Lilly’s patent on combination of pemetrexed and vitamin B12 challenged

Case No. O2018_003 ¦ Hearing of 17 June 2019

Reading time: 3 minutes

The patent in suit is Lilly‘s EP 1 313 508 B1; see the EPO Register and Swissreg for further information. The independent claims of EP’508 read as follows (emphasis added):

1.   Use of pemetrexed disodium in the manufacture of a medicament for use in combination therapy for inhibiting tumor growth in mammals wherein said medicament is to be administered in combination with vitamin B12 or a pharmaceutical derivative thereof, said pharmaceutical derivative of vitamin B12 being hydroxocobalamin, cyano-10-chlorocobalamin, aquocobalamin perchlorate, aquo-10-chlorocobalamin perchlorate, azidocobalamin, chlorocobalamin or cobalamin.

12.   A product containing pemetrexed disodium, vitamin B12 or a pharmaceutical derivative thereof said pharmaceutical derivative of vitamin B12 being hydroxocobalamin, cyano-10-chlorocobalamin, aquocobalamin perchlorate, aquo-10-chlorocobalamin perchlorate, azidocobalamin, chlorocobalamin or cobalamin, and, optionally, a folic binding protein binding agent selected from the group consisting of folic acid, (6R)-5-methyl-5,6,7,8-tetrahydrofolic acid and (6R)-5-formyl-5,6,7,8-tetrahydrofolic acid, or a physiologically available salt or ester thereof, as a combined preparation for the simultaneous, separate or sequential use in inhibiting tumor growth.

It’s all about a combination of the antifolate pemetrexed disodium, vitamin B12 and, optionally, folic acid. Briefly, pemetrexed is an antifolate that inter alia inhibits synthesis of thymidine and thus de novo DNA synthesis. Evidently, antifolates are quite toxic. But according to EP’508, toxicity can be successfully controlled by co-administration of pemetrexed with vitamin B12 and, optionally, folic acid.

Pemetrexed disodium
Pemetrexed disodium

EP’508 had already been litigated in infringement proceedings in Switzerland, resulting in a landmark decision of the Supreme Court on the Doctrine of Equivalents and how amendments of the patent during prosecution are to be dealt with in this respect; see this Blog here.

This time, validity of EP’508 is being challenged, based on a lack of novelty or, at least, lack of an inventive step; and added matter. Only inventive step has been pleaded in the hearing. With respect to the other grounds of nullity, the Sandoz merely referred to the written submissions.

It was evident from the pleadings that the opinion of the judge-rapporteur had been in favour of the defendant. This interim opinion is in line with the decision of an EPO opposition division, the Rechtbank Den Haag (Case No. C/09/533354 / HA ZA 17-581; judgment available as Dutch original and inofficial English translation), the IP High Court of Japan and the U.S. CAFC. On the other hand, the German Federal Patent Court had revoked the German part of EP’508; an appeal before the Supreme Court is still pending.

Sandoz’s logo

Sandoz started from Jackman as closest prior art in the assessment of inventive step. With reference to Worzalla et al., Jackman describes experiments in which pemetrexed was administered alongside with folic acid. Further, phase I clinical trials had been reported in which pemetrexed was administered together with folic acid (Hammond et al.). In consideration of the biochemical pathways, Sandoz argued that it had been obvious to add vitamin B12 to said known combination.

Lilly’s logo

Eli Lilly of course disagreed. In Lilly’s view, the skilled person would not have pursued a combination of pemetrexed and folic acid, let alone to add vitamin B12. In real life, phase II clinical trials began with pemetrexed alone, irrespective of the experiments of Hammond et al. Toxicity of pemetrexed had intially been deemed controllable. It was only in the course of phase II clinical trials that the therapy scheme was switched because toxicity was found to be too severe.

A significant point of discussion was whether a skilled person would have been motivated to add vitamin B12 in light of some marker experiments. Niyikiza, the main inventor of the patent in suit, had published a report that described a correlation of pemetrexed toxicity with an unspecific marker (homocysteine), but not with the vitamin B12-specific marker MMA (methlymalonic acid). Accordingly, in Lilly’s view, a skilled person would not have been prompted towards the invention.

Reported by Andreas WELCH and Martin WILMING

BIBLIOGRAPHY

Case No. O2018_003 ¦ Hearing of 17 June 2019

Sandoz Pharmaceuticals AG
./.
Eli Lilly and Company

Panel of Judges:

  • Dr. Daniel ALDER
  • Dr. Roland DUX
  • Marco ZARDI

Judge-rapporteur:

  • Dr. Roland DUX

Court Clerk:

  • Susanne ANDERHALDEN

Representative(s) of Plaintiff:

  • Dr. Markus WANG (Bär & Karrer)
  • Christoph FRAEFEL (SBMP), assisting in patent matters

Representative(s) of Defendant:

ANNOUNCEMENT

Fullscreen view (new tab)

PATENT IN SUIT

Fullscreen view (new tab)

BE ON THE KNOW

You liked this? And you would like to be notified of new posts? Here you go.

