Pemetrexed - USA

On Aug 09, 2019, Federal Circuit affirmed district court’s decision that Hospira & Dr Reddy’s Lab.(DRL) infringed methof of administration patent under doctrine of equivalents.

This appeal concerns Eli Lilly’s patent US 7,772,209. The ‘209 patent claims method of administering pemetrexed disodium for the treatment of cancer along with vitamin B12 & folic acid. Lilly markets the compound pemetrexed in the form of a disodium salt as Alimta®, which is indicated, both alone and in combination with other active agents, for treating certain types of non-small cell lung cancer and mesothelioma. Hospira & DRL (Defendants) filed NDA with USFDA to market the product with different salt, ie pemetrexed ditromethamine. Lilly sued both the companies under Hatch-Waxman regulation for infringement of US’ 209. Delaware court after trial held that pemetrexed ditromethamine product infringes the said patent under doctrine of equivalents (DOE). Additionaly, district also found that Hospira infringed under literal infringement. Both defendants appealed.

a. Literal infringement by Hospira’s product:

Hospira on appeal argued that it cannot literally infringe the claims of the ’209 patent because intravenous administration of pemetrexed ditromethamine dissolved in saline—a solution which contains pemetrexed and chloride anions alongside sodium and tromethamine cations—is not “administration of pemetrexed disodium.” Lilly counters that Hospira’s view improperly imposes a “source limitation,” requiring that the pemetrexed disodium salt exist in solid form before administration, even thoufh its label requires administration of solution. Federal circuit however, sided with Hospira & held that product administered is ditromethamine. When it goes into solution various ions are formed such as pemetrexed, sodium,c hloride & tromethamine. But solution containing these ions cannot be deemed pemetrexed disodium simply because some assortment of the ions in the solution consists of pemetrexed and two sodium cations. Therfore to infringe the claim literally, the pemetrexed disodium salt must be itself administered. Once into solution, pemetrexed disodium is not remains present as salt, so the ditromethamine. Therefore, it does not infringe under literal infringement.

b. Prosecution History Estoppel (PHE) –

On appeal defendants argued that district court erred in determining infringement under DOE because PHE applies here. Defendants conteded that, Plaintiff during prosecution limited claims from antifolate to specific pemetrexed disodium in view of the prior arts. In response, Lilly relies on only one exception to giving effect to the presumption as to the scope of surrender: that the rationale of its amendment “[bore] no more than a tangential relation to the equivalent in question.”

Federal Circuit agreed with Lilly & said that defendants view of prosecution history estoppel, and the tangential exception in particular, too rigid. Plaintiff narrowed claims because of the other antifolate (methotrexate) mentioned in the prior art & not because of salts. Methotrexed was mentioned in the prior art & therefore to remove this rejection, claimes were amended to pemetrexed disodium salt from anitfolate. The particular type of salt to which pemetrexed is complexed relates only tenuously to the reason for the narrowing amendment, which was to avoid prior art reference. Therefore, based onprosecution history it is concluded that Lilly’s amendment was merely tangential to pemetrexed ditromethamine. Thus, PHE cannot apply.

c. Disclosure-dedication rule –

Defendants argued that ditromethamine was mentioned in the one prior art which appeared in the specification. Therefore by not claiming the ditromethamine, plaintiff surrendered the claim scope for ditromethamine. But, Federal CIruit said that the prior art reference was not incorporated entirely in the specification. Moreover, there were generic structures disclosed in the reference which essentialy covers thousands of compound. Though it mentions amine salt in general  but there was no specific disclosure of pemetrexed ditromethamine. Therefore skilled person could not envision that ditromethamine was disclosed & dedicated to public.

d. Insubstantial difference test -

Defendants argued that that the district court erred in finding that its proposed pemetrexed ditromethamine product will be administered in an insubstantially different way from the claimed method. There are substantial differences between them, therefore they are not equivalents. But Federal circuit held that the activity of compound is because of pemetrexed ion & not because of salts. Therefore when both the salts go into the solution, both forms pemetrexed ions. Thus, chemical differences between sodium and tromethamine are clinically irrelevant because each undisputedly lacks therapeutic activity.

In summary, Federal Circuit concluded that neither prosecution history estoppel nor the disclosure-dedication rule bars Lilly from asserting infringement through equivalence.