T 0843/22 (GA dosage regimen for MS 1/YEDA) 07-02-2024

Summary of Facts and Submissions

I. The appeal by the patent proprietor (appellant) lies from the decision of an opposition division to revoke European patent No. 3 199 172 (the patent), which is based upon European patent application No. 17 157 735.6, which was filed as a divisional application of European patent application No. 17 153 450.6 (not published). The latter is a divisional application of European patent application No. 13 166 080.5, which is a divisional application of European patent application No. 10 810 282.3 published under the PCT as international application WO 2011/022063 (the earlier application).

II. The patent had been opposed on the grounds of Article 100(a) EPC, in relation to novelty (Article 54 EPC) and inventive step (Article 56 EPC), and Article 100(b) and (c) EPC. Oppositions were filed by opponents 1 to 5. Opponent 2 withdrew its opposition during the opposition proceedings.

III. In the decision under appeal, the opposition division decided that claim 1 of the main request (patent as granted) did not comply with Article 123(2) EPC and Article 76(1) EPC. On auxiliary request 1, the opposition division decided that the invention to which claim 4 related was not sufficiently disclosed. The same reasoning applied to claim 1 of auxiliary request 2, claim 2 of auxiliary request 3 and claim 1 of auxiliary request 4. The opposition division decided that auxiliary request 5 lacked an inventive step over the disclosure of document D1.

IV. With its statement of grounds of appeal, the appellant stated that it continued to request rejection of the oppositions (main request) and filed sets of claims of auxiliary requests 1 to 5 (identical to the requests on which the decision under appeal was based, identified as NAR1 to NAR5, the same designation used in appeal). The appellant further submitted its reply to the opposition as Annex A and its submission to the opposition division under Rule 116 EPC as Annex B and document D97.

V. Opponents 1, 3, 4 and 5 (respondents I, III, IV and V) replied to the appeal.

VI. The board summoned the parties to oral proceedings, as requested, and informed them of its preliminary opinion in a communication under Article 15(1) RPBA.

VII. In this communication, the board indicated that it agreed with the findings of the opposition division on the main request and that it considered the subject-matter of claim 1 of auxiliary requests 1 to 5 to lack an inventive step.

VIII. Claim 1 of the main request (as granted) reads as follows:

"Glatiramer acetate for use in treating a human patient suffering from a relapsing form of multiple sclerosis or who has experienced a first clinical episode and is determined to be at high risk of developing clinically definite multiple sclerosis, comprising administering to the human patient three subcutaneous injections of 40mg glatiramer acetate for every seven days with at least one day between every subcutaneous injection, wherein the glatiramer acetate is present in a pharmaceutical composition having a pH in the range of 5.5 to 7.0."

Claim 1 of auxiliary request 1 differs from claim 1 of the main request in that "a relapsing form of multiple sclerosis" was replaced by "relapsing-remitting multiple sclerosis".

Claim 1 of auxiliary request 2 differs from claim 1 of auxiliary request 1 in that the use is further specified by the addition of the wording "to increase the tolerability of glatiramer acetate in the human patient".

Claim 1 of auxiliary request 3 differs from claim 1 of auxiliary request 1 in that "relapsing-remitting multiple sclerosis" was deleted from the claim. Dependent claim 2 of auxiliary request 2 specifies that the use includes "to increase the tolerability of glatiramer acetate in the human patient".

Claim 1 of auxiliary request 4 differs from claim 1 of auxiliary request 2 in that "relapsing-remitting multiple sclerosis" was deleted from the claim.

Auxiliary request 5 differs from auxiliary request 3 in that dependent claim 2 was deleted.

IX. Oral proceedings took place on 6 and 7 February 2024. At the end of the oral proceedings, the Chairwoman announced the board's decision.

X. The following documents are referred to in this decision:

D1 |US 2007/0161566 A1 |

D2 |S. Flecther et al., "Comparison of glatiramer acetate (Copaxone**(®)) and interferon beta-1b (Betaferon**(®)) in multiple sclerosis patients: an open-label 2-year follow-up", Journal of the Neurological Sciences, 197, 2002, 51-5 |

D3 |S. Flechter et al., "Copolymer 1 (Glatiramer Acetate) in Relapsing Forms of Multiple Sclerosis: Open Multicenter Study of Alternate-Day Administration" ClinicalNeuropharmacology, 25(1), 2002, 11-5 |

D4 |O. Khan et al., "Randomized, prospective, rater-blinded, four-year, pilot study to compare the effect of daily versus every-other-day glatiramer acetate 20 mg subcutaneous injections in relapsing-remitting multiple sclerosis", Multiple Sclerosis, 14, 2008, S296, P902|

