Tuesday, 29 March 2011

T 822/07 – Bulb Fiction

Making a great discovery is one thing. Transforming it into a valid patent is quite another, as can be seen in the present decision, which deals with a refusal of an application by the Examining Division (ED). As we will see, the applicant fell into the insufficiency trap.

Claim 1 before the Board read as follows:
A glucocorticoid receptor antagonist (GRA) for use in treating mild cognitive impairment (MCI) in a patient suffering therefrom to prevent or slow further memory impairment, wherein the patient is 45 years or older and has normal levels of cortisol for a human population of that age, wherein the patient meets the following criteria :
(i) obtains at least one perfect score on the Folstein Mini Mental Status Exam in three administration of said Exam;
(ii) receives a rating of 0.5 on the Clinical Dementia Rating Scale, and
(iii) scores 1.5 standard deviations or more below the age- and education-adjusted normal value on a paragraph recall test;
wherein the GRA preferentially binds to the GR rather than the mineralcorticoid receptor (MR) at a rate of at least 100-fold.
The appellant submitted that claim 1 was drafted as purpose-delimited medical use claim. Thus, the claim sought protection for the use of any thinkable (i.e. known and/or unknown substances) GRA, which preferentially bound to the glucocorticoid receptor (GR) rather than to the mineralcorticoid receptor (MR) at a rate of at least 100-fold, for the treating mild cognitive impairment (MCI) in a particular group of patients. The specific subgroup of patients defined in the claim was suffering MCI, which was a disease on its own right.

Questioned by the Board, whether the treatment defined in claim 1 encompassed the treatment of MCI independently from its cause, meaning that the treatment claimed also encompassed the treatment of patients who had suffered from a stroke (without diagnostic), or suffering an untreated diabetes condition, hormonal imbalance (brain fog) etc., the appellant answered that it did.

The appellant further contended that the application concerned a “break-through invention” and that claim 1 was not a reach-through claim, since the claim was not a compound “per se” claim looking for absolute product protection. The “invention” lay on the function of the substances for a particular use. The gist of the invention was the fact that the antagonist blocks GR for its natural ligand. The present invention was like a “light-bulb invention”, it came as a conclusion of observations in a variety of places in relation to the compound mifepristone, which is representative for the GRA group. That was the proof that the principle worked …

[2.1] A 83 requires that the European patent application discloses the invention in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art.

It is to be reminded that the content of the whole patent application including the description and the examples, has to be investigated by the skilled person in the light of the general common knowledge of the technical field involved. It is the claimed “invention” which has to be investigated. The general legal principle is that the claims define the matter for which protection is sought and the examples illustrate specific ways of performing the invention.

As for the amount of technical detail needed for a sufficient disclosure, this is a matter which depends on an assessment of the facts of each particular case, such as the character of the technical field, and the actual technical detail disclosed.

The presently claimed “invention” is based on an alleged new and inventive medical use of an infinite number of compounds, which encompass known and unknown substances, defined by their function as a glucocorticoid receptor antagonist (GRA) (binding preferably, by a factor of about 100-fold higher, to the glucocorticoid receptor (GR) rather than to the mineralcorticoid receptor (MR)). The medical use concerns the treatment of mild cognitive impairment (MCI) independently from its aetiology (except from the exclusion of Cushing’s syndrome) in a particular patient subgroup which is characterised by including relatively young patients (45 years or older), not suffering from dementia (delimited in the claim by the criteria (i) to (iii)) and having normal levels of cortisol (for a population of that age). The technical effect specified in the claim is “to prevent or slow further memory impairment”.

Thus, the “invention” claimed in the main request addresses the general principle that each and every GRA (binding preferentially to GR rather than to MR) is able to prevent or slow further memory impairment in the particular subgroup of patients defined in the claim, independently from the cause or origin of its cognitive impairment. Thus, there are two aspects to be investigated in relation to sufficiency of the claimed “invention” which concern the biochemical basis regarding the definition of the substance to be used as GRA (binding to GR rather than to MR) and the medical basis relating to the choice of a particular subgroup of patients to be successfully treated. These two aspects require sufficient disclosure for a credible functional link to the technical effect claimed, which is to prevent or slow further memory impairment in the particular group of patients.

An inspection of the description of the application as filed shows the following passages, which have been cited by the appellant as a basis for the complete disclosure. In the general introduction, where the background is dealt with, it is stated:
“Cortisol, which is secreted in response to ACTH (corticotropin), shows circadian rhythm variation, and further, is an important element in responsiveness to many physical and psychological stress. It has been proposed that, with age, the cortisol regulatory system becomes hyperactivated in some individuals, resulting in hypercortisolemia. It has additionally been postulated that high levels of cortisol are neurotoxic, particularly in the hippocampus, a brain structure that is thought to be central to the processing and temporary storage of complex information and memory” […].
On page 3, first paragraph, it can be read:
“There has been no evidence prior to this invention, however, that a glucocorticoid receptor antagonist can be an effective treatment for memory impairment in a mature population, especially in patients having cortisol levels that fall within a normal range”.
This statement is followed by further comments about patients in which the cortisol levels increase and about those “mature individuals who have experienced an aging-associated increase in basal cortisol levels” who “can have a level of glucocorticoid receptor activity that, with time, directly or indirectly results in impaired memory function”. However, claim 1 of the main request addresses the treatment of young patients (45 years or older) with normal levels of cortisol for their age. Therefore, the mentioned passages of the description do not disclose the intended effects and functions claimed.

