This article first appeared in the digital and print editions of Pharmaceutical Patent Analyst. The authors, David Puleo, Dr. Nicholas Vincent and Dr. Anthony Sabatelli, retain the rights to the piece and have chosen to reprint this article here. To order reprints, please contact the publisher at reprints@future-science.com.

We may not realize it, but the human body is home to an astonishingly large number of microorganisms that live both in us and on us. This resident microbial population, which is estimated to number over 100 trillion microorganisms, is collectively known as the ‘microbiome’ or, more specifically, the ‘human microbiome’ [1].The microbiome can also refer to microbial communities in or on other living organisms such as our pets, livestock and food crops, as well as those external to us, for example, those found in the air, soil and sea, or those found in or on inanimate objects ranging from computer keyboards to office buildings [1].

There are intense, ongoing research efforts to understand the connection between the microbiome and human health, with an eye towards developing novel therapies. Consequently, many new discoveries will surely result, but as will be discussed in this article, there are unique challenges for obtaining commercially meaningful patent protection for these discoveries. Given that many microbiome-based inventions are likely to be viewed as ‘laws of nature’ or ‘natural phenomena’, they will likely be subject to a heightened level of scrutiny by patent examiners and the courts, as to whether these inventions represent subject matter that is eligible for patent protection. The relevant US statute defining what is referred to as ‘patent subject matter eligibility’ is 35 USC §101, which states: “Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefore, subject to the conditions and requirements of this title.” This statute will be discussed in further detail in this article.

This heightened scrutiny is the direct result of several high profile – and what some would consider controversial – US Supreme Court decisions that set a new standard for evaluating patent subject matter eligibility.

Solid patent protection is a key part of the development of many products and is particularly important for new drugs. The reason for this is that the drug development and approval process is lengthy, and can exceed 10 years from initial development to regulatory approval. Also, the development and approval process can require the investment of hundreds of millions of dollars. Most, if not all, microbiome-based therapies would be regulated and approved as new drug products. It is essential that the successful development of these products will depend upon an intellectual property strategy including the procurement and enforcement of sound patents.

Despite these challenges and the importance of obtaining solid patent protection, case law is now developing at the intermediate Court of Appeals for the Federal Circuit that provides some guidance for a path forward. Additionally, the US Patent & Trademark Office (USPTO) has issued a guidance document, memoranda and examples providing a path forward for the thoughtful practitioner to draft patent applications more likely to withstand the heightened scrutiny. Even though this article is written from a US perspective, the issues discussed here have applicability to other jurisdictions.

Background The microbiome is commonly referred to as ‘worlds within a world’ and encompasses those organisms living in or on the human body (also called ‘microbiota’) or their collective genomes [2]. Organisms within the microbiome specifically include bacteria, archaea, fungi, protozoans and viruses, with bacteria being the most numerous. These organisms secrete factors into the body that can affect human physiology. The proportion and composition of an individual’s microbiome can vary greatly, thus giving rise to different phenotypic differences and diseases [3].

Table 1: Microbiome Research and Therapies

Commercial Area Commercial Area Subset Companies/Institutions Patents

Pharmaceuticals and Therapies

Gut-Brain Axis · Nubiome

· Gut Guide

· Arizona Board of Regents

· Whole Biome

· US8927242

· US20140301995

· US20150152484

· US20150259728

Metabolic Disease · Nestec S.A.

· Jinis Biopharmaceuticals

· MicroBiome Therapeutics

· Seres Therapeutics

· Synlogic, Inc.

