T 0179/16 (Sustained release risperidone formulation / DURECT) 15-11-2021

1. Main request (patent as granted), inventive step

1.1 The claimed invention relates to injectable depot formulations of risperidone. According to the patent, the problem underlying the invention is to address the issues associated with plasma concentration peaks and troughs observed with oral pills and bolus injections and to provide a sustained, near zero-order release dosage form of the drug designed to minimize variations in plasma concentration following dosing (see paragraphs [0003]-[0004] and [0013]).

1.2 D1 has similar objectives. D1 (see paragraphs [0004]-[0008] and [0012]) addresses the issue of modulating the release of beneficial agents from drug delivery systems to achieve desirable or sustained release rates, and mentions the problems of bursts or lag time in the delivery of the beneficial agent. Claim 1 of D1 pertains to injectable depot formulations comprising, among others, a beneficial agent, a biocompatible polymer and a solvent. Although the formulations exemplified in D1 comprise different beneficial agents (namely bupivacaine and hGH), risperidone (erroneously spelled "resperidone" in paragraph [0087]) is mentioned in D1 among a long list of beneficial drugs to be used in the formulations. In one alternative of D1 (see claims 22-24), the polymer comprises a copolymer of lactic acid and glycolic acid (PLGA) having a weight average molecular weight of 3000 to 120000 and a monomer ratio of lactic acid to glycolic acid between 100:0 and 50:50.

Accordingly, D1 represents a suitable starting point for the assessment of inventive step. This was accepted by the respondent during the oral proceedings before the Board.

1.3 The Board agrees with the appellant that the starting point within D1 is the disclosure of an injectable depot formulations comprising risperidone, a biocompatible polymer and a solvent, since this direct and unambiguous disclosure results from the single selection of the active agent within D1. This is also the disclosure coming closest to the claimed subject-matter, considering that the nature of the active agent is an essential aspect in the development of formulations having desirable release properties. D1 does not, however, show this risperidone composition in combination with the selection of PLGA having a number average molecular weight of 1000 to 30000.

1.4 The respondent did not assert that the choice of the excipients or polymer from among those disclosed in D1 was associated with any particular technical effect. Rather, the respondent argued that risperidone was known to be insoluble in water, whereas D1 did not provide evidence of any sustained release profile for compositions comprising active agents other than water soluble drugs. Thus, according to the respondent, the patent would demonstrate that the incorporation of risperidone in the claimed formulation achieved a sustained, near zero-order release (see paragraph [0013] and figure 2, formulations 63 and 73). This effect would not be plausible from the teaching of D1.

1.4.1 In the Board's opinion, D1 generally states that the depot gel compositions disclosed therein allow the sustained release of any beneficial agent (see 1.2 above). The Board concurs with the respondent that the examples of D1, pertaining to bupivacaine and hGH only, provide limited support for this broad statement. Furthermore, several passages in D1 are consistent with the respondent's view that the skilled person reading D1 would realistically expect such a sustained release only for water soluble drugs (see paragraph [0089], last two sentences, and paragraph [0085]).

1.4.2 However, claim 1 of the main request is not limited to water soluble forms of risperidone. Although risperidone base is known to be practically water insoluble (see A013, page 2374), claim 1 covers any salt thereof, and consequently does not exclude salts having a substantially higher water solubility. It is well known, and confirmed by D1 (see paragraph [0039]), that the hydrophilic-hydrophobic property of a drug can be tailored by its chemical form.

Accordingly, the respondent's arguments based on a reading of D1 as limited to water soluble entities cannot succeed since such entities are allowed by claim 1 of the main request. The subject-matter of claim 1 of the main request as a whole is not characterised by any technical effect which would not be expected to arise in light of D1.

1.5 The objective technical problem is thus the provision of further risperidone compositions.

1.6 The claimed solution consists in selecting a polylactide having a number average molecular weight (namely 1000 to 30000) which, for the most part, is subsumed by the range proposed in D1 (namely 3000 to 120000). This selection does not, in the absence of any associated effect, involve an inventive step.

1.7 The respondent's further arguments based on the review article D4 do not modify this conclusion. D4 emphasises some disadvantages of certain biodegradable injectable in situ forming drug delivery systems, or, generally, the release profile's dependence on the nature of the drug incorporated (see point 4.1, page 15, right hand column; page 17, right hand column). However, D4 is not concerned with the teaching of D1 or the possibility to apply it to risperidone.

