DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application is a National-Stage entry of PCT/US2021/021790, filed 3/10/2021.
Applicant claims domestic benefit under 35 U.S.C. 119(e) to U.S. Provisional Patent Application No. 62/987,757, filed 3/10/2020. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 9/22/2022 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1, 13-14, 25, 28, 31, 34, 46, 62, 68, 70, 74, 78, 83, 85-87, 91, 115, 118, 121, 126-127, 135, and 137) in the reply filed on 11/10/2025 is acknowledged.
Claims 138, 146, 148, and 150 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/10/2025.
Regarding the species election, Applicant elected without traverse a microbial consortium wherein the first metabolic substrate is a primary bile acid selected from the group consisting of lithocholic acid (LCA), and deoxycholic acid (DCA), and the one or more than one metabolite is selected from the group consisting of iso-lithocholic acid (iso-LCA), or iso-deoxycholic acid (iso-DCA), as recited in claim 115 and claims dependent thereof. Applicant states that “claims 1, 13-14, 25, 28, 31, 34, 46, 62, 68, 70, 74, 78, 83, 85-87, 91, 115, 118, 121, 126-127, 135, and 137 encompass the elected species”. However, claim 25 recites specifically “the first metabolic substrate is oxalate; the metabolite is (i) formate or (ii) formate and carbon dioxide; and the supportive community of microbes catalyzes the synthesis of methane from formate and H2”, as discussed in the communication mailed 5/9/2025. Claim 25 is thus directed to a non-elected species of the invention, distinct from the elected species of the invention that is encompassed by species claims 115, 118, 121, and 126-127. Claims 28, 31, 34, 78, 83, 85-87, and 91 are dependent on claim 25, and thus also drawn to non-elected species of the invention.
Upon further consideration of the art and the disclosure, the requirement in the communication mailed 5/9/2025 for an election of species regarding the supportive microbial community has been withdrawn herein. The search has been expanded to include any of the options of generic claim 1, “1)”-“4)” and all alternatives therein.
Claims 1, 13-14, 46, 62, 68, 70, 74, 135, and 137 are generic to the elected species of the substrate and metabolite.
Claims 25, 28, 31, 34, 78, 83, 85-87, and 91 are herein withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Response to Amendment
Applicant’s preliminary amendments to the claims filed 9/9/2022 is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Claims 1, 13, 14, 46, 62, 68, 70, 74, 115, 118, 121, 126, 127, 135, and 137 are pending and have been examined on the merits herein.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
The disclosure is objected to because of the following informalities:
On pages 13, 163, 164, 165, 257, the specification recites the medium compositions of “Mega Media” and “Chopped Meat Media” without providing an adequate description of the composition, or a commercial source from which the media may be suppled. There is no recitation of these specific mediums in the claims. If Applicant wishes to amend these features into the claim in any future amendments or continuation applications, there will be no support for these media in the description as filed. If these are defined media which are well-known to the art, then Applicant should provide evidence explaining the compositions in order to amend the ingredients/composition without raising an issue of new matter (see e.g. MPEP § 608.04(a) and MPEP § 2163.07: “the mere inclusion of dictionary or art recognized definitions known at the time of filing an application may not be considered new matter.”).
In [0223], the phrase “administration of a microbial consortium results in enhanced conversion of primary bile acids (e.g., DCA and/or LCA) in a subject as compared to a subject administered with either a plurality of active microbes or a supportive community of microbes alone” is used. As discussed below in the claim objections, it is factually incorrect to say that DCA and LCA are primary bile acids, when they are recognized in the art as secondary bile acids. DCA and LCA are properly described as secondary bile acids elsewhere in the instant disclosure (see [0152] and [0374]). Correction is required.
TRADE NAMES, TRADEMARKS, AND OTHER MARKS USED IN COMMERCE:
The use of at least the terms Biotyper® Biotarget® (pg. 86); DNeasy® Power Soil Kit (pg. 86); and TruSeq® (pg. 87) which are each a trade name or a mark used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks (see MPEP 608.01(v) and 608.01(u)). Applicant is requested to correct any other improperly identified trade names of which Applicant may become aware of in the disclosure.
Appropriate correction is required.
Claim Interpretation
The elected claims are all directed to a composition, a microbial consortium comprising a plurality of active microbes and an effective amount of a supportive community of microbes, the supportive community of microbes comprising between 1 and 300 strains (as defined in claim 1). A product or composition claim is defined by its structure or composition (MPEP § 2112.01), or in this case, by the identity of the provided strains. Limitations regarding functional properties are being interpreted as functional characteristics arising from the provided microbes, in other words, these are considered to be intrinsic or inherent properties of the provided bacteria strains and will be afforded the proper patentable weight. See MPEP § 2173.05(g) and see also Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 76 USPQ 280 (1948) and Novitski, Ex parte, 26 USPQ2d 1389 (Bd. Pat. App. & Inter. 1993) in regards to inherent properties of organisms.
For claim 115 (and indeed, to all of the claims as they specifically pertain to the elected species having activity wherein the first substrate is DCA or LCA and the metabolite affected by the supportive community is iso-DCA or iso-LSA, the claims do not provide a full description of a consortium that would obtain this result, however, from the specification [0373] the following is determined: “One cohort of mice is colonized with a full microbial consortium that comprises a plurality of microbes including species having 7α-dehydroxylation activity and species having bile salt hydrolase (BSH) activity”. Further, claim 127 recites that the active microbes comprises one more phyla selected from Firmicutes and Actinobacteria, and one or more strains selected from Eggerthella lenta and Clostridium scindens. Thus, under the B.R.I. of the claims, a composition meeting these limitations or evidenced of having 7α-dehydroxylation activity and bile salt hydrolase (BSH) activity will be deemed capable of fulfilling the claimed function.
Claim Objections
Claim 115 is objected to because of the following informalities:
Claim 115 recites “a primary bile acid selected from the group consisting of lithocholic acid (LCA) and deoxycholic acid (DCA)”. The word “primary” appears to be an error and should instead say secondary. This is supported in [0374] of the specification, in the Examples, which discuses that “the standard diet is supplemented either with 1% (w/w) hepatotoxic secondary bile acid LCA to induce PSC, or with an equimolar concentration of the conjugated bile acid GCDCA or the primary bile acid CDCA. GCDCA can be metabolized into CDCA by a population of microbes having BSH activity, and CDCA can be metabolized into LCA by a population of microbes having 7α-dehydroxylation activity.” Further, [0152] of the specification states that “Unconjugated primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA), are substrates for 7α-dehydroxylation by select members of the gut microbiota. As shown below, 7α-dehydroxylation converts CA and CDCA to lithocholic acid (LCA) and deoxycholic acid (DCA), respectively. LCA and DCA are secondary bile acids that have been implicated in adverse health outcomes.”. Therefore, from this and the relevant prior art, it is apparent that the use of “primary bile acid” to describe the target substrates LCA and DCA is incorrect. The term should be amended to “secondary bile acid”. See also [0172]).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 13, 14, 46, 62, 68, 70, 74, 115, 118, 121, 126, 127, 135 and 137 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation “a plurality of active microbes and an effective amount of a supportive community of microbes”. There is no manner to determine what constitutes an “active microbe” and what distinguishes the active microbe from the supportive community. Further, in the case of multifunctional organisms, can an “active” microbe also be a member of the supportive community? From the description in the disclosure the supportive community of microbes are also all “active”, under the plain meaning of these terms. It is unclear if a “a plurality of active microbes” means merely a single strain with a plurality of cells, or whether this limitation requires more than one unique strain. In other words, is the term “plurality” used to indicate abundance of the microbe or the presence of multiple strains? The claim states that “the supportive community of microbes comprises between 1 and 300 microbial strains”. However, the claim does not specify any specific number for the “active microbes” and no specific structures are recited. No definite list of organisms is provided in these claims. The resulting claim is indefinite because one cannot determine the metes and bounds of the claimed communities when the boundaries which constitute the claimed consortia are undefined.
