Amgen Challenges Validity of Ariad NF-kB Patent

Amgen ^[1] has filed a complaint for declaratory judgment of patent invalidity and non-infringement ^[2] in the United States District Court for the District of Delaware (Amgen et al. v. Ariad Pharmaceuticals). Amgen is seeking a declaratory judgment that each of the claims contained in U.S. Patent No. 6,410,516 (‘516 Patent”) covering methods of treating human disease by regulating NF-κβ cell-signaling activity are invalid and that Amgen and its affiliated entities have not infringed any claims of the ‘516 Patent based on activities related to the products, Enbrel(R) and Kineret(R).

Earlier, Eli Lilly and Company ^[3] lost a jury trial in the U.S. District Court of Massachusetts in Boston in a decision in the case of Ariad Pharmaceuticals et al. v. Eli Lilly and Company ^[4]. The Jury handed down a verdict that U.S. Patent No. 6,410,516, owned by Harvard, the Massachusetts Institute of Technology, and the Whitehead Institute and licensed to Ariad Pharmaceuticals, is valid and infringed by Lilly’s sale of Evista® and Xigris®.

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.

The ‘516 patent issued from U.S. Patent Application Ser. No. 08/464,364 (‘364 application), filed June 5, 1995. 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.”

Now, Amgen is seeking a determination on its Enbrel® product (etanercept), a human therapeutic product developed by Immunex through its research on lymphokines and the immune system, and its Kineret® product (anakinra), a human therapeutic product developed by Amgen through its research on lymphokines and the immune system. Obviously, Amgen is concerned that these might infringe one or more claims of the ‘516 patent.

A separate bench trial with the U.S. District Court of Massachusetts will be held on Lilly’s contention that the patent is unenforceable and will also consider the patent’s improper coverage of natural processes. In June 2005, the U.S. Patent and Trademark Office commenced a reexamination of the patent (Reexam. C.N. 90/007,503 ^[5]). The reexamination is currently in progress although the USPTO has not issued any substantive action.

The ‘516 patent claims are directed to methods of reducing or otherwise modifying the naturally occurring transcription factor NF-κβ activity in cells affecting gene expression:

Claim 1. A method of inhibiting expression, in a eukaryotic cell, of a gene whose transcription is regulated by NF-κβ, the method comprising reducing NF-κβ activity in the cell such that the expression of said gene is inhibited.

Claim 203. A method of inhibiting expression, in a mammalian cell, of a gene whose transcriptional activity is activated by binding of NF-κβ to said gene, comprising introducing a nucleic acid decoy molecule into the cell in an amount sufficient to inhibit expression of the gene, which decoy includes a NF-κβ binding site that binds NF-κβ.

In the reexam, the USPTO has asserted that there exists a substantial new question of patentability for claims 1-203 of the ‘516 patent. The patent at issue has a very long history. Application 08/464,364 (filed 6/5/95) issued US Pat. No. 6,410,516 is a divisional of 08/418,266 (filed 4/6/95) issued as US Pat. No. 5,804,374, which is a continuation of 07/791,898 (filed 11/13/91; abandoned 5/16/95); which is a CIP of 06/946,365 (filed 12/24/86) and a CIP of 07/341,436 filed 04/21/1989, a CIP of 07/280,173 filed 12/05/1988, a CIP of 07/318,901 filed 03/03/1989, a CIP of 07/162,680 filed 03/01/1988, a CIP of 07/155,207 filed 02/12/1988, and a CIP of 06/817,441 filed 01/09/1986.

However, for priority, the USPTO contends that the above-identified CIP applications (e.g. original specification and original claims) fail to adequately describe and/or enable the methods of the reexamination patent claims and are entitled to the filing date (e.g. 11/13/91) of continuation application 07/791,898 for purposes of prior art.

For example, the pre-November 1991 applications fail to disclose:

1. an amino acid or nucleic acid sequence corresponding to NF- κβ;
2. an NF- κβ inhibitor. The 07/341,436 although mentioning nucleic acid decoy molecules fails
3. to disclose sequences thereof or a means of delivering these molecules for in vivo use.
4. support for the ‘516 patent claim limitations including (but not limited to): “reducing NF-κβ activity” in a cell (e.g. mammalian/eukaryotic) and/or an enabling means thereof (e.g. administering a NF-κβ inhibitor) to effect various functions (e.g. inhibit expression generally, reduce cytokine expression etc.) as required in all the claims; reduce binding of NF-κβ to NF-κβ recognition sites on genes which are transcriptionally regulated by NF-Iκβ” (e.g., claims 25,36,47,69,80,93,144, and 154); inhibiting modification of an LcB protein, which modification otherwise reduces 1KB binding to NF-κβ (e.g., claims 22,33, and 44); inhibiting degradation of an Iκβ protein (e.g., claims 23,34, and 45); inhibiting dissociation of NF-κβ:Iκβ complexes (e.g., claims 24,35, and 46).

