Professor Tom Moody (VP Technology Development and Commercialisation), Dr Steve Taylor and Dr Stefan Mix (Head of Biocatalysis) highlight how Almac is approaching state-of-the-art technology development and how they guide their customers through the process of deciding how to best protect their commercial interests in relation to biocatalysis.

The pharmaceutical, health care and associated chemical industries are strategically outsourcing more and more of their activities. Recent trends indicate that this is not slowing down when it comes to procurement of advanced intermediates and building blocks for their speciality chemical products. In many cases, biocatalytic processes lie at the core of such product manufacture, bringing not just their green credentials but tangible economic benefits, too, through route shortening, reducing energy requirements and a reduction in reagent and solvent use.

The service sector is changing rapidly to meet customer demands in relation to quality, security of supply, timelines and cost, with opportunities arising for companies that can deliver on these. Quality, customer care and delivery are now baseline expectations and demonstration of additional added value with its associated intellectual property at the right price is taking centre-stage. A key question that customers are now asking is whether a process should be patented or whether it should be kept secret as industrial know-how.

The rise and rise of biocatalysis

The synthetic attractiveness of enzyme technology stems from being able to use it for catalysis of many types of chemical reactions, and especially the unequalled ability of enzymes to recognize subtle differences in molecular shape. This, all under conditions that may be no more daunting than those found in a typical kitchen. Such impressive versatility is illustrated in Figure 1 using a hypothetical molecule.

Figure 1 – An illustration of enzyme versatility.

Biocatalysis was once the preserve of specialists working with limited in-house collections of enzymes and cultures. A revolution in molecular biology has enabled the rapid development of much larger and more diverse enzyme collections at Almac and other companies, and has also enabled astonishing improvements in enzyme process performance to be realized. This has elevated biocatalysis from a niche to a widely applied mainstream technology, relevant to a diverse range of chemical transformations.

The reason for the surge in the application of this green technology, in our view, is simply that success breeds success. Unlike ten years ago, we now have a suite of supporting technologies that can really make a difference in enzyme development, such as bioinformatics, enzyme evolution and high throughput screening, as well as substrate and process engineering. Figure 2 highlights the options for driving bioprocessing from enzyme selection (enzymes are derived from metagenomics, bioinformatics, protein engineering and in silico design), process optimization (process and substrate engineering, DOE, application of process intensification tools such as ultrasound and continuous flow, and enzyme immobilization) and actual delivery of API (GMP or non-GMP), advanced intermediate or fine chemical.

Inevitably, developing and exploiting cutting-edge biocatalysis technologies generates intellectual property and is accompanied by a need to protect, where possible, the processes and products surrounding it. It is useful to consider how patenting attitudes have changed as the technology has evolved and expanded in recent years.

The changing landscape of IP strategy in biocatalysis

In the early days of biocatalysis it was enough to simply patent an enzyme catalyzed reaction without too much definition of the enzyme beyond its basic classification such as dehydrogenase or nitrilase. So, a claim could be very broad as in the following example taken from EP0332379B1, granted in 1996.

“A process for the production of an L-α-amino acid which comprises causing a microorganism having enantioselective nitrile-hydrolyzing activity to act at a pH in the range of 8-12 on one or more α-aminonitrile compounds represented by the following general formula……”

Such an unspecific claim would be unacceptable today, since it quickly became common knowledge that enzymes are extremely powerful and versatile catalysts. It is no longer surprising or considered inventive that an un-specified biocatalyst might perform a certain biotransformation, even if it had never been demonstrated or published.

With biocatalysis in its embryonic years, cloning, expression and sequencing technology was driving a revolution in the health care sector, and biocatalysis – as an offshoot of this – was a major beneficiary. The amount of searchable enzyme sequence data that was readily available increased rapidly and exponentially, and this inevitably influenced IP strategy. Homology claims became the centre of attention for a period of time in an attempt to capture as many wild-type enzymes as possible, whose sequences were known, for a process of interest. Thus, typical claim language would refer to an enzyme sequence and any derivatives of the enzyme to a certain level of homology in protein sequence. It was realised, however  that claiming all enzymes to a level of 80% homology to the discovered enzyme often yielded little protection since enzymes with much lower levels of homology could be just as effective for a given biotransformation.