Claim 14 provides further limitations to the supportive community but does not further distinguish the active microbes from the supportive community. The claim is also indefinite.
Claim 46 recites that both the active microbes and the supportive community are selected from the (very large) Tables 4, 22, 23, 20, 16, 17, 18, or 19. However this does not address the issue of indefiniteness as there remains no way to distinguish “active” microbes from the supportive community. From this claim language, it appears that the “active microbes” and the “supportive community” are interchangeable.
Claim 127 specifies that the plurality of active microbes comprises one or more microbial phyla selected from Firmicutes and Actinobacteria, and one or more strain of E. lenta and C. scindens, and that the supportive community is 220 to 200 strains, however the claim is still indefinite as there appears to be substantial overlap with the organisms comprising the Active microbes and the supportive community because each can comprise members of the phyla Firmicutes and Actinobacteria. Even with this limitation, separating the two is impossible.
All other claims depend directly or indirectly from the rejected claim 1 and are, therefore, also rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for the reasons set forth above.
Claim 46 recites the limitation "the plurality of active microbes and the supportive community of microbes are selected from a group of microbes each comprising a 16S sequence at least 97% identical to any one of the microbes listed in Table 4, Table 22, Table 23, Table 20, Table 16, Table 17, Table 18 or Table 19". There is insufficient antecedent basis for this limitation in the claim. The incorporation by reference to the tables in the specification is improper. MPEP 2173.05(s) states “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table 'is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.' Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)". Under the B.R.I, in light of the issue identified above, the claims appear to be reciting that the supportive community comprises at least one microorganisms which have a 16S sequence at least 97% identical to one of SEQ ID NOs: 1-377 (see Table 4). Applicant is recommended to amend the claim as such, to cancel the claim, or to copy the table contents into the claim itself. There is no limit to the length of a claim. If the subject matter can be listed in the specification, that list can be copied and pasted into a claim.
Claim 68 recites “at least one of the plurality of active microbes has a higher first metabolic substrate metabolizing activity at a lower pH and one of the plurality of active microbes has a higher first metabolic substrate metabolizing activity at a higher pH, wherein the difference between the two pH values is at least 1.5, 2.0, 2.5, 3.0, 3.5, or 4.0 pH units. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In this case, the broadest recitation of the pH difference is “at least 1.5” difference the claim also recites “2.0, 2.5, 3.0, 3.5, or 4.0 pH units” which are narrowing statements of the range/limitation. Claim 68 is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is merely exemplary of the remainder of the claim, and therefore not required, or a required feature of the claims.
Further regarding claim 68, it is unclear what the terms of “a higher first metabolic substrate metabolizing activity” are in reference to. Is this a reference to the microbe having a higher metabolizing activity towards the first metabolic substrate at a high pH compared to a low one (or vice-versa) or does it mean that the first metabolic substrate metabolizing activity is higher than one, or all of, the other plurality of microbes? Are the “at least one of the plurality of active microbes” in line 2 the same microbe as the “one of the plurality of active microbes” in line 3? Yet, in claim 62, the term “at least one other of the plurality of active microbes” is used, however that is not recited in claim 68. Claim 62 is clearly in alternative form and recites “at least one other of the plurality of active microbes”.
For these reasons (multiple reference pHs, relative terminology, and indefiniteness as to which “one of the plurality...” means), there is no manner to decipher the meaning of the claim language and claim 68 is rejected as being indefinite.
Claim 74 recites similar language as claim 68 except for the variable is the substrate concentration and not the pH. The claim is rejected as being indefinite for all of the reasons applied to claim 68. Specifically, claim 74 recites “at least one of the plurality of active microbes has a higher first metabolic substrate metabolizing activity at a lower first metabolic substrate concentration and one of the plurality of active microbes has a higher first metabolic substrate metabolizing activity at a higher first metabolic substrate concentration” and also recites “the difference between the two first metabolic substrate concentrations is at least 1.2 fold, 2.0 fold, 3.0 fold, 4.0 fold, 5.0 fold, 6.0 fold, 7.0 fold, 8.0 fold, 9.0 fold, 10 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold”.
Claim 126 recites the element “the standardized substrate metabolization assay”, in line 2. There is insufficient antecedent basis for this limitation in the claim. This term does not appear in claim 115 on which claim 126 depends, or in claim 1, from which it depends indirectly.
For these reasons (relative terminology, multiple differences in substrate amounts which is also relative, and indefiniteness as to which “one of the plurality of active microbes” is referenced), there is no manner to decipher the meaning of the claim language and claim 74 is rejected as being indefinite.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
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 therefor, subject to the conditions and requirements of this title.
Claims 1, 13, 14, 46, 62, 68, 70, 74, 115, 118, 121, 126, 127, 135 and 137 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more.
For determining subject matter eligibility, the following analysis was considered, per MPEP § 2106.
Patent Eligibility Analysis Step 1: Step 1 of the eligibility analysis asks: is the claim to a process, machine, manufacture or composition of matter? Yes, the claims are directed to a composition. (Claims 1, 13, 14, 46, 62, 68, 70, 74, 115, 118, 121, 126, 127, 135, and 137, STEP 1: YES).
Patent Eligibility Analysis Step 2A Prong 1: Step 2A, prong 1 asks: does the claim recite an abstract idea, law of nature, or a natural phenomenon (product of nature)?
Claims 1, 13, 14, 46, 62, 68, 70, 74, 115, 118, 121, 126, 127, 135, and 137 each require a composition comprising a microbial consortium for administration to an animal, comprising: a plurality of active microbes and an effective amount of a supportive community of microbes, wherein the plurality of active microbes metabolize a first metabolic substrate to produce one or more than one metabolite, wherein the first metabolic substrate causes or contributes to disease in an animal, and the supportive community of microbes comprises between 1 and 300 microbial strains. In this case, the claims all recite a microbial consortium which includes naturally-occurring unmodified microorganisms (see Table 4 of the instant specification).
Thus, the B.R.I. of the claims include limitations encompassing natural products, specifically, any of the microorganisms which are naturally occurring and obtained from natural sources, particularly fecal samples (see [0193], [0224], [0254], [0306] of the specification).