· US8318150

· US8986675

· US9040101

· US9180147

· WO2016210384

Autoimmune Disease · The University of Tokyo

· 4D Pharma Research Limited

· US9415079

· US9421230

· US9433652

· US20160193257

· WO2016102950

Infectious Disease · Seres Therapeutics

· Synthetic Biologics

· Rebiotix

· US9028841

· US9446080

· US9464280

· US9511099

Single Agent Immuno-Oncology · North Carolina State University

· Qu Biologics

· Institut Pasteur

· Decoy Biosystems

· US7981651

· US9320787

· US20150071873

· US20160228523

Combination Therapy Immuno-Oncology · The University of Chicago

· Vedanta Biosciences

· Epiva Biosciences

· Institut Gustave Roussy

· US20150352206

· US20160144014

· US20160235792

· WO2016063263

Agricultural Crops · Cornell University · US9457077

· WO2016057991

Livestock · Biotal

· Combi Co.

· US5718894

· US7582305

Cosmetics · L’Oreal

· Whole Biome

· Azitra

· AOBiome

· US20110064835

· US20160271189

· WO2015184134

· WO2016161285

Microbiome-related therapies typically involve compositions containing bacteria – referred to as probiotics – that treat disease or promote health [4]. For example, yogurt and other cultured dairy products are common examples of probiotic foods. Some therapies change the composition of the gut microbiome by providing desirable bacterial species, nutrients that promote the growth of desirable microbiome members, or bacterial species that displace bacterial pathogens. Other therapies comprise bacteria or bacterial components that interact with the patient’s own organs, tissues and systems. Many of these therapies stimulate the immune system, and therapies are being developed to treat various metabolic, inflammatory and infectious diseases. Inflammatory bowel disease, childhood-onset asthma, diabetes, obesity, cardiovascular disease, colorectal cancer and antibiotic-associated diarrhea are some of the diseases that involve changes in the composition or functionality of the microbiome [4].

Research & therapies

Current research involves characterizing the interplay between the microbiome and the human body. Given that the composition of the microbiome is linked to certain diseases or disease states, it is clear that the microbiome has vast therapeutic potential.

Table 1 highlights the relevant areas of microbiome research and provides a sampling of published and issued patents. Key areas include the following:

Agriculture

Altering the microbiome has potential to revolutionize industrial agriculture by way of changing the physical properties of crops. These physical properties include crop yield, quality, growth, harvest time and shelf life, all of which can significantly decrease crop waste. Similarly, manipulating the microbiome of livestock can prevent antibiotic resistance as well improve livestock health [5].

Autoimmune disease

It has been shown that manipulation of the microbiome can in fact alter the immune system. Many pharmaceutical companies claim to have microbiome modulators that both attenuate as well as enhance the immune response. This area of research is of particular importance in treating autoimmune disorders, graft-versus-host disease and other inflammatory disorders [6]. The patents listed in Table 1 reflect these trends.

Cosmetics

In 2016, the US cosmetic industry generated an average of USD$62.5 billion in revenue [7]. Specifically, skin care is one of the most lucrative segments of the industry. As such, many microbiome-focused pharmaceutical companies and biotechnology companies have begun targeting this area by developing agents that alter the facial microbiome. These agents are usually in the form of a probiotic and are used to either cosmetically improve skin appearance or to treat a skin disorder [8].

Gut–brain axis

The gut–brain axis consists of the bidirectional neurochemical pathway between the intestine and the brain. For example, the brain controls the immune system and other autonomic functions that shape the bacterial populations living in the gut, while bacteria shape brain function by promoting the synthesis of neurochemicals that directly interact with the human nervous system. Relevant patents pertain to manipulating the microbiome for the treatment of obsessive-compulsive disorder, depression and autism [9].

Infectious Disease

Since most of the human microbiome is found in the gut, the majority of microbiome-based therapeutics has been used to treat gastrointestinal disorders, such as Clostridium difficile infection (CDI) and inflammatory bowel disease [4]. CDI is caused when antibiotics wipe out the host gut microbiome, thus allowing C. difficile to overtake the host gut and cause dysbiosis, or an imbalance of the microbiome. The most common form of treatment for CDI has been other antibiotics; however, this treatment does not fully alleviate the infection. Current approaches have centered on fecal microbiota transplant, whereby fecal bacteria are transferred from a healthy individual to a recipient patient. The transplant is meant to replenish bacteria that are absent in the recipient and, thus, restore eubiosis [4]. An increased number of patents in this space reflect this trend.

