T 0792/24 - Fewer side efffects as second medical use

Key points

•  This opposition appeal is about a second medical use claim. 
• Claim 1: "Plinabulin for use in reducing the neutropenia rate of a grade 3 or 4 neutropenia in a subject being administered with 75 mg/m² docetaxel, wherein the plinabulin is administered intravenously ". 
• The compound docetaxel is used for treating cancer and causes neutropenia (lack of white blood cells). It was found that plinabulin mitigates this side effect.
• "The Board considers that present claim 1 indeed defines a purpose limited product claim in the sense of Article 54(5) EPC. As stated in the impugned decision, the Board considers that the skilled person would understand the use of claim 1 as relating to the alleviation of neutropenia as a side effect of docetaxel treatment per se, i.e. in comparison to the treatment with docetaxel alone."
• "preventing the side effects induced by a therapy has a significant clinical value, and there is no justification for excluding this from being regarded as a form of prophylactic treatment." ... "the claimed use is prophylactic to the extent that it is administered before the side effect can be observed and reduces the occurrence thereof"
• "D5 is an abstract reporting the results of a phase II clinical study of docetaxel alone or in combination with plinabulin in patients with non-small cell lung cancer (NSCLC). "
• "the results section of D5 unambiguously discloses the reduction of incidence of docetaxel induced neutropenia in general when administering plinabulin"
• "The Board comes therefore to the conclusion that there is no direct and unambiguous disclosure in D5 that plinabulin indeed reduces the rate of neutropenia of specifically grade 3 and/or 4." (This is the first distinguishing feature)
• D5 also failed to teach a recited feature of the administration. " No particular effect has been brought forward for the administration time (feature (ii)). This feature was therefore arbitrarily chosen and cannot contribute to an inventive step."
• For the first distinguishing feature: "It follows that, while the provided data substantiate that plinabulin is indeed effective to reduce the rate of neutropenia grades 3 and 4 as well as grades 1 and 2, no greater reduction of grades 3 and/or 4 compared to grades 1 and 2 is achieved."
• The Board undertakes an enquiry into the technical effect of the distinguishing feature. However, the feature recites an effect (in my view), so this part of the reasoning is not entirely clear to me. 
• "starting from D5, the objective technical problem can only be formulated as the provision of a further use of plinabulin in docetaxel cancer therapy"
• " The [proprietor] argued that the skilled person would not have had any reasonable expectation of success of using plinabulin to reduce the rate of the clinically more relevant neutropenia grade 3 or 4, in particular to the extent shown in the patent and D16."
• The Board disagrees.
• "In view of the general disclosure of D5, the skilled person would anticipate that administering 30 mg/m**(2) of plinabulin would effectively mitigate the decrease in neutrophil counts in a subject in general, i.e. also in subjects susceptible to have decreased neutrophil counts corresponding to neutropenia grade 3 or 4. The appellant [respondent, I think, i.e. the proprietor] did moreover not provide any evidence that the effect of plinabulin in limiting the reduction of neutrophil count in a subject would be different depending on the level thereof. The skilled person would therefore expect that administering 30 mg/m**(2) of plinabulin would also be effective in reducing the rate of neutropenia grade 3 or 4."
• The subject-matter of claim 1 of the main request is thus not inventive when starting from D5 as the closest prior art.
  
  
• An auxiliary request specifying a dose of the plinabulin is found to be inventive. 
•  "The Board however agrees with the [proprietor], that the data in Figure 5 of the patent and in Table 1 of D16 show that the reduction of the occurrence of docetaxel induced neutropenia of grades 3 or 4 with 20 mg/m**(2) plinabulin is at least as good as with 30 mg/m**(2) plinabulin. That such an effect is achieved with the much reduced dose of 20 mg/m**(2) represents an improvement which is to be taken into account for the assessment of inventive step."
• " starting from D5, the skilled person would not have expected that the 20 mg/m**(2) plinabulin dose would be at least as effective as the significantly higher 30 mg/m**(2) dose in reducing docetaxel induced neutropenia rates of grades 3 and 4. While the skilled person would have expected some effect in reducing docetaxel induced neutropenia grades 3 or 4 also with 20 mg/m**(2) plinabulin, the extent of the reduction obtained compared to the 30 mg/m**(2) dose would not reasonably have been expected."

EPO 

The link to the decision can be found after the jump.

T 1354/23 - Crystalline form

Key points

• Claim 1 is directed to a crystalline form of a medical compound, apalutamide.
• Inventive step is at issue. "In experimental report D3, appellant I [opponent I] reworked the preparation of apalutamide according to D1 and obtained a solid which when analysed by XRPD was revealed as amorphous. Since this conclusion was not disputed by the respondents, it is accepted in the following that apalutamide prepared according to D1 is amorphous."
• Patent document D2 discloses the preparation of apalutamide and its recrystallisation from DCM/EtOH (paragraph [0091]). There is no information in D2 nor has any evidence been provided by any of the parties as to the specific form of the crystalline material prepared according to D2."
• "Claim 1 of the main request is therefore distinguished from both D1 and D2 in that a specific crystalline form of apalutamide denoted Form B is provided, while D1 discloses the amorphous form and D2 discloses an undefined crystalline form.
• "The respondents [proprietors] , relying on evidence in the patent as well as D19, argued that a technical effect of Form B was that it was less hygroscopic than the amorphous form of D1 and the other forms disclosed in the patent.
• "D19 also indicates that another crystalline form, namely Form A is significantly more hygroscopic, demonstrating a weight change of about 1.8% (D19, figure 1). "
• "On the contrary, as argued by the respondent, in relation to hygroscopicity, example 7 of the patent indicates that Forms C, D and J are "slightly hygroscopic" according to the definition provided in D18, addressed above, in contrast to Form B, which was demonstrated as negligibly hygroscopic. Since as set out above D19 also demonstrates that Form A is more hygroscopic than Form B, in the absence of any evidence to the contrary, it can be accepted that Form B is less hygroscopic than the other forms disclosed in the patent. "
• In the PCT application, forms C, D and J are solvates. The PCT application mentions an unsolvated form, form H.
•  The comparison of form H and form B using the data in the patent was not admitted into the proceedings under Art. 13(2) RPBA - the Board considered it a new 'fact' in the sense of T1914/12. 
• "Appellant II [opponent] argued that no improvement in hygroscopicity was demonstrated in relation to other polymorphic forms, in particular the undefined form of D2. The board disagrees. As argued by the respondents, the disclosure of D2 in relation to the crystalline form obtained is vague: the only information provided in paragraph [0091] thereof is that the obtained solid was recrystallised from DCM/EtOH. However, insufficient information is provided to reproduce the recrystallised product, such as relative amounts of the solvents mentioned, order of addition, addition rate, etc. As stated by the respondents, the information in the patent in combination with D19 is sufficient to render credible the effect that Form B is negligibly hygroscopic. The burden of proof in demonstrating a equally low hygroscopicity for other crystalline forms or the undefined form of D2 therefore lies with the appellants [opponents]."
• This touches on G 1/23: what about non-enabled prior art?
• See also G 2/21 r.26: " According to the established case law of the boards of appeal (see CLB, 10th edition, I.D.4.2, and the decisions therein) it rests with the patent applicant or proprietor to properly demonstrate that the purported advantages of the claimed invention have successfully been achieved.". The Enlarged Board here did not say that the proprietor has the burden of proof to show the improvement, i.e. to rework the prior art. 
• " Consequently, an improvement (i.e. reduction) in hygroscopicity relative to the amorphous form of D1 and the undefined form disclosed in D2 can be relied on in defining the objective technical problem."
• Another approach is that the objective technical problem over D2 is the provision of a 'negligible hygroscopic' form of the compound.
• The Board considers some further evidence on other properties and concludes: " On the basis of the foregoing, the objective technical problem underlying claim 1 starting from either of D1 or D2 is essentially that proposed by the respondents, namely the provision of a form of apalutamide with a beneficial combination of properties, namely improved hygroscopicity, high thermodynamic stability and high polymorphic stability." 

