T 0210/11 (PHARMACEUTICAL NANOPARTICULATE COMPOSITION OF A TACHYKININ RECEPTOR ANTAGONIST/Merck Sharp & Dohme) 17-07-2014

1. The appeal of appellant 02 is admissible.

2. Admissibility of the appeal of appellant 01

The admissibility of the appeal formed by appellant 01 has been contested by the respondent, because in the notice of appeal no name was given for he appellant.

The notice of appeal indeed did not mention the appellant's name, but referred only to the patent number and the corresponding patent-proprietor's name.

According to the decision of the Enlarged Board of Appeal G 1/12 of 30 April 2014, which confirmed the existing jurisprudence, in order for an appeal to be admissible, the appellant must be identifiable at the latest by the end of the 2-month time limit provided for in Article 108, first sentence EPC. This is the case if it is possible to derive from the information in the appeal with a sufficient degree of probability, where necessary with the help of other information on file, e.g. as they appear in the impugned decision, by whom the appeal should be considered to have been filed (point 26 of the reasons).

In the notice of appeal, the patent and the patent proprietor, as well as the decision which is impugned is identified and revocation of the patent is requested. The letter was filed by the representative having represented opponent 01 in the opposition procedure. From this it is sufficiently clear that the notice of appeal was filed on behalf of opponent 01 and thus the appeal is admissible.

3. Main request - Article 123(3) EPC

The subject-matter of claim 1 of auxiliary request 1 filed during oral proceedings before the opposition division, which is now the main request, had been amended by the addition of the following feature originating from the description:

"where "effective average particle size of less than about 1000 nm" means that at least 95% of the particles, by weight, have an average particle size of less than about 1000 nm".

This feature has been introduced in claim 1 during opposition proceedings in order to further define the effective average particle size claimed in claim 1. It does not constitute a feature which has to be read independently from the other features of claim 1, but can only be seen as a further restriction as regards said effective average particle size. The subject-matter of claim 1 can thus only be understood in that the "effective average particle of the particles size (is) less than about 1000 nm" and that "at least 95% of the particles, by weight, have an average particle size of less than about 1000 nm".

The appellants were right in saying that some particles may have a size larger than 1000 nm, but this was anyway the case even in the absence of the introduced term, since the particles were defined only by an effective average particle size of less than 1000 nm, thus potentially close from the claimed limit.

Thus, there is no broadening of the subject-matter of claim 1, and the main request meets the requirements of Article 123(3) EPC.

4. Main Request - Article 123(2) EPC

The feature "where "effective average particle size of less than about 1000 nm" means that at least 95% of the particles, by weight, have an average particle size of less than about 1000 nm" originates from the original description, on page 19, lines 25-32, with the consecutive term "when measured by the above-noted techniques" omitted.

The referred passage previously mentions that "particle size is determined on the basis of the average particle size as measured by conventional techniques well known to those skilled in the art, such as sedimentation field flow fractionation, photon correlation spectroscopy, or disk centrifugation".

The reference by the term "when measured by the above-noted techniques" is thus made to any conventional technique for determining the average particle size, and not exclusively to the three specific techniques specified in the same sentence. It is thus not necessary to complete the amended feature by the three specific methods of measurement.

In view of the broad nature of the term "as measured by conventional methods" there is no need to add this feature to the subject-matter of claim 1, which scope would remain unchanged.

The main request meets the requirements of Article 123(2) EPC.

5. Main Request - Article 100(b) EPC

5.1 The claimed invention refers to a nano-particulate composition having "an effective average particle size of less than about 1000 nm, where "effective average particle size of less than about 1000 nm" means that at least 95% of the particles, by weight, have a particle size of less than about 1000 nm".

Sufficiency of disclosure has been objected to by the appellants as regards the method of measurement of the particle size. According to the appellants, the person skilled in the art is not enabled by the disclosure of the patent to determine correctly the average particle size.

The description mentions in paragraph [0078] that "particle size is determined on the basis of the average particle size as measured by conventional techniques well known to those skilled in the art, such as sedimentation field flow fractionation, photon correlation spectroscopy, or disk centrifugation". The passage mentions specifically the Z-average particle diameter measured by photon correlation spectroscopy (PCS).

