T 1126/19 - The whole list as starting point

Key points

• The decision was taken on 21.07.2023 and the written decision was issued on 03.01.2024. A communication under Art.15(9) was sent (link).
• The file does not show any communication under Art. 15(9) RPBA to inform the parties about the delay, and the written decision itself does not acknowledge the delay in any way. 
• One can only hope that compliance with Art. 15(9) RPBA will become more visible after the amendment of Art. 15(9) as of 01.01.2024. 
• Is the starting point for an inventive step analysis under the problem-solution approach a single document, or a single embodiment of a document, or something else? 
• "Claim 1 is directed to a camsylate salt of rucaparib which is crystalline and has a PXRD pattern comprising the characterising peaks 12.2±0.2, 14.8±0.2 and 22.4±0.2."
• "The invention is based on the finding that crystalline rucaparib camsylate is particularly suitable for the preparation of solid dosage forms due to its physical stability and low hygroscopicity (paragraph [0045]). The patent identified three crystalline forms of rucaparib camsylate, which were designated as Forms A, B and C (paragraph [0054]). "
• "claim 1 defines a rucaparib salt that contains Forms A and/or B, and [optionally] Form C."
• "document D1 [is] the closest prior art. As set out in point 4.1 above, D1 relates to the use of rucaparib as a chemosensitiser: it is combined with chemotherapeutic agents for potentiating the effect of the latter in the treatment of cancer. In paragraph [0043], D1 discloses a list of about 60 pharmaceutically acceptable salts of rucaparib that can be used in therapy. The list includes camsylate, although the preferred salts are phosphate and gluconate."
• "The parties agreed that D1 was the closest prior art but disagreed on whether inventive step should be assessed starting from the whole list in paragraph [0043] or the specific disclosure of the camsylate salt in that paragraph."
• " The board agrees with the appellant-patent proprietor [] that the starting point should be the whole list rather than the specific option of the camsylate salt. As explained in decision T 970/00 (Reasons 4.1.2), cited by the appellant-patent proprietor, the disclosure of the closest prior art must be considered on the basis of its technical information, without distorting or misrepresenting it by the knowledge of the invention."
• "In paragraph [0043] of D1, the camsylate salt of rucaparib is not singled out. D1 neither illustrates the camsylate salt of rucaparib nor presents it as a standalone embodiment. Paragraph [0043] is merely a notional disclosure in which camsylate is one among a long list of possible options, but not among the preferred ones. The isolation of one of the non-preferred options from paragraph [0043] would distort the teaching of D1, putting an inappropriate weight on that option."
• "Starting from the list of pharmaceutically acceptable salts in paragraph [0043] of D1, the subject-matter of claim 1 differs in the selection of camsylate as the rucaparib salt and the additional requirements that the salt be crystalline and show three specific PXRD peaks."
• "the board agrees with the objective technical problem proposed by the appellant-patent proprietor, i.e. the provision of a solid form of rucaparib having a suitable combination of properties for development into a solid dosage form."
" On the issue of obviousness, D1 does not deal with the formulation of solid forms of rucaparib. It contains no teaching on whether any of the salts in the long list of paragraph [0043] might possibly be suitable for preparing an oral solid formulation. The skilled person would have needed to study each of the salts for assessing: first, whether they are solid; second, how many solid forms they may adopt; and third, whether there are forms with properties suitable for a solid formulation."
• As noted by the appellant-patent proprietor, it is common general knowledge that finding a salt of an active compound which has a balance of properties making it suitable for an oral solid formulation is generally a difficult semi-empirical task which requires non-routine experimentation and has an uncertain outcome. "
• "the salt of claim 1 involves an inventive step and claim 1 meets the requirements of Article 56 EPC. "

EPO 

The link to the decision is provided after the jump, as well as (an extract of) the decision text.

https://www.epo.org/en/boards-of-appeal/decisions/t191126eu1

5. Interpretation of claim 1 of the main request

5.1 Claim 1 is directed to a camsylate salt of rucaparib which is crystalline and has a PXRD pattern comprising the characterising peaks 12.2±0.2, 14.8±0.2 and 22.4±0.2.