• For obviousness, "This corresponds to the principle set down in landmark decision T 777/08. According to that decision, the technical effects or properties of the claimed polymorph (improved filterability and drying characteristics) were effects which were expected merely by virtue of being crystalline. Hence, since it belonged to the routine tasks of the skilled person involved in the field of drug development to screen for solid-state forms of a drug substance, there was an incentive for the skilled person to arrive at the claimed solution in the expectation of achieving these improved characteristics. The board stated (see headnote 2) that "the arbitrary selection of a specific polymorph from a group of equally suitable candidates cannot be viewed as involving an inventive step." The implication from T 777/08 is therefore that when the advantages or effects of the claimed crystalline form are unexpected, i.e. they are not arbitrary and do not follow merely by virtue of being crystalline, then an inventive step is present.
• "In the present case, there is no absence of unexpected properties, and the selection of Form B is not arbitrary, since Form B possesses a beneficial combination of properties as set out above."

• The question is: the non-arbitrary selection of Form B from what? What are the other members of the class it is selected from?   

• It seems a useful strategy to include a few poor crystalline forms  (solvated or not) in a patent directed to a 'good' polymorph. 

The link to the decision and an extract of it can be found after the jump.

T 1437/21 - Clinical trial protocols and inventive step

Key points

• In the case at hand, D22 is a press release of the results of Phase III clinical trials.
• However, there is also the general issue of the mandatory publication of clinical trial protocols before the clinical trial is even carried out.
• The Board, obiter it seems: "The prior disclosure that an investigational product for use in the treatment of a particular condition is undergoing clinical trials may in accordance with established jurisprudence preclude that a subsequently claimed invention involving this product for use in the treatment of that specific condition is considered to involve an inventive step, even where the results of the trial have not been made available to the public (see T 2506/12, reasons 3.10 and 3.15; T 239/16, reasons 6.5 and 6.6; T 1123/16, reasons 11; T 2963/19, reasons 4.3.1)."
• " as explained in T 2963/19, the approval of a clinical study depends on the assessment of the foreseeable risks to the participants in relation to the anticipated benefit in terms of the relevance of the findings. The approval of a clinical trial does therefore not, by way of a heuristic, imply an expected positive outcome of the treatment. Furthermore, as underlined in point 4.3.1 of T 2963/19 by reference to the "Communication from the Commission 2010/c 82/01", the authorisation of a clinical trial does not represent a scientific advice on the development programme of the investigational product tested. The considerations in T 2506/12, T 239/16 and T 1123/16 regarding the expectation of success in view of the disclosure of clinical trials are, as in T 2963/19, evidently linked to the further circumstances of the cases decided therein, in particular the nature of the investigational product and of the condition to be treated and the absence of information suggestive of failure of the trial."
• Turning to the case at hand: "The crucial issue in the assessment of inventive step starting from the teaching in documents D22/D29, in particular the reported results from Study 1245.36, thus remains whether in view of the available information in the prior art, including the information in documents D22/D29, the skilled person had a reasonable expectation that empagliflozin would be effective in treatment of diabetic patients having moderate renal impairment."
• The claim is a second medical use claim specifying a sub-population of the patient population used in the clinical trial of D22, and a different sub-population than one of the sub-populations that was specified in D22.
• "The skilled person would furthermore not have expected the efficacy of the 25 mg dose of empagliflozin in patients with moderate renal impairment on the basis of the efficacy of the 10 mg dose in patients with mild renal impairment reported in documents D22/D29 due to the distinctive status of patients with moderate renal impairment which directly affects the mechanism of action of empaglifolozin. Precisely because the efficacy of SGLT-2 inhibitors was known to decrease progressively with decreasing renal function (see D8, page 235, left column), the skilled person could not reasonably expect that any significant efficacy of empagliflozin as still observed according to documents D22/D29 within the group of patients with mild renal impairment would even be retained in the distinctive group of patients with moderate renal impairment."
• "In the absence of a reasonable expectation of significant efficacy of empagliflozin in the treatment of diabetic patients with moderate renal impairment the Board concludes that the subject-matter of claim 1 as granted was not obvious to the skilled person in view of the prior art and thus involves an inventive step."

EPO 

You can find the link to the decision and an extract of it after the jump.

T 0197/22 - First medical use claims

Key points

• "in case of a claim for a composition for use under Article 54(4) EPC [first medical use claim] it is not generally required for compliance with Article 83 EPC that a patent discloses the therapeutic suitability of the defined compositions in treatment of a plurality of diseases (see T 424/21, reasons 40)."
• A totally uncontroversial statement until you compare it with the May 2024 PTAB USPTO decision  (APR pane) Ex parte Chamberlain, Appeal 22-1944 where a claim directed to " a method of treating a patient by administering an anti-C5 antibody [, said antibody] comprising ..." was considered and found to be invalid as lacking sufficient support by the description". Moreover, the decision comes directly from the USPTO Director, along with the Commissioner for Patents and the Chief Administrative Patent Judge. (Patently-O).
• "However, as claim 1 of the main request defines a composition for use in therapy, the patent must provide the skilled person with sufficient instructions for applying the compositions within the scope of the claim in some form of therapy without undue burden. In line with the considerations in G 2/21 (see reasons 77) this requires that the patent must substantiate the therapeutic utility of the claimed composition if in the absence of experimental data it would not be credible to the skilled person that any therapeutic effect is achieved."
• "Claim 1 of the main request defines the composition to comprise mRNA encoding a functional protein or enzyme. '" 
• "The patent demonstrates in examples 7 and 8 with in vivo experiments in mice that mRNA encoding firefly luciferase (FFL) may be effectively transfected and expressed using a liposomal transfer vehicle as defined in claim 1 of the main request. As recognized by the patent proprietor during the oral proceedings, the expression of FFL luciferase serves no purpose in any therapy. According to the proprietor, examples 7 and 8 provided nevertheless with the use of FFL proof of concept that the defined transfer vehicles allowed for the effective transfer and expression of therapeutically useful proteins."
• "if the term "functional protein or enzyme" in claim 1 of the main request is understood as functionally restricted to a protein with a feasible therapeutic utility, the Board considers that the patent does not provide the skilled person with a sufficient disclosure to generally enable the therapeutic use of the claimed formulation comprising the mRNA encoding for an accordingly defined protein. "
• " the mere detection of an unquantified level of expression of FFL using a particular formulation for gene transfer does not credibly disclose the general suitability of such a transfer vehicle for use in gene therapy, because in view of documents D64 and A106 serious doubts prevail that such a formulation allows to generally achieve therapeutically effective levels of expression of the contained mRNA. The Board is therefore not convinced that the patent provides actual proof of concept regarding the suitability of the claimed formulations for use in therapy."
• "whilst document D39 thus may describe with the mentioned experimental results the in vivo expression of the administered mRNA encoding hEPO in a quantity which could indicate the described compositions to be therapeutically useful, the patent fails to disclose such a quantitatively adequate expression of mRNA from the compositions as defined in claim 1 of the main request. In accordance with the considerations in G 2/21 (see reasons 77) a lack of sufficiency of disclosure cannot be remedied by post-published evidence. The patent proprietor's argument relying on the post-published document D39 is therefore not considered persuasive.  Accordingly, the Board concludes that the main request does not comply with Article 83 EPC."
• The composition defined in the claim was as follows: " at least one mRNA molecule ...  encapsulated in a liposome having a size of less than 100 nm, wherein said liposome comprises one or more cationic lipid(s), one or more non-cationic lipid(s), and one or more PEG-modified lipid(s)," 
• EPO 

The link to the decision and an extract of it can be found after the jump.

T 1255/21 - Close reading of the clinical trial document

Key points

• A clinical trial registration document kills the patent.
• Note, I understand clinical trial pre-registration is mandatory and is public.  Whether and how that will benefit or negatively affect medical research is beyond the scope of this blog post. 
• Document D25 is a print-out from the website "International Clinical Trials Registry Platform" maintained by the WHO. It refers to a clinical trial with the title "A Phase I/II Trial of TG01 and Gemcitabine as adjuvant therapy for treating patients with pancreatic cancer" registered with EUCTR, the EU Clinical Trials Register. The proposed trial aims to "assess the potential for interference of Gemcitabine on immune responses to TG01 [...] in patients receiving TG01 and GM-CSF after primary resection of pancreatic adenocarcinoma", to "assess the safety of Gemcitabine given concomitantly with TG01/GM-CSF vaccination" and to "assess the efficacy of TG01 and GM-CSF in patients with resected pancreatic cancer" (see under "Primary Outcome(s)"). The exploratory objective is to "assess the relationship between KRAS status and recurrence".
  