Moreover, the measurements of the average particle size of particles, whatever the type of average value it might be, and even more of the weight particle size, are common measurements for the skilled person, who finds not only in the cited passage of the description but also from the common general knowledge sufficient information on how to measure any of said parameters.

There is thus sufficient disclosure as regards the parameters of average particle size, particle size by weight and their respective measurements.

5.2 Further arguments from the appellants

According to the appellants, different methods of measurement of the average particle size give rise to different results, and the method chosen has a significant influence on the final result achieved.

The Board agrees with the appellants. However, this point has no impact on sufficiency of disclosure, but rather on the uncertainty of what is covered by the subject-matter of independent claim 1, mainly limited by a parameter, namely "the effective average particle size".

It is true that in the art several types of "average particle size" and corresponding standardised test methods for determining them exist. It can be for instance a volume based particle size or a weight based particle size.

There is no doubt that variations occur according to the type of particle size as well according to the method of measurement chosen. Hence, the problem to be considered here boils down to the fact that, depending on the method of measurement, there exists an uncertainty as to the actual claimed value for "the effective average particle size" mentioned in claim 1.

This problem remains the same, however, even if a specific method of measurement was disclosed in the description since the claims would not be restricted to that method.

For these reasons, the Board takes the view that under the present circumstances the question of whether a skilled person can know what is covered by the claims is a question of definition of the claimed subject-matter, hence Article 84 EPC, rather than of sufficiency of disclosure (Article 83 EPC).

6. Main request - Article 84 EPC

The feature "an effective average particle size of less than about 1000 nm" was present in claim 1 as granted.

During the opposition procedure, this feature was further completed and restricted by the term "where "effective average particle size of less than about 1000 nm" means that at least 95% of the particles, by weight, have a particle size of less than about 1000 nm".

In claim 1 as granted, the nano-particulates were thus defined by their "effective average particle size", without any specification of the type of average size and any method of measurement of said effective average particle size in the claims.

The absence of specification of type of average particle size led to uncertainty and unclarity as to the actual claimed value for "the effective average particle size" mentioned in claim 1.

Consequently, the problem of clarity linked with the measurement of the effective average particle size was already present in the claims as granted.

So was also the presence of the term of "less than about 1000 nm".

In opposition, objections under Article 84 EPC may only be raised if they arise in relation to the amendments made, when said amendments do not derive from claims contained in the patent as granted. In present case, all unclear features were present in the claims as granted. Therefore, the objection to the clarity of the claim cannot be allowed.

As regards the term "at least 95% of the particles, by weight, have a particle size of...", there is no problem of clarity linked therewith. The size by weight is indeed a common parameter measurable by common techniques.

7. Main Request - Novelty

Examples 1 to 4 on pages 19 and 20 of document (1) refer to the preferred nano-particulate compositions comprising as active agent the "Compound A". The description mentions further on page 21 the preferred active compound of the invention, which is different from aprepitant.

It is impossible to establish a relationship with the disclosure of the examples 4-11 with the list of active agents of pages 4 and 5 of the description of document (1), among which aprepitant was named (see page 4, lines 25-26). Especially more, since aprepitant was not cited as a particularly preferred compound, which list is given on pages 7 and 8 of the description.

This document does therefore not disclose directly and unambiguously a nano-particulate composition of aprepitant.

The subject-matter of the main request is novel over document (1).

8. Main request - Inventive step

8.1 The claimed invention relates to pharmaceutical

compositions of 2- (R)- (1- (R)- (3, 5bis (trifluoromethyl)-phenyl) ethoxy)-3- (S)- (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1,2, 4triazolo) methyl-morpholine, thus aprepitant. The pharmaceutical compositions of this invention are useful in the treatment or prevention of disorders which benefit from the use of a tachykinin receptor antagonist, including central nervous system disorders such as psychiatric disorders including depression and anxiety, inflammatory diseases and emesis. The pharmaceutical compositions of the invention are also of use in the treatment of emesis induced by radiation including radiation therapy such as in the treatment of cancer; and in the treatment of post-operative nausea and vomiting (see par. [0135]). These pharmaceutical compositions have advantages over the other known pharmaceutical compositions of aprepitant in terms of increased oral bioavailability (see par. [0006], [0011], [0047]).