Additionally, at the end of the first paragraph on page 3, the compound RU486 (mifepristone) is identified as being one GRA which does not antagonise MR functions, and thus it is mentioned to be an appropriate substance for the use according to the “invention”. However, further on page 3, lines 20-21, it is stated:
“There have been no studies, however, that have shown that RU486 can improve memory function”.
The next paragraph on page 3 […] includes the mere statement that:
“The present inventors have determined that glucocorticoid receptor antagonists such as RU486 are effective agents for specific treatment of age-associated memory impairment that is not affiliated with dementia in mature patients with normal cortisol levels”. This statement has only a declaratory nature.
As regards the detailed description of the claimed “invention”, the description does not contain any model disclosing the alleged improvements in memory function attained by the use of the GRA. Neither a model based on biochemical or pharmacological in vitro assays, nor an animal model showing any beneficial effects on memory for the GRA, can be found in the description. There is also no disclosure relating to any in vivo assays, or clinical assays, irrespective of the group of MCI patients to be treated. In particular, there is a lack of disclosure in relation to the intended technical effect for the subgroup of younger patients with normal cortisol levels defined in claim 1. The statements relating to the “selective” blockade of GR by the substance to be used, without affecting the MR in order to avoid undesirable effects, are insufficient for providing a clear and complete disclosure in relation to the claimed beneficial effects on memory function in the intended medical treatment of the particular group of patients suffering from MCI.

In fact, the whole description is devoid of any data which could have served to fill the gap of an insufficient disclosure. Although part number 4, […] is dedicated to “Treatment of MCI using the glucocorticoid receptor antagonists” it does not contain any specific information relating to the claimed “invention” but only refers to the general knowledge known in the pharmaceutical field for physically providing pharmaceutical formulations and dosage forms for medical use.

It has to be kept in mind that the claimed “invention” relates to a particular medical use linked to an intended technical effect for which sufficient support and disclosure should have been provided in the description.

The only passage cited by the appellant, when asked directly by the board during the oral proceedings, was the following:
“In one embodiment, the methods of the invention use agents that act as GR antagonists, blocking the interaction of cortisol with GR, to treat or ameliorate MCI” […].
This teaching is clearly insufficient for a clear and complete disclosure of the general principle claimed, which relates to the prevention of memory impairment, or retardation of further memory impairment, in MCI patients of 45 years (or older), independently from aetiology (apart from the exclusion of patients suffering from Cushing’s syndrome) and which have normal levels of cortisol for their age.

Even if considering in favour of the appellant that the description of the application as filed establishes the existence of a link between high levels of cortisol and cognitive impairment, including memory function, in the light of which the suitability of using a GRA devoid of MR activity would appear plausible, there is still a lack of sufficiency of disclosure of the “invention” claimed. The claimed “invention” for which sufficient disclosure is lacking concerns the treatment of younger patients with normal cortisol levels, suffering mild cognitive impairment deriving from unknown causes. Moreover, there is a further lack of disclosure for the technical effect relating to a memory function improvement and/or preservation in those patients. In this respect the description rather invites the skilled person to perform a scientific research program than contains a complete disclosure of the “invention” within the sense of A 83.

Therefore, the main request does not meet the requirements of A 83.

Since the main request fails for lack of sufficiency of disclosure (A 83) in relation to the medical treatment specified by means of the technical effect on a particular group of patients, it is not necessary to further investigate the broad functional definition given in claim 1, for identifying the compounds to be used, within the sense of A 84 (clarity and support in the description) and A 83 (in relation to the method for determining the GRA activity).

As regards the appellant’s argument that the claimed invention is based on several observations in different places, unfortunately, these are not part of the content of the description.

Additionally, the argument that after the present “invention” all the development went in the sense predicted in the application, had been already answered with the board’s communication sent on 29 June 2010. With said communication the board informed the appellant that, in view of the fact that the documents it had filed with its letter of 13 May 2010 have been published several years after the effective filing date of the application in suit (one of them more than nine years later), they could not serve as a basis for defining the knowledge of the skilled person at the time of the invention, nor could they be used to fill the gap of the specification in the application in suit in order to ensure a sufficient disclosure within the meaning of A 83.

In relation to the alleged plausibility of the existence of a preventive beneficial effect on memory preservation owing to the hindrance of the binding of the natural ligand cortisol to GRs in the brain, a straight line should be drawn between the establishment of a scientific hypothesis or theory, which encourages scientific research to prove or disprove it, and the requirements for a clear and complete disclosure under A 83 justifying a broad patent protection, and its corresponding monopoly, for a particular medical use of an infinite number of compounds.

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

The file wrapper can be found here.