Pharmaceutical Evergreening: How Drug Patents Are Extended to Keep Prices High

Behind the scenes of the pharmaceutical industry, "evergreening" strategies are used to extend drug patents and keep prices high, long after the original patents have expired.

In the pharmaceutical industry, patents safeguard innovations, granting companies exclusive rights to market their drugs for a set period, typically 20 years. This exclusivity is crucial, providing time to recoup substantial research and development investments. However, as patent expiration approaches, pharmaceutical companies often employ strategies known as "evergreening" to extend their market monopoly. These tactics include minor modifications to existing drugs, such as adding salt components, which can renew patent protections and sustain revenue streams.

Understanding Pharmaceutical Patent Laws

Patents are integral to the pharmaceutical industry, incentivizing innovation and guiding significant investments in drug development. A patent grants its holder the exclusive right to sell the drug, deterring competitors and allowing the recovery of development costs.

1. Fundamentals of Patent Law:

   • Patents protect novel, non-obvious, and useful inventions, including new drug compounds, formulations, or methods of use.

   • The scope of a patent defines the boundaries of protection and is crucial in determining whether an infringement has occurred.

2. Patent Duration and Extensions:

   • Typically, a drug patent lasts for 20 years from the filing date, but actual market exclusivity might be less due to the time taken in clinical trials and regulatory approval.

   • Patent term extensions may be granted to compensate for regulatory delays, and additional protections like data exclusivity can prevent generic entry even after patent expiry.

The Strategy of Evergreening

Evergreening involves subtle modifications that legally justify new patents, extending the exclusive selling rights beyond the original patent's expiry without significant therapeutic advancements. Here are some common evergreening tactics:

• Formulation Changes: Minor tweaks in the drug’s formulation, like changing to a salt form, can be patented.

• New Dosage Regimens: Introducing new dosage schedules or delivery mechanisms that improve patient compliance.

• Combination Therapies: Combining two or more existing drugs into a single new product.

Case Studies and Examples:

Evergreening Through Minor Modifications

A notable case involved the drug Omeprazole, marketed as Prilosec, used for treating gastroesophageal reflux disease. As its patent neared expiration, the manufacturer developed Esomeprazole (Nexium), which is a slightly modified version of the same molecule. The introduction of Nexium, which involved isolating one of the isomers present in Omeprazole, effectively extended the patent exclusivity, thereby delaying generic competition. Critics argued that the therapeutic advantages were minimal, though the company maintained that Nexium offered superior efficacy. (of course they did)

Legal Battles and Regulatory Responses

The case of Abbott Laboratories with its cholesterol-lowering drug, TriCor, is another example. The company changed the drug's formulation multiple times, each time securing a new patent and withdrawing the older version from the market. Legal challenges arose accusing Abbott of anticompetitive practices, leading to settlements but also sparking debates on the need for clearer guidelines distinguishing genuine innovation from strategic evergreening.

Extended Case Studies: Pharmaceutical Evergreening and Financial Implications

Lipitor (Atorvastatin)

Overview: Lipitor, developed by Pfizer, is one of the best-selling drugs ever, used widely to lower cholesterol. The original patent was set to expire in 2011.

Evergreening Strategy: Pfizer employed several strategies to extend its market exclusivity beyond the original patent's expiration, including formulation changes and negotiating settlements with generic manufacturers (uh, bribery?) that delayed their market entry.

Financial Impact: At its peak, Lipitor generated revenues exceeding $12 billion annually for Pfizer. The extension strategies significantly boosted its profitability beyond the initial patent term, impacting generic competition and healthcare costs.

Glivec (Imatinib)

Overview: Glivec, a cancer treatment developed by Novartis, is used to treat chronic myeloid leukemia and other cancers.

Evergreening Strategy: Novartis attempted to secure a new patent for a slightly modified version of Glivec in India, claiming improved thermodynamic stability. However, the Indian Supreme Court rejected the patent application, stating the new form did not enhance efficacy significantly.

Financial Impact: Glivec's annual sales were reported to be around $4.7 billion globally. The case was particularly notable because it highlighted the tension between pharmaceutical patents and access to life-saving drugs in lower-income countries.

Humira (Adalimumab)

Overview: Humira, developed by AbbVie, is used for treating various autoimmune diseases. It is one of the highest-grossing pharmaceuticals globally.

Evergreening Strategy: AbbVie has secured over 100 patents related to Humira, effectively creating a patent thicket that delays biosimilar competition by covering various aspects of the medication and its delivery. It harkens back to Odysseus having to shot an arrow through the holes of twelve axe heads.

Financial Impact: Humira has generated annual sales of over $19 billion for AbbVie. The extensive patent strategy has allowed the company to maintain a dominant market position well beyond the original patent expiration.

Economic and Ethical Implications

The practice of evergreening raises several ethical and economic issues, affecting drug prices and accessibility.

1. Impact on Healthcare Costs:

   • Evergreening can keep drug prices high by delaying the entry of cheaper generics, impacting healthcare systems and patient access to affordable medications.