8.2 Document (3) relates to the preparation of a family of compounds useful for the prevention or treatment of nausea or emesis. It discloses in example 75 the preparation of aprepitant, and claim 1 of document (3) specifically refers to a method for the prevention or treatment of nausea or emesis induced by radiation or by cancer chemotherapeutic agents by administering aprepitant.

This document does not disclose any composition comprising aprepitant, but mentions a great number of pharmaceutical compositions and excipients which can be used for the family of compounds (see col. 53-54).

In particular, document (3) does not disclose a nano-particulate composition of aprepitant having absorbed on its surface a surface stabilizer.

This document constitutes the closest prior art, as agreed by the parties.

8.3 According to the patent, the problem of the claimed

invention is the provision of a composition of aprepitant having increased bioavailability.

8.4 The proposed solution to this problem is a nano-particulate composition of aprepitant according to claim 1 having adsorbed on its surface thereof at least one surface stabilizer in an amount sufficient to maintain an effective average particle size of less than about 1000 nm, where "effective average particle size of less than about 1000 nm" means that at least 95% of the particles, by weight, have a particle size of less than about 1000 nm".

8.5 Given that no example of the contested patent showed experimental results, and in order to prove the existence of an effect, the respondent provided document (14).

8.5.1 Document (14) is a post-published journal publication relating to a nanoparticle formulation of MK-0869, namely aprepitant. The document compares the bioavailability of milled compositions of aprepitant, of respective mean particle sizes of 5.49 mym, 1.80 mym and 0.48 mym with a colloidal NanoCrystal® dispersion of aprepitant with mean particle size of 0.12 mym (see point 2.3.1). The colloidal NanoCrystal® dispersion was prepared by a ball milling process of aprepitant in presence of hydroxypropyl cellulose, sodium dodecyl sulfate and sucrose (see point 2.2), providing thus the absorption of the excipients on the surface of aprepitant particles.

Table 1, Figures 2 and 3 of document (14) demonstrate a significant increase of bioavailability and a minimum impact of food on this bioavailability, as shown by the significantly higher values of the AUC obtained with the colloidal NanoCrystal® dispersion of aprepitant in comparison to the AUC values obtained by the other dispersions, and the absence of statistical difference in the AUC values obtained with on fasted or fed dogs treated with the colloidal NanoCrystal® dispersion.

The data provided by document (14) provide a strong confirmation that the absorption of aprepitant is dissolution rate-limited, and said absorption can be significantly increased by this specific nano-particulate composition (see point t 3.2).

Consequently, document (14) succeeds in showing that the claimed compositions have an increased bioavailability and the problem has been credibly solved.

As regards the food effect, document (14) indeed shows that food had a minimal impact on bioavailability in view of the absence of statistical difference in the AUC values obtained on fasted or fed dogs treated with the colloidal NanoCrystal® dispersion and shown in Table 1. Although not mentioned in the contested patent, this food effect is undoubtedly linked with increase of bioavailability. It is however not necessary to consider it in view of the effect observed on the bioavailability.

8.5.2 Further arguments from the appellants

According to appellant 02, it is not appropriate to rely on post published evidence to support an alleged technical effect.

The improvement of the bioavailability of aprepitant is only an alleged advantage merely referred to in the description of the contested patent, and is not properly supported by any evidence.

Moreover, document (14) mentioned that a key factor could affect the rate of dissolution of the nano-particulate formulation, namely the effectiveness of re-dispersion of the nanoparticles form a solid dosage form into the gastro-intestinal fluid (see docuemnt (14), par. 3.4).

The Board could not follow these arguments.

It is true that the improvement of the bioavailability is not supported by evidence in the description of the contested patent. The contested patent provides however a constant disclosure as regards the paramount necessity to improve said bioavailability of aprepitant and the corresponding benefits provided by the claimed composition (see paragraphs [0006],[0011] and [0047]). This necessity is seen as the main teaching of the contested patent.

