T 0358/22 (HER2 Antibody Compositions/GENENTEC) 23-01-2025

Summary of Facts and Submissions

I. The patent proprietor (appellant) filed an appeal against the opposition division's decision to revoke European patent EP 2 238 172. The patent was opposed by five parties, opponents 1 to 5. Opponents 2 and 5 subsequently withdrew their oppositions and ceased to be a party to the proceedings.

II. In the appeal proceedings, opponents 1, 3 and 4 are respondents I, III and IV, respectively.

III. In its decision the opposition division held that the subject-matter of at least claim 1 of the main request lacked novelty over the disclosure in document D1

It further held that

- the main request met the requirements of Rule 80 EPC,

- the main request met the requirements of Article 123(2) EPC,

- that the invention was patentable under Article 52(1) EPC.

It also admitted documents D88, D92 and D93 to the proceedings.

Auxiliary request 1 was held admissible under Rule 80 EPC and was also held to meet the requirements of Article 84 EPC for clarity. Furthermore the claimed subject-matter of the auxiliary request was held to meet the requirements of Articles 123(2) and 123(3) EPC. However, the subject-matter of claim 1 was held to lack novelty over the disclosure in document D1 for the same reasons as claim 1 of the main request.

IV. The appellant submitted a statement of grounds of appeal together with document D96 and also re-submitted set of claims of a main request and an auxiliary request 1. The main request and auxiliary request 1 are the same as the main request and auxiliary request 1 that were dealt with by the opposition division in the decision under appeal.

V. Only respondents I and III filed replies to the patent proprietor's statement of grounds of appeal. Respondent IV made no substantive submissions in the appeal proceedings.

VI. The patent proprietor also filed a letter dated 11 May 2023 in which it replied to the respondents' submissions and summarised its submissions.

Claims

VII. Claim 1 of the main request reads:

"1. A pharmaceutical formulation comprising a composition comprising a main species HER2 antibody that comprises light chain and heavy chain amino acid sequences in SEQ ID NOs. 15 and 16 respectively and binds to domain II of HER2, and acidic variants of that main species antibody, in a pharmaceutically acceptable carrier, wherein the main species HER2 antibody is the antibody amino acid sequence structure in the composition which is the quantitatively predominant antibody molecule in the composition and the main species HER2 antibody and the acidic variants are all intact antibodies, wherein the acidic variants include a disulfide reduced variant, a non-reducible variant, glycated variant, deamidated variant, and sialylated variant".

Documents

VIII. The following documents are referred to in this decision.

D1: WO 2006/033700

D13: Hunt G. and Nashabeh W., 1999, "Capillary electrophoresis sodium dodecyl sulfate nongel sieving analysis of a therapeutic recombinant monoclonal antibody: A biotechnology perspective", Anal. Chem., 71(13), 2390-2397.

D95: Ma S. and Nashabeh W., 2001, "Analysis of protein therapeutics by capillary electrophoresis", Chromatographia Suppl., 53, S-75-S-89.

The bibliographic data for other documents mentioned by document number in this decision are not given here because these documents played no role in the board's considerations.

IX. Oral proceedings before the board were held as scheduled. The appellant and respondent I attended the hearing, while respondents III and IV had informed the board in writing what they would not attend.

X. The submissions of the appellant relevant to the decision under appeal are summarised as follows.

Main request - claim 1

Novelty (Article 54 EPC)

Document D1 did not disclose the claimed pharmaceutical formulation. In particular, it did not disclose a pharmaceutical formulation comprising a disulfide reduced variant of pertuzumab, either in the figures (especially Figure 11B) or in the description (when contemplating 'intact' antibodies). This meant that D1 did not disclose a pharmaceutical composition comprising a disulfide reduced variant of pertuzumab, or a composition comprising a disulfide reduced variant that is also an acidic variant. Already for this reason, the subject matter of claim 1 and all dependent claims was novel over the disclosure in document D1.

D1 description page 9

Respondent I had argued that the definition of 'intact' antibody at page 9 of D1 was an explicit, literal disclosure of a disulfide reduced variant consisting of one heavy chain and one light chain (HL or half antibody). However, this passage was not a disclosure of particular antibodies at all but merely a definition of what was to be understood by 'intact antibody'. It explained that intact antibodies were antibodies that comprised the constant domains as well as the variable domains. Similarly, the definition on page 9 of D1, which states that an 'intact' antibody comprises a heavy and a light chain, did not necessarily imply that it consisted solely of one heavy and one light chain.

