Competition, Innovation, Patients and Patents in the antibodies field: Isn’t it time to reconsider and change EPO practices for the well-being of innovation, patients and competition?

B. Carion-Taravella (FR), C. Ribard (FR)

The Monoclonal Antibodies’ Competitive Market

Monoclonal antibodies (mAbs) are an approach for disease treatment and prevention which considers pharmacogenomics and individual variability to drug response. More specifically, mAbs allow the stratification of pharmacological therapies to subgroups of patients who have the genetic variant of interest, overcoming the traditional “one size fits all” drug development paradigm (i.e., the traditional blockbuster approach) and shifting to a tailored therapy. mAb therapies are revolutionizing the biopharmaceutical field: they are being approved in record numbers (at twice the rate of small molecules) and are indicated for many cancers (one of their main fields of application) and chronic illnesses. They also help to optimize the efficacy and safety of drugs administered according to the patient’s genomic profile, ideally maximizing pharmacological responses and minimizing side effects.

Consequently, the mAb market has changed rapidly in the past five years. It has doubled in size, becoming dominated by fully human and bispecific molecules. These trends are expected to continue. Besides cancers and chronic illnesses, mAbs under development treat indications including obesity, diabetes, celiac disease, Alzheimer’s disease, bacterial infections, and skin diseases (Mantalaris, January 2019).

The continued growth of mAb therapies is expected to be a major driver of biopharmaceutical product sales and prescriptions. In 2018, the global therapeutic monoclonal antibody market was valued at approximately US$115.2 billion and this market is expected to generate revenue of $300 billion by 2025. Despite this high growth potential, however, new companies are unlikely to take over large shares of the market, which is currently dominated by seven companies: Genentech (30.8%), Abbvie (20.0%), Johnson & Johnson (13.6%), Bristol-Myers Squibb (6.5%), Merck Sharp & Dohme (5.6%), Novartis (5.5%), and Amgen (4.9%), with other companies comprising the remaining 13% (Ruei-Min Lu, 2020).

The Innovative Approach Around Antibodies

mAbs have revolutionized treatment in many therapeutic areas. However, to continue this exciting trend, identification of new specific targets and improved mAbs are needed. This is a bottleneck in development of next generation therapeutic mAbs and failures in translating a target into a successful therapeutic mAb are much more frequent than successes. Although first generation antibody therapeutics focused primarily on specific binding to targets to elicit simple desired effects and establish antibodies as a valid class of drugs, they did not capitalize on all aspects of the antibody platform. Developing a novel drug based on therapeutic mAbs is far from a routine. It’s a complex, multivariate problem where solutions often require engineering interconnected attributes of potential mAbs. Hence, more recent therapeutic mechanisms have been customized not only based on the type of antigen or on a specific part of an antigen but also by antigen affinity, valency, and the paratope-epitope site. Moreover, use of different antibody subclasses allows for fine-tuning of pharmacokinetics and effector function and has introduced new proteins with new properties into the antibody framework.

While stronger antibody-antigen affinity can mean higher potency and clinical efficacy, higher antigen-binding potency does not always create a more efficacious therapeutic. For example, for mAbs targeting solid tumours, there is an ideal antigen affinity range and, if not in this ideal range, these antibodies may suffer from poor selectivity of tumour cells versus healthy tissue. In addition, higher antigen affinity can lead to accelerated internalization and elimination. Thus, the optimal antigen affinity varies on a case-by-case basis and must be optimized based on factors such as the type of tumour (i.e. patient sub-groups), the antigen concentration, and the kinetics of receptor internalization. Furthermore, mAbs targeting the same antigen may elicit different mechanisms of action by binding to distinct molecular features and thus may have different therapeutic uses and efficacy. For instance, trastuzumab and pertuzumab, both of which target Human Epidermal growth factor Receptor 2 (HER2) and act in a complementary fashion in the treatment of early HER2-positive breast cancer, have distinct mechanisms of actions. Pertuzumab binds to the extracellular domain II of HER2 and inhibits dimerization with other HER receptors, while trastuzumab binds to domain IV and prevents HER2 activation by extracellular domain shedding; however, it cannot prevent dimerization with HER receptors. In other extreme cases, mAbs targeting different epitopes on the same antigen can produce the opposite effect (see for example, CD28 and CD40; the former is useful for cancer applications and the latter for treatment of autoimmunity) (Dennis R. Goulet, 2020). Therefore, mapping the precise site of antibody-antigen binding and giving structural and essential information about the antibody binding site is needed to define the elicited response and to differentiate two mAbs targeting the same antigen.

