an individual patient sub‑population.

There have been a number of decisions in the recent years that have dealt with the obviousness of claims in light of clinical trial documents. These include T239/16, T237/15, T1123/16, T1806/18, T2963/19, T96/20 and T1437/21. The EPO often considers whether or not the skilled person would have a reasonable expectation of success when assessing the inventive step of medicaments. An inventive step is often acknowledged for APIs based on no reasonable expectation of success due to the complex and unpredictable nature of drug discovery and treatment.   In contrast, the Boards of Appeal in the cases above set out that there is an assumption of a reasonable expectation of success starting from a clinical trial publication relating to the medicament unless the state of art suggests an expectation of failure. Each decision will be discussed below to illustrate this in more detail.

T239/16

The patent in T239/16 relates to a once-a-year treatment of osteoporosis using zoledronic acid.

The closest prior art document was a letter handed out to participating patients with information on the clinical trial study (the Board found there was no obligation to maintain confidentiality). The Board considered the only difference between the claim and the closest prior art to be the direct and unambiguous disclosure in the document of the effective treatment of osteoporosis.

The Board considered that the mere fact that an active agent is being tested in a clinical study for the treatment of osteoporosis (as disclosed in the closest prior art) leads to an expectation of success, due to the fact that clinical studies are based on data obtained by pre-clinical testing both in vitro and in animals and require authority approval which takes ethical considerations into account. This means that the skilled person in the present case would expect all study arms to treat osteoporosis effectively, unless they are dissuaded from this by the prior art. As such, the claims of the patent were considered to lack an inventive step.

T237/15

The patent in T237/15 relates to a single orally administered dose of up to 400 mg of suberoylanilide hydroxamic acid (SAHA – a histone deacetylase (HDAC) inhibitor) for the treatment of cancer. In this case, the closest prior art was a review article that describes HDAC inhibitors.

The review article describes that SAHA suppresses tumour growth when administered orally to rats or mice that have solid tumours.  Later in the document, it is described that tumour regression and symptomatic improvement were observed at doses of SAHA that have no clinical toxicity. The passage goes on to state that “Studies to define the optimal therapeutic regimen are ongoing. Studies with an oral formulation of SAHA are also underway.” Finally, the last two paragraphs of the closest prior art point to the challenge of finding the optimal dose, timing of administration and duration of therapy by HDAC inhibitors, and state that further research is needed to elucidate certain mechanistic aspects.

The difference between the claims of the patent and pre-clinical animal studies in the closest prior art was principally viewed as the dosage regime. The Board considered that the step from pre-clinical animal studies to clinical studies involving human patients is an unavoidable step when developing a new medicament. In the present case, the skilled person would take this step with a reasonable expectation of success.

The Board further considered that the determination of the optimum dosage regimen required to achieve the therapeutic effect in the (human) patient is a matter of routine experimentation for the skilled person. Such routine tests do not require inventive skill and can consequently not establish an inventive step.

Of note, the UK Supreme Court decision in Actavis v ICOS and Eli Lilly [2019] UKSC 15 considered a claim to a pharmaceutical unit dosage composition suitable for oral administration comprising 1 to 5mg of tadalafil, up to a maximum total dose of 5mg per day. The Supreme Court confirmed the Court of Appeal’s finding that this dosage regime was obvious from prior art describing doses of tadalafil in the range of 0.5mg to 800mg daily for the average adult patient. It gives examples of a tablet containing a 50mg dose of the active ingredient but does not purport to set out an appropriate dosage regime as an oral treatment of erectile dysfunction.

It is counterintuitive to suggest that the skilled person would reasonably expect efficacy to remain at lower dosages, a key finding in this decision was that there was a therapeutic plateau from 10 mg to 100 mg. As such, the court considered that it would be obvious for the skilled person (without hindsight and having found a therapeutic plateau) to test lower doses and so come upon the dosage regime which is the subject matter of the patent.

In the case at issue, the patentee convincingly showed that the skilled person would not have been able to predict the outcome of study 1 of the closest prior art. As a consequence, the Board found that the skilled person would not have made any prognosis or had any expectation for the relative direction and magnitude of the food effect of apple sauce on the bioavailability of nilotinib after oral administration of the nilotinib/apple sauce formulation to adult healthy volunteers in study 1 of the PIP of closest prior art. As such, the board concluded overall that the closest prior art, when read in light of the common general knowledge, would not have led the skilled person to implement study 1 of the PIP of the closest prior art in the expectation that the nilotinib/apple sauce formulation would be comparable to the nilotinib (Tasigna) capsule formulation in terms of nilotinib bioavailability and thus be effective in the treatment of CML.

In this case, the patentee managed to show that there is: (i) an unexpected benefit to including nilotinib in apple sauce from the testing performed; and (ii) no expectation of success as demonstrated from the common general knowledge. As such, the claims were held to involve an inventive step.

