T 0456/91 (Microencapsulation/SYNTEX) 03-11-1993

Reasons for the Decision

1. The appeals are admissible.

2. Amendments (Articles 123(2) and (3) EPC)

2.1. Claim 1 of the main request differs from that of the granted patent in as much as the following limitations have been introduced:

2.1.1. Firstly the claimed "at least one polypetide" is now limited to being "water-soluble". The amendment is supported by the disclosure on page 1, line 11, of the originally filed application.

2.1.2. Secondly the biocompatible, biodegradable encapsulating polymer is now restricted to a "poly(lactide-co- glycolide) copolymer", which in the originally filed application has already been stated to be the most preferred polymer excipient (see page 13, lines 5 to 8 and lines 33 to 35; particularly page 14, lines 5 to 10).

2.1.3. Thirdly Claim 1 is now restricted to "the lactide/glycolide molar ratio of the copolymer, its molecular weight, the capsule diameter, and the polymer hydrolysis modifying agent (if present), being such that the composition exhibits sustained release of an effective amount of the polypeptide over a period of at least one month". This limitation to "at least one month" finds a basis both in the originally filed application (see page 16, lines 28/29 and 32/33) and that of the patent as published (see page 6, lines 38 and 40/41), where the release time is stated to be one which may range from one month to three years, preferably about one month to 24 months. It is not of significance for the purposes of Article 123(2) EPC that the one month limit was not stated to be an essential feature of the invention in the application as originally filed: it is sufficient that the lower limit was mentioned somewhere in the originally filed application.

2.2. The originally filed Claim 1 contained neither a lower limit nor an upper limit on the time period for effective release. The introduction of a lower limit on the time period is a restriction of the scope of the claim. No necessary connection between this lower limit and any of the specifically disclosed upper limits is mentioned in the application as originally filed, nor have the Appellants shown any reason why any reader might presume this to be the case. Accordingly the Board sees no objection to introducing the lower limit into Claim 1 without at the same time introducing an upper limit. The reference (see page 6, lines 38 to 41) in the description to upper limits remains unchanged.

2.3. There is also a basis in the originally filed application (see page 16, lines 28 to 32) for the variables relating to the encapsulating polymer being such as to provide the required release period. The qualifier "if present" for the polymer hydrolysis modifying agent has a basis in the application as originally filed which stated that the agent was optional (see page 10, lines 6 to 10).

2.4. Claim 20 specifying a molar ratio of about 50:50, has a basis in the originally filed Claims 6 and 7.

2.5. The set of claims for Austria has been modified in an equivalent way.

2.6. The main request thus complies with Article 123(2) and 123(3) EPC.

3. Clarity and support (Article 84 EPC)

3.1. According to the jurisprudence of the Boards of Appeal, the clarity of a claim is not diminished by the mere breadth of a term of art contained in it, if the meaning of such term is unambiguous for a person skilled in the art, either per se or in the light of the description (see T 238/88, OJ EPO 1992, 209 and T 688/91 of 21 April 1993 point 3.4 of the Reasons (not published in OJ EPO)). As in the present case it is clear from the claims when read in the light of the description (see page 2, line 39 to page 4, line 26) which peptides are suitable for the present invention, the present claims cannot be challenged under Article 84 EPC for the sole reason that an extremely large number of compounds can be used for carrying out the invention. Any arguments of the Appellants in connection with the large number of peptides covered by the present Claim 1 must therefore fail.

4. Sufficiency (Article 83 EPC)

4.1. The provision of Article 83 EPC that the disclosure of a patent must be sufficiently clear and complete for the invention to be carried out by a person skilled in the art, is, as has been stated by the Board of Appeal in Decision T 292/85, "Polypeptide expressions", (OJ EPO 1989, 275), satisfied "if at least one way is clearly indicated enabling the skilled person to carry out the invention". It is not necessary for the purpose of Articles 83 and 100(b) EPC that the disclosure of a patent be adequate to enable the skilled person to carry out all conceivable ways of operating the invention embraced by the claims. In view of the examples still remaining in the description and the additional experimental data submitted by the Respondent (see submission of 30 August 1990, in particular page 18, last paragraph and page 19, Table 3) showing that following the instructions of the patent, compositions for two other peptides, Leuprolide and Buserelin, with at least one month's sustained release were made, the Board is satisfied that a prima facie case exists that the disclosure is sufficient to enable the skilled person without undue burden to carry out the invention as claimed.