Immuno-oncology

Immunotherapy refers to pharmacological agents that alter an immune response. Microbiome modulators could be used to either enhance or suppress the immune response and would thus be considered immunotherapy. Furthermore, they could be used as single agent immunotherapy or in combination with current immunotherapies to increase their efficacy [10–12]. Although research on combination therapy is still in its infancy, it shows great promise.

Metabolic disease

Immunotherapy refers to pharmacological agents that alter an immune response. Microbiome modulators could be used to either enhance or suppress the immune response and would thus be considered immunotherapy. Furthermore, they could be used as single agent immunotherapy or in combination with current immunotherapies to increase their efficacy [10–12]. Although research on combination therapy is still in its infancy, it shows great promise.

National Initiatives

There is currently considerable interest in the microbiome from both national research initiatives and private ventures. The former includes the Human Microbiome Project (HMP), the Integrative Human Microbiome Project (iHMP), the National Microbiome Initiative (NMI) and the National Science Foundation (NSF)/United States Department of Agriculture (USDA). The National Institutes of Health initiated the HMP in 1998 with the overall goal of characterizing the microbiome content of both healthy and disease-ridden individuals. With a USD$115 million budget, the project lasted for 5 years and created a reference human microbiome database [14]. Established by the Obama Administration in 2016 with a USD$121 million budget, the NMI seeks to further understand the microbiome in order to restore eubiosis in unhealthy individuals. This initiative spans multiple federal agencies and more than 100 external, private-sector institutions [15]. Furthermore, many pharmaceutical companies are collaborating with academic institutions to both further microbiome research and to enter into partnerships to develop new microbiome-based therapeutics.

Big Business The extensive and burgeoning interest in the human microbiome has not only been limited to the lab or clinic. In fact, there has been a noticeable and significant increase in investors flocking to microbiome-related companies as a direct result of the research in the field and the important advances that have been made. While many researchers and followers of the field are enthusiastic about the influx of investor money, some have questioned whether the enthusiasm can truly be substantiated and sustained. Regardless, there have been several high-profile venture capital investments/partnerships and initial public offerings (IPOs) that have further bolstered the hope and energy surrounding this field and its progress.

By the fall of 2016, the extensive attention and funding that microbiome companies had been receiving for some time reached the mainstream media and financial journals. In September 2016, the Wall Street Journal published an often-cited article regarding the financial aspects of the microbiome [16]. This article highlighted what many had suspected for some time – more money is being invested in microbiome companies than ever before. For the first three quarters of 2016, over USD$600 million had been invested in companies, representing a greater than 400%increase in investments over the previous year. As the article highlights, over USD$600 million invested in the first three quarters of 2016 alone is a sum greater than all the funds invested in microbiome companies from 2011 to 2015 combined. This sharp uptick in fiscal support is, however, supported by the advances that have been seen in microbiome research, which are described above.

In particular, several notable investments in various companies have been made over the past few years. For example, Indigo Agriculture, a company that has focused primarily on producing crops, such as cotton and wheat, that are resistant to environmental stressors, received a windfall of USD$100 million in Series C funding in mid-2016, representing the largest single agricultural technology-based funding round [17]. Additionally, Human Longevity, Inc received USD$220 million in Series B funding in mid-2016 [18]. Vedanta Biosciences, a company seeking to treat immune and inflammatory diseases through modulating the microbiome, received USD$50 million in venture funding in 2016 [19]. Importantly, Indigo Agriculture, Human Longevity, Inc and Vedanta Biosciences represent only three companies that are part of a much larger and vast landscape of business efforts to harness the microbiome and to apply it therapeutically or commercially. Additional companies and highlighted funding results are included in Table 2.