When a claim recites a nature-based product limitation, the markedly different characteristics (MDC) analysis is used to determine whether the natural product has markedly different characteristics from its natural counterpart (see MPEP 2106.04(c)). MPEP § 2106.04(c) explains “Where the claim is to a nature-based product produced by combining multiple components, the markedly different characteristics analysis should be applied to the resultant nature-based combination, rather than its component parts.”
The first step in the MDC analysis requires selecting the appropriate natural counterpart to the nature-based product. MPEP § 2106.04(c)(II)(A), states “When the nature-based product is a combination produced from multiple components, the closest counterpart may be the individual nature-based components of the combination. For example, assume that applicant claims an inoculant comprising a mixture of bacteria from different species, e.g., some bacteria of species E and some bacteria of species F. Because there is no counterpart mixture in nature, the closest counterparts to the claimed mixture are the individual components of the mixture, i.e., each naturally occurring species by itself. See, e.g., Funk Bros., 333 U.S. at 130, 76 USPQ at 281 (comparing claimed mixture of bacterial species to each species as it occurs in nature)”.
In this case, for claims 1, 13, 14, 46, 62, 68, 70, 74, 135, and 137, the appropriate natural counterpart for the microbial consortium would be a community of bacteria including at least one of the natural occurring active microbial strains and at least 1 supportive microbe (e.g. a supportive community between 1-300), and comprising at least three phyla selected from the group consisting of Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria, Verrucomicrobia, and Euryarchaeota (per claim 14). For claim 137, a carrier, e.g. water, is also required.
For claims 115, 118, 121, 126, 127, the appropriate natural counterpart is a community of a plurality of microbes which metabolize bile acids comprises one or more microbial phyla selected from Firmicutes and Actinobacteria, and one or more microbial strain selected from Eggerthella lenta and Clostridium scindens, according to claim 127 and embodiments ([0146]-[0147], where this is attributed to having high amounts of 3α-hydroxysteroid dehydrogenase (3α -HSDH) and 3(β-hydroxysteroid dehydrogenase (3β-HSDH) activity). The recited bacteria are all naturally occurring, and the activities are natural properties thereof.
The second step in the MDC analysis is to identify appropriate characteristics to compare. Appropriate characteristics can be expressed as the nature-based product’s structure, function, and/or other properties, and are evaluated on a case-by-case basis. In this case, the appropriate characteristics include the biological functions and recited activities including the capability of claimed microorganisms to metabolize specific substrates and or to support another community of microbes, specifically the activity to metabolize a primary bile acid (LCA or DCA) and wherein the metabolite is one of iso-LCA or iso-DCA. Phenotypic characteristics which include functional, whereas structural characteristics such as the shape, size, color, and behavior of the microorganism, and structure and form (chemical, genetic or physical) include the genetic structure of the natural components (i.e. the naturally occurring 16S sequences, as in Table 4).
The final step in the markedly different characteristics analysis is to compare the characteristics of the claimed nature-based product to its naturally-occurring counterpart in its natural state, in order to determine whether the characteristics of the claimed product are markedly different. The courts have emphasized that to show a marked difference, a characteristic must be changed as compared to nature, and cannot be an inherent or innate characteristic of the naturally-occurring counterpart or an incidental change in a characteristic of the naturally occurring counterpart. Myriad, 569 U.S. at 580, 106 USPQ2d at 1974-75. Thus, in order to be markedly different, the inventor must have caused the claimed product to possess at least one characteristic that is different from that of the counterpart (MPEP § 2016.04(c).II.C.). If there is no change in any characteristic, the claimed product lacks markedly different characteristics, and is a product of nature exception.
The claims are directed to a product, microbial consortia, which amounts to nothing more than a combination of naturally occurring microorganism strains, which have no changed characteristics, structurally or functionally, compared to their individual characteristics.
The claims encompasses the natural bacteria, identical to the strains as they occur in nature, and the characteristics of the claimed product are all innate characteristics of the component organisms. There are no markedly different characteristics.
Please note that combining natural products does not remove the claims from reading upon a judicial exception (Funk Brothers Seed Col. V. Kalo Inoclulant Col. – 333 U.S. 127 (1948)) because there is no evidence of a marked difference brought about by combining the instantly claimed bacteria strains. See MPEP § 2106.04(b)(II), and 2106.04(c)(II)(C).
Gordon et al. (US PGPub No. 20160326574), pertains to methods for characterizing the maturity of a subject's gut microbiota to provide a measure of gastrointestinal health without having to query the whole microbiota. Gordon discuses that “the proportional representation of a minimal number of bacterial taxa defines a healthy gut microbiota as it assembles (i.e. matures). The changes in the relative abundance of these bacterial taxa over time are consistent across substantially all healthy subjects within the same age range” [0051]. Gordon also discloses that, “a group of bacterial taxa that define normal maturation of the gut microbiota in may comprise at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or at least 59 of the bacterial taxa listed in Table A” ([0063]) and “in some embodiments, “in other embodiments, a group of bacterial taxa that define normal maturation of the gut microbiota comprises (a) at least 20 bacterial taxa listed in Table B; and (b) at least 4 bacterial taxa listed in Table C” ([0064]). It is noted that these are naturally occurring bacteria, known to be found in gut microbiota samples. Gordon also describes 220 bacteria taxa whose abundances are significantly altered in the microbiota of children with severe acute malnutrition (SAM) (Table 13; [0026]-[0027]; [0128]).
Further, Rinninella et al. (“What is the Healthy Gut Microbiota Composition? A Changing Ecosystem across Age, Environment, Diet, and Diseases”. Microorganisms. 2019;7(1):14. Published 2019 Jan 10) is a review article that aims to define what would be the optimal gut microbiota composition in order to maintain these optimal microbiota immune and metabolic functions (see pg. 2, Introduction). Rinninella states that “Gut microbiota are composed of several species of microorganisms, including bacteria, yeast, and viruses... a few phyla are represented, accounting for more than 160 species [12]. The dominant gut microbial phyla are Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia, with the two phyla Firmicutes and Bacteroidetes [13] representing 90% of gut microbiota”. Rinninella thus establishes that the microbial consortia claimed herein encompasses those phylum known to be naturally present in human gut microbiota (Figure 1 and Table 1).
The instant specification provides evidence that the claimed consortiums encompass those derived entirely from donor fecal samples (e.g. [0193] of the specification states that the “microbial consortia described herein are designed to include representative microbial strains isolated from a healthy donor fecal sample, with the exception of species known to be associated with pathogenesis, which represent microbial species belonging to a diverse array of taxonomic phyla including, Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria, Verrucomicrobia and Euryarchaeota” and [0310] of the specification states that a supportive community of candidate consortium IV, used in an embodiment of the invention herein, was “constructed using strains isolated exclusively from fecal samples of two healthy donors”). See also [0311] and Table 20.
Further, the examples and embodiments in the instant disclosure indicate that the ability to degrade substrates and produce metabolites, such as bile acid compounds, are intrinsic innate characteristics of select unmodified bacteria, as they are found in nature (see e.g. [0342]-[0344]; Figure 18). The bile acid degradation was tested on individual strains, and not on the claimed consortia, thus indicated that the claimed activity is not due to any synergy or emergent properties but due to the innate characteristics of the bacteria.
