On April 20, 2006, Amgen filed a lawsuit against Ariad in the U.S. District Court for the District of Delaware seeking a declaratory judgment that each of the claims contained in U.S. Patent No. 6,410,516, covering methods of treating human disease by regulating NF-κβ cell-signaling activity, are invalid and that Amgen has not infringed any of the claims of the ‘516 Patent based on activities related to Amgen’s products, Enbrel® and Kineret®.

The ‘516 patent claims methods of treating disease by regulating a family of molecules known as NF-κβ. While Ariad contends that the patent covers all means for modulating the NF-κβ pathway, Lilly’s contention is that it discovered the drugs in question, Evista and Xigris and disclosed their medicinal properties years before the patentees’ scientists made their discovery. Ariad asserts that the claims of the ‘516 patent cover “methods of treating human disease by regulating NF-κβ activity,” “methods of treating disease by inhibiting NF-κβ,” and “methods useful for treating various disease conditions through modulation of NF-κβ activity.”

On April 4, 2005, Eli Lilly and Company filed an ex parte request in the United States Patent and Trademark Office, or PTO, to reexamine the patentability of certain claims of the ‘516 Patent. In addition, an unrelated third party filed an ex parte request in the PTO on December 2, 2005 to reexamine the patentability of certain claims of the ‘516 Patent. The PTO has granted both of these reexamination requests. On April 4, 2006, counsel for the patentees of the ‘516 Patent filed separate Petitions requesting the PTO to merge these two reexamination requests, which were granted by the PTO on May 4, 2006. Additionally, on April 7, 2006, counsel for the patentees of the ‘516 Patent filed a third ex parte request in the PTO with respect to one claim of the ‘516 Patent, which was denied by the PTO on May 5, 2006. As a result of the PTO orders described above, Lilly’s ex parte request has been merged into a single action to look at the patentability of certain claims of the ‘516 Patent by newly cited references which (i) either inherently or expressly disclose the use of a variety of prior art compounds as reducing NF-κβ activity and resulting gene expression, or (ii) are directed to the use of oligonucleotides having an NF-κβ binding site for reduction of NF-κβ activity (Reexam. C.N. 90/007,503).

The Examiner has now rejected 160 of the 203. In a quite lengthy and detailed 66- page Nonfinal Office Action, the Examiner rejected various subsets of claims as anticipated and/or obvious in light of a long list of prior art references. For example, many claims were rejected over Meichle (J. Biol. Chem. 265 (5/90) 8339-43), which teaches the reduction of NF-κβ activity in induced cells using agents that inhibit protein kinase C. In addition, because Meichle used the HIV LTR in their experiments, this reference anticipates, or alternatively, makes obvious claims drawn to regulating expression of viral genes.

The Examiner contends that the ‘516 claims are drawn to reducing NF-κβ activity in eukaryotic (e.g. claims 1 or 2) or mammalian cells (e.g. claim 11) to effect inhibited expression of a gene under transcriptional control of NF-κβ. For example, NF-κβ activity can be effected by diminishing induced NF-κβ mediated intracellular signaling (claims 6-9) to inhibit associated gene (viral gene such as HIV: claims 1-4) expression of a cytokine protein(claim 5) in a eukaryotic cell. Meichle teaches the use of Protein Kinase Inhibitor H8 (among others) to reduce NF-κβ-mediated gene transcription by reducing NF-κβ activity and reducing the binding of NF-κβ to NF-κβ binding sites.

It is noteworthy that the USPTO states that claim 1’s sole method step is functional, i.e., reducing NF-κβ activity and, therefore, the claims would encompass any in vitro or in vivo, natural (indirect) or man-made (direct) means of reducing NF-κβ activity. The Examiner contends that most of the method steps recited in the patent are purely functional with the exception of claim 7 and dependent claims 81, 83 and 85-87 which require “modifying NF-κβ activity” (which are partially functional) and claim 203 which requires “introducing a nucleic acid decoy molecule into the cell” which requires an active step.

The problem with biochemical pathway patents for generic treatments is that they represent methods of treating disease by modulating a particular pathway in the body without claiming a specific drug or class of drugs that may effect the modulation. While this may provide broad (over)reaching claims, the reverse applies, too. That is, all the Examiner needs to show is that someone, somewhere modulated the pathway – whether they knew it or not.

Prior to the ‘516 patent, there were agents that existed that are now known to act by inhibiting NF-κβ activity, e.g., ibuprofen, which has been around since 1969 even if it’s mode of action wasn’t known until 1998. The mode of action was inherent even if not appreciated. Heck, even vitamin E inhibits NF-κβ activity. There’s just going to be a lot of prior art out there.

Of concern to Amgen, of course, is that claim 69 recites “a method for diminishing induced NF-κβ-mediated intracellular signaling comprising reducing NF-κβ activity in cells such that NF-κβ-mediated intracellular signaling is diminished, wherein reducing NF-κβ activity comprises reducing binding of NF-κβ to NF-κβ recognition sites on genes which are transcriptionally regulated by NF-κβ.” Ariad claims that Evista acts by inhibiting NF-κβ binding to its binding site.

As we’ve said earlier, this is far for over. Given the time for responses and extensions, it could be a year or two before this is settled (if then). We’ll keep you posted as to a response by Amgen.

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