Humulin to Humira: An Ever-Evolving game of Evergreening

“To coin a phrase, the name of the game is the claim” – Giles Rich, Former Chief Judge of the Federal Circuit¹

Giles Rich, Former Chief Judge of the Federal Circuit, coined a phrase “the name of the game is the claim” on the art of filing patents. What started as an encouragement for creative labor involved in a specific invention, by conferring rights to the inventor for a specific period of time, the patent system has come a long way and is currently witnessing a global abuse by means of filing secondary patents which are frivolous and add no further value². This misuse results in erecting of barriers for affordable medicine.

The patent law confers a limited monopoly right to the inventor in return for the disclosure of the invention, thus encouraging competition and promoting further innovation in any given field for the benefit of the mankind. The monopoly of a patent, however, is confined to its claims and after expiration of the patent, the public has an unlimited right to practice the formerly claimed subject matter. Hence, understandably, an overwhelming number of patent litigators operate under the premise that the language and construction of the claim is the most important element in defining the scope and protecting the boundaries of the patent. Strong and effective claims will deter infringement and will allow the innovator in not just defining the scope of the patent but also in fending off competition. This is well within the legal provisions and the innovators have a right to protect their invention through clear claim strategies.

However, Evergreening, is an abuse of the system, particularly prevalent in pharmaceutical patents, wherein the monopoly is not limited to the restricted period of time but extends beyond the term. In a pharmaceutical context, when innovator companies file further patents on slight modifications of original drugs which add no further therapeutic advantage, it is called Evergreening. This is done essentially by the innovator companies to protect their markets and arguably to recoup R&D costs that are incurred in developing the original drug. Evergreening can be achieved by the innovators by filing secondary patents shortly before the expiry of the original patent. The innovators file for patents which protect the drug delivery systems, packaging or derivatives with very little improvement in efficacy of the drug etc., thus extending the term of monopoly and thereby keeping affordable medicines out of reach. This will result in the delay of the entry of the generic drugs into the market and keeps the drug prices high. Biological drugs are notorious for erecting such ‘picket fences’ or patent thickets globally. India, although has a robust patent system in thwarting the secondary patents which have very little value or improvement over the original patent, it is no exception for evergreening. In fact, rampant evergreening is happening in India with the grant of secondary patents to applicants who misuse the provisions of anti-evergreening.³,⁴ Given the impact of the hike of life saving drug prices, it is perhaps the right time to rethink the strategies to effectively combat the aggressive evergreening patent strategy and put the evergreening genie back into the bottle.

Biologics: the beginning of an era of patent wars! The magical birth of biologics, arguably the modern-day miracles which can cure from skin rashes to life threatening cancers, is mired in bloody patent wars right from the inception stage.

Diamond v. Chakrabarty⁵ was a United States Supreme Court case dealing with the Patentability of genetically modified organisms.

Chakrabarty’s patent claims were of three types:

1. Process claims for the method of producing the bacteria
2. Composition of the slurry of bacteria, its carrier liquids and its application
3. Claims over the bacteria containing two stable plasmids providing a separate hydrocarbon degradative pathway.

A bacterium from the genus Pseudomonas containing therein at least two stable energy-generating plasmids, each of said plasmids providing a separate hydrocarbon degradative pathway.

The above product claim was the point of contention which led to the rejection by the USPTO on the ground that living organisms are not patentable. The Supreme Court disagreed, deciding by a five-to-four majority that a patent may be obtained on “anything under the sun that is made by man.”

This land mark decision played a pivotal role in spurring the unprecedented growth of biotech industry which, over the last few decades, morphed into a multi-billion-dollar business empire. This case also served as the beginning of a long line of contentious patent battles between pharma companies which are continuously evolving patent strategies to prevent lawsuits and evade competition.

In the above context, a brief look at the evolution of the following three prominent biologics, and their patenting strategies, makes an interesting case for how the products of research from universities got hijacked into commercial products and blockbuster drugs making them less accessible and affordable.

Human Insulin: The discovery that the hormone insulin extracted from the pancreas of dogs saves lives was made by Frederick Banting and Charles Best in 1921 from Toronto University. Since insulin is a life-saving medicine, with the thought that it should be available for everyone, Frederick Banting sold the patent to the University of Toronto for a dollar.⁶ One hundred years later, Insulin remains one of the expensive drugs globally!

Humulin, r-DNA human insulin, is the world’s first recombinant DNA drug which was created using recombinant DNA technology. Prior to this milestone in the history of FDA and biological drugs, all insulin for human use was harvested from slaughterhouse animals, usually porcine or bovine.

Humulin was made by inserting human genes responsible for insulin production into E. Coli bacteria, thereby stimulating the bacteria to synthesize insulin, resulting in a superior quality human insulin in large quantities. Eli Lilly and company obtained the approval from FDA on October 28, 1982, paving the way for the dawn of an era of the most promising, pricey and highly contentious biological drugs. Although the original patents expired, there were several analogue patents of insulin which were substitution and/or alteration of the amino acid sequence of human insulin which include lispro, aspart, glargine, glulisine and detemir up until 2014-2015.

Human erythropoietin (EPO): Human Erythropoietin is another fine example of collaboration between academia and a biopharmaceutical company, Amgen. EPO is used to treat anemia. This was an era in which the aggressive “ever greening” was not yet in place and it reflects in the way the claim drafting and the claim construction was done in Amgen EPO patents, resulting in a loss for Amgen in a patent litigation with TKT⁷.

Human Erythropoietin was synthesized in vivo as a 166 amino acid molecule and the final Arginine gets cleaved off in the body to make the active protein. Active protein is 165 amino acids long. Amgen claimed an erythropoietin amino acid sequence of 166 amino acids. Hoechst and TKT claimed 165 amino acid form. U.S. Federal circuit concluded that Hoechst and TKT do not literally infringe Amgen’s claims. Amgen narrowed its claims during examination and the narrowed claims cover the 166 amino acid form but do not cover 165 amino acid form. Amgen has not foreseen that the amended claims no longer covered the 165 amino acid form. It was held that there was no infringement under doctrine of equivalence.

Humira-the block buster – Humira, the first fully human monoclonal antibody, manufactured by AbbVie, is an anti-inflammatory drug indicated for Rheumatoid arthritis, plaque psoriasis, Crohn’s disease, ulcerative colitis etc. Humira was approved by the FDA in December 2002 for the treatment of adults with moderate to severe RA and inadequate response to at least one disease-modifying antirheumatic drug. Humira continues to top the best-selling drugs not just as a biologic but also as one of the best-selling drugs worldwide⁸. Humira has a total of 247 patents/patent applications and is battling allegation in the U.S. that Abbvie employs what is known as patent thicket, which blocks the biosimilar competition. Biosimilars are the generic biological drugs that would cost a fraction of the original molecules and the blocking of the generic drugs keeps the drug prices high.

Innovator drug companies have a right to file patents for the innovation and commercially exploit their original patents. To this end, strong patents with focused and clearly defined scope can be drafted and filed which discourage infringement during the patent term, thus providing a limited term of monopoly with freedom to commercialize and get market exclusivity and return on investment. However, aiming for unlimited monopoly and market exclusivity by tweaking the patents without providing an improved medication with better therapeutic advantage amounts to nothing but hoarding of bad patents. To delay the entry of generic drugs which cost a fraction of the original drug prices, after the expiry of the original drug patent term, by employing frivolous patent strategies such as evergreening is nothing but a wrongful business practice and should not be encouraged.