Premature database entry infringes SPC

Reading time: 4 minutes

Case No. S2019_006 | Decision of 1 May 2019
Case No. S2019_006 | Decision of 21 March 2019

Lilly / ICOS

The SPC in suit is ICOS’ C00740668/01, the basic patent of which is EP 740 668 B1; see EPO Register and Swissreg for further information.

The SPC protects tadalafil (which is also referred to in claim 10 of the basic patent), a phosphodiesterase type 5 (PDE5) inhibitor. Lilly‘s products are Cialis® (for the treatment of erectile dysfunction) and Adcirca® (for the treatment of pulmonary arterial hypertension).

Lilly’s Cialis and its active ingredient tadalafil

The basic EP’668 had lapsed already back in 2015; and the SPC has also lapsed meanwhile, on 4 May 2019. But the present decisions relate to an apparent mishap shortly before the SPC finally lapsed.

Sandoz’s logo

Sandoz had Swissmedic’s market authorization for its generic ‘Tadalafil Sandoz’ since 7 November 2017, but did not yet put it on the market. Still, the plaintiffs came across database entries for ‘Tadalafil Sandoz’ in HCI SolutionsmedINDEX (for physicists) and pharmINDEX (for pharmacists). These databases are used by practitioners to order pharmaceuticals. Even though ‘Tadalafil Sandoz’ could not be ordered at that time, the President held that the effect of the database entries was essentially comparable to an inquiry of future needs (see S2014_001). Potential customers are made aware that the launch of a generic is imminent. This may tempt them to postpone orders for the original product and to order the cheaper generic once it becomes available. The generic manufacturer benefits from this advertising effect to the detriment of the supplier of the original product. During the term of the SPC, such advertising constitutes a violation of the exclusive rights of the owner of the SPC.

At the face of it, the situation was apparently so clear that the President granted interim injunctive relief without hearing Sandoz beforehand, and obliged Sandoz to immediately request the database provider to delete the entries.

After hearing the defendant, it turned out that Sandoz’ had not made the entries in the databases. The entries had been made the database provider, an independent third party, without Sandoz’s knowledge and intervention. The database entries had meanwhile been deleted on Sandoz’s request, and thus there was no basis anymore for interim injunctive relief. The request was thus denied.

Now, what about the costs?

As a rule, the costs are clapped on the unsuccessful party; Art. 106(1) CPC. But the court may diverge from the general principles and allocate the costs at its own discretion when a party was caused to litigate in good faith; Art. 107(1) lit. b.

The President held that even though the plaintiff’s course of action may be understandable under the given circumstances, this still does not justify that the defendant bears the costs incurred in view of the unlawful conduct of an unrelated third party:

The plaintiffs have refrained from issuing a warning to the defendant before submitting the request for action. The applicants’ action may be understandable in the circumstances, but it does not justify the defendant having to bear the costs of the proceedings. As the defendant credibly demonstrates, it had nothing to do with the unlawful conduct of a third party; it is to be regarded neither as an instigator nor as an accomplice nor as a collaborator. Nor does it exercise any control over the third party. Since the defendant is not responsible for the unlawful conduct and has not created the appearance of being responsible for it, it cannot be ordered to pay the costs.

The court fee and a compensation for legal representation of the defendant are thus to be borne by the plaintiffs.

Reported by Martin WILMING

BIBLIOGRAPHY

Case No. S2019_006 | Decision of 1 May 2019
Case No. S2019_006 | Decision of 21 March 2019

(1) ICOS Corporation
(2) Eli Lilly (Suisse) SA
./.
Sandoz Pharmaceuticals AG

Single judge:

  • Dr. Mark SCHWEIZER

Court Clerk:

  • Susanne ANDERHALDEN

Representative(s) of ICOS / Eli Lilly:

  • Dr. Christian HILTI (Rentsch)
  • Dr. Demian STAUBER (Rentsch)
  • Dr. Andrea CARREIRA (Rentsch), assisting in patent matters

Representative(s) of Sandoz:

  • Dr. Markus WANG (Bär & Karrer)

FIRST DECISION OF THE FPC
→ injunctive relief granted without hearing the defendant
Case no.: S2019_006
Decision of: 21 March 2019
Fullscreen view (new tab)

SECOND DECISION OF THE FPC
→ injunctive relief denied after hearing the defendant
Case no.: S2019_006
Decision of: 1 May 2019
Fullscreen view (new tab)

PATENT IN SUIT

Fullscreen view (new tab)

BE ON THE KNOW

Enter your name and email address below to get notified of new posts by email.