T 0787/14 - Plausibility and patient subgroup

Key points

• In this opposition appeal, the issue is inventive step of the vaccine of claim 1 over D10.
• "[claim 1] differs from the disclosure of document D10 as regards the composition used, namely in that [details of the composition] and further in that the patient has been pre-immunised at least six months previously and within 1 year of the patient's birth with a conjugate of a capsular saccharide of an organism other than N. meningitidis and a diphtheria toxoid or CRM197."
• " the board notes that the patent is silent on the pre-immunisation status of the patients enrolled in the clinical trial V59P2 [described in the examples of the patent]"
• "Thus, from the information provided in the patent for clinical trial V59P2, the skilled person cannot conclude that the patients [...] represented the subgroup of patients to be treated according to the embodiment under consideration."
• " Accordingly, any advantageous effect of the composition that may be seen in clinical trial V59P2 cannot be taken into account in assessing inventive step. "
• About plausibility: "Nor can the appellant rely on post-published documents D14, D30, D34 and D35: The assessment of inventive step is to be made at the effective date of the patent on the basis of the information in the patent together with the common general knowledge then available to the skilled person. The verification of whether or not the claimed solution actually solves the problem, i.e. whether the claimed subject-matter actually provides the desired effect, must be based on the data in the application in order to avoid that an invention is based on knowledge available after the effective date only. "
• The Board then deals with the question of whether the distinguishing features relating to the composition are obvious and considers that the skilled person is "well aware" of these features based on prior art documents. Finally, the particular combination of features does not make the claim inventive.
• "The specific vaccine considered here by the board (see point 14 above) would be one of these vaccines. However, no surprising technical effect is linked to this vaccine in the specified patient population. Thus, in terms of its technically relevant effects, this vaccine is not distinguished from any of the other possible vaccines, i.e. it is a selection of one of several equally available alternative solutions to the problem formulated. Such a situation is referred to in the jurisprudence as an "arbitrary selection". Arbitrary selections are considered to be obvious"

EPO T 0787/14 - link

Closest prior art

6. In the decision under appeal, document D10 was considered to represent the closest prior art (see Reasons, point 1.3). The appellant maintains that document D26 rather than document D10 is the closest prior art.

[D10 Rennels M. et al., The Pediatric Infectious Disease Journal (2002), vol. 21, pages 978 to 979]

7. In accordance with established jurisprudence, the closest prior art for assessing inventive step is normally a prior art document disclosing subject-matter conceived for the same purpose or aiming at the same objective as the claimed invention and having the most relevant technical features in common, i.e. requiring the minimum of structural modifications (see Case Law of the Boards of Appeal of the EPO, 8th edition 2016, section I.D.3.1).

8. The invention concerns vaccines against Neisseria meningitidis (N. meningitidis) (also referred to hereinafter as "meningococcal vaccines" or "meningococcal conjugates"), in particular vaccines based on conjugated capsular saccharides from multiple meningococcal serogroups (see paragraph [0001] of the patent). [...]

9. Document D10, entitled "Dose escalation, safety and immunogenicity study of tetravalent meningococcal polysaccharide diphtheria conjugate vaccine in toddlers", was published in the year 2002 and states that, in areas with widespread use of the heptavalent conjugate pneumococcal vaccine, meningococcus will likely become the most common cause of meningitis and sepsis in young children, and that for these reasons glycoconjugate technology has been utilised to develop conjugate meningococcal vaccines. A tetravalent (serogroups A, C, Y and W-135) meningococcal polysaccharide vaccine in which the saccharides were conjugated to diphtheria toxoid (TetraMenD) was given to 30 toddlers aged 12 to <23 months, at dosages of 1, 4 and 10 myg/ml polysaccharide of each serogroup, i.e. in a 1:1:1:1 ratio. The children were given 2 injections of TetraMenD, separated by 6 to 12 weeks. No concomitant immunisations were given.

All four serogroup saccharide conjugates contained in the vaccine were found to be immunogenic, and for each serogroup a second dose of vaccine enhanced both the serum bactericidal antibody (SBA) titres and the amount of IgG antibody. While the immune reaction was acceptable at all dosages, antibody responses were highest in children given 4 myg of polysaccharide per serogroup (see page 978, abstract; paragraph bridging left- and right-hand columns; second and third paragraphs, right-hand column; page 979, first to third paragraphs and Table 1).