The Examiner also notes that the failure of the 06/946,365 (filed 12/24/86) (ABN: 3/24/92) application to satisfy 35 USC 112, first paragraph would render the 07/162,680; 07/155,207 and 06/817,441 applications unavailable for 35 USC 120 priority because they would not be co-pending with the 07/791,898 (filed 11/13/91) application. Even then, the Griffith document (with Holschermann et al as evidence of inherency in which its publication date is not critical), establishes a substantial new question of patentability which predates the earliest possible assertion of 35 USC 120 priority (e.g. CIP of 06/817,441 01/09/1986).

The Examiner cited the following pertinent references stating:

• Bielinska et al.(e.g. at pages 197-198 and Fig. 1) disclose the use of nucleic acid decoy molecules to inhibit NF-κβ-dependent expression of a reporter gene in clone 13 B-lymphoblastoid cells. It is agreed that consideration of the newly cited Bielinska et al. document raises a substantial new question of patentability over the claims of the Baltimore patent since there is a substantial likelihood that a reasonable examiner would consider the teaching of this reference important in deciding whether or not the Baltimore patent claims are patentable
• As pointed out on pages 10-11 of the request, Tanaka et al. (e.g. at pages 3070,3072 and Figures 3 and 4) disclose the use of decoy molecules (e.g. phosphorothionates containing an NF-κβ recognition/binding sequence) to inhibit NF-κβ -dependent expression of a reporter gene in HeLa cells. It is agreed that consideration of the newly cited Tanaka et al. document raises a substantial new question of patentability ^ to the Baltimore patent claims since there is a substantial likelihood that a reasonable examiner would consider the teaching of this reference important in deciding whether or not the Baltimore patent claims are patentable
• As pointed out on pages 12-14 of the request, Eck et al. (e.g. at pages 6530-32;Figures 2, 4 and 6) disclose the use of double-stranded phosphorothionate oligonucleotides (denoted KB-PTs) containing the NF-κβ binding sequence, GGGACTTTTCC, which specifically inhibits NF-KB-mediated transcription. It is agreed that consideration of the newly cited Eck et al. document raises a substantial new question of patentability as to the Baltimore patent claims since there is a substantial likelihood that a reasonable examiner would consider the teaching of this reference important in deciding whether or not the Baltimore patent claims are patentable
• As pointed out on pages 15-16 of the request, Staal et al. (e.g. see Abstract; page 9945; Figures 4-5) disclose a method of inhibiting TNF-a by blocking NF-κβ activation in mammalian cells (e.g. Jurkat cells) by administration of N-acetyl-L-cysteine (NAC). It is agreed that consideration of the newly cited Staal et al. document raises a substantial new question of patentability as to the Baltimore patent claims since there is a substantial likelihood that a reasonable examiner would consider the teaching of this reference important in deciding whether or not the Baltimore patent claims are patentable
• As pointed out on pages 16-17 of the request, Schreck et al. (e.g. see Abstract, pages 1181,1186-1187; Figures 3 and 6) disclose blocking NF-κβ activation by suppressing NF-κβ dissociation from its inhibitor 1KB in IL-1 and TNF-a stimulated Jurkat cells by administration of dithiocarbamates and metal chelators. It is agreed that consideration of the newly cited Schreck et al. document raises a substantial new question of patentability as to the Baltimore patent claims since there is a substantial likelihood that a reasonable examiner would consider the teaching of this reference important in deciding whether or not the Baltimore patent claims are patentable.
• As pointed out on pages 17-18 of the request, the Baldwin and Sharp reference disclose (e.g. pages 724-725; Fig. 2) the use of various DNA probes to compete for NF-κβ binding in nuclear extracts of various mammalian cell types. Additionally, as pointed out on page 19 of the request, the Schorpp et al., Li et al. and Hai et al. references teach that an oligonucleotides that specifically and competitively binds a transcription factor would reduce expression of a gene controlled by the transcription factor. Further, as pointed out on page 19 of the request, Chu et al. teaches methods for transfection of oligonucleotides (e.g. DNA) into eukaryotic cells, which once introduced into cells, readily enter the nucleus through pores. See Molecular Biology of THE CELL at p.423. It is agreed that consideration of the combined teaching of the newly cited Baldwin and Sharp,. Schorpp et al., Li et al., Hai et al., Chu et al. and Molecular Biology of THE CELL documents raise a substantial new question of patentability as to the Baltimore patent claims since there is a substantial likelihood that a reasonable examiner would consider the combined teaching of these references important in deciding whether or not the Baltimore patent claims are patentable.
• Griffith et al. teach (e.g. see abstract) the administration of cyclosporin to cardiac transplant plantations. Holschermann et al teach (e.g. see page 4236, left column; Fig. 4) that the administration of cyclosporin to cardiac patients (as taught by Griffith et al.) necessarily (e.g. inherently) results in reduced NF- κβ activity. Consideration of the newly cited Griffith et al. and Ho’lschermann et al. documents would raise a substantial new question of patentability as to the ‘516 patent claims since there is a substantial likelihood that a reasonable examiner would consider the teaching of the Griffith et al. reference in view of the Holschermann et al. document (as evidence of the Griffith reference method’s reduction of NF-κβ activity) important in deciding whether or not the ‘516 patent claims are patentable.