Monday, 6 December 2010

T 294/07 – A Nice Hat-Trick

I like the present decision because the patent proprietor, whose patent had been revoked by the Opposition Division (OD), for lack of inventive step, overcame three serious hurdles: it convinced the Board both to accept post-published evidence to establish inventive step and to generalise its teaching and it dispelled doubt concerning the presence of a bonus effect.

Claim 1 as granted read:

1. An anaesthetic formulation comprising xenon and an alpha-2 adrenergic agonist.

The patent proprietor argued that there was surprising and unexpected synergistic neuroprotective effect and that this effect was a class effect of all alpha-2 adrenergic agonists. The combination of xenon and alpha-2 adrenergic antagonists was not obvious upon a combination of documents D3 and D2 and the synergistic effect could not therefore be considered as being merely a bonus effect.

According to the opponent, the patent did not contain any evidence to substantiate the existence of a synergistic neuroprotective effect of the claimed formulations. Alpha-2 adrenergic agonists were known as anaesthetic agents and their choice was purely arbitrarily and did not result in any unexpected effect.

Here is what the Board found to say:

[4] The problem to be solved by the patent in suit was the provision of an improved anaesthetic formulation […].

The claimed formulation is distinguished from the preparations according to document D3 by containing an alpha-2 adrenergic agonist.

[5] In order to decide whether the requirements of A 56 are met, it has to be examined if the problem as formulated above has indeed been solved by the subject-matter claimed, and if the claimed solution is not obvious in the light of the disclosure in the prior art.

[6] N-Methyl-D-Aspartate (NMDA) antagonists, like xenon, are known to be neuroprotective under many clinically relevant circumstances […]. Also alpha-2 adrenergic agonists are known to be neuroprotective, for instance during ischemic insults […].

According to […] the application as published […], the neuroprotective action of the claimed formulation “is more efficacious as a result of the complementary action of the two components”.

[7] The patent does not contain experimental data proving the existence of a synergistic neuroprotective effect of the claimed anaesthetic formulations containing xenon and an alpha-2 adrenergic agonist.

However, during the opposition procedure […], the Appellant has submitted Annex 2, disclosing the results of in vitro and in vivo experiments investigating the neuroprotective activity of combined xenon an dexmedetomidine dosage. The in vivo data are derived from seven-day old postnatal rat pups which underwent right common carotid artery ligation. One hour after recovery from surgical procedure, they were exposed to a hypoxic environment and concurrent administration with either air (control), 6.25 μg/kg subcutaneous dexmedetomidine, xenon or a combination of both. The data show that xenon or dexmedetomidine alone had no significant neuroprotective effect. In contrast, where a combination of both agents was used, there was a marked reduction in infarction size, indicative of a significant neuroprotective effect. Statistical analysis confirmed that the effect was synergistic […].

[8] The Board is aware of decision T 1329/04, wherein the competent Board stated that the definition of an invention as being a contribution to the art, i.e. solving a technical problem and not merely putting forward one, requires that it is at least plausible by the disclosure in the original application that its teaching indeed solves the problem it purports to solve. Therefore, although supplementary post-published evidence may in the proper circumstances also be taken into consideration, it may not be considered at all if it is the first disclosure going beyond mere speculation.

The invention in the present case is concerned with an anaesthetic formulation comprising two compounds which per se are known in the art to be used as anaesthetics and which are described as having some neuroprotective activity in certain clinical situations. The application as published contains a statement that the neuroprotective activity of a formulation containing both agents is higher than it could be expected to be […] and comprises six examples wherein the claimed formulations were administered to human patients.

In the light of the principles underlying decision T 1329/04 the Board considers this to be a case where from the disclosure of the original application it is plausible that the problem underlying the invention, namely to provide an improved anaesthetic formulation, has indeed been solved. Thus, in addition post published evidence (Annex 2) may also be taken into consideration. This evidence discloses a synergistic neuroprotective effect of the claimed formulation.

[9] Annex 2 exclusively refers to a formulation comprising xenon and dexmedetomidine, the latter being one member of the group of alpha-2 adrenergic agonists. Thus, results in the form of experimental data which show that the technical problem underlying the present application has indeed been solved, have only been provided for one member of a group of compounds.

[10] According to established case law of the Boards of Appeal, the extent of the monopoly conferred by a patent should correspond to and be justified by the technical contribution to the art. This general principle of law also applies to decisions under A 56 because everything covered by a legally valid claim has to be inventive (see Case Law of the Boards of Appeal, 5th Edition 2006, Chapter I.D.1).

[11] Decision T 939/92 contains fundamental rulings on broad claims in the field of chemistry. The Board in case T 939/92 held that in view of the state of the art the technical problem which the patent in suit addressed was provision of further chemical compounds with herbicidal activity. It was necessary for all the claimed compounds to possess this activity. The question as to whether or not such a technical effect was achieved by all the chemical compounds covered by such a claim might properly arise under A 56, if this technical effect turned out to be the sole reason for the alleged inventiveness of these compounds. The Patent Proprietors’ submission that the test results contained in the description showed that some of the claimed compounds were indeed herbicidically active could not be regarded as sufficient evidence to lead to the inference that substantially all the claimed compounds possessed this activity. In such a case the burden of proof rested with the Appellants. The requirements of A 56 had not therefore been met.

