T 1994/22 - The application is silent on photostability

Key points

• Claim 1 of the patent as granted reads as follows: "1. A Form-II crystal of [selexipag] [with certain XRD peaks].
• "D32 is a post-published document filed by the respondent [opponent] before the opposition division. [] From this light stability test, it is concluded in D32 that Form II (according to claim 1 of the main request) is more photostable than Form III (comparative)."
• "The appellant submitted that the application as filed made no mention of the photostability of Form II, let alone contained any evidence of it."
• "According to G 2/21 (headnote 2), "a patent applicant or proprietor may rely upon a technical effect for inventive step if the skilled person, having the common general knowledge in mind, and based on the application as originally filed, would derive said effect as being encompassed by the technical teaching and embodied by the same originally disclosed invention."
• I note that G 2/21 was, first of all, about effects that are mentioned in the application as filed but without any support for them.
• Separately, already since T 0184/82, there is case law about technical effects that are not mentioned the application. They can be relied on provided that "the skilled man could recognise the [asserted technical effect] as implied or related to the problem initially suggested [in the application as filed]".
• To me it seem useful to keep the requirements separate. However, the present decision illustrates how G 2/21 can also be applied to the first issue (effects not mentioned at all in the application as filed).
• "Considering order no. 2 of G 2/21, the question to be answered in the present case is thus whether the effect relied on by the respondent and demonstrated in the post-published experimental data (D32), namely that of improved photostability of Form II, can be derived by the skilled person, having the common general knowledge in mind, and based on the application as filed, as being encompassed by the technical teaching (requirement (i)) and embodied by the same originally disclosed invention (requirement (ii))."
• "All that is disclosed in paragraph [0005] of the application as filed (paragraph [0006] of the application as published), as relied on by the respondent, is a "thing of a high quality for which constant effect can be always shown and of a form which is handled easily industrially". "
• From Espacenet: "It is hoped that medicament bulk is a thing of a high quality for which constant effect can be always shown and of a form which is handled easily industrially. The present inventors have earnestly studied. As a result, the present inventors have found a novel crystal of compound A, and have completed the present invention."
• " If such a sweeping statement was sufficient, a reference to high quality would be sufficient to invoke whatever technical effect as being encompassed by an application as filed in the sense of G 2/21. This would essentially render the first criterion of order no. 2 of G 2/21 meaningless. In the present case, in more concrete terms, the application as filed is in fact directed to particle size (table 1), residual solvent content (table 2) and amount of impurities (table 3). These properties are entirely unrelated to photostability."
  
• "Therefore, based on these properties [from the tables], having the common general knowledge in mind, the skilled person would by no means have recognised that (improved) photostability is relevant to the claimed subject-matter. Going from these specific properties to the effect of photostability would also clearly change the nature of the invention, contrary to what is required by T 116/18 (point 11.13.3 of the Reasons). Hence, the effect of photostability is not encompassed by the teaching of the application as filed."
• "even if it were wrongly concluded in the respondent's [proprietor's] favour that the technical teaching of the application as filed were to encompass photostability in the sense of T 116/18, it would not do so "together with the claimed subject-matter", as required by this decision (point 11.10). More specifically, points (1) to (3) of paragraph [0006] of the application as filed (paragraph [0007] of the application as published), claims 1 and 2, and points [1] to [3] on page 37 of the application as filed, as relied on by the respondent, refer to Form I, Form II and Form III in equal terms. These passages do not teach that Form II, i.e. the form claimed in claim 1 of the main request, is the preferred polymorphic form of selexipag, let alone that it should exhibit a photostability that is improved compared with Form I and Form III. Hence, the effect of improved photostability together with Form II is not encompassed by the teaching of the application as filed."
• Turning to inventive step: "the selection of Form II is an arbitrary selection from the host of alternatives covered by the closest prior art. Such an arbitrary selection without any unexpected balance of properties being produced cannot contribute to inventive step. The subject-matter of claim 1 of the main request therefore does not involve an inventive step in view of D10 as the closest prior art."

•  

EPO 

The link to the decision and an extract of it can be found after the jump.

https://www.epo.org/en/boards-of-appeal/decisions/t221994eu1

Main request

1. Inventive step - claim 1

1.1 Claim 1 of the main request relates to Form II of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl) acetamide.

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino] butyloxy}-N-(methylsulfonyl)acetamide is known as selexipag. Selexipag is an agonist of the prostaglandin receptor PGI2. PGI2 is known for its roles in mediating inflammation and maintaining homeostasis, and acts as a vasodilator and a potent inhibitor of platelet aggregation.