The trial was carried out in Maryland (see page 978, right-hand column, third full paragraph).

Document D10 thus provides a tetravalent meningococcal polysaccharide-diphtheria toxoid conjugate vaccine which induces a boostable immune response in toddlers.

10. As regards the pre-immunisation status of the patients of document D10, the board agrees with the appellant that it can be determined on the basis of the relevant vaccination schedule from the year 2000 for the United States of America (USA). This schedule did not include a pneumococcal-CRM197 conjugate vaccine, but did include DTP, given at 2, 4, and 6 months of age (see document D15, Figure 1).

The board also agrees with the appellant that, although document D10 mentions the use of a heptavalent pneumococcal conjugate vaccine (see point 9 above), it is unlikely that the patients who took part in the Maryland trial disclosed in document D10 had been pre-immunised with a pneumococcal-CRM197 conjugate vaccine, because such a vaccine was not approved in the USA until 2000 (see document D32, page 1, lines 18 to 20), and was not integrated into the US immunisation schedule until 2001 (see document D18, Figure 1).

11. Document D26 relates to bacterial polysaccharides conjugated to protein D from Haemophilus influenzae (H. influenzae). It discloses that polysaccharide antigen vaccines are well known in the art and that (poorly immunogenic) bacterial capsular polysaccharides are linked to highly immunogenic protein carriers, which provide bystander T-cell help. According to document D26, examples of these carriers include diphtheria toxoid (DT or the CRM197 mutant), tetanus toxoid (TT), Keyhole Limpet Haemocyanin (KLH), and the purified protein derivative of tuberculin (PPD). Document D26 also states that it is known that an antigen-specific immune response may be suppressed ("epitope suppression") by the presence of pre-existing antibodies directed against TT as a carrier and that, in the population at large, a very high percentage of people will have pre-existing immunity to both DT and TT as people are routinely vaccinated with these antigens.

12. Document D26 thus provides a different carrier, protein D from H. influenzae, for use in the preparation of polysaccharide-based conjugates in order to avoid epitope suppression (see page 6, line 21, to page 8, line 11). 
Although document D26 discloses (on page 24, lines 23 to 29), that in a further embodiment a N. meningitidis vaccine, in particular comprising polysaccharides of serotypes A, B, C, W-135 and Y, is provided, it does not disclose - contrary to the submission by the appellant - immunisation with this tetravalent N. meningitidis vaccine and certainly not in a patient group as defined in the claims. Indeed, in the pertinent Examples 7 to 9, N. meningitidis polysaccharides from serotype C or A conjugated to protein D were tested in Balb/c mice. In the board's view, the disclosure in document D26 is thus further removed from the claimed invention than that in document D10.

13. Thus, neither document D10 nor document D26 discloses vaccination of a patient who was "pre-immunised at least six months previously and within 1 year of the patient's birth with a conjugate of a capsular saccharide of an organism other than N.meningitidis and a diphtheria toxoid or CRM197". However, in the board's judgement, document D10 relates to the same purpose as the patent, namely successfully vaccinating children against meningococcal disease while allowing for the continued application of existing childhood vaccines, and shares more technical features with the invention than document D26. Therefore, document D10 represents the closest state of the art for the purpose of the assessment of inventive step.

Objective technical problem and its solution

14. One embodiment falling within claim 1 of all the claim requests is a composition that comprises conjugates of the four capsular saccharides of serogroups A, C, W-135 and Y of N. meningitidis and CRM197 as the carrier protein, wherein the conjugates are mixed to give a 2:1:1:1 ratio (measured as mass of saccharide); each meningococcal antigen per dose is between 2 and 10 myg per serogroup (measured in terms of saccharide); and the meningococcal conjugates comprise an adipic acid linker, for use in a method for immunising a human patient against a disease caused by N. meningitidis comprising the step of administering the composition to the human patient, wherein the patient was pre-immunised at least six months previously and within 1 year of the patient's birth with a conjugate of a capsular saccharide of an organism other than N.meningitidis and a diphtheria toxoid or CRM197.

