The scourge of COVID-19 has expressed itself in loss of life and economic activity. The pandemic has claimed over three million deaths globally. Major economies have lost between 2.9 and 4.5% of gross domestic product (GDP) during 2020, while developing countries have suffered nearly 9% reduction of GDP during the first year of the pandemic (Statista, April 16, 2021). The response has led to extensive public-private efforts to address these twin challenges.
Most notable has been the unprecedented pace of COVID-19 vaccine development, authorisation and production, which has enabled more than 880 million vaccinations to 2.4% of the worldwide population (17.3 million vaccinations per day), according to the Financial Times, April 17, 2021.
This was the result of massive sums of funding for research and development (R&D) in and advance purchase commitments of including, as of March 16, 2021, Pfizer/BioNTech (BNT162b2) in the amount of more than $6 billion; Moderna (mRNA-1273), in the amount of nearly $6 billion; and AstraZeneca (CVnCoV-CureVac) in an amount of more than $2 billion (Bozorgmehr, K. et al, Lancet 397.10281 : 1261-1262).
This article will briefly review three main IP issues against the backdrop of the efforts by the scientific and medical communities to address the challenges posed by the pandemic.
Patent licensing and substitutes
Even before the onset of the pandemic in late 2019, considerable research on severe acute respiratory syndrome (SARS) coronavirus (type 1 and 2) has yielded almost 2, 000 patent families during 2020. Most of these filings originated in China and the US (Kunmeng, L. et al, Int J Biol Sci 2021; 17:1588-99). With accelerating R&D during the pandemic, the global and national responses to COVID-19 have brought into sharp relief the tension between public health interests and generally accepted free market rights of patent owners to enjoy profits generated fairly by their innovations.
The arguments over where the utilitarian Bentham balance of maximum benefit to the widest population lies, do not yield a single answer. The patent holder is a controlling entity but, in most countries, the government in effect acts as a monopsonist—the only buyer of the medicine. An appropriate price can be arrived at by the balance of these two controlling entities. While a fair market price is a vague term, agreement is often reached, with huge price reductions granted.
However, where an agreement is not reached, governmental actions can be taken under the World Trade Organization’s Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) to exercise compulsory licensing arrangements, such that the government grants permission to another entity to produce a patented product and compensate the IP owner with a fair market price.
Compulsory licences under article 31 of the TRIPS Agreement allow eligible drug-makers to legally manufacture and sell copycat versions of patented drugs during national emergencies, public health crises or other instances of extreme need. Article 31 states that there must have been reasonable attempts at negotiation between the parties.
The seeker of the compulsory licence is limited to domestic use alone. This historically led a few states, including China, to avoid implementation of compulsory patent licences. Some relief is now available, derived from paragraph 6 of the 2001 Doha Declaration on the TRIPS Agreement and Public Health. Article 31(f) of TRIPS allows generic medicines to be made under non-exclusive compulsory licences exclusively for export to countries that cannot produce the medicines themselves.
“The arguments over where the utilitarian Bentham balance of maximum benefit to the widest population lies do not yield a single answer.”
Eyal Bressler, AIPPI
In the case of COVID-19, countries that have excess vaccine production capacity may be afforded, under Doha arrangements, the opportunity to export to countries without such capacity. It should be noted that 13 EU member states account for more than 60% of the world’s major facilities for vaccine production and 90% of global vaccine production (Bozorgmehr, ibid).
Several countries have taken legislative steps to accelerate issue of compulsory licences for COVID-19 patents. At the beginning of the pandemic, China, Canada, Chile, and Ecuador provided a legal groundwork for the issuance of compulsory licenses to address COVID-19.
In March 2020, Israel issued a compulsory licence to import generic versions of lopinavir/ritonavir (AbbVie’s Kaletra) as a treatment for COVID-19 patients on the ground that AbbVie was unable to provide sufficient supplies of lopinavir/ritonavir. AbbVie responded by waiving patent enforcement during the pandemic.
In the Netherlands, Roche released the recipe of its external lysis buffer required for a COVID-19 test after the European Commission explored action for possible abuse by the company of its dominant position.
Other propositions, with varying degrees of practicality, have been made to relieve vaccine shortages in the face of the potential exercise of patent rights.
For example, Carlo Sala suggests overcoming compulsory licence burdens by following private use non-commercial exceptions, at least under article 68 of the Italian Code of Industrial Property (IPKat, May 2020). It would be interesting to see whether private use exemptions could be extended to cover the vaccination industry, dependent as it is on various actors in the supply chain.
Others have suggested that trade secrets can shield innovations from compulsory licensing or, at a minimum, shift significant bargaining power towards the lawful rights holder. That said, one finds difficulty in understanding how trade secrets covering all but a few components can be kept from the public given the necessity to provide full information to regulatory authorities.
Non-profit AUTM (formerly the Association of University Technology Managers) is encouraging academia to share COVID-19 licensing strategy by: “adopting time-limited, non-exclusive royalty-free licences, in exchange for the licensees’ commitment to rapidly make and broadly distribute products and services to prevent, diagnose, treat and contain COVID-19”.