Claim 13 further limits the functional properties of the bacteria, which are all intrinsic features and thus are also natural properties (see Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 76 USPQ 280 (1948)).
Claim 14 provides at least three phyla that the consortia must comprise, however, these are all natural phyla, found naturally in fecal donor samples, as discussed above for claim 1.
Claim 46 recites that the active and supportive community must have microbes selected from at least those of Table 4 (and having a 16S sequence at least 97% identical thereto), these are also natural properties and inherent features of the natural microorganisms.
Claims 62, 68, 70, and 74 all recite further functional limitations concerning natural activities of the claimed microbial consortia, and the components thereof. These are all intrinsic features and thus are also natural properties (see Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 76 USPQ 280 (1948)).
Claims 115, 118, 121, 126, and 127 further recite that the first metabolic substrate is a primary bile acid selected from the group consisting of lithocholic acid (LCA), and deoxycholic acid (DCA), and the one or more than one metabolite is selected from the group consisting of iso- lithocholic acid (iso-LCA), or iso-deoxycholic acid (iso-DCA), which limits the consortia to those having bacterial which metabolize these bile acid and bile acid precursors. Claim 127 recites that the plurality of active microbes which metabolize bile acids comprises one or more microbial phyla selected from Firmicutes and Actinobacteria, one or more microbial strain selected from Eggerthella lenta and Clostridium scindens; and the supportive community of microbes comprises 20 to 200 microbial strains. The specified organisms are all naturally occurring and found in the fecal donor samples described in the disclosure (see Tables 3 and 4).
Further, Harris et al. (“Bile acid oxidation by Eggerthella lenta strains C592 and DSM 2243”. Gut Microbes. 2018;9(6):523-539. doi:10.1080/19490976.2018.1458180) discusses a novel strain of Eggerthella lenta, strain C592, isolated from a human gut microbiota sample (Abstract, Title, pg. 524 right col, under “Results”). Harris et al. also discloses using the strain Clostridium scindens VPI 12708, a bile acid 7a-dehydroxylating gut bacteria (pg. 524, last sentence of left col). and discusses other strains of Clostridium scindens having natural bile acid metabolism activity (pg. 532, left col first paragraph under “Discussion”). Thus it is evident from both the disclosure and relevant art that Eggerthella lenta and Clostridium scindens are naturally-occurring human gut bacteria having natural bile acid oxidation activity. There are no marked differences from the natural bacteria.
Claim 135 recites the microbial consortiums, and that it decreases a concentration of the first metabolic substrate when administered to an animal. This is an intended use limitation at a high level of generality, and is recited as a conditional limitation “e.g. when administered...”. The ability of the consortium to degrade a metabolic substrate is an innate characteristic. Further, combinations of natural organisms, each performing their own intrinsic functions, does not result in a markedly different characteristic than the naturally occurring bacteria. See the fact pattern of Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 76 USPQ 280 (1948)), as described in MPEP § 2106.04(c)(1)(A), (II)(A) and (II)(B).
Claim 137 recites a composition of a microbial consortium and a pharmaceutically acceptable carrier or excipient. A pharmaceutically acceptable carrier or excipient includes natural solvents and vehicles including water, and emulsions, such as oil/water or water/oil emulsions (see [0085] of the specification), encompassing natural suspensions of bacteria.
Thus, no characteristics of the naturally-derived microbial consortia are markedly changed in the claimed subject matter, and these are all found naturally in consortia from fecal samples. When considered as a whole composition, there is no evidence or suggestion that the claimed product has any markedly different characteristic than a combination of the individual naturally occurring products.
Therefore, the claimed product lacks markedly different characteristics, and is a product of nature exception (Claims 1, 13, 14, 46, 62, 68, 70, 74, 115, 118, 121, 126, 127, 135, and 137 Step 2A, Prong 1: YES).
Patent Eligibility Analysis Step 2A Prong 2: Step 2A, prong 2 asks: does the claim recite additional elements that integrate the judicial exception into a practical application?
Claims 1, 13, 14, 46, 62, 68, 70, 74, 115, 118, 121, 126, and 127 do not recite any additional elements other than the product of nature exception, specific limitations regarding the identity of the natural composition (i.e. limitations regarding which phyla or species must be there), and innate functional characteristics thereof. There are no additional structural elements in these claims. These limitations do not integrate the judicial exception into a practical application because these are functional limitations that reflect innate capabilities of the natural products, and does not require any particular or directed application of the ineligible product(s).
Claim 135 recites that the claimed consortia decreases a concentration of the first metabolic substrate when administered to an animal, but this doesn’t differentiate the claims from the natural product, nor does it recite a practical application thereof. As discussed above, combinations of natural organisms, each performing intrinsic functions, does not result in a markedly different characteristic than the naturally occurring bacteria. See the fact pattern of Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 76 USPQ 280 (1948)), as described in MPEP § 2106.04(c)(1)(A), (II)(A) and (II)(B). This is an intended use limitation at a high level of generality, and is recited as a conditional limitation “e.g. when administered...”, and not a practical application of the ineligible product. To be considered a practical application, a claim should recite a particular method of administering an effective dose of the product to a suitable subject population to produce a specific effect (for example, treating or alleviating symptoms of a specific disease). High-level recitations of “treating” or “preventing” are also not sufficient to practically apply the judicial exception (see 2106.04(d)(2)).
Claim 137 recites a pharmaceutically acceptable carrier or excipient with the natural product, but this does not require any practical application thereof.
Therefore, the judicial exception is not integrated into a practical application because the claims do not recite any additional elements other than the naturally-occurring product(s) and innate functional characteristics thereof (Claims 1, 13, 14, 46, 62, 68, 70, 74, 115, 118, 121, 126, 127, 135, and 137, Step 2A, Prong 2: NO).
Patent Eligibility Analysis Step 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception?
The recitation of an innate property or characteristic of a natural bacteria does not result in significantly more than the judicial exception. Further, it is noted that adjustments or optimization of a concentration of a completely natural product does not result in any particular transformation of the ineligible natural product, nor does such adjustment of concentration constitute an inventive concept. Adjustment of concentrations or routine conditions such as pH to optimize a particular activity of a microorganisms (such as metabolism, fermentation, or compound degradation) does not result in significantly more than the ineligible natural product.
MPEP § 2106.04(b).I, describes that: “[t]he courts have identified the following concepts and products as examples of laws of nature or natural phenomena… ii. qualities of bacteria such as their ability to create a state of inhibition or non-inhibition in other bacteria, Funk Bros., 333 U.S. at 130, 76 USPQ at 281”. The instant claims are reciting similar naturally occurring abilities of bacteria as explained therein.