D5 |C. Caon et al., "Randomized, Prospective, Rater-Blinded, Four Year Pilot Study To Compare the Effect of Daily Versus Every Other Day Glatiramer Acetate 20 mg Subcutaneous Injections in RRMS", Neurology, 72(11), Suppl. 3, 2009, P06.141 |

D8 |Excerpt from Summary of Product Characteristics of the Copaxone 20 mg/ml product, text revised on 3 February 2009 and last updated on 17 April 2009 |

D11 |"Doubling the Dose of Glatiramer Acetate Does Not Increase Efficacy", MedScape, 22 September 2008 |

D34 |Abstract presented at the World Congress on Treatment and Research in Multiple Sclerosis: 2008 Joint Meeting of the American, European, and Latin America Committees on Treatment and Research in Multiple Sclerosis (ACTRIMS, ECTRIMS, LACTRIMS)|

D34a|Slides presented at the World Congress on Treatment and Research in Multiple Sclerosis, 2008 |

D43 |Transcript excerpt from UK High Court Case No. HP-2017-000010, font cover and page 397 |

D46 |Rebif**(®) (interferon beta-1a), 20 pages |

D52 |"High-dosage Copaxone trial results are bad news for Teva", PharmaTimes, 2008 |

D57 |Medication Guide Rebif**(®) product, 2002, 7 pages |

D70 |Prof. Brück, witness statement on EP 29 493 335 dated 15 February 2019 |

D89 |O. Khan et al., "A phase 3 trial to assess the efficacy and safety of glatiramer acetate injections 40mg administered 3 times a week compared to placebo", Abstract presented at the 28th Congress of the European Committee for treatment and research in multiple sclerosis, 13 October 2012|

D92 |K. McKeage, "Glatiramer Acetate 40 mg/mL in Relapsing-Remitting Multiple Sclerosis: A Review", CNS Drugs, ADIS Drug Evaluation April 2015, 8 pages |

D93 |J. S. Wolinski et al., "Reduced Frequency and Severity of Injection-site Reactions With Glatiramer Acetate 40 m/ml Three-times Weekly Dosing", poster P306, ACTRIMS/ECTRIMS Conference, 10-13 September 2014 |

D94 |J. S. Wolinski et al., "Reduced frequency and severity of injection site reactions with glatiramer acetate 40mg/ml three times weekly dosing", abstract P306, ACTRIMS/ECTRIMS Conference, 10-13 September 2014 |

XI. The following abbreviations are used in this decision:

multiple sclerosis (MS)

relapsing form of multiple sclerosis (RMS)

relapsing-remitting multiple sclerosis (RRMS)

secondary progressive multiple sclerosis (SPMS)

progressive-relapsing multiple sclerosis (PRMS)

clinically definite multiple sclerosis (CDMS)

clinically isolated syndrome (CIS)

glatiramer acetate (GA)

every day (QD)

every other day (QOD)

three times in a week (TIW)

subcutaneous (SC)

injection site reactions (ISRs)

immediate post-injection reactions (IPIRs)

adverse side effects (ASEs)

QD at a dose of 20 mg (20QD)

QD at a dose of 40 mg (40QD)

QOD at a dose of 20 mg (20QOD)

QOD at a dose of 40 mg (40QOD)

TIW at a dose of 40 mg (40TIW)

XII. Summary of the appellant's submissions

Main request - claim 1

Extension beyond the content of the (earlier) application as filed (Article 100(c) EPC)

The concept of intermediate generalisation invoked in the decision under appeal only arose when an example in the specification had been generalised to an extent between the specific example and the most general part of the description. This was not the case with claim 1 of the main request. However, even if such an intermediate generalisation or restriction arose in an amended claim, the question of added matter remained (see, for example, section 2.3 of T 461/05).

The term "a relapsing form of multiple sclerosis" (RMS) was used in the specification both generally (e.g. paragraphs [0017] and [0119] of the application as filed) and specifically in conjunction with the benefit derived from the GA 40TIW regimen (e.g. paragraphs [0054] and [0056]). The same passages were present in the earlier application. It was therefore clear to the skilled person that the embodiments of the invention were equally relevant to RMS and RRMS.

The (earlier) application as a whole therefore disclosed the claimed subject-matter.

Auxiliary request 1 - claim 1

Inventive step (Article 56 EPC)

Document D1 was not a suitable starting point because it contained no data on the GA 40QOD regimen in the treatment of RRMS. Furthermore, it was concerned with improving efficacy while the focus of the invention was on the balance between efficacy and tolerability. In contrast, document D1 also showed that side effects were more severe for GA 40QD (see Table 4). Data from a later phase III trial showed that increasing the dose did not improve efficacy but led to a higher number of withdrawals from the trial (see slide 14 of document D34a). Documents D11 and D52 also showed that doubling the dose did not improve efficacy.