  Mulitiple starting points for inventive step
• The OD analyzed inventive step starting only from another document, D23, as the closest prior art. The Board: "according to the established case law of the boards, the assessment of inventive step should be done from all documents that could represent alternative workable routes to the invention (see Case Law of the Boards of Appeal, 10th edition 2022, I.D.3.1). Moreover, if a piece of prior art is "too remote" from an invention, it should be possible to show that the invention would not have been obvious to a skilled person starting from this piece of prior art (ibid.).'
• "The product code "TG01" is not commonly known. It is followed by a list of seven components, each of which has a "Current sponsor code" ("12A", "12C" etc.), an "Other descriptive name" (e.g. "12-A-p21 RAS(5-21)","12-C-p21 RAS(5-21)"), a "Concentration unit" ("mg milligram(s)") and a "Concentration number" ("0.1-")."
• "It was disputed between the parties whether the skilled person would have been able to determine what the composition identified as "TG01" actually consisted of, in particular, whether they would have known that it referred to a peptide vaccine with a specific composition.  "
• " In a fast-moving field such as medical research, and in particular the field of oncology, review articles can be considered to reflect the skilled person's common general knowledge (see e.g. decision T 1110/03, point 2.3 of the Reasons). Document D15 is such a review article and it discloses that the seven most common KRAS mutations in codons 12 and 13 were "p.G12D","p.G12V", "p.G12C", "p.G12A", "p.G12S", "p.G12R", "p.G13D" (see document D15, Abstract and Figure 2). In the light of their common general knowledge, the skilled person at the relevant date of the patent would therefore have recognised that the seven one-letter-code amino acid designations in the descriptive names and in the sponsor codes of the p21 Ras peptide components of TG01 used in document D25 corresponded exactly to the seven most common KRAS mutations in positions 12 and 13. The skilled person would also have recognised that the designations "12" (six times) and "13" (once) in the descriptive names and in the sponsor codes corresponded to the positions of the mutations in the RAS peptide ("12-A-p21 RAS(5-21)", "13-D-p21 RAS(5-21)" etc.). " 
• " In conclusion the skilled person having common general knowledge in mind would have recognised that the "TG01" composition referred to in document D25 contained seven peptides consisting of residues 5 to 21 of the p21 RAS oncoprotein and carrying each one of the seven most frequent mutations at positions 12 and 13."
• "The full sequence of the 17 amino acid long peptides is disclosed on lines 1 to 3, left-hand column of page 1123 of document D6. Because of the reference to "K-ras 5-21" and the identical amino acid abbreviations at positions 12 and 13, the skilled person would understand that the peptides disclosed in document D6 are identical to the seven components of TG01 in D25 named "12-A-p21 RAS(5-21)", "12-C-p21 RAS(5-21)", "12-D-p21 RAS(5-21)", "12-R-p21 RAS(5-21)", "12-S-p21 RAS(5-21)", "12-V-p21 RAS(5-21)" and "13-D-p21 RAS(5-21)". "
• " In conclusion, the use of the code-name "TG01" in document D25 does not affect the status of this document as a realistic starting point for assessing inventive step because the skilled person would have been able to determine what the composition identified as "TG01" consisted of."
• Turnging to the distinguishing feature: "Document D25 discloses a proposal for a clinical trial for "TG01 and Gemcitabine as adjuvant therapy for treating patients with pancreatic cancer" (see "Public title"), i.e. of a composition falling under the definition in the claim. The only difference between the disclosure in the patent and the disclosure in document D25 is that the former [=the patent] discloses that the therapeutic effect which the trial is set up to test, is actually obtained. The evidence in the patent that said effect is obtained comes from the results of the DTH skin tests disclosed in the examples. It is common ground that this test is a suitable indicator for the existence of the relevant therapeutic effect."
• I.e., even if D25 explicitly discloses the claim, the claim is still novel, because for a second medical use claim, "it works" is an implicit feature that can provide for novelty (and inventive step, possibly).
• "the objective technical problem can be seen as providing an effective treatment for (pancreatic) cancer."
• "In view of these positive reports of gemcitabine in combination with peptide or nucleic acid vaccines, the board cannot conclude that there was any prejudice or teaching away from combining peptide vaccines with gemcitabine in the art, which would have dissuaded the skilled person to put the clinical trial proposal of document D25 into practice. Rather, based on the teaching in the prior art and their common general knowledge, the skilled person is judged to have had a reasonable expectation of success when putting the proposal of document D25 into practice."
• Therefore, the subject-matter of claim 1 is not inventive.
• 
  

EPO 

The link to the decision is provided after the jump, as well as (an extract of) the decision text.

T 1324/21 - Spontaneously forming polymorphs

Key points

• From Derk Lowe's weblog: "The classic story is ritonavir, the anti-HIV medication (now used as a CYP metabolism inhibitor in Paxlovid and other formulations). Eighteen months after FDA approval and the arrival of the drug on the market, a more stable and less soluble polymorph began to take over the world, first noticed as a higher dissolution-test failure rate on the manufacturing line. This extremely unwelcome development precipitated a crisis (couldn’t resist the wording) which was only solved by a great deal of experimentation under severe time pressure, and the whole affair greatly impacted severely ill patients while costing Abbott hundreds of millions of dollars." (https://www.science.org/content/blog-post/stalking-polymorphs) 
• See here for a further review, also discussing patent litigation on polymorphs: https://onlinelibrary.wiley.com/doi/full/10.1002/anie.201410356
• Turning to the present case, claim 1 is directed to a pharmaceutical composition comprising rifaximin in polymorphic form alpha and in polymorphic form delta, and comprising 10 wt% to 45 wt% filler.
• The OD found the claim to be novel, as follows: " Xifaxan tablets of batch 13012, which according to document D9 were purchased before the priority date, had been shown in document D7 to comprise the polymorph forms alpha and delta of rifaximin in the ratio and total amount as defined in claim 1 of the main request. However, it had not been demonstrated that these Xifaxan tablets could be analysed to comprise a relevant amount of filler." 
•  The proprietor argued as follows for inventive step: " The Xifaxan tablets of batch 13012 comprised in addition to rifaximin form alpha also rifaximin form delta. The presence of rifaximin form delta was contrary to the official documentation on the Xifaxan tablets, in particular document D15, according to which only rifaximin form alpha was used for the preparation of the tablets, which would not convert to other forms during manufacture or storage. Document D15 actually recommended to ensure that the commercial preparation of rifaximin is the poorly absorbed polymorphic form alpha in view of the greater oral bioavailability of other polymorphic forms. The Xifaxan tablets of batch 13012 were therefore defective and unsuitable as starting point for the assessment of inventive step." 
• The Board, on novelty: " The declaration in document D44 reports that Xifaxan 550 mg tablets as available on the market before the priority date of the patent had been prepared using the filler MCC with a water content of 3.2% in an amount which corresponded to 29.9 wt% of filler in the tablets [] Document D44 therefore indicates that the Xifaxan tablets of batch 13012 did indeed comprise an amount of filler as defined in claim 1 of the main request." 
• " The experimental report in document A55 demonstrates that the amount of filler in Xifaxan tablets of batch 13012 could be analysed using methods as described in documents A56 and A57, which were available at the relevant time. Document A55 confirms that using these methods the Xifaxan tablets of batch 13012 were found to comprise a MCC content of 28.2-29.0% on the basis of dry MCC " 
• " Accordingly, the Board concludes that the subject-matter of claim 1 of the main request lacks novelty." 
• Auxiliary Request 1 is limited to a method of preparing a tablet comprising " providing (A) rifaximin in polymorphic form alpha and (D) rifaximin in polymorphic form delta"  and compressing.
• The question is whether the public prior use is a suitable starting point for inventive step. " Whilst the originally contained rifaximin form alpha in the Xifaxan tablets of batch 13012 had thus according to document D7 apparently partially [and spontaneously, during storage] converted to form delta by 17 December 2015, these tablets had at that time not yet expired. "
  
• " Contrary to the finding in the decision under appeal the Board considers that this approved market product, which had not expired, cannot be disqualified as a realistic starting point for the assessment of inventive step with respect to the method for preparing tablets comprising corresponding amounts of rifaximin form alpha and delta as defined in claim 1 of auxiliary request 1." 
• " the Board concludes that the subject-matter of claim 1 of the auxiliary request lacks an inventive step." 
• The patent is revoked.
• EPO 

The link to the decision is provided after the jump, as well as (an extract of) the decision text.