I query, however, whether academia and their technology transfer organisations have the ability to move a product along the pharma pipeline as quickly as private industry. Perhaps a more practical approach is for pharma companies to participate in patent-pooling schemes set up by the World Health Organization, such as recently called for in Nature 591, 529 (2021). Such patent-pooling has successfully existed for years for treatments for HIV, hepatitis and tuberculosis.
“Perhaps a more practical approach is for pharma companies to participate in patent-pooling schemes set up by the World Health Organization.”
Biosimilars, patenting and scope
Traditional vaccines trigger an immune response by administering weakened or inactivated pathogens into the body. A new class of vaccines, however, transfects molecules of synthetic ribonucleic acid (RNA) into immunity cells, eg, T- and B-lymphocytes, to function as messenger RNA (mRNA), causing immunity cells to build the foreign protein (or portions therefrom) that would normally be produced by a pathogen (eg, virus bacteria or cancer cell).
These hereto synthesis proteins stimulate an adaptive immune response to create antibodies that precisely target that particular pathogen. More specifically, COVID-19 mRNA vaccines consist of synthetic N1-methyl-pseudouridine (1mΨ) modified mRNA strands encoding the SARS-CoV-2 spike glycoprotein, packaged in lipid nanoparticles (LNPs) to deliver mRNA to cells and promote endosomal escape upon cellular uptake.
As such, the Pfizer, Moderna and AstraZeneca vaccines all comprise mRNA full-length spike with amino-acid ‘proline’ substitutions (K986P, V987P) within surface of neutrally-charged LNPs, strongly enriched with apolipoprotein E (ApoE) having an important role in the uptake of the mRNA LNP vaccines after intramuscular injection.
A highly similar molecule(s), with only minor changes, may produce the same pertinent effect and therefore be regarded as “biosimilar” from a regulatory and patent point of view. A biosimilar therefore may be quite close to a reference patented and approved molecule and the free use of biosimilars would enable patient access to reduced cost biological therapies.
COVID-19 mRNA vaccines and proteins produced therefrom may well be regarded as biosimilar to other referenced commercialised or patented mRNA-originated therapeutics. The US approach to biosimilar inventions was recently defined in 42 US Code §262—following a “patent dance”, ie, a pre-suit exchange to identify and potentially narrow the list of patents litigated in the first wave of litigation between the pioneer manufacturer (patent owner) and the biosimilar manufacturer.
In Europe, the European Medicines Agency does not require the formulation of a biosimilar compound to be identical to that of the reference product. As for patenting, patents are often successfully obtained on biosimilars as well as their reference product, eg, US10561726 (bevacizumab), US10959939 (etanercept), and US8124095 (erythropoietin).
In addition, as in all pharmaceutical products, where the biosimilar is patent protected, many other aspects of biosimilars are patentable subject matter.
hese include production methods, formulation or administration routes; dosage regimen; and combination therapies (Moorkens, E. et al, MAbs 2020; 12).
The usual pitfalls in patenting apply when attempting to obtain patent protection for biosimilars, such as enablement and disclosure. An example is the patentability discussion around remdesivir patented by Gilead Sciences in WO2012012776 and WO2017049060, which claim nucleosides for treating respiratory syncytial virus and parainfluenza virus infections (Ravi, S. et al, Pharm Pat Anal 10: 9-12, 2021 01).
Rewarding indigenous knowledge
The Chinese government promotes use of traditional herbal medicines in the fight against COVID-19, and more than 80 related patent applications have been filed. Other countries where traditional medicine is used often in conjunction with “western” medicine are also active in this field. There is a growing awareness among governments and corporations that profits derived from innovations that originate, at least in part, from traditional knowledge stewarded and nurtured by indigenous peoples over centuries, should be rewarded.
Several international and national “quasi-IP rights”, for example the UN Common But Differentiated Responsibilities, the Nagoya Protocol on Access and Benefit Sharing, and other arrangements, have come into being in recent years to facilitate access and benefit-sharing partnerships between academia, industry, emerging nations, and local and indigenous peoples.
- There has been rapid growth of patent filings pertaining to COVID-19.
- Several countries are streamlining the compulsory licensing system already in place under TRIPS/Doha.
- Other proposals for increasing the availability of COVID-19 innovations include relaxation of the patent system, such as private use exemptions and patent-pooling.
- Biosimilars of COVID-19-related vaccines can be patented and protected.
- Medicaments and remedies to COVID-19 provided by indigenous people and their traditional knowledge may be protectable by various “quasi-IP rights”.
Eyal Bressler is a patent attorney and vice-chair of the Standing Committee of Development and IP of the International Association for the Protection of Intellectual Property. He can be contacted at: firstname.lastname@example.org
Images, from top: Shutterstock / Marcin Janiec, Graeme Nicol, Andy Dean Photography, Dragon Images