T 0031/18 - Imatinib and (no) plausibility

 Key points

• I missed this case when it was published in Feb. 2020.
• “The respondents [patentees] concur with the opposition division in the definition of the problem, namely the provision of imatinib tablets improving patients compliance, i.e incorporating the entire daily dosage of 400 mg imatinib in a single tablet of acceptable dimensions, or reducing the dimensions of a tablet comprising a 100 mg dose, wherein the tablets have acceptable properties, as regards hardness, and a disintegration time of 20 minutes or less.”
• “It has to be investigated whether there is sufficient evidence supporting the alleged effects. For this purpose, documents C76 and C70 were mentioned by the respondents [patentees] and discussed during oral proceedings in support of the existence of an effect.”
• “The use of document C76 was contested by [opponent] appellant 02. According to appellant 02, this document related to experiments on desired tablet properties which were carried out after the filing date and which referred to effects not plausibly shown to be achieved by the claimed tablets in the original application. There was no mention or evidence in the original application that an effect as regards hardness, abrasion resistance, friability or disintegration time had been plausibly achieved by the claimed tablets.”
• “The Board cannot share this view. This line of argumentation appears to be incompatible with the assessment of inventive step according to the problem-solution approach, ... Said technical effect or problem must either be explicitly mentioned in the application as filed or at least be derivable therefrom, but not necessarily originally supported by experimental evidence. It can indeed not be expected from a patent applicant to include an extensive number of experimental evidences corresponding to all technical features which can possibly be claimed in the application as filed and which can possibly constitute a future distinguishing feature over the closest prior art, since said closest prior art and its technical disclosure may not be known to the applicant at the filing date of the application.”
• “C76 has been filed with the intention to proof the [advantageous properties stated in the patent] reached by tablets [...] comprising cross-linked PVP in the claimed amount over the tablets obtained by wet granulation and comprising cross-linked PVP in an amount lower than 10% by weight. Hence, disregarding the tests of C76 which intend to demonstrate an improvement in the tablet properties over the closest prior art would be incompatible with the problem-solution approach.” 
• However, C76 is not a clear comparison with example 8 of the prior art document D7. “Accordingly, the experiment C76 cannot constitute evidence supporting the alleged effects.”
• This implies that the above remarks regarding the plausibility requirement being incompatible with the problem-solution approach is obiter, i.e. is also a point that Board 3.3.07 wanted to express in this decision.
• The difference was using wet granulation vs. dry compression to make the tablets, document C76A and C76B purportedly showing the same advantages but using direct compression, as in C7. However, these documents were not admitted as being late filed. 
• “Since it is not possible to establish the existence of an improvement over the prior art as regards the amount of cross-linked PVP, the technical problem must be formulated as proposed by [opponent] appellant 02, namely the provision of an alternative tablet comprising a high amount of compound I [imatinib].”
• After detailed analysis, “Accordingly, the claimed solution as regards the amount of 10-35% by weight of cross-linked PVP is obvious.”
• The patent is revoked.
• It was the 2nd appeal, after T 0571/11. The patent was granted in 2007, with PCT application filed in 2003. So the patentee managed to keep something pending for about 18 years, with the EPO needing 14 years to finally dispose of the opposition.
• Let me be clear: I think such a length of proceedings is generally unacceptable for the general public, not only but in particular for patents for medicaments.
  
  
• The Board, regarding partial problems: “The Board can however not follow this argument [of patentee, that the partial problem approach must not be used because the two distinguishing features are interrelated], since the application as filed is silent as regards this alleged interrelation or interdependence, which is also not implicitly derivable from the disclosure of the application as filed.” “the alleged interrelation between the amount of compound I of 30-80% by weight and of cross-linked PVP of 10-35% by weight does not find any basis in the application as filed and is also not implicitly derivable therefrom. The effect of each distinguishing technical feature has therefore to be considered separately.”