The approved GA 20QD regimen, as disclosed for instance in D2 to D5, was a realistic starting point as it represented the optimal balance at the priority date. The prior art contained no pointer to reduce the frequency of injection. The effect of the difference to the closest prior art was improved tolerability while maintaining efficacy, i.e. an improved patient experience. The objective technical problem was the provision of a GA dosage regimen which improved patient experience. There was no indication in the prior art that GA 40TIW could solve the problem. GA consisted of random peptides of four amino acids for which no regular pharmacodynamics applied. Therefore, it was also not comparable to other drugs, such as interferon beta-1a (Rebif**(®)). The dosage regimen GA 40TIW was therefore inventive.

Auxiliary request 2 - claim 1, auxiliary request 3 - claim 2, auxiliary request 4 - claim 1

Sufficiency of disclosure (Article 83 EPC)

The claimed regimen required two effects - that 40TIW was (a) efficacious and (b) provided improved tolerability compared to the GA 20QD regimen. Both aspects were described in the application as filed. Tolerability was described as the beneficial effect arising from the GA 40TIW regimen in paragraphs [0019], [0023], [0024], [0026], [0053], [0054], [0056] (with the aspects of tolerability described in [0057] and [0058]), [0065], [0066] and [0068] and clauses 22 to 26 and 29 to 30 of the application as filed. The application as filed included the protocol for what became known as the GALA trial where the claimed regimen was compared to placebo. Tolerability and safety were clear objectives of the trial (see paragraphs [0084], [0089], [0105] and [0106]). The disclosure of a clinical trial protocol "cannot be disregarded as void of technical significance" (T 239/16).

The improvement in tolerability was a central effect of the novel dosing regimen. The skilled person reading the specification with their common general knowledge would have no doubt as to the credibility that at least one effect to be attained by changing the GA 20QD regimen to GA 40TIW would be an improvement in tolerability as assessed by the decreased frequency and severity of ISRs and IPIRs (see also the final paragraph of document D2 and points 255 to 257 of Prof. Brück's declaration D70).

The disclosure in the specification when read with the common general knowledge met the criteria of both "ab initio plausible" and "not ab initio implausible". Consequently, the post-filing GALA and GLACIER clinical trials could be taken into consideration. The claimed regimen (GA 40TIW) was first tested against placebo in the GALA trial (essentially using the protocol in the patent specification), the initial results of which were reported in document D89 and subsequently in a head-to-head comparison with GA 20QD in the GLACIER trial reported in documents D92, D93 and D94.

The opponents failed to identify and substantiate any serious doubts substantiated by verifiable facts.

Auxiliary request 5 - claim 1

Inventive step (Article 56 EPC)

Claim 1 of auxiliary request 5 limited the patient group to "a human patient who has experienced a first clinical episode and is determined to be at high risk of developing clinically definite multiple sclerosis". Such patients were generally referred to as displaying "clinically isolated syndrome" or CIS (see pages 17 to 18 of the earlier application) and were distinct from RRMS patients. This was also apparent from the need for separate clinical trials in document D8. Only 43% of placebo-treated CIS patients converted to RRMS (see document D8, point 5.1).

The closest prior art was a document describing the treatment of CIS patients with GA, e.g. document D8 disclosing the administration of GA 20QD to CIS patients. The difference to the closest prior art was the change in dosing regimen to GA 40TIW. The effect arising from the difference was a more convenient treatment with reduced ISRs and IPIRs (improved tolerability). This was not obvious from the closest prior art because there was no motivation in the closest prior art or any other document on the treatment of CIS patients to increase the dosing amount while decreasing the frequency of administration.

XIII. Summary of the submissions of respondents I, III, IV and V

Main request - claim 1

Extension beyond the content of the (earlier) application as filed (Article 100(c) EPC)

The term "relapsing" constituted an intermediate generalisation in view of the content of the (earlier) application as filed. There was only basis for RRMS. Other forms of relapsing MS existed, such as SPMS and PRMS, (paragraph 10 of the application as filed). Paragraph [0100] of the application as filed excluded progressive forms of MS from the application of the invention.

RRMS was a subset of RMS. Therefore, any broadening of the term RRMS to RMS amounted to a generalisation, for which there was no basis in the application as filed.

