T 0405/06 (Immunoglobulins/BRUSSEL) 06-12-2007

Main request (claim 1)

Added matter (Article 123(2) EPC)

1. Whereas in the application as filed the immunoglobulins for which protection is claimed are characterised as comprising two heavy polypeptide chains "sufficient for the formation of a complete antigen binding site" (see the passage bridging pages 3 and 4, as well as claim 1 of the application as filed) in claim 1 at issue the two heavy chains are simply required to be "capable of recognizing and binding one or several antigens".

2. As stated on page 4, third full paragraph, of the application as filed, by "a complete antigen binding site" it is meant "a site which will alone allow the recognition and complete binding of an antigen", this being "verified by any known method regarding the testing of the binding affinity".

3. The qualification of the binding of an antigen as "complete" in the application as filed is understood by the skilled person as emphasising that the binding is "as great in degree or amount as it possibly can be". This underlines the fact that the immunoglobulins which are disclosed in the patent in suit should comprise two heavy chains "sufficient for the formation of a complete antigen binding site", i.e. the site should contain all the structural parts which ensure such a binding. Claim 1 at issue merely requires an "unqualified binding" and, thus, covers also situations in which binding is not "as great as it possibly can be". This, in the Board's judgement, amounts to an extension of the subject-matter of the application beyond the content of the application as filed.

4. Appellant I argues that the term "complete" does not convey any other information but the fact that there is an unexpected difference between the claimed immunoglobulins and the conventional four-chain ones. The argument is not tenable for the reason that it is not in line with the afore-mentioned definition of a complete antigen binding site given in the application as filed (see point 2, supra) which indicates that the immunoglobulins of the invention are required to offer an optimised binding site allowing a "complete" binding of the antigen.

5. Thus, the main request does not meet the requirements of Article 123(2) EPC and should be refused.

Auxiliary request 1 (claim 1)

Formal requirements (Articles 84 and 123 EPC)

6. Although appellant II has formulated no objections in this respect, the Board makes an assessment as follows. Claim 1 at issue differs from claim 1 of the main request (i.e. claim 1 as granted) in that the phrase "capable of recognizing and binding one or several antigens" has been replaced by the phrase "sufficient for the formation of a complete antigen binding site, or several antigen binding sites". A support for that amendment is found in the paragraph bridging pages 3 and 4 of the application as filed in which the same phrase is used. Thus, the requirements of Article 123(2) EPC are met. As explained on page 4 of the application as filed, by "a complete antigen binding site" it is meant a site which will alone allow the recognition and complete binding of an antigen. Therefore, claim 1 at issue features a narrower embodiment of the more general concept addressed by claim 1 as granted. Thus, the requirements of Article 123(3) EPC are met. Furthermore, claim 1 is not only supported by the description but also clear and concise. Thus, the requirements of Article 84 EPC are also met.

Sufficiency of disclosure (Article 83 EPC)

7. Claim 1 is directed to an immunoglobulin which, while being devoid of light chains, comprises two heavy polypeptide chains, the latter chains lacking a CH1 domain and being sufficient for the formation of a complete binding site.

8. The question to be answered is whether a skilled person would have found at the filing date in the application as filed a sufficiently clear and complete disclosure of the precise structure of such an immunoglobulin in order to be in a position to prepare it over the broad range of the claim. In other terms, one should assess whether all the features compensating for the absence of the CH1 domain and the light chains are disclosed.

9. The experimental part of the description as a whole and the corresponding figures (see pages 34 to 55 and Figures 1 to 8 in the application as filed) deal exclusively with camel immunoglobulins. However, claim 1 is not limited to immunoglobulins obtained from camelids.