T 0031/18 - 

https://www.epo.org/law-practice/case-law-appeals/recent/t180031eu1.html

2.4 The respondents concur with the opposition division in the definition of the problem, namely the provision of imatinib tablets improving patients compliance, i.e incorporating the entire daily dosage of 400 mg imatinib in a single tablet of acceptable dimensions, or reducing the dimensions of a tablet comprising a 100 mg dose, wherein the tablets have acceptable properties, as regards hardness, and a disintegration time of 20 minutes or less.

Appellant 09 defines the problem as the provision of a tablet comprising a high drug load, that disintegrates within a certain amount of time and that employs a compound other than microcrystalline cellulose as a binder.

Appellant 02 sees the problem as the provision of an alternative tablet comprising a high amount of Compound I.

2.5 It has to be investigated whether there is sufficient evidence supporting the alleged effects. For this purpose, documents C76 and C70 were mentioned by the respondents and discussed during oral proceedings in support of the existence of an effect.

2.5.1 The use of document C76 was contested by appellant 02. According to appellant 02, this document related to experiments on desired tablet properties which were carried out after the filing date and which referred to effects not plausibly shown to be achieved by the claimed tablets in the original application. There was no mention or evidence in the original application that an effect as regards hardness, abrasion resistance, friability or disintegration time had been plausibly achieved by the claimed tablets.

2.5.2 The Board cannot share this view. This line of argumentation appears to be incompatible with the assessment of inventive step according to the problem-solution approach, which first requires the identification of the closest state of the art, and then the identification of a technical effect and the formulation of a problem compared to this state of the art, said problem being solved by the claimed subject-matter.

Said technical effect or problem must either be explicitly mentioned in the application as filed or at least be derivable therefrom, but not necessarily originally supported by experimental evidence. It can indeed not be expected from a patent applicant to include an extensive number of experimental evidences corresponding to all technical features which can possibly be claimed in the application as filed and which can possibly constitute a future distinguishing feature over the closest prior art, since said closest prior art and its technical disclosure may not be known to the applicant at the filing date of the application.

In the present case, the technical effects relating to abrasion resistance, hardness, friability and disintegration time are explicitly mentioned in the application as filed (see pages 8, 2nd par. to page 9 2nd par., or corresponding par. [0041] and [0044]-[0046] of the patent specification). Said technical effects can therefore be involved in the assessment of inventive step, and C76 has been filed with the intention to proof the mentioned properties reached by tablets obtained by wet granulation and comprising cross-linked PVP in the claimed amount over the tablets obtained by wet granulation and comprising cross-linked PVP in an amount lower than 10% by weight. Hence, disregarding the tests of C76 which intend to demonstrate an improvement in the tablet properties over the closest prior art would be incompatible with the problem-solution approach.

The point raised by appellant 02 appears rather to relate to the ground of lack of disclosure which is a different ground of opposition and is not the point to be discussed here.

2.5.3 C76 is an experiment comparing several tablets obtained by wet granulation and differing in the concentration of cross-linked PVP. The tablets were tested for disintegration time, hardness, friability and abrasion resistance. The results demonstrate that tablets comprising 10 to 35% by weight of cross-linked PVP show a disintegration time of less than 20 minutes and an appropriate abrasion and friability, while tablets also obtained by wet granulation comprising less than 10% by weight of cross-linked PVP have a disintegration time of more than 20 minutes. These results show convincingly that tablets with the composition as claimed obtained in particular by a wet granulation process have appropriate and indeed improved physical properties over tablets obtained by wet granulation but with a lower amount of cross-linked PVP.

However, said experiments C76 do not present a comparison with the tablets disclosed in example 8 of C7, since they relate to tablets obtained only through wet granulation while the tablets disclosed in C7 are prepared by direct compression. Accordingly, the experiment C76 cannot constitute evidence supporting the alleged effects.

2.5.4 C70 is an experiment which repeats the preparation of tablets according to example 8 of C7, with the same ingredients, amounts and the same direct compression method. The prepared tablets show a disintegration time of less than two minutes and a good friability, with in particular no broken tablets. The disclosure of the experiments C70 show therefore undeniably that the tablets of the closest prior art have physical properties and disintegration which were similar to those expected from the claimed tablets.