The appellants interpreted claim 1 in different ways. According to the appellant-patent proprietor, the salt of claim 1 encompasses only a pure polymorphic form characterised by the three peaks, or a mixture of polymorphic forms in which each polymorphic form is characterised by the three peaks. In contrast, the appellant-opponent maintained that claim 1 covers any mixture of solid forms, provided that the three characterising peaks can be identified in the PXRD pattern of the mixture. This includes mixtures containing forms that are not characterised by the three peaks, in particular Form C and amorphous forms of rucaparib camsylate.

5.2 As set out at the oral proceedings (minutes, page 2, second paragraph), the board does not agree with either of the two interpretations.

On the one hand, claim 1 is directed to a crystalline salt of rucaparib camsylate. Such a wording is not open to the addition of further components. Therefore, contrary to the appellant-opponent's interpretation, the salt of claim 1 does not contain substantial amounts of amorphous forms. This interpretation is not precluded by the broader disclosure in paragraph [0053] of the patent. As noted by the appellant-patent proprietor, the description and the claims as granted are broader than claim 1 of the main request.

On the other hand, claim 1 is directed to a crystalline salt. It is not limited to a pure polymorphic form of a crystalline salt characterised by the three peaks or to mixtures of polymorphic forms in which each form is characterised by the three peaks. The crystalline salt of claim 1 may be composed of a mixture of any crystalline forms of rucaparib camsylate, provided that the PXRD pattern of the mixture exhibits the peaks 12.2±0.2, 14.8±0.2 and 22.4±0.2. This view is also in line with dependent claim 8, in which it is specified that the salt is a substantially pure polymorph of S-camsylate Form A, and with paragraph [0053] of the description, which teaches that solid forms may contain more than one polymorphic form or may exist in a substantially pure form of a single polymorph. Therefore, contrary to the appellant-patent proprietor's interpretation, although the salt must exhibit the three peaks, this is not required for each of the crystalline polymorphic forms present in the salt. It suffices that one of the polymorphs exhibits the three peaks, and that it is present in an amount sufficient for the three peaks to be identifiable in the PXRD pattern of the salt.

In this connection, the board notes that the patent identified and characterised three crystalline polymorphs of rucaparib camsylate, Forms A, B and C. It was undisputed that Forms A and B of both the S- and R-camsylate exhibit the peaks required by claim 1 (see patent: Table 9 and Figure 10; Table 27 and Figure 23; Figure 15). In contrast, Form C does not exhibit a peak at 22.4±0.2 (Table 15 and Figure 18). Therefore, the board concludes that the salt of claim 1 contains Forms A and/or B and, additionally, it may contain Form C. This conclusion is in line with the sentence in paragraph [0053] of the patent according to which where a solid form comprises two or more polymorphs, the X-ray diffraction pattern will typically have peaks characteristic of each of the individual polymorphs. For each form, the camsylate salt may have R-, S- or both configurations, as illustrated in Examples 17 to 20 of the patent.

6. Inventive step (Article 56 EPC) - claim 1 of the main request

6.1 The patent (paragraphs [0001] to [0005]) is directed to new polymorphic forms of rucaparib salts. Rucaparib is an inhibitor of PARP, an enzyme which induces DNA repair in the event of moderate DNA damage. Therefore, rucaparib is used in cancer therapy to potentiate the effect of radiotherapy or cytotoxic drugs which cause DNA damage.

The invention is based on the finding that crystalline rucaparib camsylate is particularly suitable for the preparation of solid dosage forms due to its physical stability and low hygroscopicity (paragraph [0045]). The patent identified three crystalline forms of rucaparib camsylate, which were designated as Forms A, B and C (paragraph [0054]). Form A could be prepared by the methods disclosed in paragraphs [0146], [0147] or [0165]. This form appeared to be non-hygroscopic and highly stable (paragraphs [0073] and [0158]). Form C could be prepared from Form A (paragraph [0160]). With regard to Form B, the patent showed its PXRD pattern in Figure 15.

6.2 It was common ground between the parties that document D1 was the closest prior art. As set out in point 4.1 above, D1 relates to the use of rucaparib as a chemosensitiser: it is combined with chemotherapeutic agents for potentiating the effect of the latter in the treatment of cancer. In paragraph [0043], D1 discloses a list of about 60 pharmaceutically acceptable salts of rucaparib that can be used in therapy. The list includes camsylate, although the preferred salts are phosphate and gluconate.