It is this embodiment that will be considered by the board in the following.

15. The embodiment differs from the disclosure of document D10 as regards the composition used, namely in that the conjugates comprise an adipic acid linker, in that the ratio of the polysaccharides is 2:1:1:1, in that the diphtheria toxoid carrier is the mutant CRM197 and further in that the patient has been pre-immunised at least six months previously and within 1 year of the patient's birth with a conjugate of a capsular saccharide of an organism other than N. meningitidis and a diphtheria toxoid or CRM197.

16. As to the effect of these differences, the appellant submitted that they resulted in the provision of an improved composition, which induces a better immune response to each of the serogroups. In this context, the appellant relied on clinical trial V59P2 as reported in the patent and post-published documents D14, D30, D34 and D35.

17. The patent discloses that in clinical trial V59P2, conducted in Finland and Germany with 620 subjects aged 12 to 16 months, five formulations were tested. The vaccines used the CRM197 carrier and an aluminium phosphate adjuvant. Various doses of each serogroup saccharide were tested. Subjects received an injection at time zero, and 25% of the subjects then received a second dose of the vaccine 4 weeks later. Sera of the patients were collected and tested in a SBA assay. The results are shown in Table 1. The patent concludes that "the trivalent and tetravalent vaccines were both immunogenic in toddlers. The conjugates are immunogenic at saccharide doses as low as 2.5 myg per conjugate. The immune responses are boostable, with large SBA titre increases after the second dose. No evidence of carrier suppression was seen in this trial" (see paragraphs [0114] to [0117]).

18. However, the board notes that the patent is silent on the pre-immunisation status of the patients enrolled in the clinical trial V59P2 and also on the year(s) in which the trial was carried out.

19. Thus, from the information provided in the patent for clinical trial V59P2, the skilled person cannot conclude that the patients were pre-immunised at least six months previously and within 1 year of the patient's birth with a conjugate of a capsular saccharide of an organism other than N. meningitidis and a diphtheria toxoid or CRM197, i.e. that they represented the subgroup of patients to be treated according to the embodiment under consideration.

20. Accordingly, any advantageous effect of the composition that may be seen in clinical trial V59P2 cannot be taken into account in assessing inventive step. Nor can the appellant rely on post-published documents D14, D30, D34 and D35: The assessment of inventive step is to be made at the effective date of the patent on the basis of the information in the patent together with the common general knowledge then available to the skilled person. The verification of whether or not the claimed solution actually solves the problem, i.e. whether the claimed subject-matter actually provides the desired effect, must be based on the data in the application in order to avoid that an invention is based on knowledge available after the effective date only. Post-published evidence to support that the claimed subject-matter solves the underlying technical problem can only be taken into account if it is already credible from the disclosure in the patent that the problem is indeed solved (see decision T 1285/13, Reasons, point 10 and Case Law of the Boards of Appeal of the European Patent Office, 8th edition 2016, I.D.4.6).

21. The board concludes from the above analysis that the problem to be solved cannot be defined as put forward by the appellant, namely as the provision of an improved composition, which induces a better immune response to each of the serogroups.

22. As explained above, the skilled person cannot conclude from the information provided in the patent on clinical trial V59P2 that the claimed composition induces a boostable immune response in patients pre-immunised at least six months previously and within 1 year of the patient's birth with a conjugate of a capsular saccharide of an organism other than N.meningitidis and a diphtheria toxoid or CRM197.

23. Notwithstanding this, in the board's view the skilled person would have no reason to doubt that the claimed composition also induced a boostable immune response in these patients, since there was no prejudice in the art that pre-immunisation with diphtheria toxoid or CRM197 would result in carrier suppression, as will be explained in more detail below (see points 27 to 29).

24. Therefore, the board accepts as the problem to be solved the less ambitious problem put forward by the appellant, i.e. the provision of a vaccine that induces a boostable immune response against meningococcal serogroups A, C, W and Y in patients who have been pre-immunised with a conjugate comprising diphtheria toxoid or CRM197.

