T 1203/19 - Novelty of second medical use claims, and credibility of prior art

Key points

• The decision was taken on 26.04.2022 and was notified in writing on 18.07.2023. The minutes were forwarded on 06.05.2022. No communications under Art. 15(9) RPBA are visible in the (public) online file.
• A petition for review is pending.  
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• " claim 18, is directed to the therapeutic use of an oncolytic adenovirus"
• "Use of the oncolytic adenovirus comprising a sequence encoding a hyaluronidase enzyme inserted in its genome for the manufacture of a medicament for the treatment of a cancer or a pre-malignant state of cancer, in a mammal including a human."
• "If the claimed subject-matter pertains to a use in connection with a medical treatment, for the requirement of reproducibility to be regarded as fulfilled it is necessary that the disclosure in the prior art document is such as to make it credible that the therapeutic effect on which the method of treatment relies can be achieved (see decision T 1457/09 of 17 January 2014, point 36 of the Reasons which refers to decision T 609/02 of 27 October 2004, point 9 of the Reasons). The therapeutic application of the present patent is based on the finding that the expression of a sequence encoding a hyaluronidase enzyme inserted in the genome of an oncolytic adenovirus improves the distribution of the virus through the tumour mass, increases its antitumour efficacy and induces tumour regression (see paragraphs [0017] and [0060] to [0064] and Figures 7 to 9 of the patent)."
• "Document (13) [WO 2005/018332]  does not include any experimental results whatsoever showing expression of the hyaluronidase sequence in tumour cells infected with the described adenovirus, either in vitro or in vivo, nor improved distribution of the described genetically engineered adenovirus within a tumour or tumour regression induced by administering the adenovirus. As a matter of fact, none of the examples of document (13) involves the use of an adenovirus, let alone an oncolytic adenovirus comprising a sequence which encodes a hyaluronase enzyme. Hence, document (13) itself does not provide anything of substance that makes it credible that the genetically engineered adenovirus described therein is in fact suitable for the treatment of cancer."
• "In the board's view, in the absence of relevant experimental data in the document which may support a therapeutic effect, the common general knowledge of the skilled person at the publication date of document (13) becomes highly relevant. Therefore, only if - in the light of this common general knowledge - it was credible that the genetically engineered adenovirus described in document (13), which comprises a sequence encoding a hyaluronidase, was suitable for treating cancer in a mammal, it can be concluded that the skilled person derives this technical teaching from document (13). The board considers that - in view of the common general knowledge set out below - the skilled person would have had serious doubts in this regard and that, therefore, this technical teaching cannot be seen as being derivable from document (13)"
• Regarding inventive step: "As stated above in connection with novelty, document (13) is not considered to be enabling for the use of the oncolytic adenovirus as defined in claim 1 for the treatment of cancer. If, as the respondent contended, the problem to be solved starting from this document were to provide an adequate treatment for cancer, the statements in document (8) (see page 12, last sentence of the second paragraph) would not suggest to the skilled person the use of an oncolytic adenovirus comprising a sequence which encodes a hyaluronidase, but rather the co-administration of an oncolytic adenovirus and hyaluronidase enzyme in the tumour."
• "It follows from the above that the subject-matter of claim 18 is not obvious to a person skilled in the art in view of document (13) combined with common general knowledge. Hence, inventive step is acknowledged."
• Hence, this second medical use claim appears [*] novel and inventive over a prior art document literally apparently disclosing the second medical use.
• [*] - It is not entirely clear to me what the relevant paragraphs of D13 are. The Board's decision does not seem to contain pin-point citations, as D13 is dismissed as not making certain statements credible. 

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/en/boards-of-appeal/decisions/t191203eu1

Claim 18

9. Unlike claims 1 to 17, claim 18, which is directed to the therapeutic use of an oncolytic adenovirus, does not include the limitation that the encoded hyaluronidase enzyme has the membrane-binding domain eliminated (see section V. above). While in the decision under appeal novelty was not discussed with respect to claim 18 of the second auxiliary request, the opposition division found that the subject-matter of the identical claim 1 of the fourth auxiliary request lacked novelty in view of document (13) as a whole, and in particular of claim 23 and page 40 of that document (see section 5.2.3 of the decision under appeal).

10. Document (13), a patent application filed under the PCT, discloses a method of treating cancer in a mammal by administering one or more genetically engineered microorganisms which comprise a nucleic acid encoding a protein that breaks down the interstitial matrix or targets the tumour vasculature, said administering being for a time and in an amount sufficient to destroy, slow, or arrest the cancer (see claim 17). A preferred microorganism is described as an adenovirus which comprises a mutation in the E1A CR-2 gene, the mutation resulting in the inactivation of the gene (see claim 23, which depends on claim 17, and page 5, lines 7 to 11). Document (13) also contains a list of various proteins that may break down the interstitial matrix or target the tumour vasculature, including hyaluronidase (see, e.g., the passage on page 4, lines 23 to 30 under the heading "Summary of the Invention").

