Patents, platform technologies and new therapeutic modalities

The life sciences industry is on the cusp of a revolution. There has arguably been no more exciting time than now for innovative companies at the cutting edge of biomedical research. An unprecedented confluence of technological advances in the varied fields of biotechnology, molecular biology, data science and artificial intelligence (AI) – to name but a few – is fuelling the emergence of a new breed of therapies and diagnostic tools, as well as precipitating a fundamental shift in our very approach to the treatment of disease itself.

It is no overstatement to say that within our lifetimes the cell and gene therapies, telemedicine, digital medicine, AI-assisted drug development and precision medicine approaches being developed today will likely change the face of healthcare and the life sciences industry as a whole.

This changing landscape will require new ways of thinking and new strategies for managing intellectual property. To help navigate the coming period of uncertainty, it is possible to draw on the lessons and experiences of other industries that have faced similar issues in the past. This article discusses the continuing rise of platform technologies in life sciences, the growing parallels between the tech industry and some of the current trends in life sciences and considers some of the big questions and lessons that a life sciences industry in the midst of a new era of disruption and change can take away from the tech experience.

Platform technologies and the manufacturing of complex new therapies

One of the striking features of the new cell and gene therapies now being developed is that they are of a fundamentally different nature and different order of magnitude of complexity, compared to traditional small molecule or even biologic therapies. From an IP perspective, those differences present opportunities and challenges to established strategies for the protection of the products and processes involved. The trend towards increasing complexity of manufacturing and administration processes for new forms of therapy is unlikely to be reversed.

This increased complexity and its challenges for companies and regulators have been expressly noted by Dr Scott Gottleib, commissioner of the US Food and Drug Administration, on several occasions, including at the Annual Board Meeting of the Alliance for Regenerative Medicine on 22 May 2018, where he observed that:

This increased complexity and its challenges for companies and regulators have been expressly noted by Dr Scott Gottleib, commissioner of the US Food and Drug Administration, on several occasions, including at the Annual Board Meeting of the Alliance for Regenerative Medicine on 22 May 2018, where he observed that:

In contrast to traditional drug review, where 80 percent of the review is focused on the clinical portion of that process, and maybe 20 percent is focused on the product issues, I’d say that this general principle is almost completely inverted when it comes to cell and gene therapy. The initial clinical efficacy is often established early, and sometimes in small series of patients. The more challenging questions relate to product manufacturing and quality, or questions like how much you can change, or enlarge, the gene cassette that you load into a vector before the gene insert will change the conformation of the vector in ways that also fundamentally alter the entire product’s safety or performance.

It is readily apparent that manufacturing processes and the so-called ‘platform-level technologies’ (eg, CRISPR, viral vector delivery systems and gene cassettes), which enable the production of complex new therapies, are critical not only to the clinical performance of the final product (ie, safety and efficacy), but also to the regulatory process for its approval. Small differences in process may easily result in the production of off-specification products with crucially different (and potentially inferior or even dangerous) clinical characteristics and properties. Accordingly, the protection of the whole and/or critical parts of the manufacturing process for complex new therapies may increasingly become a proxy for the protection of the final approved product itself.

At the same time, while the specifics of the particular manufacturing process for a particular therapy will be critical to the reproducible production of that approved therapy, in every case the particular process employed will likely be a specific embodiment of a more general process that has come to be used in (and will often be essential to) the manufacture of that particular class of therapy. Taking Novartis’s first-in-class chimeric antigen receptor T-cell therapy Kymriah (tisagenlecleucel) as an example – while Novartis may use a particular CD19-targeting CAR encoded lentiviral vector to modify T-cells extracted from the patient for later reinfusion, that particular vector utilises Oxford Biomedica’s proprietary LentiVector lentiviral delivery system (which Novartis licenses), which itself is a particular implementation of the broader class of lentivirus-based viral vectors in general.

In this context, those with control over intellectual property protecting the essential platform-level technologies that are fundamental to entire classes of therapy potentially have the power to control the direction of those new therapies. Such rights holders now face significant strategic commercial, reputational and moral questions about how to exploit, monetise and/or enforce their patent portfolios. The tech industry – operating in a field where complex, multicomponent products, interconnectivity of devices, industry standards and a high density of patents is the norm – has long grappled with platform technologies and such issues.

High-tech, life sciences and platform technologies

Before considering the trends reshaping the life sciences sector and what lessons may be gleaned from the experience of the technology/telecommunications industry, it is instructive to consider the traditional differences between the two sectors in terms of market, product and legal dynamics. A high-level comparison is set out in Table 1 and discussed in more detail below. For illustrative purposes this section focuses primarily on the pharmaceutical segment of the life sciences industry as the clearest counterpoint to the dynamics of the tech sector. However, many of the observations will apply to varying extents to other segments of the industry (eg, medical devices, research instruments and diagnostics).