10. Also the general part of the description contains no complete disclosure of any non-camelid immunoglobulin. Indeed, the replacement by camelid specific residues such as those at position 45 and the frequent presence of a cysteine in the CDR3 region associated with a cysteine in the CDR1 position 31 or 33 or FW2 region at position 45 (see page 13, last paragraph) are the only pieces of information made available especially for non-camelid immunoglobulins. These data per se do not amount to a disclosure which is sufficiently clear and complete to enable the skilled person to identify the minimal structural features that a non-camelid immunoglobulin comprised only of two heavy polypeptide chains should have in order to form a complete antigen binding site, in the sense that said site allows alone the recognition and complete binding of an antigen.

11. Appellant I argues that the experimental part of the description contains ample information which while relating to the preparation of camelid immunoglobulin could have been easily extended to the preparation of non-camelid immunoglobulins. The argument is not tenable for the reason that - as indicated in point 10, supra - it leaves the skilled person with the task and burden to find how the teaching related to camelid immunoglobulins can be extended to products of different origins (e.g. human immunoglobulins) which also fall under the broad area of claim 1.

12. Thus, auxiliary request 1 does not meet the requirements of Article 83 EPC and should be refused.

Auxiliary request 2

Requirements of Article 123(2) EPC

13. Claim 1 of auxiliary request 2 differs from claim 1 of auxiliary request 1 in that the wording "it is obtainable from camelids" has been added (see Section XVI, supra). The claim is objected to under Article 123(2) EPC by appellant II because in its view, due to this wording, it would also cover immunoglobulins which are not related to the immunoglobulins of camelids. It is in particular submitted that claim 1 would encompass for example immunoglobulins secreted by the cells of a camelid rendered transgenic for the expression of genes encoding immunoglobulins of human origin.

14. In the Board's judgement, the expression "obtainable from camelids" means that the claimed immunoglobulin is an immunoglobulin displaying the stated features and being "as it would be obtained from a camelid". Such immunoglobulins are disclosed in detail in the experimental part of the application as filed. The rather complicated hypothetical construction depicted by appellant II in support of its "added matter" and "clarity" objections (see point 13 supra and point 21 infra) amounts to a mere allegation: firstly, no such products are specifically claimed or described here; secondly, it is a construction which would not occur to a mind willing to understand when reading the claim (see decision T 190/99 of 6 March 2001). Thus, in the Board's judgement, there is no issue of Article 123(2) EPC here.

15. Claim 10 is directed to two fragments, namely a heavy chain of a camelid immunoglobulin according to claim 1 and the variable region of such a chain, i.e. to a so-called VHH region. The description of the application as filed provides ample and sufficient support also for such fragments (see Example II on pages 41 to 55). Therefore, claim 1O does not contain subject-matter which extends beyond the content of the application as filed.

16. Thus, auxiliary request II complies with the requirements of Article 123(2) EPC.

Requirements of Article 123(3) EPC

17. Auxiliary request 2 differs from the main request (claims as granted) essentially in that claims 1 and 11 (now claim 10) have been substantially amended (see Sections XV and XVI, supra).

18. The wording "it is obtainable from camelids" found in claim 1 at issue has a limiting effect, compared to claim 1 of auxiliary request 1 as granted. Therefore, there is no violation of the provisions of Article 123(3) EPC.

19. Similarly, the re-wording of claim 11 as granted has resulted in claim 10 at issue having a more limited scope, with only fragments of an immunoglobulin obtainable from camelids being claimed. The amendments contained in present claim 10 have not extended the protection conferred by the patent as granted.

20. Thus, auxiliary request II complies with the requirements of Article 123(3) EPC.

Clarity (Article 84 EPC)

21. The wording of claim 1 provides an unambiguous definition of the immunoglobulins for which protection is sought. These are immunoglobulins having the features of IgG2 and IgG3 of camelids as schematically represented in Figure 6 of the patent. For the reasons explained in point 14 (see supra), the expression "obtainable from camelids" is considered to have a clear meaning. The objection made by appellant II in this respect is not tenable. Thus, claim 1 meets the clarity requirement of Article 84 EPC.