Innovation around mAbs has only just begun and there is room to explore and to develop novel mAbs against new specific epitopes on a known target to bring us closer to achieving the goal of precision medicine, to address the resistance to current drug treatments and to understand target cross talk and regulation. The quest for new targets has often been more painful than rewarding for biopharmaceutical companies. These companies are extremely prudent when it comes to development of antibodies, focusing their large investments primarily on targets that are likely to work. Many challenges will have to be faced in the next decade to bring more efficient and affordable antibody-based drugs to the clinic.

The EPO Patentability Approach of mAbs: An Effective Way for Balancing Biologic Innovation and Competition in Europe?

The European Patent Office (EPO) should play a role in encouraging innovation, and more specifically in encouraging medical innovation while simultaneously allowing patients to access affordable and innovative treatments. Unfortunately, the current EPO policies and practices concerning patentability of antibodies do not help the pharmaceutical industry to promote new mAbs development in Europe. Indeed, when dealing with broad functional antibody claims, the EPO does not require that the scope of patent claims be commensurate with the inventor’s actual and technical contribution to the art, as measured by what the inventor discloses in his/her application. Instead, the EPO grants antibody patent rights that are limited only by what is theoretically possible in view of the disclosed invention, e.g., a particular antibody that binds to a particular part on a known antigen, far exceeding the inventor’s actual technical contribution to the art. However, the EPO should be mindful that a particular part of an antigen, defined by a specific feature, does not necessarily contribute to the properties of all antibodies covered by the claim. In other words, it’s not possible to extrapolate, from a particular antibody found to have a specific property, other antibodies that would inherently have the same property. Patentees should thus not be allowed to pursue overly broad claims. If they claim the right to a range of antibodies, they must disclose enough information to enable a skilled person to make the full range of what is claimed without undue burden. This means a relevant range which affects the utility of the antibody.

Paradoxically, we are now in the following situation: on one hand, the EPO grants broad claims with only functional limitations that “reach through”^{“reach through” claim : (see EPO Guidelines F-III-9): it’s about claims directed to a chemical compound (or the use of that compound) defined only in functional terms (i.e. without any limitation by any structural feature) with regard to the technical effect it exerts.} to future inventions (not yet invented) based on a known target, and on the other hand, the EPO rejects patents to mAbs to a known target that are new, structurally defined by their CDRs and non-obvious in view of known antibody structure by requiring a surprising property and, thus a threshold of inventive step beyond what is required in other technical areas.

Such EPO practice and trend of granting patents that claim a broad genus of antibodies that “reach through” to future antibody inventions based on an already known target without any antibody structural feature limitation into the claim, has significant real-world impact. First, it discourages innovation. Secondly, it has created an environment where all of the patentee's competitors working on the same known target may incidentally infringe such a patent and be threatened with the risk of injunction. Facing these real infringement and injunction threats, competitors may decide not to develop new antibody drugs, suspend their competing development programs, or discontinue the sales of competing antibody drugs already approved. As a result, all innovative antibody drugs other than the specific antibody drug developed by the patentee would be excluded from the market, with a risk of creating a situation where finally only one antibody drug exists for one target protein, even if this protein was already known in the state of the art. Such a situation is not in the best interests of patients or competition. Indeed, it will contribute to limit patients’ option for treatment of their specific disease, regardless of whether they adequately respond to or tolerate the treatment. Moreover, if we reach a situation where finally only one antibody drug will be developed for one target protein, and if this one antibody target protein is no longer available to the patients, then the patients will be left with no antibody treatment.

