T 0464/17 (Composition for the Transdermal Delivery of Fentanyl / 3M) 16-10-2020

Remittal to the examining division

1. Before assessing inventive step for the main request, the appellant's request that the case be remitted to the first instance must be examined.

Under Article 11 RPBA 2020, the Board shall not remit a case to the department whose decision was appealed for further prosecution, unless special reasons present themselves for doing so.

The Board can identify no such special reasons here. It is acknowledged that, for the main request, the appealed decision is limited to novelty over D3 (prior art under Article 54(3) EPC). However, parties do not have a fundamental right to have their case examined at two levels of jurisdiction. In addition, the examining division examined and decided on the issue of inventive step in respect of the narrower auxiliary requests 1-4. The essential facts and evidence used in the appeal proceedings for the assessment of inventive step, including document D2, were already part of the first-instance proceedings, so that no fresh case is created.

Thus, the Board carries out an examination of inventive step for the main request pursuant to Article 111(1) EPC.

Main request

2. Inventive step

2.1 The invention relates to a transdermal drug delivery composition containing fentanyl and to methods of providing sustained analgesia to subjects in need thereof.

2.2 D2 represents the closest prior art. This is not contested by the appellant. D2 belongs to the same technical field of transdermal delivery of fentanyl.

D2 discloses transdermal devices comprising 2-4% fentanyl in a single, pressure sensitive adhesive acrylate copolymer matrix (see table 3, "Materials" and Figure 2). The acrylate copolymer (Gelva 737) comprises in particular, as monomers, 67% by weight of ethyl hexyl acrylate (corresponding to monomer A of claim 1(a)(i)) and 5% by weight of hydroxyethylacrylate (corresponding to the monomer B; see D7, table 2 on page 8). This Gelva 737 acrylate matrix is thus a copolymer falling under the definition (a) of claim 1. The devices of D2 provide a sustained delivery of fentanyl, without any apparent burst effect (see Table 3 and Figure 4).

2.3 The subject-matter of claim 1 of the main request differs from the devices disclosed in D2 in that the fentanyl concentration is in the range of 8-24%.

2.4 According to the appellant, the problem to be solved is the provision of a transdermal delivery device which can safely deliver fentanyl over an extended period of time. The appellant refers in particular to examples 47 and 48 to illustrate the advantages of using a high concentration of 8-24% of fentanyl in an acrylate matrix.

2.4.1 However, the application contains no evidence that an increase of the concentration of fentanyl from 2-4% to 8-24% leads to any improvement over D2 in terms of a more sustained release of fentanyl. Nor does the application disclose any data as to the safety of the transdermal device. Examples 47 and 48 of the application show the preparation of transdermal patches comprising 17.2-20.2% fentanyl in specific compositions comprising particular copolymers. These patches are tested for permeation through the skin of human test subjects over 168 hours (see table 13). The application does not provide any comparable results for analogous patches comprising 2-4% fentanyl. Tables 1, 4, 6, 8, 11, 12 and 15 show the human cadaver skin permeation results for transdermal patches comprising varying concentrations of fentanyl in compositions comprising specific copolymers and adjuvants. However, the human cadaver skin permeation data in D2 and in the application cannot be directly compared since they pertain to patches comprising fentanyl in different compositions and were obtained under different conditions. Additionally, the appellant did not demonstrate that the claimed devices overcome any of the safety problems known for the prior art transdermal fentanyl devices with regard to life-threatening side effects when overdosed. Thus, the presence of any surprising result as regards the safety of the transdermal devices of claim 1 has not been credibly demonstrated.

2.4.2 The appellant argues that, since the application related to transdermal drug delivery devices containing the opioid fentanyl, both the safety and the release profile are essential and have to be taken into account for the determination of the objective technical problem. The objective technical problem could not be just the provision of an alternative transdermal drug delivery device because this would also cover devices which could be unsafe or even lethal to the patients.

The Board does not share this view. In the absence of any evidence as to the safety of the device, the appellant's subjective assessment of the claimed devices as safe cannot be taken into account for the determination of the objective technical problem. Additionally, a formulation of the problem as the provision of an alternative transdermal drug delivery device would anyway not cover devices which would be unsuitable for use as transdermal drug delivery devices.

2.4.3 As to the alleged effect of an increased fentanyl concentration in the range of 8-24% on its delivery for an extended period of time, the Board finds that this effect, even if accepted in the appellant's favor, would not modify its assessment of inventive step, for the following reasons.

2.5 The objective technical problem in view of D2 may be formulated as the provision of a composition with which fentanyl can be delivered for an extended period of time.

2.6 According to D2 (see Table 1), the solubility of fentanyl in the adhesive Gelva 737 is 21.9 mg/ml, thus around 2.19% by weight. D2 shows that the skin flux obtained with a concentration of 2% by weight of fentanyl in this acrylate adhesive matrix is 0.9 myg/cm**(2)/hr (see table 4). D2 also discloses (see Table 3) transdermal devices with a fentanyl concentration in the same acrylate adhesive matrix of 4% by weight, thus beyond the solubility limit of fentanyl in this adhesive. Furthermore, D2 mentions that this increase in fentanyl loading from 2% to 4% in the acrylate adhesive matrix has very little effect or no effect on the release rate constant and the apparent diffusion coefficient of fentanyl (see page 493, last paragraph). This observation is based on drug release measurements in water. As the appellant points out, the release rates measured in water do not correlate well with the skin fluxes measured on cadaver skin for different copolymer matrices (see D2, page 495, left column, lines 6-11). However this does not render less credible the trend observed in D2 for different concentrations of the drug in the same copolymer.