T 1700/19 - Tenofovir

Key points

•  The patent claims priority from D11.
• "D12 would be part of the prior art under Article 54(3) EPC, and prejudicial to novelty, only if a subject-matter is: - disclosed in D12, and entitled to priority from e.g. D13, and - covered by the claims of the main request, but not entitled to priority from D11."
• The claim is directed to a compound, TAF-HF.
• "D13 also mentions TAF-HF (as GS-7340 hemifumarate, see pages 2 and 19) but contains no example of its preparation."
• "The parties present opposing views as to whether the mere mention of TAF-HF in D13 is an enabling disclosure of this compound, considering the relevant common general knowledge. It is also debatable whether D11 provides an enabling disclosure for the preparation of TAF-HF, as a salt and/or as a co-crystal. However, in the Board's opinion, if it is accepted that the mention of TAF-HF in D13 is an enabling disclosure of this compound, then it must follow that the equivalent mention in D11 of the combination of fumaric acid and TAF at a ratio of about 0.5, as co-crystal or salt, is an enabling disclosure of TAF-HF."
• This is an interesting statement. The different filing dates oF D11 and D13 played no role in the case at hand.
• " Thus it is not possible for D12 to enjoy priority from D13 for TAF-HF without claim 1 enjoying priority from D11 for the same subject-matter. In other words, it is not necessary to take position on the validity of the priority claims with regard to enablement. Either D12 enjoys a valid right to priority from D13 in respect of TAF-HF, in which case, for analogous reasons, present claim 1 of the main request also validly claims priority from D11 in respect of the same subject-matter. Or D12 does not enjoy a valid right to priority from D13 in respect of TAF-HF. In both cases, D12 is not prior art under Article 54(3) EPC. ... Accordingly, D12 does not prejudice the novelty of the claimed subject-matter."
• "The[opponents] do not contest that example 1 of the patent describes the preparation of a mixture of TAF-HF along with GS-7339-MF and TAF-MF. However, [the opponents] contend that the patent does not give the necessary information to the skilled person as to how to separate TAF-HF from the obtained solids, so that the claimed subject-matter is insufficiently disclosed. The Board does not share this opinion. Claim 1 of the main request pertains to TAF-HF as such and does not mandate any degree of purity. Consequently, the Board shares the respondent's opinion that the criteria of sufficiency of disclosure are met already for the reason that example 1 discloses the preparation of TAF-HF."
• Inventive step over D1: "The subject-matter of claim 1 of the main request differs in that TAF is in the form of a hemifumarate instead of a monofumarate (i.e. it comprises a 2:1 stoichiometric ratio of TAF to fumaric acid)."
• "The objective technical problem to be solved can accordingly be formulated as the provision of an improved form of TAF, having improved chemical stability and an improved ability to purge TAF of its diastereomeric impurity GS-7339."
• "It was known at the priority date that, in the case of tenofovir disoproxil, the co-crystal with fumaric acid in a 2:1 molar ratio is more stable and less hygroscopic than the 1:1 fumarate salt 
• The Board: "The properties of the hemifumarate in the case of TAF could not be extrapolated from those of tenofovir disoproxil. The prior art does not point to any such predictability. On the contrary, in light of the statements regarding the unique physicochemical properties of API solid forms, including salts and co-crystals in D15 (see page 359, right column) and D28 (see page 317, left column), no such generalisation is possible. In the present case, the prior art gives no reason to assume that the modification involved, namely the use of a 2:1 molar ratio with fumaric acid instead of 1:1, would lead to the same effect in the structurally different compounds TAF and tenofovir disoproxil. Accordingly, the claimed subject-matter is not obvious starting from D1."

EPO 

The link to the decision is provided after the jump, as well as (an extract of) the text of the decision.

T 0670/20 - Non-analysis clauses and clinical trials

Key points

•  This post is from stock. 
• Documents D19 and D20 relate to phase IIa and phase IIb clinical trials in which patients received treatment .... involving administration of edoxaban for a period of up to ten days. Document D21 (see page 15, line 8) indicates that the edoxaban formulation under investigation during the clinical studies described in documents D19 and D20 [has all the features of claim 1 directed to the pharmaceutical formulation].
• The clinical trials were carried out before the filing date of the patent, the priority being invalid.
• "the appellants [opponents] relied [] on the provision of the tablets under investigation during the trials of documents D19 and D20 to the participating patients who were discharged from hospital before the end of the treatment period. This provision of the tablets to the patients discharged from the hospital before the end of the treatment was not contested by the respondent [proprietor].
• "The assessment of the ground of lack of novelty in view of the trials described in documents D19 and D20 therefore crucially depends on whether the participating patients who received the tablets are to be considered as members of the public who were free to dispose over the provided tablets and thus theoretically in a position to investigate the internal structure of the tablets. "
• " the clinical trials of documents D19 and D20 were carried out in accordance with the EMEA Guidelines for Good Clinical Practice (document D33). These guidelines explicitly require adherence to the prescribed protocol"
• "This set-up of the trials of documents D19 and D20 implies that the patients who decided to participate in the trials agreed, following their informed consent, to use the provided medication according to instruction or to return the unused medication. Accordingly, the participating patients who were provided with the tablets under investigation entered into a special relationship with the investigators of the trials and were with regard to the provided tablets not members of the public that could freely dispose over these tablets."
• "The Board acknowledges that the statements in documents D19 and D20 encouraging patients to discuss their participation in the trials indicates that the patients were not under a duty of confidence with respect to their participation to the trials and the information regarding the trial provided to them in that context. In fact, a duty of confidence regarding such information could be considered to constrain the patients in their ability to freely decide on participating in the trials on the basis of their informed consent, which would seem contrary to the above mentioned guidelines (see document D33, section 4.8). However, the Board finds no reason why the absence of the patients' duty of confidence with respect to the information relevant to their participation in the trials should affect the obligations of the participating patients regarding the use and return of the tablets provided to them, which resulted from their decision to participate in the trials as explained in section 4.3 above."
• "The Board notes, however, that the patients' agreement to use the provided medication according to instruction or to return the unused medication obliges the patients irrespectively of any sanction on non-compliance and therefore disqualifies the patients as members of the public with respect to the medication provided to them. The possibility of non-compliance to the instructed use and return of the tablets by the participating patients does not affect the essence of this agreement. Moreover, the appellants' estimation regarding the likelihood of full compliance remained speculative and therefore without consequence."
• Turning to inventive step (over other documents): " the Board considers that ...the problem to be solved may be formulated as the provision of a solid pharmaceutical composition comprising edoxaban as active ingredient which allows for excellent dissolution properties."
• " the cited prior art provided the skilled person with no reasonable expectation that the use of a combination of a sugar alcohol with pre-gelatinized starch or crystalline cellulose as a water-swelling additive allowed the dissolution of tablets comprising edoxaban to be still further enhanced by coating the tablet with a coating agent as defined in claim 1 of the main request. On the contrary, as indicated in document D23 tablet coatings were expected to have a detrimental effect on the dissolution properties or, in case of thin water-soluble polymers, to have at best no particular effect on dissolution rate of the tablets "
• "the Board agrees with the decision under appeal that the subject-matter of claim 1 of the main request also involves an inventive step."
  
  
• Kudos to the lawyer who added the clause in the protocol. 

EPO 

The link to the decision is provided after the jump, as well as (an extract of) the text of the decision.

