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Patents to biological medicines in combination: is two really better than one?

Posted: 23/09/2022

New medicines are usually protected by a patent covering the active molecule. These basic or “primary” patents usually provide robust protection for the relevant product, provided that the compound is genuinely new and inventive. Developers may be able to extend patent protection by patenting other technological advances related to the drug such as new formulations, dosage forms or regimens, and new combinations with other pharmaceuticals. These “secondary” patents can provide a significantly extended period of patent protection for the drug, provided of course that they are valid.

The same principles apply to the patenting of biological drugs (biologics). Biologics include large peptides and recombinant proteins such as insulin and growth hormone, monoclonal antibodies, recombinant DNA, antibody-drug conjugates, fusion proteins and synthetic vaccines. In contrast, “small molecule” drugs are usually chemically and thermally stable with low molecular weights.

Given the often significantly greater expense involved in the development of biologics (compared to small molecule drugs), and originator companies’ need to recoup that cost, it is unsurprising that secondary patents often play a key role in the lifecycles of biologics. As the basic patents on blockbuster biologics expire, there will be increasing interest in testing the strength of secondary patents, particularly from companies that produce biosimilars.

Patents for biologic and small molecule combinations

Secondary patents for drug therapy combinations can cover co-formulations (where the active ingredients are combined in a single product), combination products (such as dual-barrel syringes) and co-administration of different products simultaneously. For the purpose of this article, drug combinations are considered in their broadest sense, that of co-administration.

It is now common medical practice to use biologics in combination therapy, usually with a small molecule drug. But are the secondary patents to this kind of drug combination worthy of patent protection?

One reason why patents for biologic and small molecule combinations may not always be robust is because the co-administration of two or more medicines to treat disease is often a routine medical practice. In some fields, notably HIV medicine and oncology, monotherapy is unusual. This practice has transformed the efficacy of treatment of many diseases. As such, drug combinations which include at least one routinely used drug (often a small-molecule compound) are likely to be considered obvious from a patentability perspective, particularly where that drug is used in other combinations.

The approach of the European Patent Office (“EPO”)

Inventions are only entitled to patent protection if they are new and not obvious to a skilled person working in the relevant technical field. However, the approach of the EPO to the assessment of whether an invention for a combination of drugs is obvious tends to favour patent applicants. This is because the EPO does not, as a matter of routine, consider evidence on this question from relevant experts (although such evidence may be submitted by third parties opposing the grant of a patent). Rather, the EPO’s analysis centres on whether the disclosure of earlier “prior art” documents would make the invention obvious. If an applicant is able to provide data to the EPO which demonstrates that a combination of drugs is particularly efficacious, a patent is often granted. This can be the case even if one of the drugs is already in routine use for the claimed medical indication. This is because, if one of the claimed drugs is relatively new, there are unlikely to be any “prior art” publications which disclose that the particular combination works.

Whether a combination is considered obvious may also depend on the medical field in which the compounds are used. In some specialities, routinely-used combinations tend to contain the same “backbone” drug, with variation only in the remainder of the combination.

As an example, combination therapies for rheumatoid arthritis commonly contain the antifolate drug methotrexate (MTX). Although biologics may only be prescribed when conventional disease-modifying antirheumatic drugs (DMARDs) have not worked, they are often administered in combination with MTX. Some, such as adalimumab and certolizumab pegol, are primarily licensed for combination use and only used alone in cases of intolerance to MTX.

In cancer care, combination chemotherapy is the gold-standard for many malignancies. This includes regimens using biologicals such as obinutuzumab (Gazyvaro®) which is only licensed in the UK for combination chemotherapy, although it may be given on its own for subsequent maintenance therapy.

Similarly, pembrolizumab (Keytruda®) is licensed for use with a number of longstanding chemotherapy drugs and, for some indications, with newer classes of chemotherapeutic agents such as the multi-receptor tyrosine kinase inhibitors (for example, lenvatinib).

Obvious drug combinations: examples

Some major biologics have had secondary patents to combinations with small molecule drugs revoked in opposition proceedings before the EPO. One example is rituximab, a chimeric mouse/human monoclonal antibody for the CD20 protein found on the surface of B-lymphocytes that is marketed by Roche in Europe as MabThera® and by Genentech in the US as Rituxan®.

Rituximab was the first therapeutic antibody approved for oncology patients. It was first authorised in the US in November 1997 and in the EU in 1998 for a particular form of non-Hodgkin’s lymphoma (a type of blood cancer). Further approvals followed for other medical indications unrelated to cancer, as well as different treatment regimens and drug combinations.

Rituximab is now licensed to treat several autoimmune diseases and was approved in Europe in 2008 in combination with MTX to treat rheumatoid arthritis. A European patent granted to Genentech covering this indication was subsequently revoked in opposition proceedings after an appeal to the Technical Board of Appeal (TBA) of the EPO.

The TBA considered that the patent (EP1176981) was obvious because medical practice at the relevant time was to combine virtually all new agents with MTX. It therefore would have been obvious to combine a new biological agent such as rituximab with MTX. There was also an incentive for this to happen, given the urgent need for improved treatments for rheumatoid arthritis. As a result, the patent was not inventive and was revoked.

Another example is the combination of trastuzumab (the originator product Herceptin®) and a taxoid to treat malignant HER2-positive breast cancer. Genentech’s EP1037926, covering this indication, was revoked during opposition proceedings in the EPO on the basis that the invention was obvious. In those proceedings, the TBA summarised the approach of the EPO in considering obviousness as follows: “…a course of action can be considered obviousif the skilled person would have carried it out in expectation of some improvement or advantage. Thus, obviousness is not only present when results are clearly predictable but also when there is a reasonable expectation of success…” In the case of the trastuzumab combination, because monotherapy with the taxoid drug paclitaxel was a well-known treatment for breast cancer and the two drugs are directed at different molecular targets, the TBA considered that it would be obvious to combine them.

The approach of the UK courts

Despite these examples, it is likely that EPO will grant many more combination patents for biologics and small molecules where the patentee is able to provide evidence of an unexpected treatment benefit. The UK courts usually do not take the same approach to obviousness as the EPO, so these patents may be vulnerable to attack. Of particular importance is the role which experts play in invalidity proceedings in the UK, where their opinion can provide valuable context about common clinical practices at the relevant priority date. This is in contrast to the more limited, document-based review performed by the EPO.

It is, of course, possible that in certain medical fields where monotherapy is standard or at least common, drug combinations may be more likely to be considered genuinely inventive. However, combination therapy is, in principle, nothing new in medicine, leaving open the prospect of invalidity challenges to granted patents to many biologic-small molecule combinations.

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