Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co. (Fed. Cir. 2009)

    By Andrew Williams --

On Friday, the Federal Circuit issued its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., reversing the U.S. District Court for the District of Massachusetts's denial of Lilly's motion for JMOL in view of a jury verdict of infringement and validity of the asserted claims, and affirming the District Court's ruling that Lilly failed to establish the affirmative defense of inequitable conduct.

The Ariad case involved the technology of gene regulation, and specifically the transcription factor NF-κB.  NF-κB was first identified as playing a role in the expression of genes involved in the immune system, specifically in the regulation of the expression of the gene encoding the kappa immunoglobulin gene in B cells, which are specialized immune cells.  It was eventually discovered in the labs of Dr. David Baltimore and his collaborators that NF-κB did much more than regulate a single immune protein, playing a crucial role in the precise control of the expression of various genes and their protein products that are responsible for the response of cells to various and disparate stimuli, including bacterial lipopolysaccharides, certain cytokines, and even sunlight.  NF-κB is now known to be involved in expression of proteins that are associated with many different processes, including the inflammatory response and regulation of the immune system.  As can be imagined, NF-κB activity is tightly controlled in the cell.  When present in the cytoplasm, NF-κB is in an inactive state, bound to another protein, IκB, the natural inhibitor.  NF-κB is then activated when various stimuli external to the cell cause the NF-κB-IκB complex to dissociate, allowing the transcription factor to travel into the nucleus and bind NF-κB recognition sites found in various promoters.  This binding results in the production of many different proteins.  Then, when the stimulus is removed, the cell returns to a state in which NF-κB is inactive.  When this natural cycle of NF-κB control is disrupted, however, NF-κB can continue producing protein, often to the detriment of the cell, and can result in various diseases and conditions, ranging from sepsis, cancer, and AIDS.

In the mid-1980s, Drs. Baltimore, Philip Sharp, Thomas Maniatis, and ten other scientists at the Massachusetts Institute of Technology, the Whitehead Institute for Biomedical Research, and Harvard University, filed several patent applications related to their work identifying and characterizing NF-κB.  These separate applications, with Dr. Baltimore (at right) as the only common thread, were combined in a single application filed on November 13, 1991.  Eventually, on June 5, 1995, the application that gave rise to the patent-at-issue was filed, claiming priority to this previous application and containing essentially an identical specification.  The applicants, in this June 1995 application, sought claims for artificially reducing NF-κB activity in cells in order to prevent the problems when NF-κB activity runs amok.  In the end, after a lengthy prosecution, U.S. Patent No. 6,410,516 issued with 203 claims -- 197 of which contain the same single step of either "reducing" or "altering" NF-κB activity in cells (the remaining 6 claims were not asserted in this litigation).  However, none of these 197 claims, including claims 80, 95, 144, and 145 at issue in this case, indicated how NF-κB was to be reduced or altered.

The history of the present litigation dates back to June 25, 2002, when Ariad filed its complaint on the same day that the '516 patent issued, alleging that certain claims were infringed by two of Lilly's drugs, Evista®, used for the prevention and treatment of post-menopausal osteoporosis, and Xigris®, used for the treatment of adult patients with severe sepsis who are at high risk of death.  After a fourteen-day trial in April 2006, a Massachusetts jury determined that the asserted claims were not anticipated by prior art or public use, that the specification enabled and adequately described the claims, and that the use of Evista® and Xigris® infringed the asserted claims.  The jury also determined that the effective filing date of the '516 patent was April 12, 1989.  Lilly subsequently moved for judgment as a matter of law, which the District Court denied.  After a four-day bench trial in August 2006, the District Court ruled that the asserted claims were directed to patentable subject matter and that the '516 patent was not unenforceable due to inequitable conduct or prosecution latches.  Lilly appealed all of these rulings except the ruling on prosecution latches.  In the Ariad decision, however, the Federal Circuit limited its invalidity holding to the issue of written description, and as a result did not comment on all of the other validity issues.  It can be noted, however, that in a current reexamination proceeding of the '516 patent, the Patent Office has finally rejected certain claims, including the asserted claims, based on inherent anticipation -- a decision from which the patentees have filed a Notice of Appeal to the Board.  Also, the Federal Circuit's affirmation of the lack of inequitable conduct will be addressed in a subsequent post.