Selexipag has the following formula:

FORMULA/TABLE/GRAPHIC

In the following, "Form I", "Form II" and "Form III" refer to Form I, Form II and Form III crystals of selexipag.

1.2 The appellant objected to the inventive step of the subject-matter of claim 1 of the main request in view of D10 as the closest prior art.

The respondent inter alia relied on post-published data D32 and submitted that Form II as claimed had an improved photostability over Form III (comparative).

D32 is a post-published document filed by the respondent before the opposition division. D32 sets out the results of a light stability test of tablets comprising Form II (according to claim 1 of the main request) and Form III (comparative). After the stability test, the tablets comprising Form II exhibited a residual ratio of active pharmaceutical ingredient (API) of 89.3%, while the tablets comprising Form III showed a residual ratio of API of 73.4%. From this light stability test, it is concluded in D32 that Form II (according to claim 1 of the main request) is more photostable than Form III (comparative).

1.3 G 2/21 - taking into account the effect demonstrated in the post-published experimental data in D32

The appellant submitted that the application as filed made no mention of the photostability of Form II, let alone contained any evidence of it. Based on G 2/21, the respondent could not rely on the effect of improved photostability.

According to G 2/21 (headnote 2), "a patent applicant or proprietor may rely upon a technical effect for inventive step if the skilled person, having the common general knowledge in mind, and based on the application as originally filed, would derive said effect as being encompassed by the technical teaching and embodied by the same originally disclosed invention."

Considering order no. 2 of G 2/21, the question to be answered in the present case is thus whether the effect relied on by the respondent and demonstrated in the post-published experimental data (D32), namely that of improved photostability of Form II, can be derived by the skilled person, having the common general knowledge in mind, and based on the application as filed, as being encompassed by the technical teaching (requirement (i)) and embodied by the same originally disclosed invention (requirement (ii)).

The respondent relied on the statements made in T 116/18 as regards G 2/21 and submitted that, based on paragraphs [0006] and [0007] of the application as filed (A1 application), referring to the provision of a novel crystal of compound A (selexipag) and to a pharmaceutical product of "high quality for which constant effect can always be shown and a form which is handled easily industrially", the skilled person would have understood that the effect of improved photostability was implied by or at least related to the technical problem initially suggested in the originally filed application. Therefore, requirement (i), as encompassed by the technical teaching, was met. Furthermore, the skilled person would not have had any legitimate reason to doubt that the improved photostability could be achieved with the claimed polymorphic form of selexipag. Based on their common general knowledge the skilled person had been aware on the filing date that different polymorphic forms of APIs may have different, e.g. improved, photostability, and so the effect of improved photostability of selexipag Form II was not irreconcilable with the provision of a novel polymorphic form. Therefore, requirement (ii), as embodied by the same originally disclosed invention, was also met in the present case.

Before the board comments on the respondent's arguments, the relevant passages of decision T 116/18 will be reiterated here.

According to point 11.10 of the Reasons, the requirement that the purported technical effect be encompassed by the technical teaching (requirement (i)) means that this "purported technical effect together with the claimed subject-matter need only be conceptually comprised by the broadest technical teaching of the application as filed. This in turn means that said effect need not be literally disclosed in it by way of a positive verbal statement (see also point 11.13.1 below). Instead, for example, it may also be sufficient that the skilled person, having the common general knowledge in mind, and based on the application as filed, recognises that said effect is necessarily relevant to the claimed subject-matter."

In line with T 116/18 (point 11.14), in the present case the board acknowledges that the mere fact that photostability or improved photostability is not contained in terms of a positive verbal statement in the application as filed and that the application as filed does not contain any data as regards photostability, as such, does not imply that the effect of improved photostability cannot be relied on in terms of G 2/21 or T 116/18.

The board also agrees with T 116/18 (point 11.10) that the purported technical effect together with the claimed subject-matter need only be conceptually comprised by the broadest technical teaching of the application as filed and that it may also be sufficient for the skilled person, having the common general knowledge in mind, and based on the application as filed, to recognise that said effect is relevant to the claimed subject-matter; however, it is precisely this requirement that is not met in the present case.