11. Pursuant to established case law of the Boards of Appeal, the content of a document comprised in the state of the art is prejudicial to the novelty of the claimed subject-matter only if the technical teaching of the document is reproducible, i.e., if it can be carried out by a person skilled in the art (see decision T 1437/07 of 26 October 2009, points 25 and 26 of the Reasons). If the claimed subject-matter pertains to a use in connection with a medical treatment, for the requirement of reproducibility to be regarded as fulfilled it is necessary that the disclosure in the prior art document is such as to make it credible that the therapeutic effect on which the method of treatment relies can be achieved (see decision T 1457/09 of 17 January 2014, point 36 of the Reasons which refers to decision T 609/02 of 27 October 2004, point 9 of the Reasons).

12. The therapeutic application of the present patent is based on the finding that the expression of a sequence encoding a hyaluronidase enzyme inserted in the genome of an oncolytic adenovirus improves the distribution of the virus through the tumour mass, increases its antitumour efficacy and induces tumour regression (see paragraphs [0017] and [0060] to [0064] and Figures 7 to 9 of the patent).

13. Document (13) does not include any experimental results whatsoever showing expression of the hyaluronidase sequence in tumour cells infected with the described adenovirus, either in vitro or in vivo, nor improved distribution of the described genetically engineered adenovirus within a tumour or tumour regression induced by administering the adenovirus. As a matter of fact, none of the examples of document (13) involves the use of an adenovirus, let alone an oncolytic adenovirus comprising a sequence which encodes a hyaluronase enzyme. Hence, document (13) itself does not provide anything of substance that makes it credible that the genetically engineered adenovirus described therein is in fact suitable for the treatment of cancer.

14. In the decision under appeal, the opposition division stated that they did not see any prejudice in the art to the use of hyaluronidases. In their view, the cited prior art, in particular documents (19), (25) and (26) on the one hand, and document (3) on the other hand, "goes in different directions", while document (31) was regarded as "controversial" (see section 5.2.3 of the decision).

15. In the board's view, in the absence of relevant experimental data in the document which may support a therapeutic effect, the common general knowledge of the skilled person at the publication date of document (13) becomes highly relevant. Therefore, only if - in the light of this common general knowledge - it was credible that the genetically engineered adenovirus described in document (13), which comprises a sequence encoding a hyaluronidase, was suitable for treating cancer in a mammal, it can be concluded that the skilled person derives this technical teaching from document (13). The board considers that - in view of the common general knowledge set out below - the skilled person would have had serious doubts in this regard and that, therefore, this technical teaching cannot be seen as being derivable from document (13).

16. Unlike the opposition division, the board does not consider the content of document (3) to be common general knowledge at the publication date of document (13), because document (3) was published more than three years later. As regards documents (19), (25) and (26) cited by the appellants to support their argument that expression of hyaluronidase in a tumour has been associated with tumour growth and metastasis or with induction of angiogenesis, the respondent argued that the content of these documents cannot be regarded as common general knowledge of the skilled person, and that only the content of document (31), a review article on hyaluronan catabolism and hyaluronidases, qualified as such.

17. However, document (26) is a short review article published before the publication date of document (13); hence, contrary to respondent's view the content of document (26) is to be regarded as common general knowledge of the skilled person at the relevant date. This document reports on various observations which, when taken together, are said to imply that hyaluronan breakdown plays a role in tumour metastasis (see page 3, right-hand column, second full paragraph under the heading "Development and tumour formation"). Hyaluronan breakdown is effected by the hyaluronidase enzyme.

18. As regards document (31), it is apparent from the chapter under the heading "The cancer conundrum" on page 111R that there were many unanswered questions on the role of hyaluronidase enzymes regarding tumour progression and angiogenesis. It is stated in this chapter that hyaluronidases had been added to anticancer drugs in chemotherapy regimes, on the assumption that they may enhance the penetration of the drugs and decrease the turgor of malignant tissues, and that based on the results of experimental tumour studies, hyaluronidase enzymes may themselves have intrinsic anticancer activities (see second and third paragraph of the chapter). However, the clinical data are said to be inconsistent because in some studies increased levels of hyaluronidase enzyme were shown to correlate with tumour progression, while in other studies the progression was correlated with increased levels of hyaluronan synthesis (see page 111R, right-hand column, first full paragraph). Document (31) also indicates that the action of the Hyal 2 hyaluronidase provides hyaluronan fragments of intermediate molecular weight which induce the angiogenesis required for malignancy progression (see page 111R, right-hand column, third full paragraph). In sum, the picture that emerges from document (31) regarding the role of hyaluronidases and hyaluronan catabolism in tumour progression is far from clear, in fact a "conundrum".

19. In view of the above, the board is not persuaded that a person skilled in the art, in the absence of relevant experimental data which may support a therapeutic effect, and in the light of the common general knowledge as described in documents (26) and (31), may consider the genetically engineered adenovirus described in document (13) to be suitable for the treatment of cancer in a mammal.

20. Consequently, document (13) does not destroy the novelty of the subject-matter of claim 18.