Claim 1 of the main request of the application underlying decision T 939/92 referred to a triazole sulphonamide defined by its formula, which contained three residues designated (R1), (R2) and (R3). A list of possible substituents for each of these three residues was indicated in the claim, which also included three provisos. Thus, the claim, although not referring to an indefinite number of compounds, encompassed a large group of compounds whose exact size could not be judged at first sight. Moreover, as stated in detail in T 939/92 [2.6.2], the Appellants’ own submissions with regard to several prior art documents on file were such that a person skilled in the art would have been unable to predict, on the basis of his general knowledge, that all claimed compounds would have herbicidal activity.

[12] Contrary to this, the [patent proprietor] in the present case has put forward detailed arguments why the synergistic effect detected in the examples described in Annex II was not restricted to dexmedetomidine, but was a class effect shared by all members of the group of alpha-2 adrenergic agonists.

In detail it was highlighted that alpha-2 adrenergic agonists constituted a class of drugs, which, independent of their chemical structure, were defined by their specific target, namely the alpha-2 receptors. Dexmedetomidine, an example of this group, demonstrated a 1600-fold selectivity for alpha-2 over alpha-1 receptors. The actions of dexmedetomidine could therefore be attributed solely to its effects on the alpha-2 receptor.

It has been shown that the action of dexmedetomidine can be blocked by atipamezole, a highly selective alpha-2 antagonist […]. Accordingly, because dexmedetomidine and atipamezole were so selective for alpha-2 receptors, it could be stated with confidence that synergy would also occur with other alpha-2 agonists.

Further support for this argument could be found by considering the mechanicsm of the synergy on neuronal level, and in particular at the synaptic junction. Xenon had been shown to block the action of glutamate on NMDA receptors and to hyperpolarize the post synaptic membrane. Likewise the alpha-2 agonist dexmedetomidine acted on alpha-2 receptors, either preor post-synaptically, to cause hyperpolarisation. However, when xenon and dexmedetomidine were administered in combination, the hyperpolarisation synergistically enhanced the efficacy of xenon as an NMDA antagonist. As the synergy could be explained functionally, there was every reason to believe it would hold true for other alpha-2 agonists, irrespective of their structure.

[13] In the light of these arguments, which have not been called into question or even commented on by the [opponent], the Board is convinced that the present case can be distinguished from T 939/92. […]

15. The OD decided in the decision under appeal that a skilled person, trying to solve said problem, would have combined the teaching in document D3 […] with the teaching in document D2 and would have arrived at the claimed subject-matter in an obvious way. It found that the synergistic effect evidenced by the Patent Proprietor was “merely a bonus effect of the obvious combination”.

[16] According to the established case law of the Boards of Appeal, an effect which was to be expected as the result of an obvious measure could not contribute to recognition of the required inventive step, even if the scale of this effect was surprising to the skilled person. In such a case an effect whose scale surpassed the skilled person’s hopes merely represented a bonus effect following inevitably from the use of an obvious measure and obtained by the skilled person without an inventive effort on his part (see Case Law of the Boards of Appeal of the EPO, 5th Edition, 2006; Chapter I.D.9.7).

It has to be examined therefore, whether the combination of xenon and alpha-2 adrenergic agonist was an obvious measure for the skilled person, that is, as repeatedly formulated by the Boards of Appeal, whether the skilled person was in a “one-way-street” situation, when being confronted with the problem underlying the patent in suit.

[17] Document D3 itself discloses […] a list of roughly fifty substances that could be added to xenon as a further anaesthetic, analgesic, seditative of muscle relaxant. This list does not contain alpha-2 adrenergic agonists. Moreover, document D3 does not mention that the addition of any of the listed substances has any influence on the neuroprotective activity of xenon.

Document D2 demonstrates that dexmedetomidine, an alpha-2 agonist, produces a hypnotic-anaesthetic response in rats and concludes, that, if the animal data can be extrapolated to the clinical paradigm, it “may be more useful as an adjunctive anaesthetic agent.” […] The document does not refer to the neuroprotective activity of dexmedetomidine or to its influence on the neuroprotective activity of another anaesthetic agent.

[18] The patent, disclosing […] that alpha-2 agonists such as dexmedetomidine, are known in the art to have neuroprotective activity, refers also to various considerations a skilled person would have before applying alpha-2 agonists in a clinical setting. It is stated […] that “the use of alpha-2 adrenoceptor agonists in general anaesthetic practice has been hampered by their lack of anaesthetic potency and side-effect profile.” The lack of potency required the use of very high doses which could result in peripheral vasoconstriction with an increase in blood pressure. Furthermore, alpha-2 agonists have been found to be preconvulsant in some models of epilepsy. Finally, […] it is said that biologically important adaptations to the immediate effects of alpha-2 agonists, a phenomenon generally termed “tolerance”, may lead to a diminished drug effect over time. While tolerance to certain actions are considered to be desirable, “it may mitigate the clinical utility of alpha-2 agonists for chronic pain relief and prolonged sedation in the intensive care setting.”

[19] Accordingly, the Board sees no “one-way-street” situation for a skilled person, who, starting from the disclosure in document D3, tries to provide improved anaesthetic formulations. Rather on the contrary, being aware of the undesired side-effect profile of alpha-2 adrenergic agonists, the skilled person would have a tendency not to add it to a xenon containing anaesthetic formulation.

The Board decides therefore that the claimed subject-matter is not obvious in the light of the disclosure in document D3 when combined with the teaching in document D2 or any other document on file. The determined synergistic neuroprotective effect of the claimed formulation is not therefore a bonus effect following inevitably from an obvious measure.

The Board finally ordered the patent to be maintained as granted.

Should you wish to download the whole decision, just click here.