All that is disclosed in paragraph [0005] of the application as filed (paragraph [0006] of the application as published), as relied on by the respondent, is a "thing of a high quality for which constant effect can be always shown and of a form which is handled easily industrially". The board does not consider such a sweeping statement regarding high quality and easy industrial handleability which covers a plethora of potential advantageous properties to encompass photostability, let alone improved photostability. If such a sweeping statement was sufficient, a reference to high quality would be sufficient to invoke whatever technical effect as being encompassed by an application as filed in the sense of G 2/21. This would essentially render the first criterion of order no. 2 of G 2/21 meaningless. In the present case, in more concrete terms, the application as filed is in fact directed to particle size (table 1), residual solvent content (table 2) and amount of impurities (table 3). These properties are entirely unrelated to photostability. Therefore, based on these properties, having the common general knowledge in mind, the skilled person would by no means have recognised that (improved) photostability is relevant to the claimed subject-matter. Going from these specific properties to the effect of photostability would also clearly change the nature of the invention, contrary to what is required by T 116/18 (point 11.13.3 of the Reasons). Hence, the effect of photostability is not encompassed by the teaching of the application as filed.

Furthermore, even if it were wrongly concluded in the respondent's favour that the technical teaching of the application as filed were to encompass photostability in the sense of T 116/18, it would not do so "together with the claimed subject-matter", as required by this decision (point 11.10). More specifically, points (1) to (3) of paragraph [0006] of the application as filed (paragraph [0007] of the application as published), claims 1 and 2, and points [1] to [3] on page 37 of the application as filed, as relied on by the respondent, refer to Form I, Form II and Form III in equal terms. These passages do not teach that Form II, i.e. the form claimed in claim 1 of the main request, is the preferred polymorphic form of selexipag, let alone that it should exhibit a photostability that is improved compared with Form I and Form III. Hence, the effect of improved photostability together with Form II is not encompassed by the teaching of the application as filed.

During the oral proceedings, the parties discussed decision T 1989/19. The respondent submitted that the present case was in line with T 1989/19 and that it was not a requirement that the application as filed disclosed improved photostability, so that the effect proven by the technical data in D32 could be taken into account in the formulation of the objective technical problem.

The board does not agree.

In T 1989/19 (points 3.3.15 and 3.3.16 of the Reasons), the board recognised that the technical effect derivable from the application as originally filed in the sense of G 2/21 was storage stability of the claimed compound, while the effect demonstrated by the post-published documents was the improvement in this storage stability over the cited closest prior art. In that case, the board held that once the criterion of the derivability of a technical effect in the sense of G 2/21 was fulfilled, this applied equally to the improvement in this effect.

The board agrees with the view expressed in T 1989/19; however, the situation in the present case is different from that in this decision. In the present case, as set out above, photostability is not encompassed and thus not derivable from the teaching of the application as filed in the sense of G 2/21. Furthermore, unlike in the case underlying T 1989/19, the application as filed in the present case refers to three polymorphic forms in equal terms, and the present case is not one in which the purported improvement is asserted to be present for the subject-matter of the application as filed over the subject-matter disclosed in the prior art. On the contrary, in the present case the improvement is asserted for part of the subject-matter disclosed in the application as filed over other parts of this subject-matter in equal terms.

It follows that improved photostability of Form II as demonstrated in D32 cannot be taken into account in the assessment of the technical effects achieved by the distinguishing feature.

1.4 Hereinbelow, inventive step starting from D10 will be discussed.

It was common ground between the parties that example 84 can be regarded as the starting point for the assessment of inventive step within this document.

Example 84 of D10 discloses the preparation of selexipag. In this example, selexipag was purified by column chromatography. When referring to the product obtained after chromatographic purification, example 84 of D10 only refers to "272 mg to the desired compound" and does not disclose which type of solid form of selexipag is obtained, if any.

1.5 Distinguishing feature

Considering the above, the distinguishing feature of claim 1 of the main request in view of example 84 of D10 is the crystalline form, namely Form II, of selexipag. This was common ground between the parties.

1.6 Technical effects achieved by the distinguishing feature

The five following properties were relied on by the respondent as regards the technical effects achieved by the distinguishing feature:

- stability,

- particle size distribution, and linked to this, industrial processability,

- concentration of residual solvents,

- level of residual impurities, and

- improved photostability.

In view of the above conclusion under point 1.3, improved photostability cannot be taken into account. Consequently, only the first four properties will be discussed below.

