T 1090/22 (Dry BIBW2992/BOEHRINGER INGELHEIM) 15-11-2024

Main request

1. Claim 8 - Inventive step

2. Starting point in the prior art

2.1 Document D2 describes a method of treating patients suffering from cancer and harbouring mutations of EGFR in the tumour involving the administration of BIBW 2992, optionally in combination with a further chemotherapeutic agent (see D2, page 1, lines 1-6 and claim 1). Document D2 explains that the method of treatment comprises the administration of a therapeutically effective amount of BIBW 2992 or a pharmaceutically acceptable salt thereof, preferably the dimaleate (MA2) salt (see D2, page 25, lines 22-27, under the heading "Method of treatment"). Document D2 thereby unequivocally discloses the use of BIBW 2992 MA2 as preferred active substance for use in the described method of treatment.

Under the heading "Example 1: Coated tablets containing 75 mg of active substance" document D2 presents specific instructions for the production of coated tablets containing 75 mg of an active substance involving the preparation of tablets cores from defined amounts of specific excipients followed by the coating of these tablet cores with a film consisting essentially of hydroxypropylmethylcellulose (see D2, pages 34-35).

From the disclosure of BIBW 2992 MA2 as a preferred active substance in document D2 the skilled person derives directly and unambiguously that the process for the preparation of coated tablets described in example 1 of document D2 is in particular intended to prepare coated tablets containing BIBW 2992 MA2.

Accordingly the coated tablets containing BIBW 2992 MA2 prepared in example 1 represent within the teaching of document D2 a suitable starting point for the assessment of inventive step of the tablets defined in claim 8 as granted.

2.2 The patent proprietor argued that coated tablets containing BIBW 2992 MA2 do not represent a suitable starting point disclosed in document D2, because document D2 does not specify the drying conditions for the coated tablets in example 1.

It is common knowledge that a process for preparing tablets involving the film coating of tablet cores inevitably includes a drying step (see D4, page 442, right column). The Board considers that in the absence of specific instructions regarding the drying conditions in the coating process described in example 1 of document 2 the skilled person understands that conventional drying conditions are to be applied. The lack of specific instructions concerning the drying conditions in example 1 of document D2 does therefore not disqualify this embodiment as a suitable staring point in the prior art.

2.3 The patent proprietor further contested that coated tablets containing BIBW 2992 MA2 represented a suitable starting point in document D2 in view of the evidence from document D21 that further deviations from the instructions in the examples of document D2 are required for the preparation of tablets when BIBW 2992 MA2 is used as the active substance.

The Board observes that according to document D21 the instructions for preparing tablets in "example 3 of D1" are not adequate when BIBW 2992 MA2 is used as the active substance due to the hygroscopic properties of this compound (see D21, page 5 and page 10). The reference in document D21 to "example 3 of D1" concerns example 3 of document D11 in the numbering of the documents adopted in the appeal proceedings. The instructions in example 3 of document D11 are identical to the instructions in example 2 of document D2 and relate to the preparation of uncoated tablets involving a wet granulation process. The preparation of coated tablets according to example 1 of document D2 does not involve a wet granulation process. Any inapplicability of the wet granulation method of example 2 of document D2 for the preparation of uncoated tablets comprising BIBW 2992 MA2 does therefore not disqualify the coated tablets containing BIBW 2992 MA2 prepared according to example 1 of document D2 as a suitable starting point in the prior art.

3. Objective technical problem

3.1 The subject-matter of claim 8 as granted differs from the coated tablets containing BIBW 2992 MA2 prepared in accordance with process of example 1 of document D2 by the feature that the claimed tablets have a water activity of not more than 0.17.

Example 1 of document D2 does not mention the water activity of the coated tablets resulting from the described preparation method and does not describe any particular drying conditions applied during the coating process of the tablet cores. However, as explained in section 2.2 above, the skilled person understands that in the absence of more specific instructions in example 1 of document D2 a standard manufacturing procedure involving conventional drying conditions is to be applied in the method of example 1 of document D2.

According to document D21 the standard manufacturing process for producing film-coated tablets containing BIBW 2992 MA2 results in tablets having a water activity of 0.24 (see D21, page 6, lines 1-3 and page 11, Table under "Water Activity before Drying Step). The Board therefore concludes that the preparation of coated tablets containing BIBW 2992 MA2 as the active substance in accordance with example 1 of document D2 and applying conventional drying conditions during the coating process results in tablets with a water activity of 0.24.