2. Ethical Considerations:

   • The ethical debate centers on the balance between rewarding innovation and ensuring public access to affordable healthcare solutions.

Whistleblowers speak out

Peter Rost, a former Vice President at Pfizer, became well-known for his whistleblower activities after leaving the company. Rost has been particularly vocal about the pharmaceutical industry's marketing practices, which he discussed extensively after his tenure at Pfizer ended in the mid-2000s. In interviews and his book "The Whistleblower: Confessions of a Healthcare Hitman," Rost has criticized the industry's dependence on marketing over innovation. He stated in a CBS interview in 2006, "The vast majority of drugs are not invented by pharmaceutical companies... What the pharmaceutical industry does is they market the drugs and they often manipulate the findings."

John Virapen, who worked for Eli Lilly for over 35 years, turned critical of the industry's methods to widen market reach, sometimes at the expense of patient safety. His disillusionment with the industry culminated in his book "Side Effects: Death," where he shared insights into the approval and marketing of drugs. In various public talks and interviews around the publication of his book in 2008, Virapen expressed deep regret over his part in these practices, saying, "I indirectly contributed to the death of people, whose shadows now haunt me."

Dr. Marcia Angell, a former Editor-in-Chief of The New England Journal of Medicine, has long been a critic of the pharmaceutical industry's influence over medical research. In her widely cited 2009 article in The New York Review of Books, Dr. Angell discussed the compromised integrity of clinical research influenced by pharmaceutical funding. She remarked, "It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines."

The Allergan and Saint Regis Mohawk Tribe Case

In an unprecedented move within the pharmaceutical industry, Allergan, a major drug company, transferred patents of its eye drug, Restasis, to the Saint Regis Mohawk Tribe in 2017. Restasis is used for the treatment of chronic dry eye and has been a significant source of revenue for Allergan. The strategic transfer was intended to use the tribe's sovereign immunity as a shield against patent challenges in the inter partes review (IPR) process at the United States Patent and Trademark Office (USPTO).

The legal tactic employed by Allergan involved leveraging the doctrine of sovereign immunity, which protects Native American tribes from certain legal challenges, including some patent disputes. By transferring the patents to the Saint Regis Mohawk Tribe, Allergan aimed to protect these patents from being invalidated through the USPTO's review processes. In return, the tribe received an upfront payment and ongoing royalties from the sales of Restasis.

The innovative yet controversial strategy quickly drew legal scrutiny and public criticism. The case escalated to the federal courts, where the legality of using sovereign immunity in this context was challenged. In 2018, the United States Court of Appeals for the Federal Circuit ruled against Allergan, stating that tribal sovereign immunity does not apply to IPR proceedings. This decision underscored that sovereign immunity could not be used as a loophole to protect corporate patents from review and potential invalidation.

Reform and Future Directions

1. Restricting Patentable Modifications: Reforms are being considered that would limit the scope of patentable modifications to those that provide clear and significant therapeutic benefits. For instance, the proposal to amend patent laws to exclude secondary patents unless they extend significant clinical benefits could prevent companies from renewing patents for trivial changes.

2. Enhancing Transparency and Review Processes: Increasing the transparency of patent filings and improving the rigor of review processes by patent offices can ensure that only genuine innovations receive extended protection. This could involve more stringent scrutiny of patent applications linked to existing drugs. However, this would likely cost more money, which begs the questions...Where will the money come from?

3. Promoting Generic Competition: Legislators are also considering policies that would incentivize generic manufacturing and entry into the market sooner, even when original patents are still in force, under certain conditions to encourage competition and lower drug prices.

Impact of Reforms:

• Stimulating True Innovation: By tightening the criteria for patent extensions, pharmaceutical companies may redirect their focus towards more groundbreaking research and development rather than minor modifications. This could lead to the discovery of novel treatments and significant improvements in patient care.

• Economic Impacts: These reforms could dramatically reshape the pharmaceutical landscape by reducing drug prices and enhancing accessibility. By facilitating earlier entry of generics into the market, healthcare systems could see substantial cost savings and improved patient outcomes.

• Challenges and Resistance: The pharmaceutical industry would likely push back against these reforms, citing concerns about recouping research investments and the potential slowdown in drug development. 

These proposed reforms aim to refine the patent system to better serve public health interests while still rewarding true innovation and sustaining the pharmaceutical industry's capacity to invest in new drug development. The ongoing dialogue between policymakers, industry leaders, healthcare providers, and the public is crucial for achieving these goals.

Evergreening practices in the pharmaceutical industry present a complex challenge, balancing innovation incentives with the need for affordable healthcare solutions. As patent laws evolve and reform efforts continue, the industry must navigate these changes while ensuring that the drive for profits does not overshadow the commitment to improving patient health outcomes. Engaging all stakeholders—regulators, companies, healthcare providers, and patients—in this dialogue is crucial for shaping a fair and equitable pharmaceutical market.