1.6.1 Stability

The respondent relied on D21 and submitted that Form II as claimed had improved stability over Form I and Form III (both comparative).

D21 is a document filed by the respondent, discussing a stability test. More specifically, D21 demonstrates the relative stability of crystal Form I to Form III in a mixture of ethanol and methyl ethyl ketone. From this stability test, it follows that Form II (according to claim 1 of the main request) is more thermodynamically stable than Form I (comparative) and Form III (comparative). Form II thus has the highest thermodynamic stability.

This was common ground between the parties.

1.6.2 Particle size distribution

The respondent relied on table 1 of the patent. Table 1 of the patent compares the particle size distribution of the three forms, Form I to Form III (see below).

FORMULA/TABLE/GRAPHICFORMULA/TABLE/GRAPHIC

From table 1, it can be concluded that the particle size of Form II (according to claim 1 of the main request) is larger than that of Form III (comparative), but smaller than that of Form I (comparative). Based on its intermediate position in terms of particle size, Form II thus has an intermediate industrial processability. As submitted by the respondent, the particle size of the crystals is inherent to Form II, in the absence of any evidence that it would be linked to its process of preparation.

1.6.3 Concentration of residual solvents

The respondent relied on table 2 of the patent.

Table 2 of the patent (reproduced below) discloses the concentration of residual solvents contained in Form I, Form II and Form III.

FORMULA/TABLE/GRAPHIC

As submitted by the respondent, the lower concentration of residual solvent observed for the claimed Form II (2169 + 246 = 2415 ppm) as set out in table 2 of the patent facilitates more exhaustive removal of the solvent in comparison with the concentration for comparative Form III (93 + 2781 = 2874 ppm), but not in comparison with the concentration for comparative Form I (371 + 82 = 453 ppm). Form II thus has an intermediate level of residual solvent. As submitted by the respondent, the level of residual solvent is inherent to Form II, in the absence of any evidence that it would be linked to its process of preparation.

1.6.4 Residual impurities

Table 3 of the patent (reproduced below), relied on by the respondent, sets out the purity and the ratio of impurity removal of Form II (according to claim 1 of the main request), Form I (comparative) and Form III (comparative).

FORMULA/TABLE/GRAPHIC

As is apparent from the third column of the above table, the effectiveness of removing impurities for Form II (according to claim 1 of the main request) is higher than that for Form III (comparative), but lower than that for Form I (comparative). In the same vein, the purity level of Form II is higher than that of Form III but lower than that of Form I (second column). Form II thus also has an intermediate position as regards the level of residual impurity. As submitted by the respondent, the level of residual impurity is inherent to Form II, in the absence of any evidence that it would be linked to its process of preparation.

1.7 Objective technical problem

In view of the above experimental result, it can be concluded that Form II exhibits the best stability but only intermediate industrial processability, intermediate residual solvent content and an intermediate amount of residual impurities. As set out by the chairman during the oral proceedings, contrary to the situation in T 672/21 there is no balance of beneficial properties for Form II according to the main request. The objective technical problem may only be considered that of providing a crystalline form of selexipag which is the best for one property, but only intermediate for all other tested properties.

1.8 Obviousness

The respondent submitted that, in line with T 1684/16 (point 4.3.4 of the Reasons), there was no reasonable expectation based on the prior art that a suggested investigation in terms of polymorph screening would be successful in finding a form of selexipag having a balance of beneficial properties in terms of stability, industrial processability, solvent content and purity.

The board disagrees. Based on T 1684/16 and in line with T 777/08, an inventive step can be acknowledged if the claimed polymorph has an unexpected property meaning that its selection is non-arbitrary. In the present case, the board sees nothing unexpected in finding a polymorph that is optimum for one property but only intermediate for several other properties. If this were unexpected and thus gave rise to an inventive step being acknowledged, an applicant or proprietor having identified a new polymorph would simply need to carry out tests for long enough to find one single property for which the identified polymorph performs best. As pointed out by the chairman during oral proceedings, this might result in a situation in which almost any polymorph in the world becomes inventive, which would render Article 56 EPC meaningless.

Therefore, the selection of Form II is an arbitrary selection from the host of alternatives covered by the closest prior art. Such an arbitrary selection without any unexpected balance of properties being produced cannot contribute to inventive step. The subject-matter of claim 1 of the main request therefore does not involve an inventive step in view of D10 as the closest prior art.