1.8 Likewise, the respondent's further arguments based on A014 do no affect the present issue. A014 pertains to another, water soluble active ingredient, namely amitriptylene HCl. This post-published evidence A014 neither demonstrates an effect associated with the claimed risperidone compositions, nor invalidates the conclusion that the skilled person, reading D1, would in general expect a sustained release from compositions comprising water soluble drugs.

In conclusion, the main request does not meet the requirements of Article 56 EPC.

2. Auxiliary requests, remittal to the opposition division

The respondent requested, in case the Board did not allow the main request, that the case be remitted to the opposition division for consideration of the auxiliary requests.

Pursuant to 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. In the present case, no such special reasons were identified by the respondent. The opposition division took a decision inter alia on inventive step and added subject-matter, and at least auxiliary requests 1-4 do not significantly change the scope of the appeal proceedings. Hence the Board decided not to remit the case to the opposition division for further prosecution.

3. Auxiliary requests 1 and 2, inventive step

3.1 Since claim 1 of auxiliary request 1 is identical to claim 1 of the main request, the finding of lack of inventive step applies to auxiliary request 1.

3.2 Claim 1 of auxiliary request 2 limits the number average molecular weight of the polylactide to 5000 to 30000. This range does not depart from the broader range of molecular weights disclosed in the closest prior art D1, namely 3000 to 120000. Accordingly, auxiliary request 2 infringes Article 56 EPC for the same reasons as for the main request.

4. Auxiliary request 3, Article 76(1) EPC, combination of the features of claim 1

4.1 The injectable depot formulation of claim 1 of auxiliary request 3 comprises - as does claim 1 of the main request - in particular, a polylactide having a number average molecular weight of 1000 to 30000, and risperidone, in base or salt form. For the following reasons, the Board comes to the conclusion that the parent application as filed provides no basis, for the purposes of Article 76(1) EPC, for the combination of these features.

4.2 The claimed molecular weight range 1000-30000 results from a combination of the general range of 1000-120000 with the preferred range of 5000-30000 disclosed in paragraph [0017] of the parent application as filed. This combination of the general lower limit with the preferred upper limit does not per se introduce added subject-matter. However it must be seen as a first selection out of the various ranges which may be created from the general and preferred ranges.

Furthermore, the small molecule drug has been limited to one of the two drugs recited in claim 11, namely base and salt forms of R209130 and risperidone. Paragraph [0020] and the examples of the parent application as filed also recite several small molecule drugs including R209130 (base, mandelic acid salt and tartaric acid salt) and risperidone (base and pamoate). Risperidone is not identified as preferred over R209130 in the parent application as filed.

4.3 The respondent did not convincingly show that the parent application contained any pointer to the claimed combination. The argument that the combination range 1000-30000 would be more preferred than the general range 1000-120000 because it includes the preferred range 5000-30000 cannot be accepted, as any such preference would only apply to the 5000-30000 part. Since the parent application as filed does not point to the combination of risperidone with the combination range including the lower end point of 1000, the Board concludes that the subject-matter of claim 1 of auxiliary request 3 does not derive, directly and unambiguously, from the parent application as filed.

Accordingly, auxiliary request 3 does not meet the requirements of Article 76(1) EPC.

5. Auxiliary request 4

5.1 Articles 123(2) and 76(1) EPC

5.1.1 Claim 1 of auxiliary request 4 combines a monomer ratio of 100:0 to 15:85 (i.e. the broadest ratio of paragraph [0017] in the parent application as filed), a number average molecular weight of 5000 to 30000 (disclosed as preferred in paragraph [0017] in the parent application as filed), and the small molecule drug risperidone (selected from the preferred drugs in the parent application as filed). As emphasised by the respondent, this preferred molecular weight range encompasses the polylactides used in all examples, which have molecular weights ranging from 6400 to 16000. Apart from the choice of risperidone as active agent, the Board does not view the above combination of features in claim 1 of auxiliary request 4 as resulting from multiple selections or as adding subject-matter. Furthermore, the feature that the risperidone, in base or salt form, has less than 1 mg/ml solubility in water is disclosed as preferred in paragraph [0019] of the parent application as filed.

5.1.2 In the parent application as filed, the invention is defined in claims 1 and 17, and paragraphs [0005] and [0006], by the feature that "the formulation exhibits an in vivo release profile having Cmax to Cmin ratio less than 200 and lag time less than 0.2". In contrast, claim 1 of auxiliary request 4 does not comprise this feature.