Table 2: Microbiome Company Investment Statistics*

Company Areas of interest Amount (USD) Funding Type Year
AOBiome Restoring naturally occurring bacteria to the skin microbiome that humans using modern hygiene products have lost; targets include hypertension and acne 30 m** Series C 2017
Avid Biotics Targeting harmful or disease-causing bacteria in the gut microbiome to restore a healthy state in affected individuals 854,130 Venture 2014
Azitra Targeting skin diseases such as eczema and dermatitis through harnessing the skin microbiome 2.9 m Series A 2017
Biocartis Personalized medicine approaches and rapid test development 109 m IPO 2015
C3J Therapeutics (Formerly C3 Jian) Targeting dental infections and cavity-causing bacteria, while not affecting other bacteria in the oral microbiome 60 m Series D 2014
CosmosID Microbial genetics platform for rapid analysis of food sources, public health surveillance, and microbiome analysis 6 m Series B 2016
Eligo Bioscience Targeting harmful or pathogenic bacteria in various parts of the human microbiome 2.21 m Seed 2015
Enterome Bioscience Personalized medicine based on individual microbiomes 16.44 m Series C 2016
EpiBiome Personalized medicine based on individual microbiomes; targeting harmful bacteria without the use of antibiotics 1 m Debt financing 2016
Evelo Biosciences Microbial-based therapeutics targeting diseases including autoimmune diseases, inflammatory diseases, and cancer 35m Venture 2015
Evolve BioSystems Establishing and maintaining a healthy newborn gut microbiome 20 m Series B 2017
Human Longevity Individual microbiome sequencing and personalized medicine 200 m Series B 2016
Indigo Agriculture Developing crops that are resistant to environmental stressors; increasing crop yield 100 m Series C 2016
ISOThrive Developing prebiotics for improved gut health 800,000 Seed 2015
Kallyope Harnessing the gut-brain axis with regards to therapeutics and nutrition 44 m Series A 2015
MicroBiome Therapeutics Preventing disease through modulation of the microbiome; targets include pre-diabetes and newly diagnosed type 2 diabetes 743,450 Debt financing 2015
Rebiotix Restoring naturally occurring bacteria to the gut microbiome to improve disease outcomes (including C. diff) 25 m Series B 2014
Ritter Pharmaceuticals Restoring naturally occurring bacteria to the gut microbiome to improve gut diseases and dysbiosis 20 m IPO 2015
Second Genome Targeting metabolic disease and inflammatory bowel disease using small molecules that modulate the human gut microbiome 8.4 m Series B 2016
Seres Therapeutics Targeting gut diseases, including inflammatory bowel disease, C. diff, and ulcerative colitis 134 m IPO 2015
Shoreline Biome High throughput microbiome sequencing 500,000 Seed 2016
Symbiotic Health Developing novel therapeutics to target C. diff infections 100,000 Local funding 2015
Symbiotix Biotherapies Developing microbiome-derived therapeutic molecules that elicit immune appropriate immune responses to target diseases such as IBD 2 m Grant 2016
Synlogic Engineering bacteria to perform metabolic functions that target disease throughout the body 42 m Series C 2017
TargEDys Developing nutritional and therapeutic solutions to modulate appetite by harnessing microbiome modulation and the gut-brain axis 3.71 m Series A 2017
uBiome Personalized microbiome testing 22 m Series B 2016
Vedanta Biosciences Modulating the human microbiome to target immune and inflammatory diseases 50 m Venture 2016

In addition to startup companies that have pioneered early work in the area of agriculture and the microbiome, several larger companies have also taken an interest in the potential benefit that microbial communities can provide to agricultural processes. Of particular note is a collaboration that emerged in late 2016 between Monsanto and Second Genome focused on better understanding of the role that microbial communities and their products can have in improving agricultural processes and production. The financial aspects of this agreement have not been disclosed [20,21]. Additionally, companies including BASF and Bayer Crop Sciences have also entered the agriculture and microbiome space, further emphasizing the role that microbes and microbial communities may eventually play in the agriculture and farming sectors [22,23].