Claims 1, 13, 14, 46, 62, 68, 70, 74, 115, 118, 121, 126, and 127 do not practically limit the claims to anything other than the natural product, instead these merely recite specific elements or functional properties of the product. These claims only recite limitations regarding the identity of the natural composition (i.e. requiring certain phyla or species present) and innate functional characteristics thereof. These are functional limitations that reflect innate capabilities of the natural product, and further all the claims encompass consortiums of bacteria that can be obtained completely from natural sources, i.e. the fecal samples of the instant disclosure.
None of the additional elements recited in claims 135 amount to significantly more than the ineligible natural product. The claim as presented recites a generic intended use. The generally-claimed administration of the consortia to an unlimited number of possible subjects does not result in a claim that is drawn to significantly more than the judicial exception.
Regarding claim 137, the carrier, encompasses additional natural products, and thus cannot be considered an additional element that amounts to significantly more than the ineligible natural product.
When considered individual or in combination, the claims do not amount to more than the judicial exception.
Thus, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception (Claims 1, 13, 14, 46, 62, 68, 70, 74, 115, 118, 121, 126, 127, 135, and 137, Step 2B: NO).
As such, the claims do not qualify as eligible subject matter. For these reasons the claims are rejected under section 101 as being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 14, 115, and 118 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ridlon et al. (“The 'in vivo lifestyle' of bile acid 7α-dehydroxylating bacteria: comparative genomics, metatranscriptomic, and bile acid metabolomics analysis of a defined microbial community in gnotobiotic mice.” Gut microbes vol. 11,3 (2020): 381-404. doi:10.1080/19490976.2019.1618173).
Ridlon discloses colonizing germ free mice with a consortium of human gut bacterial isolates capable of metabolizing taurine-conjugated bile acids (Abstract).
The consortium of Ridlon includes bile salt hydrolase-expressing Bacteroides uniformis ATCC 8492, Bacteroides vulgatus ATCC 8482, Parabacteroides distasonis DSM 20701, as well as taurine-respiring Bilophila wadsworthia DSM 11045, deoxycholic/lithocholic acid generating Clostridium hylemonae DSM 15053 and Clostridium hiranonis DSM 13275 as well as butyrate and iso-bile acid-forming Blautia producta ATCC 27340 (Abstract, Figure 1).
Ridlon discloses that Blautia producta express both 7β-HSDH and 3α-and 3β-HSDH, and was included due to its ability to oxidize and epimerize bile acids as well as generation of butyrate important for epithelial and immune development (see pg. 383, sentence spanning cols 1 and 2). Ridlon discloses that “Bacteria that composed these consortia included human fecal isolates, such as bile salt deconjugating strains of Bacteroides uniformis, Bacteroides vulgatus, and Parabacteroides distasonis, the taurine-respiring δ-Proteobacteria member Bilophila wadsworthia, and bile acid 7α dehydroxylating Firmicutes C. hylemonae and C. hiranonis.” (pg. 382, right col, last paragraph).
Ridlon discloses measuring the bile acid metabolomics in cecum, serum, and liver of gnotobiotic mice administered B4PC2 human gut bacterial consortium (Figure 7). Ridlon states that “Lithocholic acid derivatives included isolithocholic acid (3β-monohydroxy-5β-cholan-24-oic acid) and allo-isolithocholic acid (3β monohydroxy-5α-cholan-24-oic acid). The formation of 3β-isomers of LCA can be explained by expression of 3α-HSDH and 3β-HSDH by B. producta.” (pg. 395, left col, 2nd paragraph).
Further Ridlon discloses that “Bile acid metabolism by gut bacteria is of considerable biomedical interest with implications for liver and colon cancers, gallstone disease, cirrhosis of the liver, and Clostridioides difficile (C. diff) infection (Introduction, pgs. 381-382), and also teaches that “Excess concentrations of secondary bile acids such as DCA and LCA in the GI tract are associated with subsets of cholesterol gallstone patients,6 liver cancer,1,2 and colorectal cancer” (pg. 399, left col, first paragraph).
Therefore, Ridlon discloses a microbial consortium for administration to an animal (administered to mice therein), comprising: a plurality of active microbes (e.g. the bile acid 7α dehydroxylating Firmicutes C. hylemonae, C. hiranonis in addition to B. producta which degrades LCA to form 3β-isomers of LCA, including iso-LCA) and an effective amount of a supportive community of microbes (e.g. the bile salt deconjugating strains of Bacteroides uniformis, Bacteroides vulgatus, and Parabacteroides distasonis, the taurine-respiring δ-Proteobacteria member Bilophila wadsworthia), wherein the plurality of active microbes metabolize a first metabolic substrate to produce one or more than one metabolite (the formation of LCA which is then degraded to derivatives including iso-LCA by B. producta), wherein the first metabolic substrate causes or contributes to disease in an animal (LCA is associated with various cancers), and the supportive community of microbes comprises between 1 and 300 microbial strains, as recited in claim 1.
Regarding claim 14, Ridlon discloses a consortium having members of the phyla Bacteroidetes, Firmicutes, and Proteobacteria, as indicated above.
Regarding claim 115, Ridlon discloses that LCA is a substrate which is converted to the metabolite iso-LCA by the activities of the iso-bile acid-forming strain Blautia producta.
Regarding claim 118, Ridlon discloses that microorganisms with bile salt hydrolase (BSH) activity catalyze the deconjugation of taurine from conjugated bile acids to form cholic acid (Bacteroides uniformis, Bacteroides vulgatus, and Parabacteroides distasonis, see Table 1 and Figure 8).
Thus, the microbial composition disclosed in Ridlon, is found to anticipate all the required limitations of claims 1, 14, 115, and 118
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 13, 14, 46, 62, 68, 70, 74, 115, 118, 121, 126-127, 135, and 137 are rejected under 35 U.S.C. 103 as being obvious over Henn et al. (US PGPub No. 20160030494), with supporting evidence from Rinninella et al. (“What is the Healthy Gut Microbiota Composition? A Changing Ecosystem across Age, Environment, Diet, and Diseases”. Microorganisms. 2019;7(1):14), in view of Ridlon et al. (“The 'in vivo lifestyle' of bile acid 7α-dehydroxylating bacteria: comparative genomics, metatranscriptomic, and bile acid metabolomics analysis of a defined microbial community in gnotobiotic mice.” Gut microbes vol. 11,3 (2020): 381-404. doi:10.1080/19490976.2019.1618173).
Henn et al. is drawn to therapeutic compositions containing combinations of bacteria, for the maintenance or restoration of a healthy microbiota in the gastrointestinal tract of a mammalian subject, and methods for use thereof (Abstract, Title).
Henn teaches that a bacterial composition can comprise at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21, 22, 23, 24, 25, 26, 27, 28, 29 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or at least 40, at least 50 or greater than 50 types of bacteria, as defined by species or operational taxonomic unit (OTU), or otherwise as provided herein. In some embodiments, the bacterial composition includes at least 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, or greater ([0220]). Henn also discloses various limits on the upper number of species, including “the network ecology comprises 1000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 50 or fewer types of bacteria, such as 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10 or fewer,” ([0221]). Therefore, Henn teaches microbial consortia having active microbes and supportive microbes, wherein the community comprises between 1 and 300 strains.