The Board shares the opinion of the respondent that the omission of this feature does not infringe Article 76(1) EPC, because it is not indicated to be essential or indispensable in the parent application as filed. To the contrary, paragraph [0013] discloses that it is the incorporation of the drug in the depot gel vehicle that solves the technical problem of achieving a near zero-order release. The last sentence of paragraph [0013] also indicates that "several small drug formulations have been identified in this invention" with in vivo release profiles having a Cmax to Cmin ratio less than 200 and lag time less than 0.2. The use of the word "several" supports the view that the invention is not limited to these identified small drug formulations. Furthermore, the parent application as filed contains several examples having lag time Tlag above 0.2 (see example 5, paragraph [0030]) or Cmax/Cmin above 200 (see formulation 63 in table 3, which nonetheless has a near zero order release profile similar to formulation 73 in figure 2). None of these examples are identified as reference examples. Accordingly, taking into account paragraph [0013] and the examples, it is directly and unambiguously derivable from the parent application as filed that the omitted in vivo release profile is not essential to the invention.

5.1.3 In conclusion, auxiliary request 4 meets the requirements of Article 76(1) EPC. Since the divisional application as filed includes the same disclosure as the parent application as filed, the requirements of Article 123(2) EPC are also met.

5.2 Inventive step

5.2.1 Starting from the injectable depot formulations of D1 (see 1.2 and 1.3 above) comprising risperidone, a biocompatible polymer and a solvent, the subject-matter of claim 1 of auxiliary request 4 differs not only by the choice of the polylactide having a number average molecular weight of 5000 to 30000 but also in that the risperidone, in base or salt form, has less than 1 mg/mL solubility in water. Accordingly, the claimed subject-matter is limited to formulations for which D1 does not credibly demonstrate any sustained release (see 1.4.1 above).

5.2.2 The patent demonstrates that the formulations of claim 1 of auxiliary request 4 achieve, qualitatively, a sustained or near zero-order release for a duration of about 10 days (see figure 2, formulations 63 and 73). The respondent defines the technical problem as the provision of a risperidone formulation having near zero order release in vivo. The Board concurs.

5.2.3 The skilled person reading D1 would not consider the claimed formulations, comprising water insoluble forms of risperidone, as a solution to the problem of providing a sustained release (see also 1.4.1 above). The skilled person would not be led to the claimed invention by the review article D4 either. D4 describes depot gel formulations comprising a water soluble polylactide polymer and a solvent, but does not pertain to risperidone (see 1.7 above).

5.2.4 The Board does not regard the appellant's objection starting from D3 to be convincing either.

D3 discloses pharmaceutical compositions comprising controlled release microparticles having improved shelf-life, said microparticles comprising active agents encapsulated within a polymer matrix. D3 is not concerned with the release profile of said microparticle compositions, but rather aims at reducing degradation by reducing the levels of residual processing solvent (see [0001] and [0007]). In some examples, D3 shows a polylactide polymer microparticle formulation which comprises risperidone.

5.2.5 To the extent that D3 may qualify as a starting point for the assessment of inventive step, the claimed formulations differ from those of D3 at least by the use of the injectable depot formulation comprising the excipients defined in claim 1. For the reasons set out above (see 5.2.2), the technical problem is the provision of an injectable formulation of risperidone providing sustained release in vivo.

5.2.6 As explained above, neither D1 nor D4 allow the skilled person to expect a sustained release from the claimed formulations comprising risperidone with low water solubility. The same is true of A009-A012. A009 (see pages 345-346) and A010 mention some advantage of some gel depot formulations, such as a stabilization of macromolecules and a long lasting delivery profile without initial burst, in particular with a polylactide falling within the scope of claim 1 (50/50 PLGA with a molecular weight of 12000 to 20000). However there is no indication in A009 or A010 that any such long lasting delivery profile would also arise with risperidone having low water solubility.

A011 and A012 are similar to D1, in that they disclose gel depot formulations wherein the beneficial agent may be risperidone and the polymer a polylactide (see A011, abstract and paragraphs [0101] and [0143]; A012, abstract and paragraphs [0020] and [0093]). But they are similar to D1 also in their speculative nature and lack of evidence regarding the risperidone with low water solubility of claim 1. Thus A011 and A012 do not modify the above conclusion.

Accordingly, auxiliary request 4 meets the requirements of Article 56 EPC.