Italy: PI granted against everolimus generic medicinal products for use for breast cancer

Background

The patent enforced by Novartis is EP ‘246, entitled “Rapamycin derivative for the treatment of a solid tumor associated with deregulated angiogenesis”, a second medical use patent in EPC 2000 form, claiming everolimus with an aromatase inhibitor for the treatment of hormone receptor positive breast tumors.
In particular, in May 2020 several Novartis companies filed an application on the basis of EP ‘246 seeking PI against Ethypharm and Avas[1].

Ethypharm and Avas had obtained a full label MA for everolimus (i.e. they did not carve out a combination of everolimus in combination with exemestrane for use in breast cancer) and had participated in some tenders for the supply of everolimus.

Ethypharm and Avas asked for the dismissal of the PI application for lack of the requirements provided by law:

• the “fumus boni iuris” requirement, alleging that EP ‘246 is not prima facie valid;
• the “periculum in mora” requirement, submitting that Novartis (i) was not suffering irreparable damages and (ii) waited for several months from the launch of Everolimus Ethypharm before filing PI proceedings.

In the first instance PI proceedings the Judge appointed a Court Technical Expert (“CTE”) to assess the validity and infringement of EP ‘246.

The first instance PI decision

In the decision published on 13 July 2021, the Judge (agreeing on the conclusion of the CTE) recognized the prima facie validity of EP ‘246.

The CTE considered groundless the added matter objection raised by Ethypharm / Avas, pointing out that the skilled person, in order to arrive at claim 1 of EP ‘246 starting from the embodiment disclosed in the original application (WO ‘019), would only have to select everolimus from the compounds according to that invention and such selection would have been clearly directed towards everolimus since the latter was the most preferred compound in the description of WO ‘019.

Additionally, the CTE considered unfounded the insufficiency objection, noting that even if EP ‘246 does not contain experimental data specifically relating to the use of everolimus in combination with an aromatase inhibitor for the treatment of hormone receptor positive breast cancer, the tests and data contained in the patent in suit would make that use plausible. In particular, according to the CAE, EP ‘246 shows that everolimus has both antiproliferative and anti-angiogenic properties and has an antitumour activity on all the different solid tumours tested (lung, skin, pancreas): as a consequence, considering that breast cancer is a solid tumour, it is plausible that everolimus is also effective on that tumour type.

As to the alleged lack of novelty, the CTE considered that, starting from the relevant prior art (WO ‘975), it would have been necessary to make different multiple selection to arrive at the use of everolimus in combination with an aromatase inhibitor in the treatment of breast cancer claimed by Novartis’s patent.
Finally the CTE considered groundless the objection of lack of inventive step. Adopting the EPO’s problem solution approach, the closest prior art (WO ‘467), even when taken in combination with various other documents cited, provided no teaching to the skilled team that everolimus should be used for the treatment of breast cancers through the particular mechanism claimed in EP ‘246 instead of the combination of compounds disclosed in the prior art.

The CTE also found that Ethypharm’s and Avas’ everolimus medicinal products infringed EP ‘246 based on the indication in the relevant MA, SmPC and PIL.
Taking up the reasoning of the CTE, the Judge therefore deemed the requirement of fumus boni iuris (prima facie validity and infringement of the enforced patent) met.

Then the Judge considered the urgency requirement met as well, finding that the damages suffered by Novartis for the entry in the market of a generic medicinal product would be irreparable.

According to the Judge, the assessment on urgency does not change even if Ethypharm undertook not to participate in Italy in new tenders for the supply of everolimus for the treatment of breast cancer after 22 January 2021 and not to intend to sell the contested products until the decision of the EPO Opposition Division on EP ‘246.

As a matter of fact the Judge held that such undertaking, not supported by any penalty, does not in itself constitute a guarantee that the defendant will actually refrain from participating in new tenders. The risk for damage to Novartis would therefore not have been mitigated.

In light of the above, the Judge granted the PI against Ethypharm and Avas, prohibiting, inter alia, the manufacture, commercialization and promotion of generic everolimus products for the patented use for breast cancer and in particular prohibiting the manufacture, commercialization and promotion of generic everolimus products without having adopted a series of measures to avoid infringement of this second medical use patent by:

(i) ensuring that any MA and relevant SmPC and PIL of any Ethypharm and/or Avas everolimus medicinal product does not contain any reference to the breast cancer indication;
(ii) carving-out the already granted MA and relevant SmPC and PIL of the breast cancer indication;
(iii) informing in writing all relevant subjects, including physicians’ and pharmacists’ associations, hospitals, local health authorities, procurement authorities and entities managing databases of medicinal products on the market ( including Farmadati, Codifa, AIOM, CIPOMO, SIFO, SIFACT, FARE) that Ethypharm and Avas everolimus medicinal products are not indicated and must not be used for breast cancer indication, asking the above subjects to inform their members and associates, and to include a reference to the above limitation in their databases;
(iv) informing in writing - whenever they make a commercial offer, submit a bid to participate in a tender or otherwise supply any product containing everolimus - the recipient of such offer, bid or supply that such product is not indicated, and must not be used, for the breast cancer indication, and that such offer, bid or supply does not and cannot concern populations in need of everolimus in the breast cancer indication.

The appeal PI decision

By decision published on October 4, 2021, the PI granted against Ethypharm and Avas has been confirmed on appeal.

The Panel of Judges upheld the assessment on the prima facie validity and infringement of EP ‘246, recalling both the reasoning of the first instance PI decision and that of the CTE.

Moreover the Judges pointed out that the validity of EP ‘246 was confirmed also by foreign decisions (in particular the decision of the Court of Appeal of The Hague of September 17, 2019), by a report of a different CTE filed in parallel proceedings against another generic company and by the preliminary opinion of the EPO Opposition Division of March 10, 2021. On the other hand, according to the Panel, the recent doubts raised by the EPO Examining Division on another patent of the family, EP 3345602, are irrelevant since they regard a different patent.

The Panel then agreed on the reasoning of the first instance Judge on the urgency requirement and therefore confirmed the PI already granted.

[1] The PI application was filed by Novartis within main proceedings for invalidity of the Italian designations of EP ‘246 and of EP 2 269 603 initiated in 2019 by Ethypharm and Avas. These proceedings are currently pending.