Henn states that “Network ecologies can be optimized to have specific biological properties including but not limited to being of specific size (as example a specific number or OTUs); having a frequency of being observed in a population of healthy individuals (i.e. pervasiveness)... or comprising specific functional capabilities such as but not limited to the ability metabolize secondary bile acids, or produce short chain fatty acids (SCFAs), or the biological intersection in which network ecology falls in a comparative phenotype map (see FIG. 19). The constituents of a network ecology can be optimized using both computational means as well as experimental means.” ([0482]). Henn also teaches that “The invention includes a method for catalyzing secondary metabolism of bile acids within a mammalian subject” ([0061]).
Henn teaches various embodiments of the bacterial compositions, including one that comprises at least one or more of the following: Enterococcus faecalis (previously known as Streptococcus faecalis) (e.g. SEQ ID NO3, FBI00003 in the instant Table 4), Clostridium innocuum, Clostridium ramosum, Bacteroides ovatus (e.g. SEQ ID NO 189, FBI00189 in Table 4), Bacteroides vulgatus (e.g. SEQ ID NO: 39, FBI00039 in Table 4), Bacteroides thetaoiotaomicron (e.g. SEQ ID NO:20, FBI00020 in Table 4), Escherichia coli, Clostridium bifermentans, and Blautia producta (also known as Peptostreptococcus productus) ([0224]).
Henn teaches that the composition may also include: Acidaminococcus intestinalis, Bacteroides ovatus, two strains of Bifidobacterium adolescentis, two strains of Bifidobacterium longum, Blautia producta, Clostridium cocleatum, Collinsella aerofaciens, two strains of Dorea longicatena, Escherichia coli, Eubacterium desmolans, Eubacterium eligens, Eubacterium limosum, four strains of Eubacterium rectale, Eubacterium ventriosumi, Faecalibacterium prausnitzii, Lachnospira pectinoshiza, Lactobacillus casei, Lactobacillus casei/paracasei, Paracateroides distasonis, Raoultella sp., one strain of Roseburia (chosen from Roseburia faecalis or Roseburia faecis), Roseburia intestinalis, two strains of Ruminococcus torques, two strains of Ruminococcus obeum, and Streptococcus mitis ([0226]).
Rinninella et al. (“What is the Healthy Gut Microbiota Composition? A Changing Ecosystem across Age, Environment, Diet, and Diseases”. Microorganisms. 2019;7(1):14. Published 2019 Jan 10) is a review article that aims to define what would be the optimal gut microbiota composition in order to maintain these optimal microbiota immune and metabolic functions (see pg. 2, Introduction). Rinninella states that “Gut microbiota are composed of several species of microorganisms, including bacteria, yeast, and viruses... a few phyla are represented, accounting for more than 160 species [12]. The dominant gut microbial phyla are Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia, with the two phyla Firmicutes and Bacteroidetes [13] representing 90% of gut microbiota”. Figure 1 of Rinninella demonstrates various examples of the taxonomic gut microbiota composition, and provides evidence of the species which belong to each claimed phylum.
From the evidence in Rinninella (Fig 1 and Table 1), it is can be determined that the embodiments disclosed in Henn have microbes comprising at least three phyla from Bacteroidetes (e.g. Bacteroides ovatus, Bacteroides vulgatus, Bacteroides thetaoiotaomicron), Firmicutes (e.g. Roseburia faecalis, Roseburia faecis, Clostridium innocuum, Clostridium ramosum), Actinobacteria (e.g. Bifidobacterium longum, Bifidobacterium adolescentis) and also Proteobacteria (e.g. E. coli strains).
Therefore, Henn is determined to teach microbial consortia that include active microbes and supportive microbes (including a plurality of microbes), the communities comprising compositions that are encompassed by the instant claims 1 and 14, particularly, having three or more distinct microorganisms, representing at least three phyla from Bacteroidetes, Firmicutes, Actinobacteria, and Proteobacteria (e.g. the consortium of [0226]). All of the structural features of the instant claims are thus fulfilled by this embodiment of Henn.
Regarding the functional limitations, particularly that the plurality of active microbes metabolize a first metabolic substrate to produce one or more than one metabolite and there are supportive microbes which have an activity selected from one of 1), 2), 3), or 4), Henn teaches possible metabolic substrates to provide active microbes to digest, including primary bile acids and/or bile salts (depletion of taurocholate, glycocholate, ursocholate, cholate, glycochenodeoxycholate, taurochenodeoxycholate, see claim 78, [0063]).
It is noted that the elected species is drawn to active microbes wherein the first metabolic substrate is a primary bile acid selected from the group consisting of lithocholic acid (LCA), and deoxycholic acid (DCA), and the one or more than one metabolite that is produced is selected from the group consisting of iso-lithocholic acid (iso-LCA), or iso-deoxycholic acid (iso-DCA).
Henn teaches that “Commensal bacteria are involved in processing primary bile acids to secondary bile acids in the colon. Known biotransformations of bile acids by commensal GI bacteria include deconjugation of the conjugated bile salts to liberate free bile acids and amino acid moieties, removal of hydroxyl groups principally the C-7 hydroxyl group of the cholic acid moiety, oxidative and reductive reactions of the existing hydroxyl groups, and epimerization of bile acids.” ([0181]). Further, Henn teaches that “The canonical first step in bile acid metabolism is deconjugation of the taurine or glycine group through enzymes termed bile salt hydrolases, to yield CA and CDCA. These bile acids are then substrates for a series of enzymatic steps that remove the 7-alphahydroxy group to form deoxycholic acid (DCA) and lithocholic acid (LCA)” ([0182]). Henn teaches that primary bile acids are linked to various inflammatory diseases ([0189]). Henn also teaches that candidates strains are tested for bile salt hydrolase activity and 7-alphadehydroxylase activity and are combined in communities to evaluate synergies among strains and define ecologies for further testing in animal models. Henn teaches that these “synergies include: i) the potential for more rapid conversion from conjugated primary bile salts to unconjugated, dehydroxylated bile acids; ii) the potential for a broader range of products than determined by the additive combination of activities; iii) equivalent activity at a lower concentration (cfu) of the individual strains” ([0614]).
Therefore, Henn teaches providing complementary bacteria communities, such that the supportive community increases the flux of a precursor of the first metabolic substrate into a pathway that convert the precursor into a metabolite that is not the starting substrate, as in option “2)” of claim 1. Henn also teaches that microbes can perform the deconjugation of conjugated bile acids to produce primary (unconjugated) bile acids, as recited in option 4) of claim 1.