As the improvement of bioavailability is derivable from the patent, any evidence can be taken into account to back up this information and to show an improvement over the prior art. It is thus appropriate to take into account post-published evidence submitted for the purpose of assessing whether or not the effect identified is indeed observed over the prior art. The provision of further technical teaching to support comparison with the closet prior art is even necessary and required to overcome the lack of support of the alleged advantage, and demonstrate an inventive step on the basis of an improved effect.

As regards the possible factor that could affect the increase of bioavailability of the compositions disclosed in document (14), said document provides a solution to this potential drawback, namely the adaptation of the quantities of particular excipients, namely re-dispersing agents such as sucrose (see par. 3.4). The skilled person is therefore able to adapt the formulation so that the intrinsic properties of the naoparticlaute formulation of aprepitant are conserved.

8.6 It remains to determine whether the proposed solution is obvious.

Documents (5) and (6) disclose the preparation of nanoparticulate compositions of drugs with surface stabilizers adsorbed to their surface (see document (5) claim 1, col 1, lines 49-60; see document (6), page 2, lines 12-23 and 50-55 and claim 1). The documents mention that the dissolution-rate limited bioavailability of the drug is improved by said nano-particulate compositions.

Document (7) discloses the same type of nano-particulate compositions with surface stabilizers adsorbed to their surface for NSAID drugs.

These documents do thus not mention aprepitant as possible application of their teaching, although they give long lists of active agents, among pharmacological classes of drugs, such as anti-emetics agents, are mentioned in documents (5) or (6).

The skilled person would however not have applied the solution known from documents (5), (6) or (7) to aprepitant.

(a) The mention in documents (5) and (6) of therapeutic classes of drugs to which the teaching of these documents can apply, cannot serve as a link to a specific drug defined structurally, such as aprepitant. The problem of bioavailability is indeed not linked with the pharmacological activity of the drug, but rather with the intrinsic property of the drug. A generalisation of the properties of a drug to a whole therapeutic class, such as the anti-emetics, is not possible. As to the disclosure of document (7), it applies to a category of acidic drugs having different physico-chemical properties as aprepitant.

(b) As mentioned in document (14), low oral bioavailability of a drug can be attributed to several factors, such as slow dissolution rate, poor solubility, first-pass metabolism, chemical instability in the gastrointestinal tract, efflux transport, and poor permeability across the intestinal mucosa (see page 136, right-hand column). Different solutions exist for each of these factors to remedy the poor bioavailability of said drug.

As regards the improvement of low oral bioavailability specifically linked with a poor solubility of the drug, several solutions again exist to remedy it, such as the use of alternative salts, particle size reduction and amorphous dispersion, specific complexation with cyclodextrins, addition of surfactants or of lipid-based excipients (see document (14), page 137, left-hand column).

Thus, document (4), which states that aprepitant is a sparingly soluble drug, offers, as a solution to improve its bioavailability, the preparation of a more soluble pro-drug derivate of aprepitant (see document (4) page 1234, right-hand col.).

(c) Moreover, an important prerequisite for using the milling technique used in present invention to obtain the claimed compositions, is that the drug, here aprepitant, has to be chemically and physically stable in the presence of excipients and under stressed conditions (see document (14), page 137, left-hand column, last par.).

It results that the skilled person, looking for a solution to the problem as defined above, faces multiple possible solutions to said problem of low bioavailability of aprepitant, and would not be conducted by the teaching of documents (5), (6) or (7) to the use of a nano-particulate composition of aprepitant having adsorbed on its surface thereof at least one surface stabilizer in an amount sufficient to maintain an effective average particle size of less than about 1000 nm .

Consequently, the main request meets the requirements of Article 56 EPC.

9. Reimbursement of the appeal fee

The appellants requested reimbursement of the appeal fee because the opposition division, in the oral proceedings, did not admit the objection under Article 123(3) EPC, because it was late filed and prima facie not relevant without giving any reasons in the decision for it.

According to Rule 103(1)(a) EPC, an appeal can only be reimbursed if the appeal is allowable. Since this is not the case, as set out above, the requests for reimbursement of the appeal fee are to be rejected.