Although there has been an increase in the funding of microbiome-focused companies with little sign of slowing, there have been fewer attempts at making these companies publicly traded entities. For example, Seres Therapeutics (NASDAQ: MCRB) had a very high profile initial offering in mid-2015 valued at just under USD$134 million [24]. Interestingly, the stock price had steadily declined, experiencing its highest price per share immediately after its IPO. Approximately 1 year ago, the stock lost more footing, decreasing sharply after an unsuccessful Phase II clinical trial and has likely been further hampered by a general downturn in biotechnology stocks in recent months. However, there are two important lessons related to the business of the microbiome. First, Seres has identified its study design, not the microbiome-based therapeutic, as the culprit for the disappointing clinical trial results, and has announced it will try again with this trial [25]. This suggests that it may not be the microbiome treatments that should be called into question, but rather study designs and how results are being analyzed. Second, it may be likely that other microbiome companies have not moved toward a public status because they are receiving competitive funds from early stage venture-capital funding and because they may want to ensure their data are robust and their results are reproducible, leading to expected outcomes before moving toward an IPO.

There has been at least one additional situation in which a microbiome-based company has gone public, albeit under particularly interesting circumstances [26]. In early 2017, Synlogic, which has focused on engineering bacteria to perform metabolic functions that target disease in the body, merged with Mirna Therapeutics, Inc. At the time of the merger, Mirna had no products but did have a stock symbol (MIRN). As part of the merger, Synlogic assumed this stock symbol and, thereby, went public without a formal IPO. Similar to Seres, the stock has largely decreased in recent months, including a sharp loss in mid-May 2017.

Along with new biotechnology entrants to the microbiome space, large pharmaceutical companies are also beginning to take notice of the potential gains in this area. For example, the research and development subsidiary of Nestl´e, Nestec SA, developed probiotics for weight loss and the treatment of metabolic disorders (Table 1). Similarly, larger pharmaceutical companies including Johnson & Johnson, Roche and Pfizer, are partnering with smaller biotech companies that have specialized in the microbiome. For example, the Johnson & Johnson-owned Janssen Pharmaceuticals established its Human Microbiome Institute, which is partnering with smaller biotechs. Specifically, Janssen is licensing Vedanta’s proprietary technology with reported payments of up to USD$339 million [27].

As research in the microbiome area continues to flourish and interesting and important clinical and therapeutic findings emerge, it is likely that investors will continue to embrace the promise of the microbiome and to financially support it and encourage its expansion. Although many companies are still receiving early stage funding, it will not be surprising to see some to move in the direction of filing for IPOs in the coming years, especially if they continue to produce clinically important and commercially viable results. As microbiome-based research further develops, a corresponding need for strong intellectual property protection will be warranted.

Intellectual Property Challenges: Subject Matter Eligibility

Clearly, the microbiome is big business, as evidenced from the large amount of research activity and the investments being made to fund companies to further this research and develop new therapeutics to treat human disease. This activity is generating new developments and intellectual property that need to be appropriately protected. Those seeking to invest in microbiome-based technologies and therapeutics need to have some assurance that the underlying intellectual property is patentable. After all, a robust and defensible patent estate is an important asset for attracting investment to an enterprise. However, microbiome-based inventions do raise unique challenges for patentability because they sit right at the sweet spot of the evolving law of patent subject matter eligibility. Furthermore, it should be realized that the legal patent case law is still evolving and that many currently issued patents, and those yet to issue, will likely be the subject of patent suits that will further define and direct the evolution of the law in this area.