Obviousness of the solution

25. The question to be answered is whether the skilled person, aware of the teaching of document D10 and faced with the technical problem defined in point 24 above, would have modified the teaching of the closest prior art document D10 - possibly in the light of other prior art teachings - in such a way as to arrive at the embodiment under consideration (see point 14) in an obvious manner.

26. The appellant submitted that the skilled person, aware of the risk of carrier suppression in patients who have been pre-immunised with conjugate vaccines, would not have considered treating patients pre-immunised with conjugates comprising a diphtheria toxoid or CRM197 by administering a multivalent conjugate vaccine comprising the same carrier.

27. As evidence of the fact that the problem of carrier suppression was well known in the art for conjugate vaccines, the appellant relied on paragraphs [0007],[0009],[0011] and [0013] of the patent and on

documents D23, D24, D3, D25, D4, and D5.

27.1 The patent explains that when adding conjugated vaccines to existing immunisation schedules, the issue of carrier-induced epitopic suppression ("carrier suppression") must be addressed, particularly suppression arising from carrier priming. Carrier suppression is said to be "the phenomenon whereby pre-immunisation of an animal with a carrier protein prevents it from later eliciting an immune response against a new antigenic epitope that is presented on that carrier" (see paragraphs [0004] to [0006]). In paragraphs [0007], [0009], [0011] and [0013] the patent refers to prior art studies on the phenomenon of carrier suppression as reported inter alia in references 15, 18, 24, and 21, which are documents D23, D24, D3 and D25 in these proceedings.

27.2 However, the board notes that the patent does not report any trials in which carrier suppression has been shown to exist or has been shown to be overcome (see also points 17 to 19 above).

28. The board has also considered the disclosures of documents D3, D4, D5, D23, D24 and D25.

28.1 Document D3 reports that, in order to plan for the wide-scale introduction of meningococcal C conjugate (MCC) vaccine in the United Kingdom for children up to 18 years, phase II clinical trials were undertaken to investigate whether there was any interaction between the MCC vaccines conjugated to either TT or a derivative of diphtheria toxin (CRM197) and diphtheria-tetanus vaccines given for boosting at school entry or leaving.

Children received a diphtheria-tetanus booster 1 month before, 1 month after, or concurrently with MCC vaccines conjugated to CRM197 or TT. It was found that all of the MCC vaccines induced high antibody responses to the serogroup C polysaccharide that were indicative of protection. While the immune response to the MCC-TT vaccine was reduced as a result of prior immunisation with a tetanus-containing vaccine, prior or simultaneous administration of a diphtheria-containing vaccine did not affect the response to the MCC-CRM197 vaccine.

Thus, carrier-induced epitopic expression was only seen with the MCC-TT vaccine (see abstract and page 4953, left-hand column, fourth paragraph).

28.2 Document D4 reports an interference with the immune response of several co-administered vaccines containing the same protein component, TT. Infants simultaneously receiving either a tetravalent pneumococcal vaccine conjugated to TT and a diphtheria-tetanus-pertussis-poliovirus-H. influenzae type b-tetanus conjugate vaccine showed significantly lower anti-H. influenzae type b polysaccharide antibody concentrations than those receiving either a tetravalent pneumococcal vaccine conjugated to diphtheria toxoid or placebo.

28.3 Document D23 reports that the immune response against synthetic epitopes conjugated to TT can be suppressed by pre-existing immunity against this same carrier and that, because most humans have been exposed to this antigen, this effect may have important implications for the development of synthetic vaccines (see abstract).

28.4 Document D24 reports that mice pre-immunised with either TT or bovine serum albumin (BSA) displayed decreased antibody responses to those synthetic peptides conjugated to TT or BSA carriers, respectively (see paragraph bridging columns, page 1415) and that a prospective study was undertaken in which a largely tetanus-toxoid naive Venezuelan population was compared with a control group of North Americans who were well immunised against tetanus (see page 1415, right-hand 
column, third paragraph). The authors concluded that the data suggested that the suppression might be overcome by providing higher doses of the haptenic antigen.

28.5 In document D25 non-epitope-specific suppression was observed. Thus, pre-immunisation with one conjugate (HibCP-DT) reduced the subsequent response to the carrier portion of the other conjugate (HibCP-TT).

