DETAILED ACTION
Status of claim rejections
The rejections of record under 35 USC 112(b) have been withdrawn in view of Applicant’s amendments in the response filed 08/08/25.
The rejections of record under 35 USC 112(a) have been withdrawn in view of Applicant’s amendments in the response filed 08/08/25.
The rejections of record under 35 USC 101 have been maintained/modified in view of Applicant’s amendments/arguments in the response filed 08/08/25.
The rejections of record under 35 USC 103 have been maintained/modified in view of Applicant’s amendments/arguments in the response filed 08/08/25.
The nonstatutory double patenting rejections of record have been withdrawn in view of Applicant’s filing of the Terminal Disclaimers in the response filed 08/08/25.
This Action is FINAL, as necessitated by Applicant’s amendments.
Claim Interpretations - as set forth in the previous Non-Final Office Action and as Necessitated by Applicant’s Amendments
Claim 1 recites “a bacterial fermentate mixture, the bacterial fermentate mixture comprising a first fermentate and a second fermentate of a bacterial strain belonging to the species Pediococcus acidilactici and comprising a 16S rDNA sequence with at least 99% sequence identity to the nucleotide sequence of SEQ ID NO: 1, wherein the first fermentate is produced by incubating the bacterial strain in a first fermentation medium comprising tryptophan, and the second fermentate is produced by incubating the bacterial strain under aerobic or microaerobic conditions in a second fermentation medium comprising tryptophan, wherein the first fermentation medium comprises a higher glucose concentration than the second fermentation medium, such that the first fermentate comprises more indole-3-lactic acid (ILA) than the second fermentate, wherein the second fermentation medium comprises a higher nitrogen source concentration than the first fermentation medium, such that the second fermentate comprises more indole-3- carboxaldehyde (IAld) than the first fermentate,wherein the first fermentate comprises more indole-3-lactic acid (ILA) than indole-3- carboxaldehyde (IAld) and the second fermentate comprises more IAld than the first fermentate, wherein each of the fermentates is in powder form, wherein each of the fermentates is actively dried, wherein the composition is substantially free of viable microbial cells of the bacterial strain, wherein the composition is a nutritional supplement or food product.
The term “fermentate” is defined in the specification as “a product obtained by fermenting a bacterial strain in an environment suitable for fermentation” (see pg. 54 of the specification). The claim has been interpreted under broadest reasonable interpretation to encompass a product-by-process powdered fermentation product containing at least ILA and IAld. MPEP 2113 states that "[e]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Claims 1-4 and 20 recite, inter alia, “the first fermentate is produced by incubating the bacterial strain. . .” and “the second fermentate is produced by incubating the bacterial strain. . .”. This limitation has been interpreted under broadest reasonable interpretation to encompass product-by-process limitations. (see 35 U.S.C. 112(b) rejections below). Please note that the examiner has applied prior art to the claim limitations as set forth in the second 35 U.S.C. 103 rejection below.
Claims 14-17 recite the following limitations, respectively: “wherein the composition treats a symptom of inflammation associated with itching in a subject”; “wherein the composition treats one or more symptoms of atopic dermatitis in the subject”; wherein the composition treats one or more symptoms of itch-associated allergy in the subject”; and “wherein the composition treats itching in the subject”. The instant claims, directed to the above claim language, raises the question as to their limiting effects (see MPEP 2103). The claims have been interpreted under broadest reasonable interpretation (BRI) to encompass statements of inherent properties of the composition of claim 1, and as such, anything that meets the limitations of claim 1 (i.e., a mixture of ILA and IAld) would be capable of performing the treatments as claimed.
New 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 1-4, and 7-20 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, inter alia, “wherein the composition is substantially free of viable microbial cells of the bacterial strain” (emphasis added). The term “substantially free” in claim 1 is a relative term which renders the claim indefinite. The term “substantially free” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In the instant case, it is unclear what the term “substantially free” encompasses. It is unclear whether the term means that there can be no cells of the bacterial strain in the composition (i.e., zero cells), or if the composition can still have some (e.g., a de minimis amount) of the microbial cells in the composition. Thus, the claim is indefinite. For the purposes of compact patent prosecution, the examiner has interpreted the claims to encompass no bacterial cells in the composition (i.e., the cells have been removed). Please note that the dependent claims are also indefinite due to dependency on indefinite claim 1.