Auxiliary request 1 - claim 1

Inventive step (Article 56 EPC)

The GA 40QOD regimen in document D1 was no less enabled than that of the patent in suit. Neither the patent nor document D1 contained any data relating to the GA 40QOD or GA 40TIW regimen, respectively. Thus, if document D1 was non-enabled, the technical effect of the patent was implausible. While experimental data were not always required, if the invention relied on a technical effect that was "not self-evident nor predictable or based on a conclusive theoretical concept", some evidence had to be provided at the filing date to show that a technical problem has been solved. A "mere verbal statement" was not sufficient (see T 488/16). As pointed out by the board in decision T 184/10 (Reasons 3.2), even in the absence of experimental evidence, if speculation was reasonably based on data available at the time, the skilled person would not dismiss statements made in the prior art as speculative.

The adverse events that did take place with GA administration were well known to be associated with administration frequency. To reduce injection-related adverse events, such as ISRs, the skilled person would be motivated to reduce the frequency of the injections.

There was no evidence in the patent that an improvement had been made over the objectively structurally closest known dosage regimen of GA 40QOD in document D1. Indeed, the TIW and QOD Copaxone**(®) administration regimens had to be considered "materially identical in terms of equivalence" (see document D43, page 397, lines 7 to 17). Thus, the only technical difference between a TIW and QOD administration regimen was the frequency, not the efficacy. The problem to be solved was an alternative dosage regimen of GA. Given that the advantages of convenience and compliance associated with TIW dosing were already known from the prior art (see e.g. documents D46 and D57), the invention was obvious.

Auxiliary request 2 - claim 1, auxiliary request 3 - claim 2, auxiliary request 4 - claim 1

Sufficiency of disclosure (Article 83 EPC)

The appellant had stated that the improvement in tolerability was relative to the GA 20QD administration. However, there was no such point of reference in the claim. Moreover, the patent did not present the skilled person with any evidence or rationale for the tolerability of the claimed regimen, per se or relative to any particular prior-art regimen.

The appellant had advanced evidence which showed that a 40 mg dose led to higher adverse events. In the absence of contrary evidence in the patent, it had to be assumed that all 40 mg doses shared such an adverse event profile. Therefore, taking into account the lack of teaching in the common general knowledge, the lack of evidence in the patent and the contradictory evidence given by the appellant's experts, the opposition division was correct to conclude that it was not plausible that the GA 40TIW regimen would be more tolerable than any other regimen, let alone the GA 20QD regimen. As argued by the appellant's experts, the outcome of increasing dosage while decreasing frequency was not predictable without carrying out a clinical trial (paragraph 171 of document D70). Therefore, in the absence of any such trial, something that is unpredictable cannot be plausible. The invention to which the claims relate was not sufficiently disclosed.

Auxiliary request 5 - claim 1

Inventive step (Article 56 EPC)

The definition of CIS was found on page 17, second paragraph of the earlier application. This defined CIS as (1) a single clinical attack suggestive of MS and 2) at least one lesion suggestive of MS. In the paragraph bridging pages 17 and 18, CDMS was defined as "[t]wo attacks and clinical evidence of two separate lesions or [t]wo attacks; clinical evidence of one lesion and paraclinical evidence of another separate lesion". In other words, this appeared to define CIS as simply the first attack having MS symptoms.

The skilled person understood CIS to be symptomatically identical to MS but not having reached the frequency threshold to be formally diagnosed as CDMS.

In document D1 (paragraph [0059]), the MS subjects had to have "at least one lesion" to fulfil the inclusion criteria. This meant that the patient group could include CIS patients. In addition, document D8 also disclosed that CIS patients were treated in the same manner as other MS patients and further taught that Copaxone**(®) delayed the progression from the first clinical event to further episodes (paragraph 5.1 on page 5 of D8). In this regard, if document D8 was considered to be common general knowledge, it taught that there was effectively no difference in the therapeutic management of CIS patients compared to other MS patients.

Copaxone**(®) was not a cure for CIS but only delayed the time until the second attack, by which time it could be classified as CDMS. It then worked in the same way to delay subsequent attacks.

The post-published GALA or GLACIER trials (documents D92 to D94) did not disclose any results in CIS patients and only related to RRMS. Therefore, even if taken into account, these trials still proved nothing about the efficacy of the claimed regimen for such patients.

Document D1 was the closest prior art, and the technical problem to be solved was merely an alternative dosing regimen for administration to patients suffering from MS symptoms. As the problem to be solved was a mere alterative, the solution was obvious for analogous reasons to auxiliary request 1.

XIV. The appellant requested that the decision under appeal be set aside and the patent be maintained based on the claims of the main request (claims as granted) or, alternatively, one of the sets of claims of auxiliary requests 1 to 5 (dealt with in the decision under appeal).

The respondents requested that the appeal be dismissed and the decision to revoke the patent be upheld. They further requested that documents D92 to D94 and D97 not be admitted into the proceedings.