Last month, Abbott Laboratories was sued by Bayer AG’s HealthCare unit alleging that drugmaker Abbott Laboratories’ best-selling drug, the arthritis drug Humira, infringes on a Bayer patent.  (Bayer HealthCare LLC v. Abbott Laboratories, 08cv507, U.S. District Court for the Eastern District of Texas).  Bayer claims that Humira®, a recombinant human IgG1 monoclonal antibody specific for human TNF used to treat severe types of arthritis and other immune disorders, infringes on US Pat. No. 5,654,407, issued August 5, 1997.

Bayer’s lawsuit was filed six years after Humira was approved for sale in the U.S. in the District Court for the Eastern District of Texas, a venue considered to be very favorable for patent-holders. The lawsuit seeks triple damages for past and future patent infringement, attorney fees and other relief, but does not seek an injunction against sales of Humira.  Bayer does not sell any products of its own that compete with Humira.

One issue that may come into play here is the Doctrine of Laches, an equitable defense that arises from a delay in taking action. Laches defenses have been successful in cases in which a patent owner knows about an infringement and then delays many years before bringing suit. Laches typically bars the recovery of any past damages but allows for the recovery of damages arising after the filing of the lawsuit.  Once the laches defense has been raised, the plaintiff may still offer evidence that the delay either was reasonable or not prejudicial to the defendant.

Ultimately, the burden of proving laches rests with the defendant, who must prove that there was an unreasonable delay in bringing suit and that this delay prejudiced the defense. However, a rebuttable presumption of laches arises when the patentee waits more than six years from the time when he or she discovered (or reasonably should have discovered) the infringement to file a lawsuit.

The ‘407 patent, set to expire in 2014, very broadly covers human monoclonal antibodies that bind specifically to human tumor necrosis factor alpha. It is doubtful that Bayer suddenly realized that it held the ‘407 patent.  The filing of a lawsuit at this late stage may have been prompted by Humira sales, which increased 50% to $1.2 billion in the third quarter of 2008 after Abbott received regulatory approval to sell the drug for treatment of psoriasis and juvenile rheumatoid arthritis. In October, the company boosted its forecast for full-year sales to $4.4 billion.  See SEC filings.

Humira (adalimumab) is the third TNF inhibitor, after infliximab and etanercept, to be approved in the U.S. and is used to treat rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis. It is also used to treat Crohn’s disease after other drugs have been tried without successful treatment of symptoms.  Humira competes with the drug Remicade, made by Johnson & Johnson’s Centocor unit. That company and New York University filed a patent infringement suit against Abbott in April 2007, also in the Eastern District of Texas.

Humira binds to TNFα, preventing it from activating TNF receptors; adalimumab was constructed from a fully human monoclonal antibody, while infliximab is a mouse-human chimeric antibody and etanercept is a TNF receptor-IgG fusion protein. TNFα inactivation has proven to be important in downregulating the inflammatory reactions associated with autoimmune diseases.

Tumor necrosis factor (TNF, cachexin or cachectin and formally known as tumor necrosis factor-alpha) is a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction.  The primary role of TNF is in the regulation of immune cells. TNF is also able to induce apoptotic cell death, to induce inflammation, and to inhibit tumorigenesis and viral replication. Overproduction of TNF have been implicated in a variety of human diseases, as well as cancer.

In one new twist, Abbott Labs has now turned around and sued Bayer AG’s HealthCare unit, claiming that the Bayer patent is invalid, not infringed or unenforceable. The competing lawsuits could set up a dispute over where the case will be heard.  Abbott, in its complaint, said the case should be heard in Boston because some of its research and manufacturing of Humira is done at the company’s Worcester facility.  (Abbott Laboratories v. Bayer Healthcare LLC, 09cv40002, U.S. District Court for the District of Massachusetts).

It could be that Abbott feels that Humira can be distinguished from the claims of the ‘407 patent since its monoclonal antibodies were created using phage display technology resulting in an antibody with human-derived heavy and light chain variable regions and human IgG1:κ constant regions. However, it appears that Humira antibodies are  fully humanized monoclonal antibodies.  So, we could see a detailed battle over the definition of “human”antibodies.

Theoretically, Bayer could go after other producers of anti-TNF-alpha drugs as well such as Enbrel (etanercept), co-marketed by Amgen and Wyeth, and Remicade (infliximab), sold by Schering-Plough and Johnson & Johnson. However, Bayer HealthCare has noted in its complaint that its lawsuit against Abbott is “an exceptional case,” whatever that means.  Although, infliximab is actually a chimeric antibody so it could fall outside of the scope of the “human” claim in the Bayer patent. Likewise, etanercept is not really an antibody but rather a receptor-Fc fusion protein, which also could fall outside of the scope of Bayer’s claims.

Generally, it is possible to make mouse-human hybrid antibodies including chimeric antibodies, where the antibody combines the antigen-binding parts (variable regions) of the mouse antibody with the effector parts (constant regions) of a human antibody, and humanized antibodies, where the antibody combines only the amino acids responsible for making the antigen binding site (the hypervariable regions) of a mouse (or rat) antibody with the rest of a human antibody molecule thus replacing its own hypervariable regions.

However, you can make transgenic mice that have had human antibody gene loci inserted into their bodies so that they produce fully human, not mouse, antibodies against the antigen and can yield cells that can be fused with myeloma cells to manufacture all-human monoclonal antibodies. Unlike some related technologies that create chimeric or partly humanized proteins, the antibodies produced by these mice are 100% human protein.

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  1. Fantastic summary, Stephen – thank you.

    One minor clarification: Humira is actually a fully *human* antibody, not a humanized antibody. It was isolated from human repertoires using phage display.

    Infliximab is actually a chimeric antibody, making it fall outside of the scope of the “human” claim in the Bayer patent. Likewise, etanercept isn’t really an antibody, but rather a receptor-Fc fusion protein (as you noted), which also falls outside of the scope of Bayer’s claims.

    However, golimumab, J&J’s “next generation” anti-TNF antibody may be entering the market in the near future. This antibody *is* human, and its potentially imminent approval may also be a reason why Bayer chose to act now.

  2. the obvious question is whether they have been in licensing negotiations which broke down. that would constitute exceptional circumstances and explain delay.

  3. […] alleging non-infringement, invalidity, and unenforceability of the ‘407 patent.  As predicted on Patent Baristas, the doctrine of laches was cited in Abbott’s […]