Thus, D2 discloses transdermal devices comprising fentanyl in a copolymer as defined in claim 1, with fentanyl concentrations both below (2%) and above (4%) the solubility limit. The skilled person would not regard the solubility of fentanyl in the acrylate as an upper limit for its concentration in the adhesive matrix. Furthermore, D2 teaches that this increase in fentanyl concentration has no effect on the release rate of fentanyl. It would be obvious to the skilled person that an increased concentration of fentanyl coupled with a constant release rate lead to prolonged release. Thus, when faced with the problem of delivering fentanyl for an extended period of time, the skilled person would consider increasing the concentration of fentanyl in the adhesive matrix beyond its solubility limit, such as 8% by weight or more.

2.7 According to the appellant, the prior art teaches away from, or shows a prejudice against, considering fentanyl concentrations beyond its solubility limit. The Board is not convinced.

2.7.1 Firstly, according to the appellant, since fentanyl is a highly potent narcotic analgesic which can cause serious side effects and even death if it is overdosed, a skilled person would be very careful in increasing the dosage of this drug in a matrix and would only do so if there is a clear pointer in the art that a functioning transdermal drug delivery composition would result which would not endanger the health and life of the patients. The appellant cites D9 (see points 13 and following, especially point 20) to show the difficulty in predicting how the change of one component will affect the properties of the transdermal drug delivery device as a whole.

In the Board's view, D9 mentions numerous aspects to be taken into account for the formulation of drug-in-adhesive transdermal patch, including the selection of the adhesive matrix and various properties of the drug. However, the only change to be considered here is the increase, in the acrylate matrix of D2, of the fentanyl concentration from 4% to e.g. 8% (as in claim 1). Considering that the value of 4% is already nearly twice the solubility limit indicated in D2 for fentanyl in the acrylate matrix, and in view of the statement that this increased concentration had essentially no effect on the release rate and diffusion coefficient of the drug, the skilled person had no cause to expect that a further increase to 8% would compromise the properties of the transdermal drug delivery device. Likewise, there were no reasons for the skilled person to anticipate that issues with respect to integrity of the matrix, adhesion or the alleged catastrophic crystallisation would occur in the context of the device and acrylate copolymer of D2 when merely going from 4% to 8% fentanyl.

2.7.2 The appellant also refers to D10 (see page 8, third paragraph), D11 (see column 1, line 47 to column 2, line 5) and D2 (see the conclusions) to show the existence of a prejudice, namely that the amount of drug in the dosage form should be kept to a minimum due to the severe, or potentially fatal side effects.

According to the case law of the boards of appeal, inventiveness can sometimes be established by demonstrating that a known prejudice, i.e. a widely held but incorrect opinion of a technical fact, needs to be overcome (see Case Law of the Boards of Appeal of the European Patent Office, 9th edition, 2019, I.D.10.2).

Here, it is not proven that any prejudice has been overcome. Firstly, it is doubtful that the citizens' petition D10 or the patent specification D11 can represent suitable evidence of a widely or universally opinion held by experts in that field. Secondly, even if the existence of such a widely held opinion were accepted, it is not shown that this opinion is incorrect, i.e. that the invention overcomes any such prejudice. D10 and D11 emphasize the need to keep the amount of drug or dosage level of fentanyl to a minimum because of the potential for abuse or the risk that excessive amounts of the drug be delivered. There is however no demonstration that, despite the higher concentration of fentanyl in the claimed devices, these safety concerns do not arise (see 2.4.1 above). Additionally, the concerns expressed in D10 and D11 pertain to the dosage or (absolute) amount of fentanyl in the device, which cannot be equated with concentration of fentanyl without taking into account the size of the transdermal delivery device. The dosage or amount of fentanyl in the device is not a feature of claim 1.

2.8 In conclusion, the Board finds that the skilled person, starting from D2, not only could, but would consider higher concentrations of fentanyl such as 8% by weight or more in order to provide a fentanyl delivery for an extended period of time.

The subject-matter of claim 1 of the main request does not involve an inventive step.

3. Since the main request must be rejected for lack of inventive step, an assessment of novelty over D3 is not necessary.

Auxiliary requests

4. None of the auxiliary requests 1-9 comprise any further differentiating feature over D2 with regard to the adhesive copolymer, since the Gelva 737 acrylate matrix comprise 5% of hydroxyl-containing monomer. Furthermore, the reasoning set out above regarding the choice of a fentanyl concentration of 8-24% applies equally to the range of 8-12% defined in auxiliary requests 1, 3, 5, 7 and 9.

Thus, the subject-matter of auxiliary requests 1-9 also lacks an inventive step.