Regarding claims 13, 62, 68, 70, 74, 121, and 126, in particular the recitation of “substrate metabolization assay” and “substrate metabolizing activity”, Henn teaches that multiple methods are available and well-known in the art for determination of bile acids, including thin layer chromatography, high performance liquid chromatography, mass spectrometry, tandem mass spectrometry, and gas chromatography using high resolution glass capillary columns and mass spectrometry ([0190]). Elsewhere Henn teaches “extracted metabolites are first separated by liquid chromatography followed by mass spectrometry (LC/MS).” ([0596]). In terms of pH and other conditions, Henn teaches that “For bacterial compositions for human use, this is often at 37° C. temperature, pH, and other parameter with values similar to the normal human niche”, which includes cultures grown at 37° C, pH 7 ([0318]). Henn also teaches that the bacterial composition can be tested for pH resistance, bile acid resistance ([0367]), and such conditions including pH, growth time, and substrate concentrations are known variables in the art. Further, regarding concentrations of bile salt, Henn teaches that “CA, CDCA, GCA, GCDCA, TCA, and TCDCA are then added at 0.5 to 5 mM and the resulting culture is sampled at 1, 2, 4 and 8 hours” ([0607]). Henn also teaches extensively testing the bile salt/acid degradation activity of the bacteria ([0608]-[0614]).
Regarding claim 46, Henn discloses that “Bacterial compositions may be prepared comprising at least two types of isolated bacteria, chosen from the SEQ ID Numbers (OTUs) in Table 1” and that “OTUs can be defined either by full 16S sequencing of the rRNA gene (Table 1), by sequencing of a specific hypervariable region of this gene (i.e. V1, V2, V3, V4, V5, V6, V7, V8, or V9), or by sequencing of any combination of hypervariable regions from this gene (e.g. V1-3 or V3-5). The bacterial 16S rDNA is approximately 1500 nucleotides in length and is used in reconstructing the evolutionary relationships and sequence similarity of one bacterial isolate to another using phylogenetic approaches” ([0237]-[0238]). Because the species exemplified in the embodiments of Henn overlap substantially with at least one or more of the instantly claimed species, they are deemed to be the same as those of Henn, which were also identified via sequence of the 16S rRNA gene. As the organisms are defined by this sequence, used in both the reference art and the instantly claimed invention, it is evident that they will have the same or nearly identical sequence if so compared.
Regarding claim 118, Henn teaches that the supportive community may enhance the conversion of one or more conjugated bile acids selected from the group consisting of taurochenodeoxycholic acid (TCDCA), glycochenodeoxycholic acid (GCDCA), taurocholic acid (TCA), and glycocholic acid (GCA), to cholic acid (CA) or chenodeoxycholic acid (CDCA) (see e.g. [0181]-[0183]).
Regarding claim 127, Henn teaches that the microbes comprising the community therein include multiple Firmicutes and Actinobacteria ([0226]), and further teaches that the species Clostridium scindens is among those which may be added to the consortium ([0228]).
Regarding claim 135, Henn teaches the composition is capable of inducing the depletion of various target compounds in a mammalian subject (i.e. an animal) which includes the targets “glucose, pyruvate, lactate, cellulose, fructans, starch, xylans, pectins, taurocholate, glycocholate, ursocholate, cholate, glycochenodeoxycholate, taurochenodeoxycholate, ursodeoxycholate, or chenodeoxycholate...” ([0063]).
Regarding claims 137, Henn teaches a composition further comprising a pharmaceutically-acceptable excipient, where in one embodiment, the composition is formulated for oral administration ([0063], claim 88).
However, Henn does not explicitly teach that the microbial consortium has the activity of the acting on lithocholic acid (LCA) or deoxycholic acid (DCA) thus producing iso-lithocholic acid (iso-LCA), or iso-deoxycholic acid (iso-DCA), as in the instantly examined invention.
Ridlon teaches colonizing germ free mice with human gut bacterial isolates capable of metabolizing taurine-conjugated bile acids (Abstract). Ridlon teaches that this consortium included bile salt hydrolase-expressing Bacteroides uniformis ATCC 8492, Bacteroides vulgatus ATCC 8482, Parabacteroides distasonis DSM 20701, as well as taurine-respiring Bilophila wadsworthia DSM 11045, deoxycholic/lithocholic acid generating Clostridium hylemonae DSM 15053 and Clostridium hiranonis DSM 13275 as well as butyrate and iso-bile acid-forming Blautia producta ATCC 27340 (Abstract, Figure 1). Ridlon teaches that Blautia producta express both 7β-HSDH and 3α-and 3β-HSDH, and was included due to its ability to oxidize and epimerize bile acids as well as generation of butyrate important for epithelial and immune development (see pg. 383, sentence spanning cols 1 and 2). Ridlon teaches that “Bacteria that composed these consortia included human fecal isolates, such as bile salt deconjugating strains of Bacteroides uniformis, Bacteroides vulgatus, and Parabacteroides distasonis, the taurine-respiring δ-Proteobacteria member Bilophila wadsworthia, and bile acid 7α dehydroxylating Firmicutes C. hylemonae and C. hiranonis.” (pg. 382, right col, last paragraph).
Ridlon teaches measuring the bile acid metabolomics in cecum, serum, and liver of gnotobiotic mice administered B4PC2 human gut bacterial consortium (Figure 7). Ridlon states that “Lithocholic acid derivatives included isolithocholic acid (3β-monohydroxy-5β-cholan-24-oic acid) and allo-isolithocholic acid (3β monohydroxy-5α-cholan-24-oic acid). The formation of 3β-isomers of LCA can be explained by expression of 3α-HSDH and 3β-HSDH by B. producta.” (pg. 395, left col, 2nd paragraph).
Further Ridlon teaches that “Bile acid metabolism by gut bacteria is of considerable biomedical interest with implications for liver and colon cancers, gallstone disease, cirrhosis of the liver, and Clostridioides difficile (C. diff) infection (Introduction, pgs. 381-382), and also teaches that “Excess concentrations of secondary bile acids such as DCA and LCA in the GI tract are associated with subsets of cholesterol gallstone patients,6 liver cancer,1,2 and colorectal cancer” (pg. 399, left col, first paragraph).
Therefore, Ridlon teaches that Blautia producta expresses both 7β-HSDH and 3α-and 3β-HSDH and converts lithocholic acid into the metabolite iso-lithocholic acid (iso LCA).
To one of ordinary skill in the art, before the effective filing date of the claimed invention, it would have been obvious that when producing or administering a microbial consortium as taught in Henn, comprising essentially identical microorganisms as those encompassed by the instant claims, for the degradation of conjugated primary bile acids and the production of secondary bile acids (such as LCA and DCA), the presence of Blautia producta in the community taught in Henn would cause the degradation of lithocholic acid into the metabolite iso-lithocholic acid, as taught in Ridlon.
One would have been motivated to do so by the teachings of Ridlon concerning LCA degradation, in view of all of the teachings of Henn concerning bile acid metabolism (i.e. the deconjugation of conjugated primary bile acids and the production of secondary bile acids from primary acids), performed by consortia of microbes. Ridlon teaches selecting a strain of Blautia producta because it is known in the art to express both 7β-HSDH and 3α-and 3β-HSDH, and therefore was included due to its ability to oxidize and epimerize bile acids as well as generation of butyrate important for epithelial and immune development. Ridlon also teaches that secondary bile acids such as DCA and LCA in the GI tract are associated with certain diseases.