T 0795/21 - Deleting alternative from Markush formula

Key points

• Claim 1 is directed to a class of compounds ("A chemical compound having formula I"). The Board finds that claim 1 of the main requests lacks an inventive step over D36 (after an extensive analysis).
• Claim 1 specifies as one of the features "X is independently selected from the group H, F, Cl, Br, I, OH and methyl (-CH3)" and "Y is F".  The embodiment wherein X is H is found to be obvious because of structural similarity with D36 (with further reasons).
• The Board turns to Auxiliary Request 4. Herein, H is deleted from the list of alternatives for X. 
• In the application as filed, the definition was: "X and Y are independently selected from the group comprising H, F, Cl, Br, I, OH and methyl (-CH3)". Hence, in AR-4, H is deleted from the list for X and Y is limited to F.
• The Board recalls that according to established case law, for this type of amendment, Article 123(2) requires that "the amendment may not lead to a particular combination which is not derivable from the original application and is therefore potentially suitable to provide a technical contribution to the originally disclosed subject-matter as opposed to a mere restriction of the required protection which does not result in the definition of a new sub-class of compounds and is therefore not potentially suitable to provide a technical contribution to the original subject-matter." (T 615/95, T 859/94, T 50/97, T 783/09, T 948/02 and T 801/02) 
• As the amendment is made to restore inventive step, the proprietor argues that this case law no longer applies after G 2/10: the proprietor argues that "with reference to G 2/10 and T 1937/17 that the notion of a technical contribution should actually not be taken into account at all"
• The Board:  "amendments by the deletion of options from multiple lists of separate characteristics inherently include an aspect of combination and potentially involve an aspect of arbitrariness, which may complicate the assessment of whether such amendments remain within the limits of what the skilled person would directly and unambiguously derive from the original disclosure."
• The Board recalls that G 2/10 referred to the "body of jurisprudence ... with respect to cases in which the limitation could lead to the singling out of compounds or sub-classes of compounds or other so-called intermediate generalisations not specifically mentioned nor implicitly disclosed in the application as filed" and indicated that this body of case law was to be applied (r.4.5.4). 
• Therefore, the notions used in the existing case law, namely "mere restriction of the required protection" versus "generating another invention" or "suitable to provide a technical contribution to the originally disclosed subject-matter" are to be applied as considerations which may arise from the application of [the gold standard test] when assessing amendments by deletion of options from multiple lists and which may affirm the result of such assessment.
• "the Board considers that the observation that the deletion of options for X and Y in accordance with claim 1 of auxiliary request 4 is suitable to provide a technical contribution to the originally disclosed subject-matter supports the assessment that this amendment is not in compliance with the "gold standard".
• The technical contribution is provided by the amendment omitting the alternative that overlapped substantially with D36 and was held to be obvious. 
• "The Board therefore concludes that auxiliary requests 4 does not comply with the requirement of Article 76(1) EPC."
• As a comment, I wonder whether the allowability of the amendment here depended on the content of D36 as prior art. 
• The decision was taken 24.03.2023. On that day, the stock price of the proprietor decreased from 1.24 USD to 0.80 USD. The patent is EP2955190, also at issue in [2023] EWHC 611 (Pat) of 21 March 2023. That decision states that Sofosbuvir falls in the Markush group of the claims of the patent (at 11).

EPO 

The link to the decision is provided after the jump, as well as (an extract of) the text of the decision.

T 1079/18 - Febuxostat II and III

Key points

•  This is another patent directed to Form I of Febuxostat , now having the additional feature that it is a pharmaceutical composition "wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of fillers, sweeteners, buffering agents, glidants, flowing agents, flavouring agents, lubricants, preservatives, surfactants, wetting agents, binders, disintegrants and thickeners."
• The filing date is in 2011.
• The Board comes to the same conclusion:  "by performing a DSC analysis of form A, the skilled person aiming at higher solubility would have identified form I as being the desired form, i.e. a higher-melting form that results from form A by an endothermic phase transition at higher temperatures. In view of the heat-of-transition rule, they would have expected form I to be an enantiotrope of form A and form I to have a higher solubility than form A at temperatures below the transition temperature (somewhere between approx. 175 and 200 °C), i.e. at ambient temperature. Further, the fact that form I merely retains the non-hygroscopicity of form A (in the absence of a comparison, one cannot speak, at any rate, of an improvement - see above) can be considered merely as a bonus effect that the skilled person inevitably achieves because they are primarily looking for a crystalline form of febuxostat with higher solubility."
• The claims are found to be obvious, and the patent is revoked.
• In decision T 0546/21, a separate patent for a method using the crystalline form to prepare a pharmaceutical composition is also revoked. 
• Oral proceedings in cases T 1065/18 and T 1079/18 were joined and lasted until 18:00; oral proceedings in case T 0546/21 were held the next day and took only an hour. 

EPO 

The link to the decision is provided after the jump, as well as (an extract of) the text of the decision.

T 1065/18 - Febuxostat I / Preparative DSC

Key points

• In this post: polymorphs, a bonus effect, and a try-and-see situation. As well as clarity issues. 
• Claim 1 reads as follows (amendments shown vis-à-vis claim 1 as granted):

  "Crystalline form of Febuxostat having an X-ray powder diffraction pattern as [follows], further characterized as being an anhydrous form [...]"

• ""Pharmaceutical composition comprising a crystalline form of Febuxostat [having a certain X-ray powder diffraction pattern] wherein the pharmaceutical composition is packaged or filled into a container.""

• The compound referred to in claim 1, febuxostat, is a medicament used in the treatment of hyperuricemia and gout. 

• " The feature according to which the pharmaceutical composition "is packaged or filled into a container" is not contained in the granted claims. Hence, with respect to this additional feature, claim 1 of auxiliary request 2 is open to an assessment under Article 84 EPC "

• " Although the claim features in their entirety define the claimed subject-matter, a claim may nevertheless be unclear. In the board's view, this is the case here. Due to its wording ("Pharmaceutical composition ... packed or filled into a container."), claim 1 puts the emphasis on a pharmaceutical composition rather than a container comprising said composition. This makes it unclear whether the protection sought is limited to the pharmaceutical composition per se, or whether a container comprising a pharmaceutical composition is to be protected (see T 352/04, point 2.8 of the Reasons for a similar case).

  Thus, claim 1 of auxiliary request 2 lacks clarity. Auxiliary request 2 is not allowable."

• Auxiliary Request 4: Claim 1 reads "Pharmaceutical composition comprising a crystalline form of Febuxostat ..., wherein the pharmaceutical composition is an oral dosage form."

• It was common ground between the parties that D2 is the closest prior art. The board saw no reason to deviate from this unanimous view. D2 relates to solid forms of febuxostat, referred to as crystalline forms A, B, C, D and G, and as amorphous form E. [the crystalline form specified in the claims is yet a further form].

• "The subject-matter of claim 1 is distinguished from form A of D2 in that - it relates to a pharmaceutical composition in oral dosage form [and] - the pharmaceutical composition comprises form I rather than form A. "

• The Board carefully formulates the objective technical problem.

• " With regard to the assessment of obviousness, the board considers it appropriate to first summarise the following aspects concerning polymorphs relevant to the present decision (for useful overviews: D9, page 532, right column, second paragraph; D11, chapter III on page 18 f. and table 4; D17, paragraph bridging pages 166 and 167; D27, pages 11 ff.; A38, pages 2437 f. and 2446 to 2449; A39, pages 186 to 188; A45, pages 97 ff.). There was agreement between the parties that these aspects belong to the skilled person's common general knowledge.

  - The transition between two polymorphs can be categorised as either enantiotropic or monotropic." [follows an extensive technical analysis].

• "Against the background of this common general knowledge, the skilled person, faced with the problem of providing a crystalline form of febuxostat that has a higher solubility than form A, will clearly be inclined to check whether form A undergoes an endothermic phase transition into a new higher-melting form at higher temperatures. This is because, according to the heat-of-transition rule, such a new solid form should then be an enantiotrope of form A having a higher solubility than form A below the transition temperature, such as at ambient temperature in the present case (see point 12.3 above). Either such a form exists or it does not. The board concurs with opponent 1 that the skilled person would have been in a "try and see" situation."

• "It may be true that the skilled person - as argued by the patent proprietor - does not generally think of using DSC to find new solid forms. However, against the background of the common general knowledge summarised above and the objective technical problem, they would most certainly have done so - if only because DSC measures heat flow and is the method of choice for determining exo- and endothermic processes when heating a sample."

• The Board gives an extensive analysis of the evidence on file regarding DSC.

• "Thus, by performing a DSC analysis of form A, the skilled person aiming at higher solubility would have identified form I as being the desired form, i.e. a higher-melting form that results from form A by an endothermic phase transition at higher temperatures. In view of the heat-of-transition rule, they would have expected form I to be an enantiotrope of form A and form I to have a higher solubility than form A at temperatures below the transition temperature (somewhere between approx. 175 and 200 °C), i.e. at ambient temperature. Further, the fact that form I merely retains the non-hygroscopicity of form A (in the absence of a comparison, one can, at any rate, not speak of an improvement - see above) can be considered merely as a bonus effect that the skilled person inevitably achieves because they are primarily looking for a crystalline form of febuxostat with higher solubility."

• The patent is revoked.
  
  

EPO 

The link to the decision is provided after the jump, as well as (an extract of) the text of the decision.

T 1825/21 - Inventive crystalline form

Key points

•  The Board finds a crystalline form to be inventive.
• Claim 1 is directed to the compound ceritinib in free base form (i.e. not in the form of a salt).
• the subject-matter of claim 1 of the main request lacked inventive step starting from D1 as the closest prior art.
• the ceritinib HCl of example 7 of D1 is amorphous, and represents the disclosure in D1 which is structurally closest to the claimed crystalline ceritinib. This amorphous ceritinib HCl represents the starting point for the assessment of inventive step of the claimed crystalline ceritinib.