For an invention to be patentable, it must be useful (i.e., possess a utility), be novel (i.e., not already be publicly known or have been disclosed) and nonobvious (i.e., it must represent an inventive step and not be readily derived from ‘prior art’ teachings). The US statutes setting forth utility, novelty and nonobviousness are 35 USC §101, 35 USC §102 and 35 USC §103, respectively. In the USA, it is the utility requirement, which is codified at 35 USC §101, which sets forth four threshold categories of patent eligible subject matter – processes, machines, articles of manufacture and compositions of matter. In 1981, after two landmark decisions, the US Supreme Court broadened these classes of patent eligible subject to include genetically modified living organisms (Diamond v. Chakrabarty) and computer/software based inventions (Diamond v. Diehr). The case of Diamond v. Chakrabarty, 447 US 303 (1980), involved genetically engineered microorganisms, ‘oil-eating bacteria’ genetically modified to incorporate different degradation pathways for metabolizing hydrocarbons. Prior to this case, microorganisms and higher animals were not patent-eligible subject matter. The other case, Diamond v. Diehr, 101 S. Ct. 1048 (1981), involved a process for curing precision rubber products where the operation of the mold was controlled by a computer using the Arrhenius equation and a temperature probe. The important holding was that controlling the execution of a physical process by a computer program did not preclude patentability. These cases swung open the doors and helped launched the biotech and computer revolutions, because it was now clear that a wide range of biotechnology and computer/software inventions would be patent eligible under 35 USC §101. In finding such inventions patent eligible, the Court seemingly sent the message that a wide range of biotechnology and computer/software inventions could be patent eligible, thus helping fuel the biotech and computer/software revolutions.

However, despite this broadening of 35 USC §101, it must be remembered that it is also constrained with some long-standing judicial exceptions. Specifically, the case law has defined three classes of inventions that are not patent eligible subject matter – laws of nature, natural phenomena, and abstract ideas. For example, one could not patent gravity or Einstein could not have patented his famous equation, E = MC2. Similarly, one could neither patent the element gold, nor an idea or concept in its abstract form. However, inventions related to these exceptions could be patented. For example, even though gold itself cannot be patented, a new gold alloy having unique physical and chemical properties would be patent eligible.

It is against this backdrop that the US case law on patent subject matter eligibility has more recently been further evolving. The Supreme Court has since pulled back from its decisions in Chakrabarty and Diehr,totighten the standards under which certain classes of inventions are evaluated for subject matter eligibility. Two of these decisions, Mayo Collaborative Services v. Prometheus Laboratories, Inc (a biotech case) and Alice Corp. Pty. Ltd. v. CLS Bank Int’l (a computer/software case), established the basis for a two-part test for evaluating inventions for patent subject matter eligibility – the Mayo/Alice test. A number of cases are important here: Funk Bros., Parker v. Flood, Chakrabarty, Diehr, Bilski, Mayo, Myriad, Alice. However, two of these will be focused on: Mayo and Alice.

This test is further discussed below.