It is noted any interpretation of the claims set forth above does not relieve Applicant of the responsibility of responding to this rejection. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejections and art may be readily applied in a subsequent final Office action.
Maintained 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 1-4, 7-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (natural product) without significantly more. This judicial exception is not integrated into a practical application and the claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
Step 1 (Statutory Category): This part of the eligibility analysis evaluates whether the claim falls within any statutory category. Here, the claims recite a bacterial fermentate mixture composition. This is a composition of matter, therefore the claim falls within a statutory category of invention. [Step 1: YES]
Step 2A (Judicial Exceptions), Prong 1: This part of the eligibility analysis evaluates whether the claim recites a judicial exception. A claim “recites” a judicial exception when the exception is “set forth” or “described” in the claim (see MPEP 2106.04(II)). Because the claim recites a nature-based product limitation, the markedly different characteristics analysis is used to determine if the nature-based product limitations are a product of nature exception (see MPEP 2106.04(c)(I)). This analysis is performed by comparing the nature-based product limitations in the claims to its naturally occurring counterparts to determine if it has markedly different characteristics (see MPEP 2106.04(c)(II)).
As discussed above, the term “fermentate” has is defined as “a product obtained by fermenting a bacterial strain in an environment suitable for fermentation” (see pg. 54 of the specification). The claim has been interpreted under broadest reasonable interpretation to encompass a powdered fermentation product containing at least ILA and IAld. The appropriate natural counterpart to the bacterial fermentate mixture composition is naturally occurring ILA and IAld produced by bacteria (such as the metabolites produced by lactic acid bacteria) as found in nature. The second step in the analysis requires identifying appropriate characteristics to compare. In this case, the appropriate characteristics pertain to the physical, structural, and functional characteristics of ILA and IAld.
Sprunck et al (Indole-3-lactic acid is a weak auxin analogue but not an anti-auxin. J Plant Growth Regul 14, 191–197 (1995)) teaches Indole-3-1actic acid (ILA) is a naturally occurring indole derivative, found in various bacteria and only in low amounts in plants (pg. 191, col 1). Sprunck also teaches that ILA is a common tryptophan metabolite in various bacterial strains (pg. 191, col 2). As the claimed invention requires ILA, and does not impart any different structural, biochemical, or functional characteristics to the naturally occurring ILA, the claims encompass naturally occurring ILA.
Zhao (From gut to skin: exploring the potential of natural products targeting microorganisms for atopic dermatitis treatment. Food Funct. 2023 Aug 29;14(17):7825-7852) teaches that tryptophan, an essential amino acid, and its metabolite ligands inhibit the production of inflammatory cytokines in the skin and intestine through AHR signaling to decrease the inflammatory response (pg. 7829, col 1, paragraph 2). Zhao teaches various microbiota in fermented foods that are useful in the treatment of atopic dermatitis, including Pediococcus acidilactici (pg. 7833, Table 2) Zhao further teaches bacterial metabolites include indole-3-carbaldehyde (i.e., indole-3-carboxaldehyde), which is capable of decrease in the expression of IL-4, IL-5, IL-6, IL-13, IL-22, and TSLP in skin cells (see pg. 7829, col 1, paragraph 2). As the claimed invention requires IAld, and does not impart any different structural, biochemical, or functional characteristics to the naturally occurring IAld, the claims encompass naturally occurring IAld.
Henn teaches therapeutic bacterial compositions useful for treating and reducing dysbiosis in a subject (title, abstract). Henn teaches various purified compositions consisting of bacteria comprising 16S rDNA sequences 97% identical to SEQ ID NO: 1 (see claim 1), for use in food products, beverages, snacks, capsules containing lyophilized powder, etc. (see col 6, lines 35-46). Henn further teaches a suitable bacterial strain of Pediococcus acidilactici, which has 99.7% identity with SEQ ID NO: 1 (see alignment below). Thus, the claim encompasses a naturally occurring P. acidilactici 16S rDNA sequence (where the bacteria is used to produce the fermentate product).