22. Claims 13, 14, 20, 23 and 36 are objected to by appellant II in view of the presence therein of terms ("especially" in claims 13, 20, 27 and 36, "for instance" in claim 14 and "for example" in claim 23) which render unclear the subject-matter for which protection is sought. Nevertheless, the defect was present in the corresponding granted claims 17, 18, 24, 27 and 40. Lack of clarity not being a ground for opposition (see Article 100 EPC) the objections are not admissible. Other claims contain erroneous back-references. But, for the same reason as for claims 13, 14, 20, 23 and 36, they cannot be objected to and any attempt to remedy the deficiency would have contravened Rule 57a EPC.

Sufficiency of disclosure (Article 83 EPC)

23. As indicated in point 14 (see supra), in the Board's judgement, claim 1 is directed to immunoglobulins with the stated features and as they would be obtained from a camelid. For such immunoglobulins a sufficiently clear and complete disclosure is provided in the experimental part of the application as filed (see points 9 and 15, supra).

24. The appellant II's argument that non-camelid immunoglobulins are not sufficiently disclosed needs not be considered as, indeed, claim 1 does not cover such immunoglobulins (see point 14, supra).

25. Therefore, auxiliary request 2 meets the requirements of Article 83 EPC.

Novelty (Article 54 EPC)

26. Appellant II objects to claim 1 for lack of novelty over document D1, interpreted in the light of documents D6 and D43.

27. Document D1 describes the sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) under reducing conditions of a camel-IgG preparation recovered after chromatography on a DEAE-Sephacel column of camel serum precipitated with 50% ammonium sulfate. On the picture of the SDS-PAGE represented on Figure 2 (see page 200), three components are identified corresponding to (as enumerated in the sentence bridging pages 199 and 200) "a gamma-like heavy chain of AMW [apparent molecular weight] 55 kd, an L-chain of 22 kd and an additional protein band of 40 kd" (emphasis added by the Board). This latter band is not further characterised in the rest of the document.

28. Appellant II argues that this latter band corresponds to a protein which is an immunoglobulin as recited in claim 1, the presence of a similar band in a SDS-PAGE electrophoregram having been later on confirmed in document D43 and structurally identified in document D6:

28.1 Document D6, which is dated 3 June 1993 and, therefore, does not belong to the state of the art, reports that its contributors, including the designated inventors of the patent, have "investigate[d] the presence of considerable amounts of IgG-like material of Mr 100K in the serum of the camel (Camelus dromedarius)**(6)" (see the abstract on page 446 with citation "6" being document D1). These molecules were found to yield upon reduction only heavy chains of respectively, 46 kDa (IgG2 fraction) and 43 kDa (IgG3 fraction), devoid of light chains and lacking CH1 domains (see the abstract on page 446 and the left-hand column on page 448).

28.2 Document D43, which was published after document D6 (see the footnote on page 195, the citation "Hamers-Casterman et al., 1993" as referred to therein being D6) and, therefore, is not part of the state of the art, describes the isolation and provides a preliminary characterisation of camel immunoglobulins. It contains a reference to document D1 (see the citation "Ungar-Waron et al., 1987" in the "Introduction" on page 187). It reports that SDS-polyacrylamide gel electrophoresis of either the IgG fraction collected from ACA-34 gel filtration separation of an ammonium sulfate precipitate of camel serum or the three major peaks produced by an ion exchange chromatography of the same on an FLPC Mono-Q (DEAE) column showed a protein band of 42kDa (see pages 190 to 191).

29. The appellant II's argument is not tenable for the following reasons:

29.1 As pointed out in decision T 100/01 of 5 February 2004, when considering how far the teaching in a written description of an allegedly novelty-destroying document also makes available certain features which are not explicitly stated, i.e. implicit or intrinsic features, all that matters is the whole contents of the said document alone as read and interpreted by the skilled person on the background of common general knowledge, i.e. the knowledge generally available at the relevant filing date, not later.

