When does pre-clinical data plausibly support a therapeutic effect? (T 966/18)

The timing of a patent filing is critical to the patent's validity. The earlier a patent is filed, the lower the risk of disclosures before the priority date destroying novelty and inventive step. Yet, the later a patent application is filed, the more time there is to obtain data and satisfy the requirement that the invention is sufficiently supported and disclosed. The recent Board of Appeal decision in T 0966/18 is an example of a case in which pre-clinical data, together with common general knowledge, was deemed as plausibly demonstrating a claimed therapeutic method.  In fact, the data provided in the patent in question was surprisingly light. The patentee was able to compensate for this by reference to a strong body of supporting evidence from the prior art. However, this strategy may come back to bite the patentee when the question of inventive step is considered. 

Legal Background: Plausibility at the EPO

It is established case law of the Boards of Appeal that clinical data is not absolutely necessary to demonstrate the plausibility of a claimed invention (T 0609/02, Case Law of the Boards of Appeal, II.C.7.2, see also Warner-Lambert v Actavis [2018] UKSC 56 (IPKat)). Indeed, at the time a patent application is filed for the new therapeutic effect of a drug, clinical trial data are often not available. Even if the inventors are pursuing the drug candidate in clinical trials, the patent application may be filed well before any read-out of results from the trial. Early filing is often necessary to avoid the clinical trial summary and protocol becoming prior art, particularly in jurisdictions other than Europe (IPKat).  

"Bring your pet to work" day in the lab

Instead of relying on clinical data, an applicant may rely on data from animal models that are representative of the human disease. This practice reflects regulatory requirements, in which potential treatments must first be tested in animal models before they are translated to the clinic (IPKat). So how effective is reliance on pre-clinical data to support a medical use invention?

Case background: A prophylactic treatment of Parkinson's Disease

The patent (EP1578253) related to antibodies for the treatment of Lewy body disease. Lewy bodies are abnormal deposits of aggregated α-synuclein (α-SN) protein in the brain that are associated with neurodegenerative diseases such as Parkinson's Disease. The patent covers use of Prothena/Roche's anti-α-SN antibody Prasinezumab, which is currently being assessed in a phase IIb clinical trial for treatment of early Parkinson's Disease (NCT04777331). 

The patent was revoked at Opposition for insufficiency (Article 83 EPC). Claim 1 of the Main Request on appeal related to the use of α-synuclein (α-SN) fragments or anti-α-synuclein antibodies to treat or protect against Lewy Body disease, particularly Parkinson's disease. The question before the Board of Appeal was whether the data provided in the application as filed, in combination with the common general knowledge, plausibly demonstrated this effect. 

Does the application as filed plausibly demonstrate a therapeutic effect?

The Board of Appeal noted numerous suggestions in the academic literature that α-SN aggregation was likely linked to Parkinson's disease pathology. The Board of Appeal thus found it plausible at the filing date that anti-α-SN antibodies would treat Parkinson's Disease. But did the application as filed support the use of the particular claimed anti-α-SN antibodies to reduce α-SN aggregation and treat disease?

The patent included data showing reduction of α-SN aggregates in a mouse model of Lewy Body disease following administration with α-SN in order to elicit production of α-SN antibodies. In other words, the use of α-SN or anti-α-SN antibodies to vaccinate against Parkinson's Disease. The animals were treated with α-SN, or a no α-SN control. After treatment, those animals who had received α-SN were divided into 2 groups: those with either a resulting low or high titre of α-SN antibodies in the brain tissue. There were only 4 mice in each group and statistical significance was not assessed.

Given the lack of any statistical assessment and the known variability of biological data, the Opponent argued that the data did not credibly demonstrate a treatment effect of anti-α-SN antibodies. The Board of Appeal, however, noted the correlation between the titre of the anti-α-SN antibodies present in the tissue of the mice and the average reduction in α-SN aggregates in the mice. For the Board of Appeal this correlation was indicative of a real effect of the antibodies. The Board noted but disregarded the overlap in the range of effects between the control, low titre and high titre groups (e.g. a range of 15-29 mm2 in the low titre, and 18-29 mm2 for the control group). For the Board of Appeal, the quantitative data were enough to plausibly demonstrate an effect (r. 40). 

The application as filed also included data showing the in vitro binding effect of the claimed anti-α-SN antibodies. The patentee further submitted post-filed evidence from clinical trials for Prasinezumab showing a clinical effect. However, the Board of Appeal found the data provided in the application as filed, in combination with the common general knowledge, to be good enough to the claimed therapeutic use without recourse to the post-filed data. The BA thus set aside the Opposition Division decision that the patent was not sufficiently disclosed, and the case was remitted to the opposition division. 

Final thoughts

The Board of Appeal decision in T 966/18 appears to confirm a relatively low bar for establishing the plausibility of a medical use claim. To this Kat, the Board of Appeal in this case were surprisingly lenient with regards to the quality of the data needed to support a medical use claim. Quantitative pre-clinical data, without evidence of statistical significance, was enough to satisfy the sufficiency requirement for a relatively ambitious therapeutic effect, at a standard below what might be expected for peer-reviewed publication. It is of course possible that the Board of Appeal was inadvertently influenced by the post-filed positive clinical trial results that the patentee was able to provide. In view of these data, a negative decision on sufficiency might have appeared unreasonable.  

However, whether or not the Board was in fact swayed by the post-filed data, a large factor in the Board's decision was undoubtedly the strong body of evidence from the prior art that there was a link between the target and disease pathology. The prior art effectively lowered the bar for the quality of pre-clinical data that was required in the patent. However, the question of inventive step of the claims has not yet been considered, either by the Board of Appeal or the Opposition Division. It will thus be interesting to see whether the patent holds up at Opposition in view of the Board of Appeal's observation that the skilled person would have been aware of a body of evidence linking the target and disease, and prior art suggesting the use of anti-α-SN in a vaccine strategy for Parkinson's Disease. Whilst the patent has successfully jumped the sufficiency hurdle, the potentially larger hurdle of inventive step remains. 

Further reading

Plausibility at the EPO

• Lost in translation: Are animal models predictive of a treatment effect?
• Second medical use dosage regimen claim successfully traverses both insufficiency and "obvious-to-try" attacks (T 0799/16)

Plausibility in the UK

• No pain, no gain: Plausibility in Warner-Lambert v Actavis
• Takeda v Roche: "Is it plausible? Is it true?"

Sufficiency of medical use claims in other jurisdictions

• Untested hypothesis in a clinical trial protocol destroys novelty of a method of treatment claim in Australia (Mylan v Sun Pharma)
• Canadian Federal Court considers whether Teva's COPAXONE second medical use patents were obvious-to-try (Teva v Pharmascience)