Gut check: microbiome patent update



May 19, 2017

Patent Law Alert

Author(s): Mark James FitzGerald, Ph.D., David S. Resnick

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.

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 9,616,094

  • Issued April 25, 2017
  • Titled “Probiotics in a pre- and/or post-surgical environment&rdquo
  • Assignee: Nestec S.A. (Vevey, CH)

Claim of Interest:

  1. A method comprising administering a composition comprising a probiotic to an adult patient scheduled to undergo surgery, the probiotic acts on the colon of the adult patient and is selected from the group consisting of Lactobacillus johnsonii La1 (CNCM I-1225), Bifidobacterium longum CNCM I-2170, Bifidobacterium lactis Bb12 (DSM20215), Lactobacillus paracasei CNCM I-2116, Lactobacillus paracasei CNCM I-1292, Streptococcus faecium SF 68 and combinations thereof.

This claim recites the administration of specific strains of Lactobacilli, Bifidobacteria and Streptococcus, and combinations thereof, for probiotic pre-treatment of an individual before surgery. The applicants overcame an obviousness rejection on the basis of surprising results, with evidence showing that even different strains of the same species do not necessarily have the same beneficial effect on the colon. While instrumental in the grant of this patent, this rationale may pose issues for future applicants.

U.S. Patent 9,610,307

  • Issued April 25, 2017
  • Titled “Probiotic compositions containing clostridiales for inhibiting inflammation&rdquo
  • Assignee: Evelo Biosciences, Inc. (Cambridge, MA)

Claim of interest:

  1. A pharmaceutical composition comprising: an isolated population of anti-inflammatory bacterial cells consisting essentially of 3 or more strains of anti-inflammatory bacteria, wherein the 3 or more strains comprise Blautia producta, Ruminococcus torques and one or more strains selected from Eubacterium rectale, Ruminococcus obeum and Eubacterium ventriosum, wherein each strain of anti-inflammatory bacteria selected for inclusion in the composition is capable of increasing secretion of Interleukin 10 (IL-10) by a population of human peripheral blood mononuclear cells (PBMCs) in vitro, and wherein the isolated population of anti-inflammatory bacterial cells increases IL-10 secretion by PBMCs by at least 80% or more relative to each strain individually and a pharmaceutically acceptable excipient.

This composition claim recites a combination of anti-inflammatory bacterial strains of the species Blautia producta, Ruminococcus torques and one or more strain of the species Eubacterium rectale, Ruminococcus obeum and Eubacterium ventriosum. The claim includes the functional requirement that each strain can increase secretion of the anti-inflammatory cytokine IL-10 in an in vitro assay, and that the combination provides synergistic IL-10 induction. Synergy was mentioned in the specification, but data demonstrating synergies between certain species was provided in a post-filing declaration.

This is an interesting claim combination of specific species (not specific strains) in combination with a functional requirement and synergy between the species in that requirement. The non-strain-specific claims are supported by a lengthy specification teaching numerous strains of the various bacterial species.

U.S. Patent 9,642,882

  • Issued May 9, 2017
  • Titled “Composition for inducing proliferation or accumulation of regulatory T cells”
  • Assignee: The University of Tokyo (Tokyo, JP)

Claim of interest:

  1. A composition, comprising a purified bacterial mixture of three or more live bacterial strains belonging to Clostridium clusters IV and/or XIVa, wherein the bacterial mixture induces proliferation and/or accumulation of regulatory T cells, wherein the bacterial strains are spore-forming bacteria and are isolated from a human, and wherein the composition is formulated for delivery to the intestine.

This composition claim is interesting because it requires only three or more spore-forming bacterial strains belonging to Clostridium clusters IV and/or XIVa. Functional or process requirements include induction of Treg cells, isolation from a human, and formulation for delivery to the intestine. The application was prosecuted under the Track One accelerated examination procedure.