Traditionally, the tech and life science industries have been characterised by dynamics that are almost polar opposites of one another, both in terms of product R&D and in terms of their key markets. Leaving aside the over-the-counter and consumer healthcare sectors, which do not typically drive bottom-line revenue for major pharmaceutical companies, medicines (and certainly the most valuable innovative products) tend to cater for relatively small, specialised patient cohorts defined by the indications for which the medicines are approved. At the same time, the R&D costs to bring a single new product to market are massive and the return on R&D investment in pharma has been steadily decreasing for almost a decade, according to analyses of the top 12 pharma companies by 2009 R&D spend conducted by Deloitte’s Centre for Health Solutions. That study found that – between 2010 and 2017 – returns on investment in pharma R&D for that group had fallen from 10.1% to 3.2%, and the cost of bringing a new drug to market had increased from approximately $1.2 billion to $2 billion.

The pricing of innovative specialised medicines is driven by the imperative to compensate for the high risk of R&D and to recoup the substantial upfront investment made by pharma companies. The orphan drug system – which is expressly designed to reward investment in the development of treatments for small population or rare diseases – is the epitome of this dynamic. In order to maintain pricing freedom and the practical and commercial viability of developing such specialised treatments, life sciences companies rely on the product exclusivity afforded by the patent system, which also drives the invention of new formulations, presentations and indications for their products to maintain and extend that exclusivity.

Significantly, the nature of the small molecule and biologic products that form the vast majority of the current crop of approved medicines also lends itself to this dynamic of exclusivity. Typically comprising a new, patentable compound/protein with a distinct structure, and often able to be produced through well-established chemical and biological processes that are long out of patent, such compounds are relatively simple, self-contained and distinct from a technology and freedom-to-operate perspective.

On the other hand, the market, product dynamics and very mentality of the high-tech industry stand in marked contrast with the more siloed and exclusivity-focused nature of life sciences R&D. Consumer electronics continues to be a driving force in tech and, compared to the specialty medicines market in life sciences, brings an entirely different scale and economics to the strategic equation. In addition, advances in the tech field tend to be more incremental and iterative (Moore’s law is a good illustration of this), compared to the binary success or failure of the R&D programme for a new compound or class of drug.

Further, of necessity and by their nature, high-tech devices operate within a complex ecosystem of existing (typically proprietary) hardware and software, with which new products must be able to interact. A single high-tech device may comprise a phenomenally complex combination of myriad individual components, each of which is essential to the proper functioning of the whole. Accordingly, such products are confronted with licensing and freedom-to-operate issues on a different scale to that faced in most pharma R&D.

The net results of these different dynamics have been:

• the emergence of a high-density patent environment in the tech industry;
• the practical and commercial necessity of establishing industry standards-setting agreements and bodies; and
• the adoption of a very different approach to licensing, exclusivity and the monetisation/commercialisation of inventions.

From an IP and competition law perspective it has also precipitated the evolution of mechanisms such as the designation of SEPs and FRAND licensing rates and the rise of NPEs as a serious litigious force.

Questions and lessons for life sciences

Faced with the dawning of an unprecedented new era of disruption and change, it will be incumbent upon leading life sciences companies and their counsel to innovate in their IP and commercialisation strategy – just as they do in respect of their product R&D. While companies have already begun to experiment with new initiatives (eg, outcomes-based pricing and public policy-based licence restrictions), it is also instructive to turn to the experience of the tech industry to extrapolate relevant learnings from a sector that has been dealing with platform technologies, standards, and complex licensing and freedom-to-operate landscapes for a long time now. With the benefit of those insights, we consider a number of big questions and potential answers for the future of IP strategy in the life sciences industry.

Will NPEs rise as a force in life science patent litigation?

The influence of NPEs on patent litigation and strategy in the tech industry has long been felt. Armed with a portfolio of patents, without R&D, marketing, sales and manufacturing expenses, and free from reputation and brand management concerns, NPEs can aggressively seek to enforce their portfolios to obtain royalty streams with singular focus. NPEs are relatively free from the usual risks that innovators must take into account in strategic decisions to enforce their patents – that is, a potential finding of invalidity of a key patent granting a product exclusivity – as they have no product exclusivity or markets to protect (although they do still risk endangering patents that generate licensing revenue). Additionally, NPEs have no need to seek freedom to operate and cross-licences for themselves, which removes a key negotiating tool from the arsenal of the implementers they may target.