In Mayo v. Prometheus [28], the Supreme Court heard a patent subject matter eligibility case having a claim directed to a method of optimizing the therapeutic efficacy of a drug. The claim can essentially be summarized as follows: a method of optimizing a thiopurine drug for treating an autoimmune gastrointestinal disorder by administering the drug to a patient; and then measuring the level of the drug in the patient, wherein the measured level of the drug indicates the need to increase or decrease a subsequent dose of the drug. The central issue in this case was whether the patent claims recited a patent ineligible law of nature. The issue was not so clear-cut, as seen from the complicated procedural history as the case made its way up to the Supreme Court. The District Court for the Southern District of California ruled that the claims were ineligible. The Court of Appeals for the Federal Circuit (also referred to as the Federal Circuit or the CAFC) reversed the District Court decision and found the claims patent eligible. In fact, the procedural history is even more complicated because the Federal Circuit decided the case twice – first on the original appeal and then on remand from an intermediate order of the Supreme Court. The en banc decision was then appealed to the Supreme Court. In a unanimous decision, the Supreme Court reversed the Federal Circuit, ruling that the patent essentially claims an underlying law of nature. The Court also added that the claims lack other elements that would amount to significantly more to make it patent eligible. The following year, another high-profile biotech case, Association for Molecular Pathology v. Myriad Genetics, Inc, 133 S. Ct. 2107 (2013), was decided. Although not part of the Mayo/Alice test per se,theMyriad decision made a number of important pronouncements on the question of patent subject matter eligibility and cited back to the Mayo decision. This case centered around patents directed to the discovery of mutations in the two genes, BRCA1 and BRCA2, responsible for certain forms of breast and ovarian cancer and lead to the development of the now fairly standard BRACAnalysis test kit. For a variety of public relations and public policy issues involving women’s health, the American Civil Liberties Union brought suit to have the underlying patents declared patent subject matter ineligible under 35 USC §101. The case was litigated all the way to the Supreme Court. The Court basically held that DNA is not patent eligible (but cDNA can be), that isolated biomolecules such as proteins and nucleic acids are not patent eligible, but unknown or modified versions can be. This case, in conjunction with Alice,sent shock waves through the biotech industry and has had further issues for diagnostics [29].

In 2014, the Alice case, from the computer/software business, made it to the Supreme Court [30].This case had patent claims essentially directed to a method for reducing the risk that the parties to a financial transaction will not pay their obligations (i.e., a computerized scheme for mitigating settlement risk). Also, the patent had claims directed to the computer system and medium. Again, the question of patent subject matter eligibility was not clear-cut. The District Court for the District of Colombia found that the claims were directed to an ineligible abstract idea. However, the Court of Appeals in a divided decision first reversed the District Court holding, but on appeal again, in a divided decision then affirmed the District Court. In a unanimous decision, the Supreme Court ultimately affirmed the District Court ruling that the patent effectively claims an abstract idea, and that it lacks other elements that integrate it into something more. Also, the Supreme Court tied together this computer/software case with its biotech ruling in Mayo by stating that introduction of a computer does not alter its earlier analysis in Mayo.

The Two-part The Two-part Mayo/Alice Test

As a result of these recent cases, and also a guidance document, memoranda and patent claim examples issued by the USPTO, there is now a two-part test for evaluating whether an invention that has subject matter ‘directed to’ one of the three judicial exceptions is patent eligible. In other words, inventions that are ‘directed to’ laws of nature, natural phenomena or abstract ideas, must pass what is referred to as the two-part Mayo/Alice test, to determine whether the patent claims recite eligible subject matter. The Mayo/Alice test can be summarized as follows:

The Two-Part Mayo/Alice Test Part 1: In part 1 of the test, the initial inquiry is:

  • Is the patent claim directed to a law of nature, a natural phenomenon, or an abstract idea (i.e. one of the 3 judicial exceptions)?

If No – the claim passes the test (no further inquiry is needed and the patent claim is deemed to recite patent eligible subject matter).

If Yes – proceed to Part 2 of the test.

Part 2: In part 2 of the test, the next inquiry is:

  • Does the claim recite additional elements that amount to significantly more (than the exception) to make it patent eligible?

If Yes – the claim passes the test. The patent claim is deemed to recite patent eligible subject matter.

If No – the claim fails the test. The patent claim is deemed to recite patent ineligible subject matter.

Most microbiome-based inventions are likely to be viewed as laws of nature or natural phenomena and thus almost certainly to be subjected to the two-part Mayo/Alice test. Although the test sets forth the current framework under which US patent examiners should be examining US patent applications, however, it is also the standard under which claims of patent validity are evaluated in patent infringement cases. Furthermore, in a patent infringement suit, a defendant can raise the affirmative defense that the patent relates to patent ineligible subject matter under 35 USC §101 and is therefore invalid and not infringed. Despite the potential subject matter eligibility challenges facing many microbiome-based inventions, there is a path forward for the thoughtful patent practitioner to identify appropriate intellectual property from these inventions to craft patent claims that will have the best chance to withstand the Mayo/Alice scrutiny.

