This is the sixth installment in a series on advancements in microbiome research and development. Our goal with this series is to inform readers about developments in this important field. Previous articles have reviewed efforts to manipulate the microbiome to treat disease, and this installment will discuss developments in diagnostics that utilize the microbiome. This article will also explore the significant patent challenges for this nascent area of microbiome-based diagnostics, particularly in view of current patent litigation that is likely to make it to the Supreme Court next term. Previous editions from this series of articles can be found at the following links: Part I – R&D Leaders, Part II – 2015 Patent Trends, Part III – Psychobiotics, Part IV – Metabolic Disorders, Part V – Patents Relating to Obesity and Metabolic Disorders.

With the passage of the Patient Protection and Affordable Care Act (PPACA) in 2010, preventive medicine – services that focus on disease prevention, rather than disease treatment – became a major focus of healthcare and the market for medical diagnostics expanded to meet a growing demand. During the same time, faster and less expensive next-generation DNA sequencing (NGS) and improvements in cloud storage, which facilitated the analysis of sequence data, boosted the development of microbiome-based diagnostics.

NGS-based approaches: an early success

NGS-based approaches for detecting infection were an early area of success for the emerging field and overcame several limitations of existing methods. Traditional methods for surveying and identifying pathogens employ bacterial culture, which requires knowledge of the optimal growth conditions of a given infectious agent and biases detection by excluding potential pathogens that require different conditions. Growing a pathogen from a patient sample can take anywhere from a few days to a week or more, and contamination in the lab can lead to false positives.

These advances relied on the growing practice of metagenomics, which involves the analysis of microbial DNA extracted directly from a sample of interest (the field was first described by Yale scientist Jo Handelsman). In medical settings, metagenomics is used to evaluate the microbial community associated with a patient; DNA sequence data obtained from patient samples is compared to reference genomes to identify pathogens. Unlike culture-based methods that target a specific pathogen, this analysis bypasses the need to grow the suspected pathogen in culture, removing bias and allowing clinicians to identify pathogens in-real time. Furthermore, NGS-based diagnostics provide information on an organism’s antibiotic resistance profile, which informs treatment. A 2014 report from the New England Journal of Medicine highlighted the contribution of NGS to the diagnosis of a bacterial infection, validating this technique[1]. Earlier this year, the growing prominence of NGS-based diagnostics was featured in the 2016 Yale Healthcare Case Competition, of which Dilworth was a proud sponsor.

Current landscape of microbiome-based diagnostics

Diagnosis of bacterial infection remains a focus of some more recent diagnostics. Microbiome, a Dutch company active in the infectious disease space since 2005, teamed up with Biocartis, a Belgium company specializing in personalized medicine, last year to develop a multiplex, real-time PCR test for bacterial sepsis. However, innovation in the diagnosis of chronic disease, rather than bacterial infection, is driving the development of new technologies, which use patient samples from a variety of body sites. For example, the gut microbiome, which harbors more bacteria than any other organ, has been an early target for diagnostics. These technologies use NGS-based approaches to evaluate the composition of a patient’s gut microbiome, as the presence or absence of certain microbial community members can be associated with disease. Other diagnostics evaluate the small molecules released by residents of the gut, a characteristic signature of a gut microbiome called a metabolite profile. Often the metabolite profiles of healthy patients differ from those with disease.

An early entrant in microbiome-based diagnostics space, Metabiomics, is developing molecular diagnostics for detecting markers of colorectal cancer. Existing screens for colorectal cancer rely on invasive colonoscopies; the non-invasive test developed by Metabiomics uses a stool sample to evaluate patient’s gut microbiome. Based in Virginia, the company has also entered into a distribution agreement with English company Origin Sciences Limited, which will enable Origin to distribute its patented (according to its website) OriCol™ Microbiome Sampling Kit stateside. The kit provides for rapid sampling of the rectal mucosa, enriching for mucosal-associated bacteria whose relative abundance may indicate a diseased state.