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The specification further evidences that ILA and IAld are produced by naturally occurring bacteria such as P. acidilactici and L. plantarum and act as AhR agonists (see pg. 13 of the specification). The bacterial fermentate mixture composition as claimed contains no markedly different characteristics from the naturally produced bacterial ILA and IAld fermentation products with respect to structure, function, or any other characteristic that would distinguish it from its naturally occurring counterpart. The structure and function of the claimed ILA and IAld are the same as the naturally occurring counterpart. [STEP 2A, Prong 1: YES]
Thus, the claim recites a judicial exception, a natural product. Therefore, the analysis proceeds to Step 2A Prong 2.
Step 2A (Judicial Exceptions), Prong 2: This part of the eligibility analysis evaluates whether the claims as a whole integrate the recited judicial exception into a practical application of the exception. This evaluation is performed by (a) identifying whether there are any additional elements recited in the claims beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claims as a whole integrate the exception into a practical application. Claim 1 and 20 is limited to only the judicial exception (a naturally occurring ILA and IAld). The production of the fermentates under microaerobic and aerobic conditions with glucose, tryptophan, and manganese (encompassing naturally occurring glucose, tryptophan, and manganese; see claims 2-4, 20), the species of bacteria producing the fermentates (claim 1), active drying of the fermentates (claim 1), the inclusion of maltodextrin (claim 7-8), spray drying the fermentates (claim 9), the form of the nutritional/food supplement (claim 10), the additional indole derivatives (claim 11), the dosage formulation (claim 12), the amount of fermentate in the composition (claim 13), the use of the composition to treat various itching inflammatory diseases in a subject (claims 14-18), and the subject being a cat or dog (claim 19) do not impose a practical use or application of the claimed natural products. In this regard, the claims fail to recite any additional elements that integrate the judicial exception natural product into a practical application. [Step 2A, Prong 2: NO]
Step 2B (Significantly More): This part of the eligibility analysis evaluates whether the claims as a whole amount to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim (MPEP 2106.05). The claim elements recited in claims 2-4, and 7-20 above merely links the use of the judicial exception to the technological field of treatment of inflammatory disorders (such as skin disorders). Furthermore, such elements within this field are well-known, routine, and conventional in the art.
For example, Zhao further teaches that administration of indole-3-carbaldehyde (i.e., indole-3-carboxaldehyde), both topically and orally, effectively alleviated symptoms such as skin thickness and itch, induced a significant decrease in the expression of IL-4, IL-5, IL-6, IL-13, IL-22, and TSLP in skin cells see pg. 7829, col 1, paragraph 2).
Yang (Microaerobic Fermentation of Lactobacillus acidophilus within Gut Microbiome Physiological Conditions by BioFlo® Bioprocess Control Stations; September 2019; p. 1-8) teaches microaerobic fermentation of lactic acid bacteria like L. acidophilus (title, abstract). Yang teaches that there is growing interest across the food and feed and biofuel industries in microaerobic fermentation, a process occurring at close to anaerobic conditions, but still requiring small amounts of oxygen at concentrations of less than 5% (abstract). Yang teaches that many probiotics are bacteria that naturally thrive in the human gut microbiome, which is microaerobic (abstract); pg. 1, col 2). Yang teaches successful and robust growth of lactic acid bacteria using microaerobic fermentation (see Fig. 6-8 and 10). Yang further teaches that better control of the microaerobic bioprocess is critical and urgent, shows a detailed example of precisely controlling the DO at 4 % to support microaerobic fermentation (pg. 7, col 2).
Singh et al (Strategies for Fermentation Medium Optimization: An In-Depth Review. Front Microbiol. 2017 Jan 6;7:2087) teaches strategies for fermentation optimization (title, abstract). Singh teaches that optimization of production medium is required to maximize yield of metabolites (see abstract). Singh teaches that the most suitable fermentation conditions (pH, temperature, agitation speed) and the appropriate medium components (carbon, nitrogen, etc.) must be identified and optimized accordingly, especially in chemical, food, and pharmaceutical industries (pg. 2, col 1, paragraph 1; Fig. 1; pg. 4, col 2-pg. 5, col 1). Singh also teaches that carbon and nitrogen sources present in the medium influences metabolite production through rate of assimilation (pg. 2, col 2). The nature of the carbon source (like glucose) also affects the type and amount of product produced, and microorganisms can use organic and inorganic nitrogen sources (pg. 2, col 2; see Tables 1 and 2). Singh further teaches various optimization strategies including one-factor-at-a-time, statistical, etc. (see pg. 5-12) and that novel approaches of using integrated modes of microbe cultivation including combining aerobic and anaerobic conditions or switching anaerobic/aerobic conditions during cultivation (pg. 13, col 2, paragraph 2).