• the subject-matter of contested claim 1 is distinguished from this embodiment of D1 in that it concerns: - ceritinib in free base form, rather than as its HCl salt, - in crystalline, rather than in amorphous form.

•  the board acknowledges that the patent - or the application as filed, respectively - does not comprise any data comparing the claimed crystalline ceritinib with the amorphous ceritinib HCl of D1 [.] The board nevertheless concludes that the technical effects mentioned below may be accepted as being credible on the basis of the information in the patent and the common general knowledge of the skilled person.

• ", it is credible on the basis of this common general knowledge, which was known before the priority date of the claimed invention, that the effects of stability and ease of drying, demonstrated in the patent for crystalline ceritinib, represent improvements over the amorphous ceritinib HCl disclosed in D1. Therefore, an improvement over amorphous ceritinib HCl of D1 is acknowledged without taking the appellant's post-published evidence into account as proof of said improvement (supra). It follows also that case G 2/21 [still pending at the time of the decision], in which this issue is addressed, is not relevant to the present appeal case."

• The objective technical problem starting from the amorphous hydrochloride salt of D1 is hence the provision of a form of ceritinib having improved stability and ease of drying.

• "The appellant argued that the skilled person attempting to obtain a form of ceritinib with improved stability and ease of drying would have tried to prepare the ceritinib HCl known from example 7 of D1 in crystalline form. However, as set out in point 5 of D23, a declaration of a technical expert, any attempt to prepare ceritinib HCl only resulted in amorphous (i.e. non-crystalline) precipitates having chloride levels inconsistent with a stoichiometric salt.

  The board agrees. Having failed to solve the above problem in the most obvious way by providing a crystalline ceritinib HCl, there would have been no reason for the skilled person to turn to ceritinib free base in the expectation that it would provide a solution. "

• 
  

• EPO 

The link to the decision is provided after the jump, as well as (an extract of) the text of the decision.

T 0435/20 - Anti-IL-23 antibodies binding at conformational epitope

Key points

•  Claim 1 as granted: "1. An antibody ... that binds to  human IL-23p19 [i.e. subunit p19 of human interleukin-23] at an epitope comprising residues 82-95 and residues 133-140 of SEQ ID NO: 29."
• Hence, no sequence or structure of the antibody is specified, only of the epitope, i.e. the substrate.
• The patent is roveked for insufficiency of the Amgen/Sanofi type (https://patentlyo.com/patent/2022/11/rethinking-enablement-grants.html) 
• The Board: "The claim is not for a single antibody but for a pool of antibodies each of which binds human interleukin-23 at an epitope as defined in the claim."
• "While the epitope bound by the claimed antibodies must include both stretches of amino acids, the claim does not unambiguously delimit the spatial extent of the epitope. Interpretation is therefore required to determine its extent. The board does this according to the normal rules of claim construction, in which the terms used in the claim are given their broadest technically sensible meaning in the context in which they appear and having regard to the common general knowledge and the teaching in the patent"
• "in an embodiment, although the claim is not limited to this embodiment, the claim encompasses antibodies that are functionally defined by their ability to bind to human IL-23p19 and contact several of the amino acid residues within both amino acid stretches recited in the claim, i.e. antibodies with the same specificity as the exemplified antibody 7G10 [i.e. the antibody shown in the examples of the patent, probably with the sequence specified in the sequence listing /description], but which are not structurally related to it."
• "Antibody 7G10 is therefore one way of performing the claimed invention. However, claim 1 is not limited to antibody 7G10 and structural related variants but encompasses antibodies which are solely defined by the functional feature that they have the same specificity as the exemplified antibody 7G10"
• That the skilled person can manufacture 7G10 based on the patent is not disputed.
• Turning to sufficiency, "In a first line of argument the appellant [patentee] submitted that, at the priority date of the patent, the generation and screening of antibodies that bind to the p19 subunit of hIL-23 did not amount to an undue burden of experimentation for a skilled person and that according to the case law of the Boards of Appeal, it was a matter of routine to raise and screen antibodies to a known antigen "
• "The board acknowledges that raising and screening antibodies involves only routine experimentation. However, this is the case only if the skilled person knows from the disclosure in the patent or from common general knowledge (i) which antigens are suitable for raising antibodies having the desired properties and (ii) which screening process should be used to select these antibodies without undue burden"
• " the generation and screening of antibodies that bind (anywhere) to the p19 subunit of hIL-23 would not involve an undue burden for the skilled person.  However, the patent in suit discloses neither a suitable antigen nor a screening process that would ensure the reliable generation and selection of antibodies having the required properties by applying routine methodology and a reasonable amount of experimentation. It is common ground that peptides consisting of the primary sequence of the claimed conformational epitope are unsuitable for raising the claimed antibodies or screening for them."
• "It is moreover undisputed that the patent does not disclose how antibody 7G10 was prepared, i.e. which antigen/immunogen was used for its generation or the screening process that was used to select for it. The board must therefore conclude that the patent contains no guidance regarding a suitable antigen or screening process for the generation and selection of antibodies that are structurally unrelated to antibody 7G10. "
• The Board then discusses the issue of sufficiency in more detail, discussing screening with ELISA, and the choice of the immunogen.
• "that the evidence on file does not support the appellant's assertion that suitable methods for screening a pool of anti-hIL-23 antibodies for p19-specificity were part of the skilled person's common general knowledge at the priority date. Since the patent provides no guidance in this respect either, the skilled person wanting to perform the claimed invention would have to develop a screening process for identifying antibodies that bind an epitope on the p19 subunit of hIL-23 and without risking to miss antibodies that bind the claimed conformational epitope, an undertaking that cannot be regarded as routine."
• "the functional definition of the claimed antibody amounts to an invitation to perform a research program without any guarantee of success. Such a situation is considered to amount to an undue burden for the skilled person "

• 
  

EPO 

The link to the decision is provided after the jump, as well as (an extract of) the text of the decision.

https://www.epo.org/law-practice/case-law-appeals/recent/t200435eu1.html

Main request (patent as granted) - claim 1

The claimed invention - claim construction

16. Claim 1 is directed to antibodies (or antigen binding fragment thereof) that bind to subunit p19 of human interleukin-23 (hIL-23p19) at an epitope comprising amino acid residues 82 to 95 and amino acid residues 133 to 140 of the amino acid sequence of mature hIL-23p19 (SEQ ID NO: 29). The claim is not for a single antibody but for a pool of antibodies each of which binds human interleukin-23 at an epitope as defined in the claim.

17. The two amino acid stretches recited in the claim are not contiguous along the primary sequence of the hIL-23p19 protein chain, thus the epitope defined in the claim is a so-called discontinuous or conformational epitope.

18. While the epitope bound by the claimed antibodies must include both stretches of amino acids, the claim does not unambiguously delimit the spatial extent of the epitope. Interpretation is therefore required to determine its extent. The board does this according to the normal rules of claim construction, in which the terms used in the claim are given their broadest technically sensible meaning in the context in which they appear and having regard to the common general knowledge and the teaching in the patent (see also CLBA, II.A.6.1).

19. The broadest technically sensible construction of the epitope defined in the claim is one where the epitope includes amino acid residues outside the two recited stretches of amino acids, recited in claim 1. Firstly, this is in keeping with the claim wording "comprising". Secondly, it is supported by dependent claim 2, according to which the bound epitope comprises 16 residues located within the recited stretches and 1 additional residue, H106, that is located outside these stretches. Indeed, the claimed antibodies need not bind exactly the amino acid residues recited in the claim as long as their epitope comprises these amino acid residues.

20. The appellant's submission that binding at least one amino acid residue in each stretch would be the broadest technically sensible interpretation is not found persuasive for the following reasons. First, the appellant's interpretation is not supported by the teaching of the patent in the general part of the description (see paragraph [0019] of the patent) and second, it is also no supported by antibody 7G10, relied on in this context by the appellant. Indeed, antibody 7G10 was determined by X-ray crystallography (X-RC) to be within 4.0 Å of the antibody (i.e. to "bind") at 9 of the 14 amino acid residues in stretch 82 to 95 of SEQ ID NO: 29 and 7 of the 8 amino acid residues in stretch 133 to 140 of SEQ ID NO: 29 (see paragraph [0180] of the patent).