Other companies are also mining the gut microbiome for biomarkers of cancer. To advance the cancer therapeutics in their pipeline, Evelo Therapeutics has developed an Oncobiotic™ Platform to identify and characterize bacteria that are associated with cancer. The company, which has received $35 million from the venture capital firm Flagship Venture, is an emerging player in the market for microbiome-based cancer therapies, an area which will be reviewed in detail in a future installment of this blog series.

As companies look to strengthen their pipelines, they are advancing biomarker and diagnostic discovery to stimulate drug development. Like Evelo, these biotechs are simultaneously developing diagnostics and drugs. Among this group is the UK-based 4D pharma. Started in 2014, 4D pharma has three products in its pipeline, including MicroRx, their proprietary platform for screening probiotic bacteria. In February, the company acquired Tucana Health, a small start-up founded by the prominent microbiome researchers Fergus Shanahan and Paul O’Toole from the APC Microbiome Institute of University College Cork in Ireland. With the acquisition, 4D pharma plans to build on Tucana’s expertise in assessing microbiome signatures, such as metabolite profiles, to expand the discovery and diagnostic side of its pipeline.

This deal also highlights the growing role of university spin-outs and public-private partnerships in microbiome R&D, which have been highlighted in previous installments of this series – one example is the partnership between Second Genome and the Mayo Clinic to develop therapies for IBD, metabolic disorders, and colorectal cancer. The Mayo Clinic is also active in the diagnostics space, having partnered with Whole Biome in 2014 to target women’s health. The collaboration is initially focused on identifying microbiome signatures of preterm labor, which can cause infant death and disability in children. Whole Biome, whose Complete Biome Test uses a specialized, NGS-based assay to provide a high-resolution profile of the microbiome, is a San Francisco startup advised by scientist Peter Turnbaugh (whose work has been mentioned in previous articles). The company is one of 29 at the life science incubator Janssen Labs @QB3, collaboration between Johnson & Johnson Innovation and QB3.

Challenges of the IP Landscape: Barriers to Patent Protection of Diagnostics

Despite on-going improvements in NGS technology and growing commercial activity in microbiome-based diagnostics, getting patent protection on biological diagnostic tests has become increasingly difficult in the wake of recent Supreme Court decisions. Under 35 USC §101, a patent may be issued for a “new and useful” process or method, but several decisions have made it more difficult to determine whether a method is patent eligible. In Bilski v. Kappos, a 2010 case, a patent claiming a series of steps for managing investment risk was invalidated, portending future issues for claims directed towards abstract ideas. Mayo v. Prometheus mounted an additional challenge for diagnostics, as the court ruled that methods claims directed toward administering a drug, measuring its metabolites, and deciding on a further treatment course based on those measurements were not patent eligible. The Association for Molecular Pathology v. Myriad Genetics and Alice Corp. v. CLS Bank International decisions placed additional restrictions on what inventions are considered patent eligible, leaving the US Patent and Trademark Office to deal with the fallout of these decisions by issuing a Guidance and several updates in an attempt to clarify patent eligibility of life sciences and software innovations. The latest test for diagnostics claims is Ariosa Diagnostics v. Sequenom. In last summer’s ruling, the Federal Circuit, citing the Supreme Court’s Mayo decision, held that claims directed to a naturally occurring phenomenon and were not patent eligible if they recited methods that were “conventional, routine and well understood applications in the art.” Sequenom filed a petition of writ certiorari in late March, and 20+ amici have been filed in support of this certiorari. Although the court seems likely to grant review, in the meantime, the barriers to patent protection imposed by the Sequenom decision and other rulings remain in effect, threatening innovation in biotechnology.

Closing

By leveraging the microbiome to identify and characterize an array of acute and chronic disorders, microbiome-based diagnostics represent a key area in the microbiomics space. The consulting firm MarketsandMarkets estimates that the human microbiome market will be worth almost $300 million in 2019 and reach more than $650 million by 2023. As NGS and metabolite profiling technology improves, microbiome-based diagnostics will represent an important part of the field’s expansion. Concomitant with this growth, we also expect to see swift increases in patent activity in this area in the next 5-10 years.