Also issued were claims drawn to methods of treating an infectious disease, an autoimmune disease or an allergic disease by administering the composition of claim 1. Data are presented for efficacy in a murine colitis model. Specific diseases recited in dependent claims include organ transplant rejection, inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, sprue, rheumatoid arthritis, Type 1 diabetes, graft versus host disease, multiple sclerosis and Clostridium difficile infection.

U.S. Patent 9,642,880

  • Issued May 9, 2017
  • Titled “Microbiota restoration therapy (MRT), compositions and methods of manufacture.
  • Assignee: Rebiotix (Roseville, MN)

Claim of interest:

  1. A method for treating ulcerative colitis, the method comprising: administering a microbiota restoration therapy composition to a patient with ulcerative colitis; wherein the microbiota restoration therapy composition is pre-screened for bacterial diversity; wherein the pre-screened microbiota restoration therapy composition includes bacteria from at least seven different families and has a Shannon Diversity Index of 0.4-2.5 when calculated at the family level; and wherein the microbiota restoration therapy composition comprises a mixture of an effective amount of fecal microbiota from a fresh human fecal sample and a mixture of polyethylene glycol and saline, the polyethylene glycol added to the fresh human stool sample at a concentration of 30-90 g/L.

Applicants overcame an obviousness rejection by addition of language requiring the fecal sample to be fresh (as opposed to frozen) and requiring the use of polyethylene glycol (PEG) . The applicants argued that the prior art teaching regarding polyethylene glycol  was directed to frozen fecal samples, and noted that PEG is known for a purgative effect—not what one might logically choose for a therapy one hopes to re-establish a healthy microbiota.

U.S. Patent 9,636,369

  • Issued May 2, 2017
  • Titled “Supplementation of maternal diet”
  • Assignee: Nestec, S.A (Vevey, CH).

Claim of interest:

  1. A method for reducing the risk of a condition associated with gestational diabetes mellitus in infant(s), the method comprising: administering to a pregnant woman a therapeutically-effective amount of a composition comprising a probiotic mixture of Lactobacillus rhamnosus CGMCC 1.3724 and Bifidobacterium lactis CNCM 1-3446.
  2. The method of claim 1, wherein administration of the composition to the woman continues after delivery.

These claims require administering a mixture of two specific strains of Lactobacillus and Bifidobacteria to a woman during and after pregnancy to reduce risk to the infant posed by maternal gestational diabetes. Among other things, the claim illustrates that while “preventing” disease is often difficult to support under the § 112 enablement standard, reduction of risk for developing a disease or disorder can pass the test. This claim is also interesting from a purely scientific standpoint—reduction of the risk of the infant developing metabolic syndrome by treating the mother with probiotics during gestation is another illustration of the far-reaching power and potential of the microbiome!

U.S. 9,636,325

Claim of interest:

  1. A method for treating an individual suffering from Huntington's disease, which comprises administering to said individual indole lactic acid or a mixture of indole-3-propionic acid and indole lactic acid or a salt or ester or protein complex or inorganically bound  preparation thereof and a pharmaceutically acceptable carrier therefor, whereby to increase available levels of indole-3-propionic acid in the gut of the individual

This method claim focuses not on the microbe, but on administering gut metabolites of microbes for therapeutic effect. The applicant overcame an obviousness rejection over prior art indicating that indole-3-propionic acid could benefit certain neurodegenerative disorders by requiring the administration of indole lactic acid or a combination of indole lactic acid and indole-3-propionic acid.

In summary, surprising results, demonstrated by data in the specification, provides a very reliable pathway to allowance of microbiome-related claims. The same can be said for synergy—importantly, under some circumstances, synergy referred to in the specification but demonstrated only in a post-filing submission can be persuasive.

While different behaviors of different strains of the same species can help support surprising results, the other side of that coin is that when different strains of the same species behave differently, broad claims defining the subject microbes at the genus or species level may face rejection for lack of enablement due to unpredictability

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