If the convergence of new therapies around a number of key platform technologies and class targets and an increasing density of patents granted in relation to those technologies does eventuate, those developments would yield conditions ripe for the emergence of NPEs in the life sciences industry (provided that a prospective NPE could secure a suitable portfolio of patents to begin a licensing/enforcement campaign). The exponential rise in the number of patents that are being filed and granted relating to CRISPR suggests that such conditions already exist – at least in respect of some portions of the industry.

In a sense, the life sciences industry has already been dealing with NPEs for some time, in the form of the technology transfer offices of academic institutions, albeit such offices are generally subject to and act in accordance with altruistic goals and public interest considerations that reflect their institutional origins. A further step closer to a true NPE are the companies spun out of academic institutions to commercialise technologies invented by their researchers. However, those often maintain a degree of public-mindedness as a result of their traditionally close leadership ties with the founding institutions and researchers, and are usually focused on the commercial implementation of the founder’s research, as opposed to pure licensing activity and revenue generation. A wholly private and profit-focused NPE concerned only with monetising its portfolio would be an entirely different beast. As the new wave of complex therapies develops and formal or informal standards in life sciences arise (see box out), life sciences companies should be alert to the emergence of NPEs, which have the potential to dramatically alter the landscape of life sciences patent litigation and strategy, just as they have done in the tech industry.

Will competition law and associated concepts (eg, SEPs and FRAND) become increasingly influential in life sciences patent litigation?

The potential adoption of formal or informal standards in the life sciences industry raises the spectre of competition law as a constraint on the freedom of patentees to deal with and enforce their patents, to the extent that certain agreements and/or actions may be considered to be anti-competitive and/or to constitute the abuse of a dominant position in the relevant market. Indeed, quite apart from the issues raised by the prospect of SEPs in life sciences, recent times have already seen heightened competition authority scrutiny of settlement agreements in the pharmaceutical sector (ie, so-called ‘pay for delay’ settlements between innovator and generic companies) and significant fines in a number of cases.

The experience of the tech industry, and in particular decisions such as that of the European Court of Justice (ECJ) in Huawei v ZTE (Case C 170/13), suggests that, in appropriate circumstances, competition law issues may be employed strategically in patent litigation, as both sword and shield. Offensively, the threat of investigation by competition authorities already turning their eye to the life sciences may be a significant deterrent to the aggressive enforcement of key platform technology patents that may constitute a standard (and it is in the power of companies threatened with such action to initiate a dialogue with the authorities). Defensively, competition law may be used by an implementer to resist being enjoined and instead seek a licence on FRAND terms from the patentee. Such competition law defences have become a staple in tech patent litigation (particularly in respect of telecommunications standards) and are now starting to be used in a life sciences context. This is a trend that is likely to continue.

The potential rise of SEPs and FRAND licences in a life sciences context also brings a number of difficult strategic questions that patentees and implementers will need to consider. Perhaps the biggest question, which is still unresolved in the tech industry, is how the FRAND rate should be calculated. The UK Court of Appeal decision in Unwired Planet v Huawei ([2018] EWCA Civ), while affirming Justice Colin Birss’s first-instance decisions and confirming that a global licence can be FRAND, disagreed with the the finding that there is only one FRAND rate for a given set of cicumstances, instead finding that multiple rates and sets of terms may all be fair and reasonable in a given set of circumstances. Parties will also likely face a strategic question of forum shopping, as courts around the world adopt different approaches to calculating FRAND rates and to the question of whether a FRAND rate is to be calculated on a global basis that is within the competence of that court to order.

Should competition law factors continue to grow in influence in the life sciences industry, companies will need to be alive to the consequences this will have on their patent strategy, whether seeking to enforce or to challenge a patent. Keeping abreast of the shifting developments on this front in the tech industry may offer forward-thinking companies an edge in this regard.

Will we see a gradual move away from an emphasis on product exclusivity and increased monetisation of patents through non-exclusive licensing?

The current climate of intense public and political pressure on pricing in healthcare is forcing life sciences companies to be more creative in their pricing and strategies to maintain and grow revenue. Recent events in the United States in particular have placed a spotlight (and for some, a temporary postponement) on the traditional practice of implementing regular price increases to ensure revenue growth over a product’s lifetime. Against this backdrop, it seems only sensible to begin to ask a question that in the past may have seemed laughable – is the life sciences industry’s general assumption of product exclusivity, and the pricing and revenue models built around that assumption, still viable? Regardless of the answer to that question, what new strategies might life sciences companies start to employ to maximise revenue and fully monetise their IP rights in the face of pressure on medicines pricing?