6.2.1 The parties agreed that D1 was the closest prior art but disagreed on whether inventive step should be assessed starting from the whole list in paragraph [0043] or the specific disclosure of the camsylate salt in that paragraph.

6.2.2 The board agrees with the appellant-patent proprietor (reply to the appellant-opponent's statement of grounds of appeal, point 7.2) that the starting point should be the whole list rather than the specific option of the camsylate salt. As explained in decision T 970/00 (Reasons 4.1.2), cited by the appellant-patent proprietor, the disclosure of the closest prior art must be considered on the basis of its technical information, without distorting or misrepresenting it by the knowledge of the invention.

In paragraph [0043] of D1, the camsylate salt of rucaparib is not singled out. D1 neither illustrates the camsylate salt of rucaparib nor presents it as a standalone embodiment. Paragraph [0043] is merely a notional disclosure in which camsylate is one among a long list of possible options, but not among the preferred ones. The isolation of one of the non-preferred options from paragraph [0043] would distort the teaching of D1, putting an inappropriate weight on that option.

6.3 Starting from the list of pharmaceutically acceptable salts in paragraph [0043] of D1, the subject-matter of claim 1 differs in the selection of camsylate as the rucaparib salt and the additional requirements that the salt be crystalline and show three specific PXRD peaks.

6.4 As to the technical effect brought about by these differences, the board set out in point 5.2 above (last paragraph) that claim 1 defines a rucaparib salt that contains Forms A and/or B, and that, additionally, it may contain Form C.

6.4.1 The patent shows in paragraphs [0073] and [0158] (application as filed, page 36, lines 15 to 18 and page 86, lines 16 to 20) that Form A of rucaparib camsylate is non-hygroscopic and highly stable even under conditions of high temperature and humidity. These properties were confirmed in declarations D30 and D33, the content of which was not disputed by the appellant-opponent.

According to D30 (paragraph [0004]), rucaparib camsylate can be prepared as R- or S-camsylate and both stereoisomers have an equivalent crystalline Form A. Therefore, the physico-chemical properties of the R- and S-camsylate salts should be identical. D30 (paragraphs [0007], [0008], [0010] and [0011]) confirmed that rucaparib S-camsylate Form A is highly stable and soluble. Similar statements can be found in D33 (paragraphs [0013] to [0021]).

On the relationship between Form A and the other two polymorphs of rucaparib camsylate identified in the patent, D30 (paragraphs [0003] and [0005]) states that Form A is thermodynamically the most stable of the three forms and that it is preferentially formed during crystallisation. Therefore, Form A can be easily crystallised to provide highly crystalline material in a controlled manner and a very pure form, preventing the formation of Form C. Form A is also highly soluble and dissolves rapidly (D30, paragraphs [0010] and [0011]).

Form C is an anhydrous polymorph which converts to Form A in solvent-mediated systems (D30, paragraph [0003]). Therefore, the presence of Form C can easily be avoided but, if present, Form C would not impair the anhydrous properties of crystalline rucaparib camsylate for solid oral formulations.

As to Form B, D30 states that Form A and Form B repeatedly and reversibly convert into each other by heating within the range 128 to 140°C (D30, paragraph [0003]). In other words, Form B exists only at high temperatures incompatible with storage or therapeutic conditions; at temperatures lower than 128°C, Form B converts into Form A.

The low number of crystalline polymorphs of rucaparib camsylate, and the relationship between these polymorphs and the physical properties of Forms A and C, the only existing forms in use, make crystalline rucaparib camsylate particularly suitable for the formulation of a solid dosage form.

6.4.2 The appellant-opponent argued that because claim 1 encompasses salt mixtures that could contain only low amounts of Form A, the advantageous properties shown for Form A would not arise across the whole breadth of claim 1. Therefore, a technical effect could not be considered for the formulation of the objective technical problem. This was the situation in the case on which decision T 1555/12 (Reasons 5.2 and 7.3) is based.