21. Contrary to the decision under appeal, a technically meaningful interpretation of claim 1 does not require that it be implied that X-RC must be used to determine binding of the antibody at the target epitope. First, the use of X-RC is not a necessary consequence of the express language of the claim and thus not an implicit feature. Second, construction of the claim in light of the teaching of the patent does not imply the use of X-RC either. While the patent discloses that binding may be determined by X-RC (see paragraph [0019] of the patent), it discloses further methods for determining binding of the antibody at the epitope, (see e.g. paragraphs [0110], [0111] and [0113]).

22. Accordingly, in an embodiment, although the claim is not limited to this embodiment, the claim encompasses antibodies that are functionally defined by their ability to bind to human IL-23p19 and contact several of the amino acid residues within both amino acid stretches recited in the claim, i.e. antibodies with the same specificity as the exemplified antibody 7G10, but which are not structurally related to it. Binding to the conformational epitope may be determined by X-RC, but this is not mandatory.

Disclosure of the invention (Article 100(b) EPC)

23. According to the established case law of the Boards of Appeal, a patent complies with the requirement of sufficiency of disclosure if the skilled person, on the basis of the information provided in the patent and taking into account the common general knowledge, is able to perform the invention as claimed in the whole range claimed without undue burden, i.e. with reasonable effort (see CLBA, II.C.1).

24. The patent discloses, inter alia, a mouse anti-human IL-23p19 antibody termed 7G10 (see Tables 2 and 3), and a humanised version of this antibody, hum7G10 (see Example 2 and Tables 2 and 3). As mentioned in

point 20. above, antibody 7G10 was determined by X-RC to bind 9 of the 14 amino acid residues in stretch 82 to 95 of SEQ ID NO: 29 and 7 of the 8 amino acid residues in stretch 133 to 140 of SEQ ID NO: 29 (see Example 6).

25. Antibody 7G10 is therefore one way of performing the claimed invention. However, claim 1 is not limited to antibody 7G10 and structural related variants but encompasses antibodies which are solely defined by the functional feature that they have the same specificity as the exemplified antibody 7G10 (see also point 22. above).

26. For meeting the requirement of sufficiency of disclosure it is required that the patent, when considered in combination with the common general knowledge at the priority date, provides technical guidance which is sufficiently clear and complete to allow the skilled person to reliably obtain the above mentioned, functionally defined antibodies without an undue burden.

27. In a first line of argument the appellant submitted that, at the priority date of the patent, the generation and screening of antibodies that bind to the p19 subunit of hIL-23 did not amount to an undue burden of experimentation for a skilled person and that according to the case law of the Boards of Appeal, it was a matter of routine to raise and screen antibodies to a known antigen (see decision T 431/96).

28. The board acknowledges that raising and screening antibodies involves only routine experimentation. However, this is the case only if the skilled person knows from the disclosure in the patent or from common general knowledge (i) which antigens are suitable for raising antibodies having the desired properties and (ii) which screening process should be used to select these antibodies without undue burden (see also decision T 431/96, Reasons, points 6, 7, 10, 11, 12).

29. Indeed, the generation and screening of antibodies that bind (anywhere) to the p19 subunit of hIL-23 would not involve an undue burden for the skilled person.

30. However, the patent in suit discloses neither a suitable antigen nor a screening process that would ensure the reliable generation and selection of antibodies having the required properties (see

point 22. above) by applying routine methodology and a reasonable amount of experimentation. It is common ground that peptides consisting of the primary sequence of the claimed conformational epitope are unsuitable for raising the claimed antibodies or screening for them.

31. It is moreover undisputed that the patent does not disclose how antibody 7G10 was prepared, i.e. which antigen/immunogen was used for its generation or the screening process that was used to select for it. The board must therefore conclude that the patent contains no guidance regarding a suitable antigen or screening process for the generation and selection of antibodies that are structurally unrelated to antibody 7G10. For these reasons, the conclusion reached in decision T 431/96 that generation of antibodies to known antigens is routine, does not apply.

32. In a further line of argument the appellant maintained that the process of generating antibodies to hIL-23p19 involved immunisation with hIL-23 heterodimer to raise a pool of antibodies, and then identifying those antibodies that bind specifically to the p19 subunit. Selected anti-hIL-23p19 antibodies could then be analysed by X-RC to determine their epitopes. Since suitable methods for raising and screening antibodies were part of the skilled person's common general knowledge at the priority date, the requirement of sufficiency of disclosure was met.

33. The board is not persuaded by this this line of argument for the following reasons.

Choice of immunogen

34. The patent does not teach that the complete hIL-23 heterodimer should be used for the generation of antibodies that bind to hIL-23p19 at the claimed conformational epitope (see paragraphs [0079] and [0080] of the patent).

35. The appellant asserted that the common general knowledge would have led the skilled person to understand that not any fragment or the p19 monomer but the complete hIL-23 heterodimer (composed of a p19 and a p40 subunit) was the most suitable immunogen to raise antibodies that bind to hIL-23p19 at the claimed conformational epitope. No evidence supporting the pertinent common general knowledge was provided by the appellant.

36. Since p19 is one of the two subunits of hIL-23, the board accepts, for the sake of argument, that the skilled person might consider that the complete hIL-23 heterodimer was a suitable immunogen to raise the claimed antibodies.

37. It is common ground that in using the hIL-23 heterodimer for immunisation, the skilled person would obtain a pool of antibodies recognising (linear and conformational) epitopes anywhere on the surface of the hIL-23 heterodimer and its subunits, p19 and p40.

38. Moreover, since the generation of antibodies to the claimed epitope on p19 cannot be controlled by using the hIL-23 heterodimer, it is a matter of chance whether the antibody pool comprises an antibody that has the same specificity as the exemplified antibody 7G10 (see point 22. above).

39. Therefore, if the skilled person were to choose the hIL-23 heterodimer for raising antibodies, they would obtain a pool of antibodies, which may or may not comprise antibodies having the required properties.

40. However, the board holds that starting from the above mentioned pool of antibodies, the skilled person would not be able to arrive at the claimed antibodies without an undue burden of experimentation for the following reasons.

Screening antibodies for p19 specificity

41. The appellant submitted that, having raised a pool of antibodies against the hIL-23 heterodimer, the skilled person, seeking to put the claimed invention into practice, would have screened the pool to identify those antibodies that bind an epitope on the p19 subunit using any conventional assay available in the art, e.g. an enzyme-linked immunosorbent assay (ELISA).

42. The board acknowledges that at the priority date of the patent, the skilled person was familiar with ELISAs, e.g., for screening hybridoma supernatants for antibodies that bind to a given antigen. For this, the antigen is offered in an ELISA as a binding partner allowing the selection from a pool of antibodies those candidates that bind the antigen.

43. The patent does not disclose which antigen should be used in an ELISA to screen the pool of antibodies raised by immunisation with the hIL-23 heterodimer to obtain those antibodies that bind a conformational epitope on the p19 subunit of hIL-23 (see paragraphs [0082] and [0084]). The only ELISA mentioned in the patent refers to testing of antibodies "for specificity of binding by comparing binding to IL-23 to binding to irrelevant antigen or antigen mixture under a given set of conditions" (see paragraph [0118]).

44. Document D32, relied on by the appellant as evidence that ELISAs were well known in the state of the art, merely confirms that an ELISA can be set up, provided an antigen suitable to screen for the desired property is available (see page 168, second and third paragraph). However, document D32 provides no information as regards antigens or screening steps, e.g. positive and/or negative, which would be suitable to select antibodies that bind an epitope on the p19 subunit, nor does it address the difficulties in selecting an antibody as claimed from a pool of antibodies raised against hIL-23 and without missing antibodies that bind at p19 in the conformation that this subunit adopts in the presence of p40.

45. Documents D13 and D43, relied on by the appellant to confirm that ELISA tests were commonly used in the field at the priority date, and in the "specific context of determining p19-specificity" are production information sheets for commercially available anti-IL-23p19 antibodies. These documents do not constitute what is commonly understood to represent the common general knowledge of the person skilled in the art (see CLBA I.C.2.8.1).

46. Furthermore, document D13 discloses an anti-p19 antibody that was selected for its ability to neutralise the bioactivity of human IL-23. As regards ELISA tests, document D13 discloses that the selected antibody detects the human IL-23 heterodimer and does not cross-react with rhIL-12 p35, rhIL-12 heterodimer, rmIL-23 p40, or rmIL-23 heterodimer. Document D13 does not disclose that any of these ELISA tests was used for isolating the antibody. As for document D43, it discloses another anti-p19 antibody, which was selected by passing sera from immunised goats over a human IL-23 affinity column and then passing the bound fraction over a human IL-12/23 p40 column to remove p40 specific IgG. However, neither document D13 nor document D43 discloses an ELISA that can be used to screen a pool of anti-hIL-23 antibodies to identify antibodies that bind to p19. A fortiori, these documents are unsuitable to provide evidence that the skilled person could have used a routine ELISA to identify and isolate antibodies that bind a conformational epitope on the p19 subunit of hIL-23.

