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.

https://www.epo.org/en/boards-of-appeal/decisions/t211255eu1

Main request - claim 1

Inventive step (Article 100(a) EPC and Article 56 EPC)

Choice of a suitable starting point

1. In its decision, the opposition division considered document D23 represented the closest prior art. Starting its analysis of inventive step from this document it came to the conclusion that the subject-matter of the claims as granted was not obvious. Although the opposition division in point 17 of the decision under appeal had recognised that the opponent had raised "several inventive step attacks starting from D1, D7 to D9, D12, D14, D23 or D25", it only assessed inventive step starting from document D23 (referring to the Guidelines for Examination in the EPO, November 2019, G-VII, 5.1).

2. However, 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.).

3. According to the decision under appeal "D25 discloses a proposal for a phase I/II trial of a peptide mixture, referred to as 'TG01', and gemcitabine. D25 does not disclose the sequences of the peptides and no results for the trial are shown, and, thus, D25 is not considered to be a promising springboard for the invention." (see point 17.6). The board disagrees because, as also acknowledged in the decision under appeal (see above), the composition disclosed in document D25, even at first glance shares at least several features with the composition of the claim and is intended for the same purpose, namely "treating patients with pancreatic cancer" (see "Public title").

4. Document D25 must therefore be taken into account in the assessment of inventive step.

Disclosure of document D25

5. 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".

6. Under the heading "Intervention(s)" three compounds are listed: TG01, GM-CSF (Amoytop) and Gemcitabine. GM-CSF is a commonly known protein and commercially available in lyophilised form. Gemcitabine is a pyrimidine analogue and chemotherapeutic agent which is commercially available ("GEMZAR 1000"). 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-").

7. From this list the skilled person would understand that the product "TG01" consists of seven components having the same concentration (0.1 mg) and whose descriptive names differ only in one letter ("A", "C" etc.). They would further understand that the product "TG01" relates to the oncoprotein "p21 RAS" because this is part of each of the seven other descriptive names and also appears as "KRAS status and recurrence" in the context of the exploratory objectives. p21 RAS is well known in the field of oncology as an oncoprotein (see e.g. document D16, which is a review article).

8. 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. The appellant was of the view that the disclosure on page 2 under "Primary Outcome(s)": "TG01/GM-CSF vaccination" of a combined vaccination of TG01 with the protein GM-CSF would have indicated to the skilled person that "TG01" consisted of peptides or proteins rather than nucleic acids or whole cells. The appellant further noted that this view was reinforced by the reference to the "TG01 specific DTH skin test reaction" proposed in document D25 to determine the immune response to "TG01", because DTH skin tests were known to be commonly used to test peptide vaccines.

9. The respondent questioned this and was of the opinion that vaccinations could also be carried out with other modalities such as yeast vehicles, DNA or RNA which could also be used in DTH skin tests (referring to document D37, points 5 and 6).

10. While the board agrees with the respondent that other vaccine formats were in principle known to the skilled person, the envisaged "TG01 specific DTH skin test reaction" and the concomitant vaccination with GM-CSF would have led the skilled person to conclude that "TG01" consisted of peptides or proteins because a specific DTH skin test reaction requires the antigens to be available to the immune system in the skin, and therefore they could not be encoded by RNA or DNA or hidden in a cell. This is also apparent from points 5 and 6 in document D37 referred to by the respondent which state that "DTH responses are in vivo cell mediated immune responses initiated by the detection of an antigen", i.e. the antigen has to be accessible. Moreover, both the patent and the references provided in D37, point 7, disclose DTH skin tests only for peptide vaccines.

11. Document D25 contains further indications that "TG01" refers to a peptide composition. Firstly, no reference is made to genetic material or gene therapy. Such a reference would have been required if such material was going to be used in the proposed clinical trial, because of the safety and regulatory requirements within the EU for genetic material (e.g. RNA or DNA). Secondly, the codes A, C, D, R, S, V, D in the seven descriptive names of the components of "TG01" were well known as one-letter amino acid codes and were (with the exception of A and C) not used for individual nucleic acids. The board therefore agrees with the finding in the decision under appeal that the skilled person would have recognised that "TG01" denotes a peptide composition (see point 16.3, first sentence, of the decision under appeal).