The patent proprietor argued that the reference to "the standard manufacturing process" in document D21 only concerned an internal standard as applied by the patent proprietor and that the water activity of 0.24 resulting from such process could therefore not be attributed to tablets prepared according to document D2. The Board observes, however, that document D21 describes in the identified passages film-coated tablets prepared by "the standard manufacturing process" as opposed to the tablets of the claimed invention having a reduced water activity due to special drying (see page 6 and 11). Document D21 thereby clearly refers to a conventional process involving standard drying conditions during coating and not to a special process according to some internal standard. The patent proprietor's argument is therefore not considered convincing.

3.2 Document D21 further describes a stability study performed on film-coated tablets comprising BIBW 2992 MA2 within a wide range of values for the absolute water content as well as the water activity involving their storage in tight packaging materials (aluminium blister packings or glass bottles) over 6 months at 40 C/75% relative humidity (see D21, pages 7-9 and 12). The results of this study are presented in diagrams under the Headings "Correlation of Degradation Rate with Water Content" and "Correlation of Degradation Rate with Water Activity" (see D21, page 13). The diagrams indicate individual values for the percentage-increase of hydrolysis product (Y-axis) depending on the absolute water content and water activity (X-axis) by the entry of squares (aluminium blister) and circles (glass bottle). The diagrams are reproduced as follows:

FORMULA/TABLE/GRAPHIC

Document D21 does not provide any particular statistical analysis with respect to the presented results. However, the presence of two squares having different values on the Y-axis, i.e. corresponding to different amounts of hydrolysis product, for the same value of water activity (see the two squares at a water activity of about 0.08 and the two squares at a water activity of about 0.25) indicates that the measurement of the degradation at a given water activity is affected by variation. It is further observed that the determination of the precision of the reported results is limited by the size of the squares and circles relative to the scale for the degradation and water activity in the diagram.

Taking account of the indicated variation and the limited precision of the presented results, the Board considers that the stability study reported in document D21 does not demonstrate any reduction in the level of degradation when the water activity in the tablets is lowered from about 0.25 to about 0.15. Accordingly, document D21 does not provide convincing evidence of an advantage of the tablets as defined in claim 8 as granted having a water activity of not more than 0.17 with respect to the conventionally prepared coated tablets for which document D21 reports a water activity of 0.24.

3.3 In the absence of evidence of any demonstrated advantage the Board formulates the objective technical problem underlying the subject-matter of claim 8 as granted as the provision of alternative tablets with respect to the coated tablets containing BIBW 2992 MA2 conventionally prepared in accordance with example 1 of document D2.

4. Assessment of the solution

4.1 It is not in dispute that documents D4 and D9 represent common general knowledge in the relevant field of technology. Document D19 is an excerpt from the US Pharmacopoeia from 2009 and is therefore also considered to represent common general knowledge in the relevant field of technology.

Document D4 points out that drying is an important operation in pharmaceutical manufacture, because it is usually the last stage of manufacturing before packaging where it is important to prevent product deterioration and to ensure free-flowing properties during use (see document D4, page 380, under "Introduction"). Document D4 explains that once the solid to be dried reaches its equilibrium moisture content with the ambient air the prolongation of the drying time will not further reduce its moisture content and that the only way to further reduce the moisture content is by reducing the relative humidity of the ambient air. According to document D4 this can on a large scale be achieved with an air-conditioning system and on a small scale with a desiccator, for instance using silica gel, which reduces the relative humidity to around 5-10%. Document D4 emphasizes that moisture may be quickly regained from the atmosphere after drying and that sealing is necessary if the aim is for a low residual moisture content in view of hydrolytic instability in the material. Document D4 further notes that tablet granules have superior compacting properties with a small amount (1-2%) of residual moisture (see D4, page 382, under "Loss of water from wet solids" and Figure 26.3).

Document D9 describes the water activity of a pharmaceutical solid, which is defined by the relative equilibrium humidity that arises from it, as a relevant alternative parameter in addition to the absolute moisture content (see D9, page 286, left column). Document D9 explains that the water activity influences the processing properties of granulates as well as the qualities of the tablets prepared therefrom and indicates in this context a practical window for the water activity of 0.2 to 0.6 (see D9, page 286, right column). Document D9 further points out that the temperature and relative humidity are important factors in the process for granulates. In this context document D9 indicates that the drying is best carried out at temperatures between 35 C and 40 C (see page 284, right column) and that depending on the relative humidity of the ambient air the granulate will absorb or loss moisture until an equilibrium is reached (see page 284, right column and page 285, left column).

Document D19 reports for the water activity of compressed tablets a representative value of 0.36 (see D19, page 608, Table 2).