47. The appellant's further argument that alternatively, or in addition, a routine ELISA could have been used to screen for antibodies that bind to the hIL-23 heterodimer but do not bind to the related hIL-12 heterodimer (which lacks the p19 subunit) or to p40 alone and a conventional bioassay to screen the antibodies for inhibition of IL-23 activity but not IL-12 activity is not found persuasive either.

48. There is no teaching or guidance in the patent that would suggest the use of any of these ELISA assays, nor has the appellant referred to any evidence that they were common general knowledge at the priority date. A fortiori, there is no guidance or information with respect to how these assays would need to be performed and whether they would at all be suitable to reliably identify antibodies that bind a conformational epitope on the p19 subunit of hIL-23.

49. Screening for antibodies inhibiting the biological activity of hIL-23, as also suggested by the appellant, cannot differentiate between antibodies binding to the p19 and the p40 subunit of hIL-23. Therefore, this method is not suitable to specifically select antibodies that bind a conformational epitope on the p19 subunit of hIL-23.

Optional additional pre-screening to narrow down the pool of anti-hIL-23p19 antibodies

50. The appellant's argument that the skilled person could narrow down an initial pool of anti-hIL-23p19 antibodies to a smaller group of candidates by a conventional cross-blocking assay to eliminate antibodies that are unlikely to bind at the claimed conformational epitope is not found persuasive either. In fact, the patent proposes to use such an assay for exactly the opposite purpose, namely "to screen for antibodies that bind to the epitope on human IL-23 (i.e. the p19 subunit) bound by an antibody of interest" (see paragraph [0110]), not to eliminate antibodies that are unlikely to bind.

51. Moreover, the appellant's reasoning for using a cross-blocking assay to eliminate antibodies that are unlikely to bind at the claimed conformational epitope is based on its knowledge of antibody 7G10's footprint on hIL-23. However, this footprint is only disclosed in post-published document D18 (see page 948). Based on the teaching in the patent, the skilled person had no reason to expect that a cross-blocking assay would significantly reduce the number of candidate antibodies in a preselected pool of anti-p19 antibodies.

52. Finally, even if the skilled person were to use a cross-blocking assay to eliminate antibodies unlikely to bind at the claimed conformational epitope, they would be aware that the remaining antibodies will not necessarily bind at the claimed epitope. Indeed the patent confirms that not all cross-blocking antibodies necessarily bind at precisely the same epitope, since cross-blocking may result from steric hindrance (see paragraphs [0110] of the patent).

53. As regards the further strategy proposed by the appellant to reduce a pool of anti-p19 antibodies, the board notes that the patent does not teach that grouping of antibodies based on CDR sequences should be included in the process for identifying antibodies that bind at the epitope defined in the claim. No evidence was presented by the appellant that such an assay represented common general knowledge or was routine for the skilled person. Furthermore, the board has seen no evidence to support the thesis that the probability of finding an antibody with the desired binding properties increases by grouping the candidate antibodies into such sub-classes (see also documents D80, points 20 and 21 and document D81, point 58).

Undue burden

54. It is apparent from the above considerations (see points 41. to 49.) that the evidence on file does not support the appellant's assertion that suitable methods for screening a pool of anti-hIL-23 antibodies for p19-specificity were part of the skilled person's common general knowledge at the priority date. Since the patent provides no guidance in this respect either, the skilled person wanting to perform the claimed invention would have to develop a screening process for identifying antibodies that bind an epitope on the p19 subunit of hIL-23 and without risking to miss antibodies that bind the claimed conformational epitope, an undertaking that cannot be regarded as routine.

55. The appellant's argument that it was a matter of routine for the skilled person to perform further screening and narrow down a pool of p19-specific antibodies to arrive at a subset of antibodies that is "most likely to bind the claimed epitope", is not supported by the evidence on file either. Indeed, none of the screening assays proposed by the appellant selects specifically for antibodies that have the same specificity as the exemplified antibody 7G10 (see points 50. to 53. above).

56. Moreover, as set out above (see points 38. and 39.), there is no guarantee that even a single antibody having the same specificity as the exemplified antibody 7G10 is generated when using hIL-23 heterodimer for immunisation. Therefore, removing antibodies that are unlikely to bind at the claimed epitope, does not guarantee that any of the remaining antibodies is more likely to have the required specificity. Indeed, there is no guarantee that even a single antibody that is taken forward to determine its epitope, by X-RC or otherwise, has the same specificity as the exemplified antibody 7G10.

57. The patent does not provide any information regarding the epitopes recognised by the antibodies raised against hIL-23 heterodimer. In particular, the patent provides no evidence that antibodies having the required properties would be generated frequently enough to be identified reliably. Whilst the appellant submitted that the pool of antibodies raised against hIL-23 heterodimer would be expected to include many p19-specific antibodies that are highly unlikely to bind to hIL-23p19 at either of the epitope regions recited in claim 1, it provided no argument let alone evidence on how likely it was that such a pool of antibodies would include ones that do have the required specificity.

58. In summary, given the lack of relevant guidance in the patent or in the common general knowledge, the skilled person attempting to carry out the claimed invention is confronted with having to develop an elaborate screening strategy, without a reasonable expectation of success. Indeed such a screening strategy relies on chance, without the skilled person having any knowledge of the likelihood of success.

59. Finally, if after such a screening process, the antibody taken forward for epitope determination does not have the required specificity, i.e. in case of failure, neither the patent nor the common general knowledge provides adequate information regarding what should be changed or how to guarantee success.

Conclusion on disclosure of the invention (Article 100(b) EPC)

60. An invention may be regarded as sufficiently disclosed even if it requires a certain amount of experimentation by the skilled person to carry it out, as long as this experimentation is not an undue burden on the skilled person. Such a situation may exist where the skilled person has sufficient information to lead them directly towards success through the evaluation of initial failures. Based on the evidence on file, the board considers that in the present case, critical information on the antigen suitable for raising antibodies with the desired properties and screening assays for reliably identifying them is lacking. Moreover, the board has seen no evidence that antibodies binding at the claimed epitope can be generated frequently enough and can be identified reliably enough to guarantee success (see points 34.

to 59. above). Therefore, the functional definition of the claimed antibody amounts to an invitation to perform a research program without any guarantee of success. Such a situation is considered to amount to an undue burden for the skilled person (see also CLBA, section II.C.6.7 and II.C.7.4).

61. Contrary to the appellant's submissions, the fact pattern of the case under consideration (see points 34. to 53. above) is comparable to the facts underlying the case considered in decision T 1466/05. Thus, also in decision T 1466/05, the claimed antibodies were defined functionally (by their binding activity) and while the application provided one exemplary antibody having this function, it failed to provide (i) the antigen required to raise further antibodies as claimed and (ii) a screening process for the specific selection of the same (see Reasons, points 9 and 25).

62. Disclosure of the specific regions within the p19 subunit of hIL-23 that are comprised in the epitope of the claimed antibodies does not distinguish the case at hand from the case underlying T 1466/05 because it does not equate with disclosure of a suitable antigen that can be used for raising and screening antibodies binding at the claimed epitope by applying routine methodology (see also point 30. above).

63. In the circumstances of the case at hand, serious doubts arise from the verifiable fact that there is no relevant guidance in the patent and in the common general knowledge with respect to (i) an antigen suitable for raising antibodies with the desired properties and (ii) screening assays for reliably identifying them. Contrary to the appellant's assertion, the respondents were therefore under no obligation to provide experimental evidence to support the insufficiency objection.

64. The claimed invention is not sufficiently disclosed in the patent and therefore the ground for opposition under Article 100(b) EPC prejudices the maintenance of the patent as granted.

Auxiliary requests 1 to 49

Disclosure of the invention (Article 83 EPC)

65. Claim 1 of these claim requests is directed to antibodies defined solely by the functional feature of binding the conformational epitope defined therein (see section VI. above). The provision of these antibodies involves an undue burden for the reasons set out in points 23. to 64. above. The invention defined in auxiliary requests 1 to 49 is thus not sufficiently disclosed within the meaning of Article 83 EPC.

Order

For these reasons it is decided that:

The appeal is dismissed.