API and IP Newsletter
Contents
Delhi High Court: Once licence is revoked, use of trademark by ex-licencee amounts to infringement
USFDA approves new version of diabetes drug Mounjaro for weight loss
ANDA approvals in the month of October 2023
We follow ANDA approvals by Indian companies. In October 2023 total 66 ANDAs were approved. Out of which about 20 were tentatively approved. Most of the tentative approvals are of Sugammadex.
Eugia, Lupin and Alembic are at the top of the list with 4 approvals each. Lurus received 3 approvals.
General information
Delhi High Court: Once licence is revoked, use of trademark by ex-licencee amounts to infringement
The Delhi High Court has held that once the licence is revoked by the licensor, any use of the mark by the ex-licensee would amount to an infringement of the trademark. It would mean the ex-licencee was deceiving the public by making them believe it was still connected with the licensor.
News here.
USFDA approves new version of diabetes drug Mounjaro for weight loss
A new version of the popular diabetes treatment Mounjaro can be sold as a weight-loss drug, US regulators announced on Wednesday.
The US Food and Drug Administration approved Eli Lilly's Zepbound, or tirzepatide. The drug helped dieters lose about a quarter of their body weight, or 60 pounds (27 kilograms), in a recent study.
News here
Intellectual Property
T 2735/19 (TAS-102 administration/TAIHO) 19-07-2023
This invention relates to TAS-102.
TAS-102 ie trifluridine/tipiracil (FTD/TPI), sold under the brand name Lonsurf, is a fixed-dose combination medication that is used as a third- or fourth-line treatment of metastatic colorectal cancer or gastric cancer, after chemotherapy and targeted therapeutics have failed
The decision under appeal at EPO, is the opposition division's interlocutory decision finding that EP 1849470 was maintained as amended. EP 1849470 is issued to Taiho Pharmaceutical Co., Ltd. (Patent proprietor)
This was opposed by Stada Arzneimittel AG and Generics UK Limited. (Appellants)
Claim 1 of the request considered allowable by the opposition division was identical to claim 1 as granted. It read as follows:
"1. A cancer therapeutic drug, which is a composition comprising alpha,alpha,alpha-trifluorothymidine (FTD) and 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride in a molar ratio of 1:0.5, for use in the treatment of cancer in a human patient in need thereof by orally administering the drug at a dose, as a dose of FTD, of 20 to 80mg/m**(2)/day twice daily."
The composition defined in claim 1 is known as TAS-102
The documents cited by the parties during these opposition and appeal proceedings include the following:
D1 EP 0763529
D4 S. Dwivedy et al., Proceedings of ASCO, 20, 2001, abstract No.386
D5 M.B. Thomas et al., Proceedings of AACR, 43, 2002, abstract No.2754
D6 T. Emura et al., International Journal of Molecular Medicine, 13, 2004, 249-55
D7 M.C. Green et al., Journal of Clinical Oncology, 24(18suppl), 2006, 10576
D10 Declaration of A. Mita
D11 Summary of clinical data filed on 19 March 2018
D14 EMA summary of product characteristics relating to Lonsurf
D16 Summary of clinical data in D11 with additional data on continuity
D17 Table summarising data in D16
D22 Declaration of A. Ohtsu
This is relatively lengthy decision. Let us discuss about Inventive step starting from D4 – for the claim 1 of the main request.
At EPO opposition proceedings are very methodical. Following steps are always broadly followed
As a first step a reasonable starting point among the available prior art documents aka “closest prior art” is identified.
Second, the technical results or effects achieved by the claimed invention and defining the objective technical problem is assessed.
Third whether alleged invention is solving the identified objective technical problem is determined.
Fourth, whether or not the skilled person, having regard to the state of the art, would have modified the closest prior art in the claimed manner in order to solve this problem is examined.
Now let is see how these steps are followed in the present case.
This invention (EP 1849470 ) relates to the treatment of cancer by oral administration of TAS-102 at an FTD dose of 20 to 80mg/m**(2)/day, wherein the dose is divided for twice daily administration.
The appellants ie Stada and Generics UK cited D4 as the closest prior art. D4 is the abstract of a poster presented at an annual meeting of the American Society of Clinical Oncology.
It reports the results of a phase I clinical trial of TAS-102 and the preliminary results of an on-going phase II clinical trial. In both trials, TAS-102 was orally administered once daily.
The maximum tolerated dose found in the phase I trial was 50mg/m**(2)/day.
In the phase II trial, it was intended to increase the dose by introducing rest periods within the administration regimen: for two weeks, TAS-102 was provided for five consecutive days followed by a two-day rest.
The treatment was repeated every four weeks. Six gastrointestinal cancer patients were treated with TAS-102 at doses of 70 and 80mg/m**(2)/day.
Nevertheless, no objective responses were observed. Only one patient demonstrated stable disease for more than three months.
The parties did not dispute that the subject-matter of claim 1 differs from D4 in that TAS-102 is administered twice daily instead of once daily.