4.2. The mere argument of the Appellants that because the Claim 1 covers an extremely large number of polypeptides, whereas the examples of the patent in suit all relate to a single polypeptide, Nafarelin, is not adequate to make out this ground of invalidity, in the absence of any evidence that there exists at least one polypeptide falling within the definition of Claim 1 for which a one month sustained release composition cannot be made following the teaching of the patent. Here the Appellants who are asserting this ground of invalidity have the burden of proof, and they have failed to discharge it (see T 219/83, OJ EPO 1986, 211).

4.3. Appellant 09 was the only one to submit evidence on the time it takes and the cost of arriving at a single sustained release formulation, and to argue that these were by themselves so great as to be evidence that the patent in suit contained insufficient instructions. However it is well known that developing and testing a marketable product in the medical field is commonly very expensive and time consuming even once the basic research has already been completed. Development of a product that is to achieve sustained release over one month, can be expected to be more expensive than average. In view of this the Board does not consider that the time scale and costs quoted by Appellant 09 are so different from what could reasonably be expected, as to amount to evidence of the description of the patent being insufficient because an undue burden is imposed on anyone wishing to carry out the teaching of the patent in suit.

5. Novelty (Article 54 EPC)

5.1. Lack of novelty was only alleged in respect of (32), an earlier application by the Respondent with claims directed to particular polypeptides (including Nafarelin the polypeptide specifically referred to in the patent in suit) irrespective of whether they were used in a sustained release composition or not. (32) contained references to the desirability of the polypeptide being provided in a sustained release form. On page 41 in Example 8.B.2 there was disclosed a pharmaceutical composition comprising a LH-RH analogue in biodegradable microcapsules made of a 25/75 glycolide/lactide copolymer. Further (32) specifically referred to (9) stating on page 12, lines 16-21 that "Another type of slow release depot formulation for injection would contain the compound or salt dispersed or encapsulated in a slow degrading, non-toxic, non-antigenic polymer such as a polylactic acid/polyglycolic acid polymer for example as described in U.S. 3,773,919".

5.2. Example 8.B.2 did not specifically refer to the LH-RH analogue being Nafarelin, but as this was the preferred compound of (32) this seemed the natural interpretation. The Respondent provided evidence that if Example 8.B.2 was carried out using Nafarelin, the sustained release obtained was much less than one month. Appellant 01 provided evidence of some alleged attempts to repeat Example 8.B.2. The results did not show a sustained release for at least one month in all cases, and the cases where at least one month release occurred the conditions of Example 8.B.2 had been departed from to such an extent that the Board does not consider that such results can be attributed to any normal way a skilled man might carry out 8.B.2. In particular, the only results showing an effective release time longer than one month, were obtained with either a drug loading very much higher than in Example 8.B.2 or a suspension different from the one disclosed in this example. The Board thus finds that Example 8.B.2 does not itself deprive Claim 1 of the main request of novelty.

5.3. (9) is concerned with sustained release compositions for pharmaceuticals using glycolide/lactide copolymers, but does not disclose any specific example of microencapsulation, though it refers to this possibility. The reference in (32) to (9) thus does not tell the skilled person to use anything in particular, but merely suggests this as a helpful publication for making further developments. What (32) and (9) taken in combination may suggest to the skilled person is something that might be taken account of when considering inventive step, but not when considering novelty. Novelty is interpreted narrowly by the Boards of Appeal, and when it is said that a document must be interpreted as it would be understood by the skilled person, this means only that what a skilled person would immediately understand without it being explicitly stated, can be read into a document. It does not mean that one can consider that for the purposes of novelty anything that reading a document may suggest to a skilled man has been actually disclosed.

6. Priority (Article 87 EPC)

6.1. The above finding that (32) does not destroy the novelty of Claim 1, necessarily implies that the subject-matter of Claim 1 is not disclosed in (32A), whose content can for this purpose be considered identical to that of (32). Thus (32A) cannot for the purposes of Article 87 EPC be considered as the first application for the same invention as now claimed.