In view of the extensive teachings of Henn concerning cooperative consortia or networks of microorganism, and it view of the specific teachings of Ridlon, one would have been motivated to provide such consortia, essential identical to those so instantly claimed, for the express purpose of degrading primary bile acids, which would have led to the production of the secondary bile acid LCA and then the formation of its metabolite iso-LCA, with a reasonable prediction of success, according to the teachings of Ridlon. Further, due to the enzymatic activity of Blautia producta, the formation of iso-DCA from DCA, as indicated by the teachings of Henn, is also likely although not explicitly taught in the references.
Regarding claim 14, both Ridlon and Henn teach providing consortia having members of these phylum.
Regarding claim 46, Henn teaches a number of microbes that are explicitly the same as those referred to in the Tables of the instant specification, along with similarity to the reference 16S rRNA sequences. Thus, these are found to be essentially identical to those of the instant application, absent evidence to the contrary.
Regarding claim 115 and 118, the combination of Henn and Ridlon explicitly teaches consortia of microorganisms that will predictably degrade LCA (or DCA) and form the metabolite iso-LCA. Further, the references both disclose at least the conversion of conjugated bile acids (TCDCA, GCDCA, TCA, GCA, to cholic acid and/or CDCA. One would be motivated to select such consortia, for all the reasons discussed above.
Regarding claim 127, both references teaching consortia having Firmicutes, and Henn teaches that Clostridium scindens is present in some embodiments. Thus, the selection of bacteria from among those taught in Henn would have been a matter of judicial selection and optimization for any desired result. Regarding the size of the supportive community, the sizes of the consortia taught in Henn clearly overlap substantially with that of “20 to 200” strains. The providing of strains in any particular number would be a matter of optimization based on the teachings of the art. There does not appear to be any evidence of critically of having at least 20 strains. The activity and relative abundance of the active strains is critical, not necessarily the total number of present strains (i.e. there might be hundreds of minorly represented strains that have no bearing on the final result or activity of the community).
Regarding the intended administration in claim 135, such administration would be prima facie obvious over the combined teachings of Henn and Ridlon. Ridlon explicitly teaches giving animals a similar consortia and measuring the effects on bile acids, including on LCA. If one desired to change the relative abundance of any particular substrate, the teachings of Ridlon and Henn would direct them to develop suitable consortia, given what is known in the art about these activity of various microbes.
Regarding claim 137, Henn teaches applying the consortia with a pharmaceutically-acceptable excipient, and such carriers and excipients are well-known in the art.
Claims 13, 62, 68, 70, 74, 121, and 126, recite further conditional limitations that pertain only to desired results, or purely functional aspects of the claimed consortium. In this case, the general conditions for testing the abundance of bile acids, and testing the activity of various strains of microbes, are taught in Henn (note also that LC/MS is used in Ridlon also).
MPEP § 2144.05 describes that the determination of suitable or effective concentration of a known composition (or performing a known method) can be determined by one of ordinary skill in the art through the use of routine or manipulative experimentation to obtain optimal results, as these are variable parameters attainable within the art. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Similarly, the determination of suitable experimental variables for temperature and pH can be determined by one of ordinary skill in the art through the use of routine or manipulative experimentation to obtain optimal results.
The parameters discussed in the dependent claims 13, 62, 68, 70, 74, 121, and 126, include the pH value for the testing and the concentration of the substrate applied. These are well-known result effective variables for enzymatic activity. Further, the pH, temperature, and concentrations used for testing microbe activity for bile acid activity in Henn is within that of the recited pH ranges and the concentration ranges (which are near to physiological conditions). Any other differences recited in the instant claims (i.e. a desired fold difference in concentration or a pH difference) amount to testing the properties that are inherent to the bacteria of the references, which appear- for all intents and purposes- the same as those instantly claimed.
Even if the composition is not identical to the referenced composition, with regard to some unidentified characteristics, the differences between that which is claimed and that which is disclosed, is so slight that the referenced composition is likely to inherently possess the same characteristics of the claimed composition, particularly in view of the similar characteristics which they have been shown to share and by the functions of the component materials (i.e. having substantially the same selection of bacteria, and the teachings in the art regarding bile acid metabolism of said bacteria) which are inherently present in each and which functions are inclusive of those appreciated in the instant disclosure as being present (see MPEP 2112.02 at Ex parte Novitski, in reference to reference-silent functioning of biological materials providing anticipation of the functions based upon the material itself (noting the reference of “Dart” therein did not appreciate the claimed function but still anticipated the function based on the inherent function of the material, and that the Applicant’s disclosure appreciating the function upon usage thereof as further evidence of the presence of the function).
Please note, since the Office does not have the facilities for examining and comparing Applicants’ composition with the composition of the prior art, the burden is on applicant to show a novel or unobvious difference between the claimed product and the product of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980), and “as a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith.” In re Brown, 459 F.2d 531, 535, 173 USPQ 685, 688 (CCPA 1972).
From the teachings of the cited references, it is apparent that there would have been a reasonable expectation of success in combining the teachings therein to arrive at the claimed invention because both Henn and Ridlon pertain to the use of bioactive microbial consortia for manipulating bile acid metabolism in a subject. Ridlon teaches specifically that a consortia having B. producta results in the formation of LCA derivatives, including iso-LCA.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, as evidenced by the cited references, especially in the absence of evidence to the contrary.
Citation of Pertinent Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Martinez et al. (WO 2019227085 A1, published 11/28/2019) discloses bacterial compositions designed to have certain functional features that are useful for treating and/or preventing a range of diseases and disorders, such as those associated with dysbiosis of the gastrointestinal microbiome (e.g. inflammatory bowel disease (IBD), for example, ulcerative colitis and certain cancers) (Title, [0002]). Martinez discloses a compositions having a first purified bacterial population and a second purified bacterial population ([0007]) and states that “In some embodiments, the second purified bacterial population comprises one or more bacteria that are capable of producing a secondary bile acid” ([0011]).
Nandakumar et al. (WO2019036510 to Seres Therapeutics Inc., published 2/21/2019), is drawn to formulations including a plurality of viable bacteria, including at least one bacterial OTU or species that exhibits a first bile metabolizing activity (e.g. a bile acid or bile salt hydrolase activity) and a pharmaceutically acceptable excipient, wherein the plurality, i.e. the consortium of bacteria, comprises at least two different bacterial OTUs or species (or more) (Summary, pg 2, lns 17-39).
Gordon et al. (US PGPub No. 20160326574) discloses a microbial consortium, (i.e. an artificial human gut microbial community), which comprises 14 species, including Ruminococcus obeum, R. torques, Faecalibacterium prausnitzii, Dorea longicatena, Collinsella aerofaciens, Bacteroides ovatus, Bacteroides vulgatus, Bacteroides caccae, Bacteroides uniformis, Parabacteroides distasonis, Eubacterium rectale, Bacteroides cellulosilyticus, Bacteroides thetaiotaomicron, and Clostridium scindens (the last three which are “three prominent members of the adult human gut microbiota that have known capacity to process dietary and host glycans”, [0119] and Table 23).
Conclusion
No claims are allowed.
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/A.T.M./Examiner, Art Unit 1655
/ANAND U DESAI/Supervisory Patent Examiner, Art Unit 1655