D1 Figure 11B

Contrary to the respondents' arguments, Figure 11B of D1, a non-reduced CE-SDS electropherogram (non-reduced capillary electrophoresis-sodium dodecyl sulfate analysis), did not contain sufficient information for the skilled person to derive the presence of such a variant. Firstly, the skilled person would not have forensically examined Figure 11B in the way suggested. Instead, the skilled person would have relied on the conclusions expressed in D1 by the authors themselves. These had concluded that there was "no evidence of significant product fragments" (see page 48, bottom), which contradicted the respondents' interpretation that Figure 11B disclosed a disulfide reduced variant.

The small peak to the left of the main peak in Figure 11B, relied upon by the respondents, did not have the characteristic fingerprint of a disulfide reduced monoclonal antibody, as additional peaks expected for such a variant were absent.

The conclusion concerning the results in Fig. 11, made by of the authors of D1 themselves was that the pertuzumab samples did contain non-glycosylated heavy chain because there is a small bump to the left of the heavy chain peak which was labelled as such in Fig. 11A. Fig. 11B was an experiment designed to determine whether or not disulfide variants were present and the conclusion reached was that the pertuzumab samples did not contain such disulfide variants. The skilled person considering Figure 11A and the authors' conclusion that pertuzumab contains non-glycosylated heavy chains was therefore primed to regard the tiny bump to the left of the intact antibody peak in Figure 11B as attributable to non-glycosylated heavy chain.

The respondents argued that documents such as D13 supported the interpretation that the small peak in Figure 11B of D1 corresponded to a disulfide reduced variant. They contended that D13 showed that very small non-reduced CE-SDS analysis peaks could be attributed to the presence of disulfide reduced antibodies and therefore, a similar peak in D1 Figure 11B should be interpreted in the same way.

This was not correct. Firstly, D13, provided information not available to the skilled person reading D1 on its own. Any conclusion reached by interpreting D1 using D13 meant that the information was not directly and unambiguously disclosed in D1. The skilled person reading D1 in isolation would not have understood the additional peaks in Fig. 11B to be indicative of a disulfide reduced variant, as D1 itself stated there was "no evidence of significant product fragments".

Secondly, alternative explanations existed for the small peak in Figure 11B. Specifically, it could have been attributed to either:

- a non-glycosylated intact antibody, as Figure 11A of D1 confirmed the presence of non-glycosylated heavy chains in pertuzumab samples; or

- an artifact arising from the CE-SDS sample preparation process, which was known to induce disulfide reduction (as documented in D74, D13, and D15).

An explanation for the tiny bump in Figure 11B that would have come to the mind of the skilled reader was that it was attributable to a non-glycosylated intact antibody (LHHL - two heavy and two light chains).

Furthermore, the skilled person knew that non-reduced CE-SDS (the method used to generate Figure 11B of D1) was subject to artifact. The skilled person reading D1 would have considered the presence of an artifact as a plausible explanation for the results presented in Fig 11B.

Even if the small bump in Figure 11B of D1 had been considered significant enough to warrant serious contemplation by the skilled person, they had several equally plausible explanations for it. It might have been dismissed as attributable to a non-glycosylated intact antibody.

Inevitable result

The respondents has also argued that a pertuzumab formulation as defined in claim 1 was inevitably produced by the generic process disclosed in D1. This "inevitability" type of attack was based on the argument that all five of the claimed variants are always and unavoidably produced by the type of generic recombinant methods mentioned in D1 itself.

This argument was not correct because D1 only described generic cell culture methods for producing pertuzumab and did not provide details of specific culture conditions that would necessarily lead to the formation of a disulfide reduced variant.

Decision T 1990/18 confirmed this approach. It distinguished between a specific chemical reaction inevitably producing a particular product and a more general biological process where multiple outcomes were possible. In fact the production of disulfide reduced variants depended on specific factors such as scale of cell culture, time in harvested cell culture fluid, harvesting conditions, dissolved oxygen levels, and the presence of certain metal ions, none of which were disclosed in D1.

Furthermore, decision T 12/81, which established the concept of inevitability in prior art disclosures, related to a defined chemical reaction with specific reagents and conditions. Such reasoning was inappropriate in the context of recombinant protein production.

Remittal (Article 111(1) EPC and Article 11 RPBA)

If as requested, the board overturned the decision of the opposition division, then the case should be remitted to the opposition division for further prosecution based on the main request.

There were special reasons for remittal in the present circumstances, namely that the decision under appeal only dealt with the formal requirements of claim requests (Rule 80, Article 123(2) EPC) and novelty. The remaining substantive issues of sufficiency and inventive step were not discussed at all in the first instance proceedings.