To answer the first question squarely, given the already astronomical (and still rising) cost of life sciences R&D, and even with all the change that is to come, it still seems inconceivable that product exclusivity will cease to be the number one priority in the IP strategy of innovative life sciences companies. However, the almost singular emphasis on reserving and deploying IP assets for the purpose of maintaining exclusivity may shift somewhat.

The density of the patent landscape in life sciences around certain key platform technologies has already started to increase, as companies recognise and pour resources into developing those key technologies along with their patent portfolios for both offensive and defensive purposes. As those portfolios grow, companies may seek to monetise a greater proportion of them (ie, those parts which are not regarded as core elements for the protection of product exclusivity) through licensing and collaboration agreements. Indeed, in certain circumstances companies may be able to secure more revenue (and with less risk than a full in-house development programme) by encouraging the adoption of a particular technology or standard through non-exclusive licensing than by pursuing a strategy of exclusivity.

In an ideal scenario, maintaining a well-defined core of key exclusivity protecting patents while actively exploring licensing and collaboration opportunities throughout the broader portfolio could achieve the multiple aims of:

• maintaining the exclusivity required to recoup R&D investment;
• maximising the value of the broader portfolio; and
• facilitating the advance of research in the relevant field as a whole.

However, achieving such a feat is far easier said than done and would require a clear and consistent understanding of the strategic priorities of the company and direction of the field of research itself.

The emergence of key platform technologies will likely see an increase in cross-licensing and patent pooling

In any event, whether companies like it or not, it seems inevitable that the convergence of the industry around certain key platform technologies will force an increase in cross-licensing and/or patent pooling in respect of those technologies, as companies realise that they cannot secure freedom to operate and mitigate litigation risk without taking licences from other parties working in the field. It is significant that MPEG LA – which successfully pioneered the formation and licensing of tech patent pools (starting with the MPEG-2 video compression standard) – is actively looking for patent pooling opportunities in the life sciences sector and has been seeking to form a CRISPR patent pool since December 2016.

While those efforts have yet to bear fruit, the fragmented patent ownership landscape in respect of CRISPR and other life sciences platform technology lends itself to such initiatives, as a way to provide certainty to companies looking to secure freedom to operate in the field, and to efficiently create and administer licensing frameworks for a wide range of users, at scale. The certainty provided by a clear licensing solution such as a patent pool or cross-licensing arrangement may also ‘expand the pie’ by encouraging parties that might otherwise have practised patent hold-out to come forward and take a licence.

Indeed, the industry may look to its past for inspiration in this regard, in the form of the storied 1974 Cohen-Boyer patent application for recombinant DNA technology, often hailed as the first biotech patent. The non-exclusive licensing programme developed by assignee Stanford University for that patent family has been upheld as a shining example of the patent licensing and commercialisation system at work and proved to be one of the drivers of the success of the modern biotech industry, generating hundreds of millions of dollars in licensing revenue and leading to the creation of an estimated 2,442 new products, which in turn have generated over $35 billion in sales over the life of the patents.

By contrast, there has been much scrutiny and some criticism of the academic institutions at the heart of the recent disputes over the fundamental patents covering CRISPR-Cas9 gene editing technology – the Broad Institute of Harvard and MIT and University of California, Berkeley – which are seen to be pursuing more exclusive licensing and commercialisation strategies, in conjunction with the biotech start-up companies spun out of those institutions (notably, Editas Medicine, Caribou Biosciences and Intellia Therapeutics). In respect of the ongoing CRISPR-Cas9 dispute between the Broad and the University of California it is notable that no settlement and cross-licensing or patent pooling agreement has yet been reached. Although the Broad has successfully maintained the finding in its favour of no interference-in fact in the United States, the relative positions of the parties and patent landscape across the globe remain fragmented and in flux. Despite the certainty that a global (or at least territorial) cross-licensing or patent pooling solution would provide for industry and potential licensees, and the potential benefit that both parties could stand to gain, neither has shown any sign of compromise. Indeed, the press release from the University of California’s general counsel immediately following the adverse decision of the Court of Appeals for the Federal Circuit emphasised that the decision was not a ruling on the validity of any patents and indicated that they were “currently evaluating our further legal options in the courts and/or the USPTO”. Whatever the outcome, the legal and commercial consequences flowing from the parties’ respective strategies in this high-profile platform dispute may be influential in informing patent strategy for future platform technologies.

Learn the lessons

With such dramatic change in the life sciences industry just around the corner, companies will do well to draw on all of the apposite knowledge and experience they can to help determine the optimal IP strategy for their organisation. By considering how patent litigation in the tech industry responded to similar forces and market trends as those the life sciences industry is now starting to face, we have attempted to identify a number of key potential trends, risks and opportunities. How life sciences companies respond to the changing IP landscape will go a long way to determining who will be on top in the brave new world of life sciences to come.