However, as explained above, Form B does not exist at in-use temperatures. The only possible components in the salt of claim 1 when present in a solid formulation are Forms A and C. Contrary to the case on which T 1555/12 is based, the less-stable form of crystalline rucaparib camsylate, i.e. Form C, also confers advantageous properties on the formulation since it is anhydrous. Furthermore, the only polymorph to which Form C can evolve is Form A. The evolution of Form C to the most advantageous Form A can only improve the properties of the formulation even further. Therefore, the crystalline rucaparib camsylate according to claim 1 is particularly suitable for the formulation of oral dosage forms of rucaparib.

The appellant-opponent also argued that the advantageous effects of Form A had only been shown for the S-camsylate. Nevertheless, as stated in D30 (paragraph [0004]), the S- and R-camsylates have equivalent Forms A and are expected to have the same physical properties.

6.5 Consequently, the board agrees with the objective technical problem proposed by the appellant-patent proprietor, i.e. the provision of a solid form of rucaparib having a suitable combination of properties for development into a solid dosage form.

6.6 The board is satisfied that the subject-mater of claim 1 solves this problem, as explained above in the context of the technical effect achieved by the difference from the closest prior art.

6.7 On the issue of obviousness, D1 does not deal with the formulation of solid forms of rucaparib. It contains no teaching on whether any of the salts in the long list of paragraph [0043] might possibly be suitable for preparing an oral solid formulation. The skilled person would have needed to study each of the salts for assessing: first, whether they are solid; second, how many solid forms they may adopt; and third, whether there are forms with properties suitable for a solid formulation.

As noted by the appellant-patent proprietor, it is common general knowledge that finding a salt of an active compound which has a balance of properties making it suitable for an oral solid formulation is generally a difficult semi-empirical task which requires non-routine experimentation and has an uncertain outcome. This is confirmed for instance by the encyclopaedia excerpt D7 (page 453, introduction) or review articles D20 (page 1, paragraph bridging the two columns, and page 16, conclusions), D19 (page 277, left-hand column, first paragraph and page 286, left-hand column, first paragraph) and D6 (page 201, introduction, and page 213, conclusion). Therefore, the salt of claim 1 was not obvious from D1.

6.8 The board does not find a pointer to the salt of claim 1 in any of the combination documents cited by the appellant-opponent either. The appellant-opponent's arguments were mainly based on the assumption that the closest prior art was the camsylate salt rather than the whole list of paragraph [0043] of D1. As set out in point 6.2.2 above, this assumption was wrong.

The appellant-opponent cited D3 and D35 to show that it was common general knowledge that crystalline forms are less hygroscopic and more stable than amorphous forms (D3, page 557), and that searching for stable solid forms is part of the development of solid oral dosage forms (D35, page 83, Figure 4.7). This can be accepted by the board. However, starting from the list of salts in paragraph [0043], it goes beyond routine work to find whether any of the listed salts, if at all, exhibit the set of properties required for solid oral dosage forms.

The appellant-opponent also cited D4 (page 217, point 8.3.4) and D5 (page 433, left-hand column, first paragraph) to show that camsylate was known to be a salt that could be used for the formulation of drugs. This can also be accepted by the board. But the teaching that camsylate can be used for the formulation of drugs is nothing more than the teaching of paragraph [0043] of D1, which lists salts that are pharmaceutically acceptable. It has already been explained that this paragraph does not render the salt of claim 1 obvious.

The appellant-opponent also referred to the headnote of decision T 777/08. In that decision, in particular in point 2 of the headnote, the competent board dealt with the situation in which the starting point for assessing inventive step was the amorphous form of a drug, and the skilled person was seeking a solid form with improved filterability and drying characteristics. That is clearly not the situation at hand, in which the skilled person does not start from the amorphous form of the salt but has a long list of possible salts to investigate.

The appellant-opponent cited T 41/17 (Reasons 1.2 to 1.4) too. In this decision the competent board held that finding the most stable crystalline form of sorafenib tosylate was a matter of routine screening. In that case, the skilled person started from a known crystalline form of sorafenib tosylate and sought a more stable form. Such a situation is again not comparable with the one at hand, in which the skilled person has to start from a long list of possible salts.

6.9 Therefore, the salt of claim 1 involves an inventive step and claim 1 meets the requirements of Article 56 EPC.