XI. The respondents' arguments relevant to the decision are summarised as follows.

Main request - claim 1

Novelty (Article 54 EPC)

As correctly set out in the decision under appeal, the claimed pharmaceutical formulation lacked novelty over the disclosure in D1. In particular, it disclosed formulations comprising a disulfide reduced variant of pertuzumab for three main reasons:

1) document D1 contained an explicit disclosure of a half-antibody (one heavy and one light chain - HL) on page 9, lines 7 to 11. This paragraph read: "An 'intact antibody' is one which comprises an antigen-binding variable region as well as a light chain constant domain (CL) and heavy chain constant domains, CH1, CH2 and CH3. The constant domains may be native sequence constant domains (e.g. human native sequence constant domains) or amino acid sequence variants thereof. Preferably, the intact antibody has one or more effector functions, and comprises an oligosaccharide structure attached to one or two heavy chains thereof". This taught that a half-antibody (HL) was the minimum entity of an "intact" pertuzumab. The HL fragment was a disulfide reduced variant because the disulfide bridges between the two heavy chains were broken.

2) there was experimental data in D1 (Fig. 11B) confirming the presence of small amounts of 'intact' antibody variants (HHL, HL) in all recombinantly produced monoclonal Pertuzumab compositions analysed.

All electropherograms of Fig. 11B showed the commonly known characteristic fingerprint of these well-known size variants (HHL, HL etc.) that migrate in front of the 'native' (HHLL) antibody. D1 therefore directly and unambiguously disclosed that the recombinantly produced pertuzumab compositions comprised such size variants, including the prominently visible HHL fragment, which was a disulfide reduced variant. The original characteristic peak assignment consistent with common general knowledge (as evidenced in D13 or D95) matched that in Fig. 11B in D1 and confirmed that such variants were present in the disclosed compositions.

3) document D1 disclosed standard recombinant production methods for Pertuzumab using CHO cells. Disulfide reduced variants were inevitably formed during recombinant production. It was demonstrated by experimental data (e.g. in D92, D3, D26 to D28, D88) that disulfide reduced variants were inevitably formed in such conditions. No counter evidence had been provided by the appellant to challenge this technical fact. The spike-in data in the patent clearly demonstrated that disulfide reduced variants are formed in the chemical environment of the cell culture medium due to degradation events.

D92 was evidence that the majority of these disulfide reduced variants were formed during the incubation in standard cell culture medium, as demonstrated by the much smaller amount of these variants found in the starting material. Therefore, the experimental data of D92 provided clear and conclusive proof that disulfide reduced variants, especially the HHL variant, were automatically formed during incubation in standard cell culture medium as acidic variants.

The respondents had provided conclusive proof of lack of novelty. Since the Patentee failed to submit counter experiments refuting the inevitable formation of disulfide reduced variants, the burden of proof had shifted, and the claim could not be considered novel.

Remittal (Article 111(1) EPC and Article 11 RPBA)

There were compelling reasons not to remit the case to the opposition division for further prosecution, should the board, despite the arguments and evidence presented by the respondents, arrive at the conclusion that either the subject-matter of the main request or the auxiliary request met the requirements of Article 54 EPC. This was because it was evident that the requirements of Article 56 EPC were not met in view of the same technical facts and considerations that had been carefully worked-up by the opposition division and discussed by the parties in conjunction with the novelty assessment. The appellant should not benefit from the fact that the question of inventive step had not arisen at the oral proceedings before the opposition division because of a finding of lack of novelty. The same considerations applied to objections raised by the respondents under Article 83 EPC. Moreover, the remaining objections in the case could be dealt with without undue burden for either the board or the parties. Finally, other considerations such as the patent term spoke against remittal,

Requests

XII. The appellant requested that the decision under appeal be set aside and the case be remitted to the opposition division for discussion of the remaining requirements of the EPC based on the claims of the main request, as submitted with the statement of grounds of appeal.

Alternatively, the case be should remitted to the opposition division based on the set of claims of auxiliary request 1, as submitted with the statement of grounds of appeal. Further alternatively the appellant requested that the patent be maintained on the basis of the claims of the main request or auxiliary request 1.

The appellant further requested that document D96 be admitted into the proceedings.

XIII. Respondent I requested that the appeal be dismissed and that the case not be remitted to the opposition division for further prosecution but that the board itself decide on the further grounds of opposition under Article 100(a) EPC in conjunction with Article 56 EPC and Article 100(b) EPC, should it come to the conclusion that either the main request or auxiliary request 1 met the requirements of Article 123 (2) EPC and Article 54 EPC.

XIV. Respondent III requested in writing that the appeal be dismissed.

XV. Respondent IV made no requests in the appeal proceedings.