The parties disagreed on the technical effect brought about by this difference. According to the patent proprietor, the data in the patent examples and in D11 demonstrate that twice daily administration provides an improvement over once daily in the efficacy and safety of TAS-102 irrespective of cancer type. Stada and Generic UK maintained that no effect had been demonstrated.
Regarding the anticancer effect aspect, the Board agrees with Stada and Generic UK that the results of the clinical trials in the patent do not allow any conclusion to be drawn as to the relative efficacy of once and twice daily administration of TAS-102. This is true solely because the patients in the once daily regimen trial (Trial 1) had a different cancer type from the twice daily regimen trials (Trials 3 and 4).
With regard to the results of the clinical tests in D11, the appellants (Stada and Generic UK) argued that they could not be compared with each other because they had not been carried out under the same conditions. The Board does not deny that a comparison of the data in D11 is not straightforward. However, comparative tests on patients having a serious illness cannot be carried out in a discretionary manner; they are subject to ethical concerns and are often not even feasible. In the case in hand, the Board holds that the tests in D11 at least show a tendency allowing the conclusion to be drawn that the administration of TAS-102 twice daily indeed results in a higher efficacy compared with once daily administration.
The appellants (Stada and Generic UK) focused on the result for individual patients to argue that the claimed treatment did not work. But such an approach does not make technical sense since, as explained with regard to sufficiency of disclosure, in the treatment of cancer it cannot be expected that all patients will respond. The technical contribution to the art lies rather in the response of a significant portion of patients.
In D11, three groups involving a total of 28 patients with colorectal cancer were treated at doses of the order of 100mg/m**(2)/day administered once daily.
The disease control rate was on average about 35%. Similar results were obtained for the over 140 patients with colorectal cancer on pages 8 and 9 of D11, who were treated once daily at FTD doses ranging from 50 to 180mg/m**(2)/day.
In contrast, the over 700 colorectal cancer patients treated with TAS-102 twice daily at FTD doses of 30 to 70mg/m**(2)/day on pages 1 to 5 and 11 to 15 of D11 experienced an average disease control rate of about 45% (see also the table on page 42 of the patent proprietor's reply to the appeals).
Therefore, D11 shows that the treatment of colorectal cancer with TAS-102 administered twice daily provides better disease control than when it is administered once daily, even if the doses of the once daily regimen are considerably higher. This finding is consistent with the fact that TAS-102 has been approved by the EMA for the treatment of metastatic colorectal cancer with a dosage regimen as defined in claim 1 (D14).
At the oral proceedings before the Board, the appellants Stada and Generics UK did not contest this improvement. Their position was rather that the improvement had been demonstrated for colorectal cancer only and that it was not credible for other cancer types.
As discussed with regard to sufficiency of disclosure, TAS-102 can be expected to have a general effect on tumours and not to be limited to a single cancer type due to the direct effect of FTD on DNA.
Furthermore, the appellants (Stada and Generics UK) relied in their discussion of obviousness on the teaching in D6 (abstract and last paragraph on page 254) that FTD incorporates into DNA in a time-dependent manner, this implying that dividing the daily dose increases the contact time of FTD with DNA and can be expected to produce a more potent anticancer effect.
Therefore, the Board finds it credible that twice daily administration does indeed enhance the anticancer effect of TAS-102 over once daily administration irrespective of cancer type.
On the aspect of safety, as taught in the patent (paragraph [0007]) and demonstrated in D11, the administration of TAS-102 twice daily produces an anticancer effect at doses considerably lower than those required when the product is administered once daily.
Therefore, the occurrence of side effects may credibly be expected to be reduced accordingly.
On the basis of these effects, the objective technical problem may be defined, in line with the patent proprietor's proposal, as the provision of measures for improving the anticancer efficacy and the safety of TAS-102.
The appellants (Stada and Generics UK) argued that the combination of D4 with the teaching of documents D1 or D6 rendered the subject-matter of claim 1 obvious. The Board disagrees.
D4 itself does not point to the solution in claim 1 since it proposes improving the anticancer efficacy of TAS-102 by introducing rest periods that could possibly allow the maximum-tolerated dose to be increased beyond 50mg/m**(2)/day. The document does not suggest any administration regimen other than once daily.
D1 is directed to a family of compounds that inhibit human-derived thymidine phosphorylase, and to the use of these compounds as potentiators of antitumour agents.
5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride, referred to as Compound 29, is one of the preferred compounds in D1 (page 6, line 27 and page 25, line 31).
Test 3 ((Antitumor Effects here) of D1 evaluates the antitumour effect of solutions containing combinations of FTD with Compound 29 in different ratios, including TAS-102 (solutions 11 to 15 on page 56).
D1 generally states on page 21, lines 2 and 3 that the preparations according to the invention can be administered once a day or in about 2 to 4 portions per day.
However, this general statement does not suggest in any way that twice daily administration could improve the efficacy or the safety of TAS-102. In fact, all the in vivo tests in D1 are based on the administration of preparations according to the invention once daily.
Therefore, the combination of D4 with D1 would not lead the skilled person to the subject-matter of claim 1 in an obvious manner.
Consequently, the Board concludes that the subject-matter of the main request meets the requirements of Article 56 EPC.
Decision here