On appeal, the Federal Circuit had the opportunity to further expand its written description jurisprudence, potentially extending the rules as established in cases such as Univ. of Rocherster v. G.D. Searle & Co., 358 F.3d 916 (Fed. Cir. 2004) and Carnegie Mellon Univ. v. Hoffmann La Roche Inc., 541 F.3d 1115 (Fed. Cir. 2008).  However, the Ariad decision predominantly turned on the lack of evidence to support a finding that the inventors were in possession of the claimed invention on April 21, 1989, the effective filing date of the patent as determined by the jury, mainly because Ariad's evidence was directed to demonstrating possession as of November 13, 1991.  As the Court pointed out, "evidence of what one of ordinary skill in the art knew in 1990 or 1991 cannot provide substantial evidence" that the claims were adequately described in 1989.  Another important factor mentioned in determining possession is the context of claimed invention, but because Ariad had touted the fact that the subject matter of the patent "required years of hard work, great skill, and extraordinary creativity," the Court easily found that this patent was "in a new and unpredictable field where the existing knowledge and prior art was scant."  The Court concluded that because there was insufficient evidence that the '516 patent described any method for reducing NF-κB activity as of April 21, 1989, including a description of the molecules that are necessary to perform these methods, the asserted claims were invalid for failing the written description requirement.

Turning to what the Federal Circuit did determine to be disclosed in the '516 application family as of April 21, 1989, there were three, and only three, hypothetical classes of molecules that were disclosed as potentially being capable of reducing NF-κB activity:

• Specific inhibitors -- molecules that are able to block NF-κB binding to DNA in the nucleus.  The Court noted that there was only one example of a specific inhibitor provided in the specification, the naturally occurring IκB.  The Court also found that almost of the evidence provided regarding the disclosure of IκB relied on a particular drawing in the application, figure 43.  However, figure 43 was not present in the 1989 application, and was not added until the 1991.  Further, the only other testimony by Ariad's expert was his opinion that one of ordinary skill could have isolated natural IκB through experimentation.  The Court held that such a vague functional description and an invitation for additional research cannot constitute written disclosure of a specific inhibitor, much less written disclosure of a method for reducing NF-κB activity by using IκB.

• Dominantly interfering molecules -- truncated forms of the NF-κB molecule that would retain the DNA binding domain, but lack the RNA polymerase activating domain, resulting in a binding event that would be unproductive, and blocking the natural form of the protein from inducing expression.  The Court noted that there were no examples of this class of molecules.  In fact, the '516 specification merely states that dominantly interfering molecules could be theoretically possible, but only if the two domains are spatially distinct on the molecule.  If the patentees of the '516 patent didn't know whether the two domains were distinct, the Court surmised, what hope was there for one of ordinary skill.  The Court also found it irrelevant that others were practicing dominantly interfering molecules of NF-κB shortly after the 1989 application, because the description of this class of molecules in the application as of the effective filing date was merely a wish, or arguably a plan, for future research.

• Decoy molecules -- molecules designed to mimic the NF-κB-binding site on genes whose expression would normally be induced by NF-κB, thereby competing for binding of the transcription factor, and preventing NF-κB from binding to its natural target.  The Court did find that the specification adequately described actual decoy molecules, albeit hypothetically, in a table providing the NF-κB binding sites for various genes.  However, the Court felt that this disclosure did not describe a method of using those molecules to reduce NF-κB activity, and therefore the application contained nothing more than a mere mention of a desired outcome.

It is worth noting that even if the effective priority date had been November 1991, the outcome would likely have been the same.  The Court noted that the '516 patent contains "no working or even prophetic examples of methods that reduce NF-κB activity, and no completed syntheses of any of the molecules prophesized to be capable of reducing NF-κB activity."  And, because the state of the art was primitive and uncertain, Ariad could not rely on "prior art knowledge to fill the gaping holes in its disclosure."  Even with the finding that decoy molecules were provided for in the specification, there was no accompanying description that they could be used to reduce NF-κB activity.  Of course, had Ariad argued for the later effective priority date, then it is possible that they would have had a different set of problems, such as the anticipation rejection(s) found in the Reexamination proceeding where the Patent Office assigned the November 1991 priority date to the asserted claims.  This fact was not mentioned by the Court.

The Court also quickly dispensed with Ariad's attempt to distinguish this case from the prior cases of Rochester, Fiers, and Eli Lilly by arguing that the asserted claims of the '516 were claiming methods for reducing NF-κB, and not specific molecules.  As such, Ariad posited, they were not required to describe the compositions required to carry out the claimed methods.  Ariad pointed out that each of the previous cases explicitly required the non-described compositions in the claims, whereas the '516 patent claims do not.  The Court pointed out, however, that even if a composition is not part of a claim, the specification must demonstrate that Ariad possessed the claimed method by sufficiently disclosing molecules capable of reducing NF-κB activity to demonstrate the patentee was in possession of the invention that is claimed.

Interestingly, the Federal Circuit commented on how broad the claims were, and appeared to take Ariad to task for maintaining such breath through claim construction and into trial.  However, the Court appeared to ignore the fact that Ariad was forced to seek such a broad claim construction in order to maintain infringement suits against such diverse pharmaceuticals as Evista, a small molecule, and Xigris, a recombinant human protein.