6.2. Claim 1 is thus entitled to the priority claimed, which is earlier than the publication date of (32). Accordingly (32) is not prior art when it comes to considering inventive step under the provisions of Article 56 EPC.

7. Inventive step (Article 56 EPC)

7.1. For the purpose of considering inventive step the Board agrees with the Appellants that the closest state of the art is document (19), which discloses a decapetide, now known as Triptorelin, having potent LH- and FSH- releasing hormone properties (see column 3, line 44 ff.) falling within the terms of Claim 1 of the main request.

7.2. (19) states that "when the decapeptide, preferably in the form of an acid addition salt, is employed in human medicine, it is administered systemically, either by intravenous, sub-cutaneous, or intramuscular injection, or by sublingual, nasal, or vaginal administration, in compositions in conjunction with a pharmaceutically acceptable vehicle or carrier" (see column 6, lines 38 to 45), and that "it is often desirable to administer the decapeptide continuously over prolonged periods of time in long-acting, slow-release, or depot dosage forms" (see column 7, lines 23 to 25) and that such dosage forms "may contain the decapeptide in the form of a water-soluble salt together with a protective carrier which prevents rapid release" (see column 7, lines 29 to 31).

7.3. A different procedure of obtaining such dosage is referred to subsequently in column 7, lines 48 to 56 where it reads: "Long-acting, slow-release preparations of the decapeptide may also be obtained by microencapsulation in a pharmaceutically acceptable coating material, for example gelatine, polyvinyl alcohol or ethyl cellulose. Further examples of coating materials and of the processes used for micro- encapsulation are described by J.A. Herbig in "Encyclopedia of Chemical Technology", Vol. 13, 2nd Ed., Wiley, New York, 1967, pages 436-456". This latter is document (51) cited by the Appellants.

In this paragraph, microencapsulation is mentioned for the first and only time in document (19) and for details the skilled person is referred to (51) which provides a general overview of microencapsulation (see pages 436 to 450) in a great variety of technical fields (see pages 451 to 455), among which "Pharmaceuticals" takes a small place only (see pages 453, last paragraph to page 454, third paragraph).

7.4. In relation to this closest prior art, the Board considers that the problem to be solved can be stated as being to make available a pharmaceutical composition designed for sustained release of an effective amount of a water-soluble LH-RH polypeptide of the known type over a period of at least one month. This problem is to be solved by the pharmaceutical composition as defined in Claim 1 of the main request (see section III above).

7.5. Taking into account the results with the successful batches in Table II of the patent in suit (originally termed batches C, E, F) and the test results submitted by the Respondent (for details see under point 4.1 above) for additional compositions of effectively the same polymer system, giving at least one month's release as set out in present Claim 1, the Board considers that the above-stated problem has been plausibly solved by the pharmaceutical composition with the features required by Claim 1 of the main request.

7.6. Starting from (19) and set this problem the skilled person first turns to the suggestions made in (19) itself of long-acting, slow-release preparations based on gelatine, polyvinyl alcohol or ethyl cellulose as coating material, combined with the microencapsulation techniques given in (51). If this line is followed something other than what is covered by Claim 1 would be arrived at, as there is no suggestion that glycolide/lactide copolymer should be used for microencapsulation. There is no reason to believe that what is actually suggested would not be seriously contemplated by skilled persons.

7.7. The Board has no evidence that microencapsulation taken together with the biodegradable glycolide/lactide copolymers of (9) is a combination that the skilled person in the art at the priority date of the patent in suit would have seriously contemplated as a possibility. (9) itself is not referred to in (19), and while microencapsulation is mentioned as a possiblity in (9) there are no specific examples of this. Further there exists a later document (53) referring to (9) and stating that the polymers of (9) presented several drawbacks as, inter alia, the formulation described in document (9) produced slow absorption in the body (see column 1, lines 19 to 27). (53) suggests what it considers as better polymers than those of (9), namely a specific group of linear polyester salts with relatively low molecular weight which yet are hard, brittle and non-tacky solids (see Claim 1 and column 1, lines 19 to 68. of the description). Contrary to the Appellants' evaluation of the teaching of (9), this demonstrates how narrow the disclosure content of document (9) in substantiated form actually is.