12. 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.).

13. The skilled person was further aware of clinical trials of cancer vaccines involving "synthetic RAS peptides encompassing residues 5 - 21 of p21 RAS" (see review article D16, page 274, right-hand column). The length and residues of these peptides matches the nomenclature used in document D25 for the components of TG01 ("...p21 RAS(5-21)").

14. 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.

15. The review article D16 further cites documents D5 and D6 (see paragraph bridging pages 274 and 275, references 15 and 16). Document D5 discloses vaccination of pancreatic cancer patients with synthetic ras peptides encompassing residues 5-21 of p21 ras and carrying substitutions of glycine (Gly or G) at position 12 with aspartate (Asp or D), cysteine (Cys or C), valine (Val or V) or arginine (Arg or R) (see page 442, paragraph bridging both columns). Document D6 discloses vaccination against mutant K-ras of patients with pancreatic cancer using "synthetic peptides encompassing residues 5-21 of p21 ras". The mixture CTN-98010 disclosed on page 1123, first full paragraph, contains seven peptides comprising substitutions A, C, D, R, S and V at position 12 and substitution D at position 13 ("12ACDRSV13D/HCL", wherein "HCL" denotes that the peptides are in the form of salts) and is administered with GM-CSF as adjuvant (see page 128, left-hand column, 4th full paragraph). 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)". The skilled person would equally understand that the peptides disclosed in document D5 are identical to the four components of TG01 in D25 having substitutions with Asp, Cys, Val or Arg at position 12, i.e. "12-D-p21 RAS(5-21)", "12-C-p21 RAS(5-21)", "12-V-p21 RAS(5-21)", "12-R-p21 RAS(5-21)".

16. 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.

Difference and technical effect

17. 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 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.

18. The respondent argued that an improvement of the therapeutic effect could not be expected from the disclosure of document D25 thus rendering the combination treatment inventive. The board does not agree because document D25 already proposes the treatment of cancer patients with a combination of RAS peptides and the pyrimidine analogue, gemcitabine. Putting this proposal into practice would inevitably have resulted in an improved therapeutic effect, if such effect was indeed achievable (see point 19. below). Such improvement therefore represents a bonus effect, which according to established case law does not contribute to an inventive step (see Case Law of the Boards of Appeal of the European Patent Office 10th edition, 2022, I.D.10.8). Notwithstanding this finding, the board will nevertheless address the arguments of the parties in relation to the alleged improvement.

19. Even if the evidence in document D26 were taken into account, it does not provide evidence for an improved treatment compared to the disclosure in document D6. This is because it does not disclose any data for a comparison with a treatment with TG01/GM-CSF alone, but only compared to gemcitabine alone (see Tables 3 and 4). In view of the already successful treatment of patients with TG01/GM-CSF alone reported in document D6, an improvement over gemcitabine alone as reported in document D26 is irrelevant. Moreover, the statement in D26 that "these findings may suggest synergism between TG01/GM-CSF and chemotherapy" is rather cautious (see page 5, right-hand column, penultimate paragraph). As pointed out by the appellant, the median overall survival of 33.3 months reported in document D26 is similar to the overall survival for patients receiving TG01/GM-CSF monotherapy reported in document D6 (see Table 1).

20. The effect of improved treatment compared to the vaccination with TG01/GM-CSF alone can therefore not be taken into account for the formulation of the objective technical problem.

Objective technical problem

21. In view of the differences between the claimed subject-matter and the closest prior art, the objective technical problem can be seen as providing an effective treatment for (pancreatic) cancer.

Obviousness

22. The question to be answered in assessing the obviousness of the claimed subject matter is whether or not the skilled person starting from the disclosure of the clinical trial proposal in document D25 would have reasonably expected that putting it into practice would result in an effective treatment for pancreatic cancer patients.