Hence, in view of C70, the claimed tablets do not present any improvement linked with the amount of cross-linked PVP as to their properties, i.e regards hardness and the disintegration time of 20 minutes or less.

2.6 Since it is not possible to establish the existence of an improvement over the prior art as regards the amount of cross-linked PVP, the technical problem must be formulated as proposed by appellant 02, namely the provision of an alternative tablet comprising a high amount of compound I.

2.7 The solution is a tablet comprising an amount of 30-80% by weight of compound I and an amount of 10-35% by weight of cross-linked PVP.

2.8 The question remaining is whether the skilled person, starting from example 8 of C7, would arrive at the subject-matter of claim 1 of the main request in an obvious manner in order to solve the problem posed.

2.8.1 As regards the claimed high amount of Compound I, the previous decision T 571/11 concluded that no reason would give rise to an expectation of failure, or to a prejudice, which would discourage and prevent the skilled person, seeking to solve the technical problem, from carrying out the obvious solution of preparing tablets having a high drug load of imatinib active moiety, as defined in claim 1. Thus the board concluded in T 571/11 that the skilled person would indeed prepare such tablets in order to solve the technical problem (see point 1.16 of the decision). This conclusion is still valid for the present case.

2.8.2 As regards the claimed amount of 10 to 35% by weight of cross-linked PVP, several documents teach explicitly that the usual amount of cross-linked PVP to be used in tablets does not exceed 10% by weight and is usually around 1-5%by weight as shown by the following documents:

- C3: "low levels (2-4%)".

- C6: "lower use levels" and typical amounts used of "0.5-5%".

- C57: "2-5% concentration in tablets".

- C77: "rarely, if ever, necessary to use more than five per cent in a tablet".

2.8.3 Other documents, namely C81, C84 and C78, mention however the use of cross-linked PVP in higher amounts, in particular in the context of directly compressed tablets or when using cross-linked PVP as an excipient that serves more than one function.

C81 studies the properties of tablets comprising cross-linked PVP as regards its compressibility, binding and disintegrating properties in comparison with starch and cellulose. The tablets are prepared by direct compression and cross-linked PVP is used in amounts of inter alia 10 and 20% by weight of the tablet. The tablets obtained with cross-linked PVP showed a good compressibility, good binding properties and fast disintegration times.

C84 studies the properties of tablets as regard friability and disintegration when obtained with cross-linked PVP as disintegrating agent at various concentrations such as 15% by weight (see Table I), and inter alia through direct compression. The study compared cross-linked PVP with alginic acid or starch and concluded that cross-linked PVP could act as binder and disintegrating agent at low concentration (2-5%) and showed a quick disintegration time when used at a concentration of 20% by weight.

C78 studies the binding and disintegrating properties of cross-linked PVP used in tablets in amounts inter alia of 14% by weight (see Tab. 4) or 10% by weight (see Tables 2, 8, 13 and 14). The results show in Tables 6-8 that tablets prepared with high amount of cross-linked PVP have an acceptable hardness and a quicker disintegration time.

2.8.4 Consequently, the teaching which stands out from all these documents is that there is indeed a usual concentration of use of cross-linked PVP, but that a use at higher concentrations is also known, in particular in the case of tablets obtained by direct compression or for use as an excipient with multiple functions, i.e as binding and disintegrating agent.

The skilled person is therefore not bound to the usual amounts of use of cross-linked PVP and would not see any technical prejudice in using a higher amount of cross-linked PVP such as amounts comprised between 10 and 35% by weight, even though it was shown in C70 that tablets with a lower amount of cross-linked PVP had already acceptable properties. The choice of a higher amount of cross-linked PVP is in particular known and desirable when cross-linked PVP is intended to be used as a excipient acting simultaneously as binding and disintegrating agent.

Accordingly, the claimed solution as regards the amount of 10-35% by weight of cross-linked PVP is obvious.

2.9 Consequently, the subject-matter of claim 1 is not inventive and the main request does not meet the requirements of Article 56 EPC.