This contrasts drastically with what we can observe in the chemical field and more specifically in the field of small molecule drugs. Indeed, in small molecule drug development, fortunately claims for small molecules are not so broadly granted (see Markush type claims). Consequently, there is a plurality of competing small molecule drugs developed for one target protein or even a target protein specific mechanism. In addition, developing a plurality of competitive small molecule drugs for one target protein allows patients to select the drug most suitable for them, and is also a way to allow patients to switch from one drug to another if they are resistant to one drug or experience adverse effects. Moreover, the development of multiple competing small molecule drugs for a single target protein has reduced the risk of disappearance of a drug for the target protein.

The practice of rejecting patents claiming alternative mAbs defined by non-obvious structural features^{Structural non-obviousness means that in the absence of any particular technical effect linked to the specific structure, the claimed antibody sequences were regarded as arbitrary selections which could not render the antibodies inventive over the prior art.}, follows a similar pattern of limiting patient choice and competition. The EPO does not generally consider that a unique structure can confer inventive step on an antibody to a known target. Indeed, even if an antibody comprising a unique sequence is novel, non-obviousness arguments are rejected by the EPO due to its requirement that a new antibody to a known target must demonstrate “an unexpected effect” relative to pre-existing antibodies to the same target for inventive step to be acknowledged. Once again this is different from the EPOs approach on small molecule patents.

Through these two examples we see how the current EPO’s approach is inexplicably inconsistent and restricts patient choice and competition in the field of biologics. On the one hand, if you are claiming a functional genus of new antibodies to a known target, you may be entitled to the full scope of this claim even if you did not invent all the compounds covered by this claim and if you have only one or a few examples in your description. On the other hand, for later generation antibody inventions, a unique sequence provides novelty and restricts the scope of the claim, but a demonstration of a new or surprising functional effect is required to show inventive step, the challenge here being that this must be demonstrated at the time of filing when the drug has not been given to patients and/or when the contribution to the art of previous publications has not been restricted to its real contribution or is very vague and unclear. Without rationale, the EPO seems too lenient when it assesses broad functional antibody claims (based only on functional features) and too restrictive when it comes to limited sequence specific antibody claims based on structural features. It is urgent to find the right balance. While patent examiners should not be influenced by public or stakeholder opinion in applying the patentability requirements set forth in the EPC to a given case, the EPO cannot disregard how its policies and procedures can, in certain situations, significantly curtail competition. In this regard, a delegation from the epi Biotechnologies committee and also a group of patent representatives from various biopharmaceutical companies met with the EPO in October 2019 to draw its attention to the impact of how the EPO is currently examining patent applications claiming antibodies, and more specifically how biopharmaceutical innovation in Europe may be impaired by its practices. Moreover, considering that one of the EPO's strategic focuses for 2020-2023 is to help boost innovation, two questions can be raised to the EPO to highlight the inconsistency issues discussed herein: (1) How does EPO intend to prevent the grant of overly broad functional antibody claims based on an already known target, which represent an increased risk of blocking the development of new therapeutic antibodies? And (2) how does EPO intend to apply a less rigid approach towards granting claims to a specific antibody defined by structural features, thereby allowing the applicant to obtain much needed exclusivity for its product to treat specific patient needs?

Both patents and competition are vital for the wellbeing of patients. Policy makers should be especially concerned about these EPO practices: isn’t it time to reconsider and change these practices for the well-being of patients and competition?

References
Dennis R. Goulet, W. M. (2020). Considerations for the Design of Antibody-Based Therapeutics. Journal of Pharmaceutical Sciences, 109; 74-103.
Mantalaris, A. L. (January 2019). The Increasingly Human and Profitable Monoclonal Antibody Market. Trends in Biotechnology, Vol. 37, No. 1.
Ruei-Min Lu, Y.-C. H.-J.-C.-Z.-J.-C. (2020). Development of therapeutic antibodies for the treatment of diseases. Journal of Biomedical Science , volume 27, Article number: 1.

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