4.2 Faced with the objective technical problem of providing alternative tablets with respect to the coated tablets containing BIBW 2992 MA2 as conventionally prepared in accordance with example 1 of document D2 the skilled person may rely on the common general knowledge as represented in documents D4, D9 and D19.

On the basis of this common general knowledge the skilled person would be aware that that practical values for the water activity of solid pharmaceutical compositions may typically range from 0.2 to 0.6. (see D9, page 286, right column and D19, page 608, Table 2) and that granulates with a residual moisture of 1-2% may provide superior compacting properties (see D4, page 382, right column). In view of the mentioned lower value of 0.2 for typical values of the water activity the skilled person would consider a water activity of 0.17 still within the range of typically suitable values. Moreover, the results of the stability studies in document D21, in which the correlation of the degradation with the water activity as well as the water content are presented (see section 3.2 above) indicate that as a matter of fact a water activity of less than 0.15 in tablets comprising BIBW 2992 MA2 may still include a water content of 1-2%. In view of the common general knowledge the skilled person would therefore expect tablets containing BIBW 2992 MA2 with a water activity of not more than 0.17 to represent suitable alternatives to the coated tablets containing BIBW 2992 MA2 as conventionally prepared in accordance with example 1 of document D2.

Moreover, having regard to the common knowledge that the loss of moisture from a pharmaceutical composition will continue during drying until the equilibrium moisture content with the ambient air is reached the skilled person would be aware that in order to achieve a water activity of not more than 0.17 the relative humidity of the drying air must be sufficiently reduced. The skilled person was therefore well able to determine suitable drying conditions for coated tablets containing BIBW 2992 MA2 in order to reduce the water activity in the final tablets to not more than 0.17.

4.3 The patent proprietor argued that document D21 demonstrated that only unconventionally harsh conditions allowed for an adequate reduction of the water activity in tablets containing BIBW 2992 MA2. Document D21 presents in this context the following results regarding the water activity of tablets following drying with air of 25 C at different levels of relative humidity (see D21, page 12):

FORMULA/TABLE/GRAPHIC

The Board considers that the presented results are in line with the common general knowledge that during drying the loss of moisture may only continue until the equilibrium moisture content is reached. In this context the Board further observes that drying conditions involving a relative humidity below 15% are by no means unconventional. To the contrary, such conditions correspond to the conditions during drying in a desiccator using the common laboratory desiccant silica gel, which reduces the relative humidity to around 5-10% (see D4, page 382, right column). The patent proprietor's argument is therefore not considered persuasive.

4.4 Accordingly, the Board concludes that the subject-matter of claim 8 as granted represents an obvious solution to the identified objective technical problem and does therefore not involve an inventive step.

Auxiliary request 1

5. Claim 8 - Inventive step

Claim 8 of auxiliary request 1 differs from claim 8 as granted in that the water activity is defined as not more than 0.15 instead of 0.17.

For the reasons presented in section 2.1 above, the coated tablets containing BIBW 2992 MA2 as conventionally prepared according to example 1 of document D2 represent a suitable starting point in the prior art. As explained in section 3.1 above, the conventional preparation according to example 1 of document D2 is considered to result in tablets having a water activity of 0.24.

As pointed out in section 3.2 above, document D21 does not demonstrate any reduction in the level of degradation by lowering the water activity in the coated tablets from about 0.25 to about 0.15. Document D21 does therefore not provide convincing evidence of an advantage of the tablets as defined in claim 8 of auxiliary request 1 having a water activity of not more than 0.15 with respect to the conventionally prepared coated tablets with a water activity of 0.24. In the absence of evidence of any demonstrated advantage of the subject-matter of claim 8 of auxiliary request 1 the objective technical problem is to be formulated as the provision of alternative tablets.

In line with the explanations in section 4.2 above, the skilled person would in view of the common knowledge (see D9, page 286, right column and D4, page 382, right column) consider a water activity of 0.15 still within the range of typically suitable values for solid pharmaceutical compositions. The skilled person would therefore on basis of the common general knowledge expect tablets with a water activity of not more than 0.15 to represent suitable alternatives with respect to the coated tablets containing BIBW 2992 MA2 as conventionally prepared in accordance with example 1 of document D2.

In line with the explanations in section 4.2 above, the skilled person was well able to determine suitable drying conditions for coated tablets containing BIBW 2992 MA2 in order to achieve a water activity in the final tablets to not more than 0.15 on the basis of the common general knowledge that the loss of moisture during drying continues until the equilibrium with the ambient air is reached.

Accordingly, the Board concludes that the subject-matter of claim 8 of auxiliary request 1 represents an obvious solution to the identified objective technical problem and does therefore also not involve an inventive step.