Figure 2 – Enzyme selection to product isolation.

Meanwhile, enzyme engineering and evolution technology became a widely practised technology, thus introducing another level of complexity to the landscape. In the formative years of this technology, the focus of attention turned towards broadly protecting enzymes and engineered mutants in patent claims with less regard for any particular intended use. This had the unintended consequence of revealing much about the underlying technology and approach involved, disclosing how subtle changes in enzyme structure were able to influence catalyst performance. Furthermore, it fired up an argument as to whether a biocatalytic process should be patented at all for fear of teaching others about the underlying technology. This is aside from the ongoing concerns of others’ regard for respecting intellectual property rights.

Today a strong biocatalysis patent will most likely combine three elements into its main claims to give the assignee the best chance of securing a competitive advantage:

• First, it will have a reaction focus, defining the core reaction that is of commercial interest together with varying amounts of detail on the reaction conditions required for the biocatalytic reaction to occur.
• Second, there will be enzyme/catalyst definition to describe the origin of the enzyme/catalyst, which can be either the commercial source or the sequence data elsewhere in the patent. If the sequence is given, there may be an attempt to capture homologues by a traditional claim of percentage sequence identity to the originating sequence.
• Third, and critically, there will be definition of changes that have been made to the engineered or wild-type enzyme sequence that endows the enzyme with properties that enhance its performance to a level where its use allows the reaction of interest to become viable. This immediately raises the bar for others to find something similar and change, for example, an enzyme of lower homology in other ways at the sequence level, since it is now prior art and has been shown to be possible.

When these three elements are combined, the patent application has a good chance of satisfying three key requirements: commercial value, novelty and inventiveness. This last requirement of inventiveness is of course the hardest to satisfy. If an assignee can argue that their target reaction is greatly improved and enabled through deliberate and inventive choice or design of the enzyme, then they have the best chance of securing a granted patent. It should be noted that a mere sequence of an enzyme (standard enzyme catalysis) is no longer patentable, may it be a wild type or even an engineered enzyme within a screening kit. For the process to be both novel and inventive, the application must show or demonstrate reasons why the enzyme is superior or enables the specific A to B transformation which would not have been obvious to anyone skilled in the art. This means that the selected enzyme from a commercial kit needs to be further engineered for the A to B transformation to identify a new sequence that has superior enabling power to allow the transformation to work commercially.

Choose the IP strategy that suits best

The options for the customer are as follows:

1. Substance of matter patent – this is the best for the customer as they control their end product (independent of the technology used to synthesize it).
2. Process patent – protects their A to B transformation, whether using an enzyme or not. This is the easiest patent to file, however it may be harder to get granted in the future due to meeting novelty and inventiveness criteria. The enzyme can simply be stated in the patent as the commercial code just like any other chemical reagent.
3. Process patent with sequence and homology claims. To get this granted, the divulged sequence will need to be designed for the specific A to B transformation and show both novelty and inventiveness. Simply taking a wild type or engineered enzyme sequence from a commercial kit is not enough to be novel and inventive and therefore not patentable in its own right. It is best to go for option 2 above by not showing the sequence to the world.
4. New catalysis for a said enzyme, eg an unexpected reaction not known for being catalyzed by an enzyme in prior art. This is probably the best and tightest patent. When claims are broad, the patent becomes very hard to police. If it is a very specific reaction, good commercial planning needs to be assessed to ascertain if return on investment is achievable.

For all the above points, the customer needs to assess the commercial landscape and what their shareholders expect as key milestones in the company’s lifespan and their product development. However, even where the chances of securing a strong patent appear to be good, in all of this there is still a healthy debate needed for every biocatalytic process as to whether to keep it as a trade secret or embark on a patent filing.

What we see at Almac is different customers have different concerns and/or objectives. Some companies may have little concern about how an intermediate is synthesized since their value is captured and secured in the drug substance of matter’s patent and they would like suppliers to compete to make intermediates for their drugs at the lowest possible cost.

