Despite challenges imposed by U.S. patent law regarding naturally occurring organisms and their products, patents relating to the microbiome and microbiome-based therapeutics are issuing from the U.S. Patent and Trademark Office. Issues encountered and the strategies used to overcome them are illustrated by the following selected examples of recently issued patent claims.
U.S. Patent 9,688,967
Issued: June 27, 2017
- Titled: “Bacteria engineered to treat diseases associated with hyperammonemia”
- Assignee: Synlogic, Inc. (Cambridge, MA)
Claims of interest:
- 1. A bacterium comprising a gene sequence encoding an arginine feedback resistant N-acetylglutamate synthetase (ArgAfbr), wherein the ArgAfbr has reduced arginine feedback inhibition as compared to a wild-type N-acetylglutamate synthetase from the same bacterial subtype under the same conditions,
- wherein the gene sequence encoding the ArgAfbr is present in the bacterial chromosome and is operably linked in the chromosome to a promoter that is induced by low-oxygen or anaerobic conditions;
- wherein the bacterium has been modified to lack a functional ArgR; and
- wherein the bacterium is an auxotroph in a gene that is complemented when the bacterium is present in a mammalian gut.
These claims are of interest in being drawn to an engineered bacterium that inducibly expresses a transgene under the low-oxygen conditions of the mammalian gut and is auxotrophic for a factor present in the gut. As noted from the title, the specific application is treatment of disorders involving ammonia accumulation, or urea cycle disorders. The approach takes advantage of the arginine amino acid biosynthetic enzyme ArgA to stimulate the conversion of ammonia to carbamoyl phosphate.
The Applicants used the Track One accelerated examination procedure and issued without a formal Office Action. It is noted that the independent claims are not limited with regard to the bacterial species or the specific variant ArgA enzyme sequence; the 383-page specification includes extensive sequence information, from a range of species.
U.S. Patent 9,682,108
- Issued June 20, 2017
- Titled: “Probiotic Recolonisation Therapy”
- Assignee: Crestovo LLC (Cambridge, MA)
Claims of interest:
- 1. An oral pharmaceutical composition in a capsule or microcapsule adapted for enteric delivery and comprising a plurality of viable non-pathogenic or attenuated pathogenic Clostridium spores, a plurality of viable non-pathogenic or attenuated pathogenic Bacteroides, and a plurality of viable non-pathogenic or attenuated pathogenic Escherichia coli, wherein said oral pharmaceutical composition comprises between about 107 and about 109 viable microbes or between about 109 and about 1011 viable microbes.
- 2. The oral pharmaceutical composition of claim 1, wherein said oral pharmaceutical composition is effective for treating a Clostridium difficile infection.
- 3. An oral pharmaceutical composition in a capsule or microcapsule adapted for enteric delivery and comprising a plurality of viable non-pathogenic or attenuated pathogenic spores of at least two Clostridium species, wherein said oral pharmaceutical composition comprises between about 107 and about 109 viable microbes or between about 109 and about 1011 viable microbes.
- 12. The oral pharmaceutical composition of claim 1, wherein said oral pharmaceutical composition is effective for treating a regressive disorder in a patient with the presence of abnormal or an abnormal distribution of gastrointestinal microflora, said disorder is selected from the group consisting of autism, Asperger syndrome, Rett syndrome, attention deficit hyperactivity disorder (ADHD) and attention deficit disorder (ADD).
These composition claims are of interest in that they broadly recite subject microbes at the genus level for Clostridium and Bacteroides. Dependent claim 12 is noted for encompassing treatment of the specified neurological conditions. The Applicants used the Track One procedure, interviewed the Examiner and moved the case to allowance by addressing obviousness-type double patenting issues without receiving an Office Action. The specification is concise, at 18 pages as issued, nine of which list references cited to the Examiner by Information Disclosure Statement.
U.S. Patent 9,676,641
- Issued: June 13, 2017
- Titled: “Therapeutic phages and methods for delivery of nucleic acids for therapeutic uses”
- Assignee: SynPhaGen LLC (North Potomac, MD)
Claims of interest:
- 1. A method for delivering a nucleic acid sequence comprising the steps of:
- administering to a subject a bacteriophage-derived particle including at least one nucleic acid sequence and a bacterial origin of replication and a receptor binding protein where the particle is devoid of one or more functional phage replication genes rendering it incapable of independent production of phage progeny;
- wherein the receptor binding protein attaches the particle to a target bacteria in a microbiome; and
- wherein the nucleic acid sequence is expressed in the target bacteria where the expression of the nucleic acid sequence and the expressed nucleic acid sequence are non-lethal to the target bacteria and the expressed nucleic acid sequence produces a therapeutic effect to the subject.
This claim is of interest as it relates to a method of using an individual’s microbiome to express a therapeutic product by infecting target cells of the microbiota with non-replicative phage that do not kill their microbial hosts. Despite issuing at a concise 13 pages, the claims are not limited with respect to specific bacteria or bacteriophage species. Indications set out in dependent form make it clear that both gut- and non-gut microbiomes can be exploited, targeting, for example, gluten intolerance (e.g., via the gut microbiome) and hair loss (e.g., via the skin microbiome).