Judge Linn joined the opinion of the Court, but provided a separate concurrence.  He reiterated his belief that he expressed dissenting in the denials of rehearing en banc of the Rochester case and Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956 (Fed. Cir. 2002), that the engrafting of a separate written description requirement is misguided.  According to Judge Linn, § 112, first paragraph, should require no more than the specification enable a person skilled in the art to make and use the claimed invention and set forth the best mode for carrying out the invention.  Moreover, Judge Linn noted that because the Court decided the validity issue solely on written description, the majority failed to consider the important enablement issue raised by Lilly.  Thus, the issue of whether claims that are broad enough to cover any method to achieve a particular result can ever be valid, since the specification cannot enable unknown methods, was left unresolved -- an outcome that would not have occurred, Judge Linn noted, if there was not a separate written description requirement.

Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co. (Fed. Cir. 2009)
Panel:  Circuit Judges Linn, Prost, and Moore
Opinion by Circuit Judge Moore; concurring opinion by Circuit Judge Linn

Additional Disclaimer:  MBHB represented Eli Lilly and Co. at trial in the U.S. District Court for the District of Massachusetts.  To the extent that this case summary contains any opinions, the opinions would be of Dr. Williams and not Eli Lilly and Co. or MBHB.

Comments

[moondoggie]

So what is the fate of the claims in the re-examination that were found to be patentable? Is there any overlap between the claims asserted in the litigation (all, most, some, certain ones) and those claims? Ultimately, my question is: are there any claims in the '516 patent left for Ariad to assert?

[Andrew Williams]

Dear Moondoggie,

The reexamination has not concluded, so it would be premature to say anything about the fate of the claims of the '516 patent as a result of that proceeding. As mentioned in the post, the patent owners have filed a Notice of Appeal with the Board in view of a final rejection by the examiner. It could be some time before a Reexamination Certificate is issued. However, all four claims that were at issue in the present litigation (80, 95, 144, and 145) were rejected by the Examiner.

As for your ultimate question, it depends on what you are asking exactly. If you are asking whether claims will emerge from the reexamination proceeding, the answer is likely yes. If you are asking whether any of the claims as presently found in the '516 patent will survive, it is unclear at this point (which is important because any claim that is added or amended during reexamination is subject to intervening rights). What is unclear from your question, however, is the party you are asking about that Ariad would be able to assert claims against. Are you asking about Lilly, or are you asking whether there is any company that Ariad would be able to assert claims against? And perhaps it is better phrased whether there is any company that Ariad would be able to assert claims against and have a reasonable likelihood of success. At this time, however, the answer is that it is likely that claims will survive that Ariad could possibly assert in some future litigation, but I wouldn't want to speculate on the scope of those claims, much less speculate on whether anyone is practicing (or at least arguably practicing) the scope of those claims. Also, please keep in mind that even if claims survive the reexamination proceeding, there is no guarantee that they will survive a validity challenge in Federal Court should Ariad choose to assert them.

[Keep It Real]

Kevin: "Interestingly, the Federal Circuit commented on how broad the claims were, and appeared to take Ariad to task for maintaining such breath through claim construction and into trial. However, the Court appeared to ignore the fact that Ariad was forced to seek such a broad claim construction in order to maintain infringement suits against such diverse pharmaceuticals as Evista, a small molecule, and Xigris, a recombinant human protein."

LOL. Who "forced" Ariad to sue all those entities?

[Kevin E. Noonan]

Dear Keep It:

I think the sentence in its entirety makes the point: if Ariad did not ask for such a broad claim construction they would have had no infrigement case. Since patents are not novelty items or trophies, it makes sense that they would try to enforce them; unfortunately for them, the claims were not sufficiently supported by what the inventors knew and put in their specification.

Remembering this was a stellar cast of inventors, we might give Ariad some deference in deciding to press their suit.

Thanks for the comment.

[Andrew Williams]

Dear Keep It Real,

This is Andrew responding to your comment. Thanks for your observation. I didn't mean to imply that Ariad was "forced" to sue anybody. I was only noting that Ariad had to walk a fine line between seeking claims broad enough that they could win their infringement suit, but narrow enough that they would survive an invalidity challenge. Of course, this is true of a lot of patent infringement suits, but the court's opinion appeared not to acknowledge this fact.

[Keep It Real]

Andrew: "Of course, this is true of a lot of patent infringement suits, but the court's opinion appeared not to acknowledge this fact."

I guess I don't understand what you mean by "acknowledge this fact." The "fact" we are referring to appears to be the "fact" that businesses (including those run by "stellar inventors") play games with their patents that are sometimes disturbingly aggressive to onlookers.

The Federal Circuit does occasionally "go there" but usually only when making a snide remark (a la "be careful what you wish for") after declaring broad claims invalid for one reason or another.

In any event, I think we agree that no circumstances or entities "forced" Ariad to pursue those broad claims so zealously, just as nobody forced Carl Denham to take King Kong to New York City. But I'm sure this will all turn out profitably for everybody, just like in the movie.