29.2 In the present case, a skilled person would have only derived from document D1 that an undetermined protein of an apparent molecular weight of 40 kDa as determined by SDS-PAGE under reducing conditions was present in the camel serum examined. Moreover, as it is unlikely that the experiments of documents D6 and D43, both published after the relevant filing date (here the priority date) in 1993, i.e. six years after the publication of document D1, were performed starting from the serum obtained from the same adult female camels as referred on page 198 of that document, the skilled person would not have been in a position to inevitably derive from document D1 that the undetermined protein was a camel IgG2 or IgG3. One can even not exclude that he/she could have thought it was not an immunoglobulin but a contaminant protein.

30. Therefore, the subject-matter of claim 1 is new. As the other claims are either dependent on claim 1 or contain a back-reference thereto, auxiliary request 2 meets the requirements of Article 54 EPC.

Inventive step (Article 56 EPC)

31. Appellant II objects to claim 1 for lack of inventive step on the basis of document D2 taken as the closest state of the art.

32. Neither document D2 nor document D24, which is proposed by appellant I, but document D1 represents the closest state of the art. Indeed, D2 reports the results of an investigation in which the interactions with antigen of individual domains of anti-lysozyme antibodies were analysed, a matter which is far from the key subject-matter of the patent, and D24 is a textbook which generally describes the immunoglobulins as molecules consisting of two heavy polypeptide chains associated with two light chains. Neither of these two documents alone or in combination can have a bearing on the inventive step discussion. In contrast, document D1, as explained above (see point 27), is directly concerned with the isolation and characterisation of camel immunoglobulins. It describes the presence in the camel serum examined of an undetermined protein of an apparent molecular weight of 40 kDa as measured by SDS-PAGE under reducing conditions, without any indication of whether it is an immunoglobulin, let alone an immunoglobulin lacking light chains, or a contaminant protein (see point 29.2, supra).

33. In view of document D1, the technical problem to be solved may be seen as being the identification and characterisation of immunoglobulins of the camel family, in particular of the IgG component described in document D1 as having an apparent molecular weight of 40 kDa as determined by SDS-PAGE. The solution proposed in the claims is the finding in camelids of functional immunoglobulins comprising two heavy chains lacking the CH1 domain and devoid of light chains.

34. The question to be answered is whether this particular structure would have been suggested to the skilled person by document D1 in combination with further prior art or whether its finding would have been the inevitable result of further obvious experimental steps starting from the 40 kDa component of document D1.

35. At the relevant filing date, the only prior art documents describing naturally produced (in contrast to bioengineered) immunoglobulins not having the conventional accepted four-chain structure with two complete heavy chains and two complete light chains were immunoglobulins produced by cells in the context of a disease. Exemplary of such immunoglobulins are those described in documents D3 and D12. In document D3, immunoglobulin lacking a CH1 domain produced by mouse myeloma cells are described while document D12 reports that immunoglobulin heavy chain fragments not associated with immunoglobulin light chains and lacking the entire CH1 domain (but not proved to be involved in antigen-antibody interactions) were found in the urine of a patient having developed a common clinico-pathologic presentation of H Chain Disease (HCD). Therefore, it is unlikely that the skilled person might have found any guidance in such documents.

36. The remark made on page 192 of post-published document D43, that the finding of a protein band of 42 kDa (see point 28.2, supra) "requires further investigation to determine whether this protein is an integral part of the camel immunoglobulin molecule or an associated molecule, such as a complement molecule", reinforces the Board's view that it was unlikely that a person skilled in the art trying at the relevant filing date with further experiments to identify the structure of camel immunoglobulins would have directly and inevitably arrived at the structure indicated in claim 1.

37. Therefore, it is concluded that the subject-matter of claim 1 involves an inventive step. Thus, as the other claims are either dependent on claim 1 or contain a back-reference thereto, auxiliary request 2 meets the requirements of Article 56 EPC.