Other companies though, may have different priorities and pressures, for example emanating from venture capital investment and related stakeholders. Process technology for making their drugs and/or intermediates may be much more important to these companies.

Often companies that are keen to protect the developed enzyme processes as much as possible, (especially where such processes are wrapped up in critical pathways) do so for company development and the need to increase shareholder value.

Companies must ascertain what creates the most value, eg is speed of process development and product delivery or commercial protection key at this point?; Is this intermediate important to a family of valuable compounds or are there multiple technologies available to make the product?; Is there assurance that the enzyme (or technology) will be available at scale if needed?; or is there freedom to operate, etc.

For processes enabled by extensive and costly enzyme and process engineering programmes, filing a patent protecting the novel design is most common, particularly in contested market spaces, so as to prevent others from doing the same. A simple publication in a scientific journal would also have the effect of securing permanent access to the technology while avoiding hefty fees. However, this also enables access by others, and is therefore chosen when this is not deemed problematic. Examples have arisen, for example, from Big Pharma research into future generics space, or from API maker’s inventions towards improved supply with key raw materials and building blocks.

A number of factors therefore need to be weighed up in the argument for or against secrecy. Can a good case for inventiveness really be made? Is a competitor likely to find a similar process and obtain a patent themselves? Does it make sense to reveal the sequence of a catalyst and how it was improved? Is the life-time cost of the patent justified? These are just some of the questions that need to be considered.

In conclusion

The proven ability of biocatalytic technology to produce hard cost savings for pre-existing processes or to provide economical access to NCEs in the pharmaceutical sector ensures increased investment year on year in this area. With the use of this cutting-edge technology comes much opportunity for intellectual property generation and this needs careful evaluation in the context of how this is exploited. Almac’s approach is to listen carefully to customer needs and to follow the best path forward that takes account of the numerous risk factors at play. Some cases merit patent application whilst others favour a trade secrecy approach, or the opposite – publication in a journal.

 

The Authors:

Professor Tom Moody graduated from The Queen’s University of Belfast with a 1st Class BSc (Hons) in chemistry in June 1998 before returning to gain a PhD in Physical Organic chemistry in December 2001. He has also completed a Masters in Business graduating with distinction in July 2007 specializing in business strategy. His work has earned him numerous accolades and he is co-author and author of more than 90 publications and patents. He is currently VP Technology Development and Commercialisation for Arran and Almac in Ireland and works in the area of Chemistry & Biocatalysis and its application towards the synthesis of chiral molecules, metabolites and labelled compounds. He is responsible for managing a multi-disciplinary team of both chemists and biologists to obtain commercially useful biocatalysts and their intended applications, developing biocatalytic processes from mg to tonne scale manufacture including development of fermentation processes to yield the desired biocatalyst. He has been a scientific leader and problem solver in >50 commercial projects in the past three years and acts as a consultant in the area of biocatalyst development for pharmaceutical and biotech companies. He is also an honorary Professor at Queen’s University of Belfast in the area of biocatalysis. He may be contacted at tom.moody@almacgroup.com.

 

 

Dr Stefan Mix was born in Berlin, Germany, where he completed his secondary education. After graduatiing with a Diploma in chemistry, he received his doctorate in 2004 from the Technical University of Berlin after working in the group of Professor Siegfried Blechert on stereoselective synthetic methodology and olefin metathesis. He is the author of several publications, and has been working with Almac Group since 2005. He has gained broad industrial experience including in applications of biocatalysis, crystallization development, process development for chiral building blocks and APIs, and technology transfer to manufacturing network partners. Hemay be contacted at stefan.mix@almacgroup.com

 

Dr Steve Tayloris an experienced practitioner of biocatalysis having spent many years allied to the pharmaceutical industry developing enzyme catalyzed processes for small biotech companies through to global chemical companies. He has worked with Almac Sciences for more than 15 years since the inception of the biocatalysis group. In addition to working with Almac, he has interests in projects to biotransform and repurpose natural products for use in cosmetic, food and drug industries through his work for Celbius Ltd.

 

Further information

E: tom.moody@almacgroup.com