28.6 Document D5 is a scientific paper published after the priority date and thus cannot have influenced the expectations of the skilled person before the priority date. The document needs not therefore be considered.

28.7 In summary, documents D3, D4, D23, and D24 report carrier suppression in those instances where TT was used as a carrier of conjugated vaccines in patients who had been pre-immunised with tetanus toxoid. The sole document looking at carrier suppression in the context of pre-immunisation with diphtheria toxoid, document D3, does not report any carrier suppression. Indeed, document D26 also explicitly mentions carrier suppression only for TT but not for diphtheria toxoid (DT or CRM197 mutant) as carrier (see above, point 11).

29. The board is thus not persuaded that the skilled person would have been concerned about the risk that carrier suppression would reduce the response to tetravalent MenACWY conjugate vaccines comprising diphtheria toxoid or CRM197 in patients who had been pre-immunised with non-meningococcal conjugate vaccines comprising diphtheria toxoid or CRM197 at least 6 months beforehand.

30. As explained above, document D10 reports that the TetraMenD vaccine induced a boostable immune response in the immunised children (see point 9). In the board's view, the skilled person reading document D10 would have been aware that most if not all of the children had previously been immunised with a diphtheria toxoid as part of their childhood vaccination with DTP at the age of 2, 6, and 8 months (see above, point 10). Notwithstanding this, the study reported in document D10 neither tested nor reported any differences in immunological responses between "pre-immunised" and "non-pre-immunised" patients. The board agrees with the respondent that this is further evidence of a lack of concern in this regard, rather than of a prejudice.

31. The board also agrees with the respondent that it is technically irrelevant, and thus would not have influenced the skilled person, whether the patients were pre-immunised with DTP rather than with a conjugate comprising diphtheria toxoid or CRM197, since the relevant point is that the patient's immune system, having been exposed to the carrier protein before - here a diphtheria toxoid - still raises an immune response against the polysaccharide antigen presented on that same carrier.

32. In the board's view, faced with the problem formulated above and aware of the teaching of document D10, the skilled person is thus motivated to provide a tetravalent ACWY meningococcal polysaccharide vaccine conjugated to a diphtheria toxoid as carrier for use in the population specified.

33. The skilled person starting from the teaching of document D10 will generate vaccines in line with the recommendations in the prior art for the production of polysaccharide antigen conjugated vaccines. The skilled person is well aware that an alternative carrier to diphtheria toxoid is the mutant CRM197 diphtheria toxoid (see for example document D1, page 16, first table; document D7, page 4, lines 15 to 16), that linkers, such as adipic acid linkers, can be used to conjugate the saccharide to the carrier protein (see document D1, page 5, lines 1 to 3; document D7, page 5, lines 8 to 10) and that the ratio for saccharides from serogroups A:C:W135:Y can be varied (see document D1, page 2, lines 26 and 27; document D7, page 5, lines 24 to 27, and page 6, lines 11 to 12).

34. The board has no reason to doubt that any of the vaccines that would be obtained by following the teaching in the prior art is suitable for inducing a boostable immune response in the patient group specified, i.e. that the skilled person would have considered any of them as a solution to the technical problem at issue here.

35. The specific vaccine considered here by the board (see point 14 above) would be one of these vaccines. However, no surprising technical effect is linked to this vaccine in the specified patient population. Thus, in terms of its technically relevant effects, this vaccine is not distinguished from any of the other possible vaccines, i.e. it is a selection of one of several equally available alternative solutions to the problem formulated. Such a situation is referred to in the jurisprudence as an "arbitrary selection". Arbitrary selections are considered to be obvious (see Case Law of the Boards of Appeal of the EPO, 8th edition 2016, I.D.9.18.7).

36. In conclusion, the embodiment under consideration is obvious. Thus, one embodiment falling within the scope of claim 1 of all the claim requests lacks an inventive step. Therefore, the subject-matter of claim 1 as a whole of all the claim requests must be considered to fail to meet the requirements of Article 56 EPC.

Order

For these reasons it is decided that:

The appeal is dismissed.