The Board considered that the approval of a clinical study depends on the assessment of the foreseeable risks in relation to the anticipated benefit in terms of relevance of the findings, which does not necessarily imply an expected positive outcome and does not represent a scientific advice on the development programme of the investigational product tested. The Board was therefore not convinced that the mere fact that the closest prior art reports the testing of the dosage regimen in a Phase 3 clinical trial already by itself provided the skilled person with a reasonable expectation that the treatment under investigation would be safe and effective.

However, the Board also considered reports of beneficial triple treatment of gemcitabine refractory pancreatic cancer patients involving non-liposomal irinotecan with 5-FU and leucovorin in Phase 2 studies published before the publication of the closest prior art. In this context, the Board took the view that the information regarding the claimed dosage regimen was safe and effective was already known from these documents to the extent that the patent proposed. As such, the Board considered that a positive outcome for the described triple therapy could reasonably be expected from the presentation of the clinical trial in the closest prior art. The Board concluded that the claimed invention lacked an inventive step.

The Board cited T239/16 above stating

“clinical trials are conventionally based on earlier preclinical studies, and the potential therapeutics tested in clinical trials are duly selected based on experimental data suggesting their success.”

The patentee submitted various documents to support the fact that MG was difficult to treat, as evidenced by the fact that no therapy for generalised MG had been approved in more than 60 years. This was intended to evidence a diminished expectation of success for the specific clinical trial of the closest prior art.

However, the Board concluded that no evidence was on file calling into question that MG could be treated with eculizumab in humans, as proposed in the Phase 2 clinical trial study disclosed in the closest prior art. As such, the claims were considered to lack an inventive step.

T1437/21

As mentioned in respect to novelty, the EPO Boards of Appeal have recently provided a decision in T1437/21 that addresses the patentability of treatment of specific sub-populations. As noted above, the difference between the closest prior art and the claims was considered the the efficacy in treatment of the defined forms of diabetes in patients with moderate renal impairment. The effectiveness of the treatment is shown in the patent and in post-published data.

Importantly, the Board in this case refers to T 2963/19 above and states:

“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.”

The patentee filed documents that the mechanism of action of empagliflozin by SGLT-2 inhibition evidently depends on the GFR of the kidneys, which by definition is reduced in patients with renal impairment. As confirmed in post-published data, efficacy of treatment was not expected in patients with severe renal impairment. The Board therefore considered 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 the closest prior art 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.

The Board reviewed other documents cited by the Opponent but concluded that there was an absence of a reasonable expectation of significant efficacy of empagliflozin in the treatment of diabetic patients with moderate renal impairment, and as such the claims were considered to involve an inventive step.

The EPO case law sets out that novelty of medical use claims arising from clinical trials can be achieved over published clinical trial protocols (or similar plans for clinical trial studies yet to be carried out).

Medical use claims will find it difficult to be considered inventive if the outcome of the clinical trial simply confirms the effectiveness of medicament being tested. The outcome of each case will depend heavily on the facts of each case. However, the EPO case law has established that there is an assumption of a reasonable expectation of success starting from a clinical trial publication relating to the medicament. The reasoning is given in T239/16 and repeated in for, example, T96/20, as

“clinical trials are conventionally based on earlier preclinical studies, and the potential therapeutics tested in clinical trials are duly selected based on experimental data suggesting their success.”

This assumption is countered by the viewpoint in T2963/19 and mentioned in T1437/21 that

“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.”

As shown in T1806/18 and T1437/21, an inventive step can be acknowledged by the EPO where there is an unexpected result arising from the clinical trial. It may also be possible to diminish the reasonable expectation of success if it can be shown in the common general knowledge that there is a reasonable expectation of failure. This was shown in T1806/18 but T96/20 suggests that the level of evidence to show a reasonable expectation of failure is high.

Similarly, dosage regime claims benefit from having a good story as to why the claimed dosage regime would not be obvious to try from routine clinical trial investigation. It is helpful to have in the application (or potentially filed during prosecution) an indication of how routine investigations did not or would not lead to the claimed range and potentially any unexpected benefits of the claimed range.

As discussed above, it is also important to ensure that participants in clinical trials are bound by confidentiality and an obligation to return unused medicament if it is intended for medicament to be taken away from the hospital before the end of treatment.

It is also worth noting that a number of the closest prior art documents in these cases are press releases from the company. Such documents, often produced by the marketing team, might be detrimental to the arguments on inventive step if they are overly positive about the outcome of the trial. Ideally marketing departments are well-versed in the implications of issuing press releases and know to reach out to their legal or IP department if in doubt.

Ultimately, the value in these secondary patents outweighs the high bar to inventive step as discussed above. A key consideration for overcoming such inventive step hurdle is to work with the investigators/inventors (ideally in drafting the application) to ascertain the surprisingness of the results.