The application was prosecuted under the Track One accelerated examination procedure.
U.S. Patent 9,670,550
- Issued: June 6, 2017
- Titled: “Method for examination of carcinogenic risk”
- Assignee: JAPANESE FOUNDATION FOR CANCER RESEARCH (Tokyo, JP)
Claims of interest:
- 1. A method for screening whether a test subject has a liver cancer and/or an increased risk of liver cancer, comprising: assaying gut microbiota in a sample collected from the test subject and determining whether a ratio of Gram-positive bacteria to Gram-negative bacteria in the assayed sample collected from the test subject exceeds a range of ratios of Gram-positive bacteria to Gram-negative bacteria in gut microbiota in samples collected from a healthy group.
- 3. The method according to claim 1, wherein the gut microbiota of the test subject is assayed on a regular basis, and an increase in the ratio of Gram-positive bacteria to Gram-negative bacteria for the test subject indicates an increased risk of cancer.
These claims are of interest as a recently issued screening method/diagnostic claim. The claims were not subject to rejection under § 101 during prosecution but arguably require the non-conventional step of assaying gut microbiota (i.e., the whole gut microbiota) for ratios of Gram-positive to Gram-negative bacteria to examine risk or presence of liver cancer; the claims also do not recite a “comparing” step that often triggers rejection under § 101. The claims were initially rejected as overly broad for encompassing screening for any cancer; amendment to recite liver cancer, as demonstrated in the Examples, overcame the rejection.
U.S. Patent 9,670,548
- Issued: June 6, 2017
- Titled: “Methods of diagnosing colorectal cancer by detecting FADA expression”
- Assignee: Case Western Reserve University (Cleveland, OH)
Claim of interest:
- 1. A method of identifying a subject with increased risk of colorectal cancer, the method comprising:
- obtaining a biological sample from the subject;
- measuring the level of FadA expression in the biological sample, wherein FadA expression is measured by measuring FadA mRNA levels using PCR wherein a first primer having SEQ ID NO: 44 and second primer having SEQ ID NO: 45 is used in the PCR to amplify the mRNA in the sample; and
- determining whether the subject has an increased risk of colorectal cancer by comparing the measured FadA expression to a control level,
- wherein an increased measured FadA expression compared to the control level is indicative of increased risk of colorectal cancer in the subject.
This claim is also of interest as an issued screening method/diagnostic claim. The claims were subject to a § 101 rejection, which was overcome by reciting specific PCR primer sequences. It was also noted that measurement of FadA mRNA level is not a conventional way to assay for the presence of the colorectal cancer hallmark species Fusobacterium nucleatum.
US Patents 9,668,992 and 9,668,991
- Issued June 6, 2017
- Titled: “SCFA colonic composition”
- Assignee: INTERNATIONAL BUSINESS MACHINES CORPORATION (Armonk, NY)
Claims of interest:
- 1. A colonic composition, consisting of: a core consisting of at least one short chain fatty acid selected from the group consisting of butyrate, acetate and propionate, and combinations thereof, or a pharmaceutically acceptable salt or ester thereof; wherein at least one of acetate or propionate is present in said core; and at least one digestion-resistant layer covering said core, said digestion-resistant layer disintegrating in the colon.
- 1. A method of treating a patient suffering from a weight loss disorder, a condition that benefits from reduction of cholesterol, a condition of a colon, or diabetes or increased risk of diabetes, the method comprising:
- administering to said patient a dosage form containing a therapeutically effective amount of a colonic composition, said composition consisting of:
- a core consisting of at least one short chain fatty acid selected from the group consisting of butyrate, acetate and propionate, and combinations thereof, or a pharmaceutically acceptable salt or ester thereof; wherein at least one of acetate or propionate is present in said core; and
- at least one digestion-resistant layer covering said core, said digestion-resistant layer disintegrating in the colon; and releasing the core within the lumen of the colon.
While not directly involving a microbe, the claimed compositions and methods are of interest because they deliver short chain fatty acid products to the colon that are known to be key beneficial products of the healthy human microbiome. The method of treatment claims are notable for reciting a range of disorders that includes metabolic and weight loss disorders, disorders of the colon and a condition that benefits from reduction of cholesterol.
Both applications were prosecuted under the Track One accelerated examination procedure.
- Two documented sightings reported here of the elusive diagnostic method claim in its natural habitat.
- Patents highlighted herein further demonstrate that claims broadly reciting microbes at the genus level or even without reference to a particular bacterium are being allowed. In our experience, broad claims of this type have most often issued from lengthy, highly detailed disclosures, but several of the patents featured herein issued at 15 pages or fewer.
- Track One examination remains very popular and very efficient, and the cases featured herein demonstrate that relatively broad claims are readily attainable under this procedure.
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