7.8. The evidence by Appellant 05 that the Nobel Prize winning inventor of (19) at some unspecified date was aware of (9), but did not use it because of fears of possible patent infringement (quite apart from the fact that such hearsay evidence provided for the first time at the oral proceedings is a highly questionable form of evidence), allows no deductions to be made as to what the average skilled man would have known or considered at the priority date, nor does it explain why the possiblity of using the polymer of (9) is not referred to in (19), even though (9) was published more than one and a half years before the filing date of (19).

7.9. The argument that the Respondent's own patent (32) can be used as an expert opinion (German "gutachtlich") to show that at its priority date (9) was well known fails because no such deduction follows inevitably. For all that appears, the Respondent may have been the only one to have taken this publication seriously. The clear prohibition contained in the second sentence of Article 56 EPC against the use of Article 54(3) EPC documents when considering inventive step, cannot be swept aside merely by the suggestion that a patent application might be relied on as an "expert opinion" as to the state of the art at its filing date.

7.10. Nevertheless even assuming that the skilled person would come across (9), it is by no means clear that this would have led him to make something falling within Claim 1. (9) related not only to PLGA but to copolymers with comonomers other than lactide or glycolide, such as other specific lactones or intermolecular cyclic esters of certain hydroxycarboxylic acids. The skilled person is thus faced with a document making numerous suggestions as to polymers of various chemical compositions and properties (see column 7, line 12 to column 9, line 10) which are applicable in the field of galenics (see column 1, line 61 to column 3, line 6). Even under the headline "preparation and administration of the formulation" a great variety of formulations result from the different procedures of coating (among which microencapsulation is mentioned), embedding and intimate mixing (see column 9, lines 12 to column 11, line 46). While it is true that the skilled person is told that "Drug compounds of the classes mentioned earlier may be coated, embedded, or intimately mixed in or with a matrix of one or a combination of different chain-length biodegradable polylactide polymers defined previously, to give a drug-polymer mixture which will provide a controlled sustained release of the drug compound over a period of 8 hours to 2 months or longer when administered parenterally" (see column 9, lines 65 to 72), and is taught different types of procedures (coating, embedding and intimate mixing) for this the preferred embodiments relate only to embedding. In the examples, without any exception, the polymer is melted at 225 to 250 C and a steroid drug is mixed into the melt. In two out of the nine examples given, it is disclosed that gross pellets of the product (80 mg or 100 mg) produced an oestrogenic response lasting for about one month (see Examples 5 and 6). From the entirety of the disclosure provided by document (9) in substantiated form, the skilled person does not get any guidance whatsoever that just microencapsulation (see column 10, lines 39 to 57) might be successfully applicable in an attempt towards solving the technical problem underlying the patent in suit.

7.11. At the priority date of the patent in suit there was a multitude of possibilities, from the viewpoint of galenics, to formulate compositions for drug delivery over a prolonged period of time. However anything from 8 hours to two months was regarded as a prolonged period of time, and there was hardly any information as what should be chosen if a particular minimum release period was to be achieved for a particular drug.

7.12. It is not enough for the Appellants to show that by a judicious selection of one part of the teaching of one document, and another part of the teaching of another document the skilled man might have arrived at the invention claimed in Claim 1 of the main request. They must also show this selection is something the skilled person would have made with a reasonable expection of success in achieving the release period of at least one month. Even taken together (19) and (9) neither suggest that microencapsulation together with PLGA will necessarily provide a solution, nor that this is at least as likely a way of achieving success as any other. The Appellants have failed to show any other reason why biodegradable PLGA and microencapsulation would be considered as the, or at least a, preferred route to successfully solving the problem at the priority date.

7.13. The Appellants have thus failed to show that the invention of Claim 1 of the main request lacks an inventive step. The other claims of the main request depend on Claim 1, so that they need not be separately considered. Accordingly, the main request is allowable.

7.14. In view of this finding, it is not necessary for the Board to consider the arguments relating to commercial success or to acknowledgements by third parties that there was an invention. Particularly in the medical field where inventions take a very long time to get on the market so that it is hard to assign precise causes for success or failure, such matters may generate a lot of paper, but provide little or no assistance on the issues actually to be decided.