23. It is common ground that TG01/GM-CSF had a therapeutic effect in pancreatic adenocarcinoma patients, as evidenced by their DTH response and their prolonged overall survival (see e.g. document D6, Table 1 and page 1124, right-hand column, last paragraph). It is also undisputed that gemcitabine was a standard treatment of pancreatic cancer at the relevant date of the patent (see e.g. document document D7, page 105, right-hand column, first full paragraph: "Gemcitabine has been the standard first-line treatment for patients with advanced pancreatic cancer, ..."; document D8, page 36, right-hand column, lines 7 to 10: "Gemcitabine (GEM) is currently one of the standard therapies for advanced pancreatic cancer, ..."; document D19, page 837, left-hand column, lines 14 to 17: "Gemcitabine is usually given at day 1 [...] as a single-agent therapy for pancreatic and cholangiocarcinoma."; document D23, page 2, right-hand column, "Background: Patients with resected pancreas cancer treated with standard of care gemcitabine ..."; document D33, page 1480, right-hand column, lines 1 to 2: "Gemcitabine treatment, which is the standard treatment [for non-resectable pancreatic cancer] in many countries, ..."). The skilled person therefore knew that each of the two components to be tested in the clinical trial proposal set out in document D25 could separately achieve a therapeutic effect at least in patients with pancreatic cancer.

24. The respondent argued that the skilled person would not have had a reasonable expectation that the clinical trial proposed in document D25 would yield positive results. It suggested that the skilled person would in fact have been dissuaded from implementing said clinical trial proposal because of a possible interference of gemcitabine with TG01/GM-CSF vaccination. This view was said to be supported by the disclosure in document D25 itself because the main objective was given as assessing "the potential for interference of Gemcitabine on immune response to TG01". The respondent further referred to documents D31 and D32 which reported that clinical trials of a peptide vaccination combined with gemcitabine had been stopped because of a lack of improvement in patient survival. The respondent also referred to paragraph [0023] of the patent as giving a rationale for why gemcitabine might interfere with peptide vaccination: "it had previously been believed that administering an anti-metabolite chemotherapeutic agent, such as gemcitabine, to a patient causes cell death of proliferating immune cells, including proliferating T cells, which would thereby reduce the activity of the patient's immune system and thus lower the immune response of the patient to a peptide vaccine that is administered simultaneously or sequentially".

25. However, the board is not convinced that the above mentioned considerations would have dissuaded the skilled person from putting the clinical trial proposal set out in document D25 into practice. The skilled person would have understood the reference to interference in document D25 as a standard indication for any combination therapy, and as such it would not impart to the skilled person any particular prejudice against the proposed clinical trial. The clinical trials reported in documents D31 and D32 relate to a particular peptide (GV1001 from human telomerase), the effect of which together with gemcitabine was compared to gemcitabine alone. Therefore the finding of no therapeutic improvement for the combination tested was not due to interference of the peptide with gemcitabine, but rather was a result of a lack of effect of the particular peptide vaccine. Finally, the passage on interference in the patent itself was not available to the skilled person at the relevant date and appears to reflect general theoretical observations which are not backed up by any specific evidence. In contrast, the appellant has referred to a number of documents published before the relevant date of the patent which report successful therapy using peptide or protein vaccines in combination with gemcitabine (see e.g. document D7, Summary and page 113, left-hand column, first full paragraph: "Despite its cytotoxicity, gemcitabine reportedly has immune-modulating functions, such as increase in antigen cross-presentation, and inhibition of B-cells, myeloid-derived suppressive cells and regulatory T cells, resulting in enhancement of the antigen-specific CTL function"; document D8, Summary: "IFN-gamma-producing cells were induced by the KIF20A-derived peptide vaccine at a high rate, even in combination with GEM."; document D10, page 81, right-hand column: "... low-dose gemcitabine did not suppress the host's immune response, but potentiated the antitumor activity of the qVEGFR vaccine."). Also document D19 which investigates the effect of gemcitabine on regulatory T-cells and vaccine-specific cytotoxic T-cells in the context of DNA or mRNA vaccination concludes that "... chemotherapy [gemcitabine] transiently lowers regulatory T-cell frequency and boosts subsequent antitumor vaccination." (see page 837, last paragraph).

26. 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.

27. In view of the above considerations, it is concluded that the subject-matter of claim 1 lacks an inventive step (Article 56 EPC).