A Path Forward

Since the Alice decision, there have now been several Federal Circuit decisions that have found patents from the biotech and computer/software area to be patent eligible. While many of these decisions have focused on software and computing, one biotech case in particular sheds important light directly on the life sciences and biotechnology fields, and provides guidance for the patent practitioner to draft patent eligible claims.

In Rapid Litigation Management v. CellzDirect, Inc [31], a case that addresses the patent eligibility of a method of cryopreserving liver cells, the Federal Circuit ruled that the claims were not directed toward a patent ineligible concept, but instead were directed toward a new and useful method for preserving liver cells that is, in fact, patent eligible. This was an important and encouraging holding, given that the District Court in the Northern District of Illinois had previously ruled that the claims failed both parts of the Mayo/Alice test. The significance of this case lies in the fact that the Federal Circuit commented on the detailed and concrete aspect of the claims and how they related to an important and practical development and not merely a patent-ineligible concept. As such, it provides important guidance to those seeking to patent inventions and developments in the life sciences, and in particular, microbiome research.

In addition to the encouraging case law shifts that have been occurring over the past year at the Federal Circuit, the USPTO has also shown interest in providing guidance on crafting patent eligible claims that may have previously been ruled ineligible under 35 USC §101. In its December 2014 Update: subject matter eligibility examples: Nature-based product examples – Example 6, Bacterial Mixtures, the USPTO provided important guidance on developing patent eligible claims for bacterial mixtures – something that has previously been very difficult to achieve, but also something that will be very relevant for microbiome-related intellectual property protections.

In the first of two presented sample claims, the guidance illustrates that unmodified bacterial mixtures are not patent eligible. This is based on an early landmark Supreme Court case, Funk Brothers Seed Co. v. Kalo Inoculant, Co. [32], in which a claim similar to this was ruled to be patent ineligible. However, the second presented sample claim focuses on how a bacterial mixture could be ruled patent eligible. Although this example claim has come under some criticism for its perceived lack of clarity, the focus is meant to be on how the proposed mixture provides ‘something more’ than what is found in nature; that is, it is not a product of nature, but a patent eligible composition.

It should also be pointed out that the USPTO has compiled a webpage on subject matter eligibility on its website that has information on its guidance, the memoranda, Court decisions and other materials [33]. This is a useful resource that the practitioner should consult for further guidance.

Future Perspective

The next few years will be telling for the microbiome from both a business and patent perspective. Even though microbiome-based products such as yogurt probiotics are already on the market, we are still awaiting approval and marketing of a major pharmaceutical product developed from a microbiome-based research project. Such a major approval would validate the microbiome and establish it as a major, and perhaps the most important therapeutic target for future pharmaceutical research. Also, the next few years will be telling as more microbiome-based patents continue to issue and are eventually challenged in patent infringement lawsuits and other legal actions. It is still too early to tell from recent US Federal Circuit Court decisions whether the patent subject matter eligibility pendulum is beginning to swing back from the maximum it attained under the Mayo and Alice decisions. Further court decisions, will likely define the future for patenting new developments from this important area.

Conclusion

The microbiome represents a new frontier in health and disease. A number of microbiome-based therapies are now in the early stages of development. This recent flurry of commercialization would not be possible without basic research from laboratories both small and large. These trends will surely continue as research and development in this field progresses. Furthermore, patents continue to be filed and issued in the microbiome area, despite the challenges that they are likely to face. Because so much time, money and resources are needed to bring a microbiome-based therapy to market, it is important that the intellectual property underlying the therapy be critically and intelligently evaluated to devise the most robust strategy for navigating and meeting the significant patent challenges for this burgeoning field.