Toutain (Pharmacokinetic/pharmacodynamic integration in drug development and dosage-regimen optimization for veterinary medicine. AAPS J 4, 38 (2002)) teaches pharmacokinetic (PK)/pharmacodynamic (PD) modeling is a scientific tool to help developers select a rational dosage regimen for confirmatory clinical testing (pg. 1, col 1). Toutain teaches the 2 most important questions in drug development are "Has the right drug been selected?" and "Has the optimal dosage regimen been established?" (pg. 1, col 2, paragraph 1). Toutain teaches that the PK/PD model helps developers select a rational dosage regimen for confirmatory clinical testing and failure to determine a safe and effective dosage regimen for use in pivotal clinical trials has been acknowledged as a frequent flaw encountered during the development of many drugs, and in veterinary medicine, the situation is even more complex because of potential interspecies differences in kinetics and dynamics (pg. 1, col 2, paragraph 2). Toutain also teaches that using dose-effect relationships versus PK/PD for establishing clinically relevant dosage regimens (see Fig. 3). Toutain further teaches that “whereas dose is merely a nominal mass (with no intrinsic biological information), the concentration versus time profile reflects dose, formulation, and the major physiological processes affecting the distribution and residence of that drug within the animal (clearance, rate constant of absorption, etc). In addition, plasma concentration profiles provide information on temporal changes in response, allowing time to be an independent variable in PK/PD trials. For this reason, a PK/PD trial is the most suitable method for simultaneously determining the 2 main components of a dosage regimen: dose and dosage interval” (pg. 5, col 1).
Thus, the claims fail to recite any additional elements that are sufficient to amount to significantly more than the judicial exception. [Step 2B: NO]
Therefore, the claims do not qualify as eligible subject matter under 35 U.S.C. 101.
Response to Arguments
Applicant's arguments filed 08/08/2025 and the Declaration under 37 CFR 1.132 filed 08/08/25 have been fully considered but they are insufficient to overcome the rejection for the reasons set forth below:
On pg. 9-11 of the remarks, Applicant argues the broadest reasonable interpretation of the term “fermentate” does not mean broadest possible interpretation. Applicant argues that the Declaration (given its fullest consideration) discusses that the skilled artisan would appreciate that “a fermentate produced by fermenting a bacterial strain contains a collection of metabolites produced by the bacterial strain during fermentation. It is not scientifically reasonable to discount the presence of other components produced by fermentation as recited just because ILA and IAld are recited specifically. The composition of each fermentate produced using the recited fermentation media and of their resulting combination are entitled to consideration.” Applicant points to data in the specification (example 1, and 22; Fig. 6-7B) which disclose improved canine AHR activation/inhibition of inflammatory cytokines, etc. and argues that separate fermentation (using one medium with more glucose and the other with more nitrogen) mitigates competing effects of glucose and nitrogen on tryptophan metabolism, allow production of the combined fermentate mixture, and the distinct amounts of ILA and IAld are a second structural and functional difference compared to what is produced in nature. Applicant further argues that the claim reciting that the fermentate is actively dried, concentrating amount of bacterial metabolites allows formulation into the food product that allows ingestion and improved texture, etc. further qualifies the claims as eligible subject matter.
In response, the examiner disagrees for the same reasons as set forth above. While the examiner appreciates Applicant’s data and Declaration, the claimed composition is drawn to a bacterial fermentate product having at least IAld and ILA (see interpretation above), and is claiming product-by-process limitations as to how each fermentate is made (see interpretation above). Thus, the instant claims are drawn to the fermentate product itself, and not the method of making the fermentate or a method of using the fermentate.
As conceded by Applicant, the fermentate contains a collection of metabolites produced by the bacterial strain during fermentation (i.e., the fermentate itself is a natural product of bacterial metabolism). The examiner is not discounting the presence of any other components and recognizes that there may be other components present during fermentation, however, these additional elements merely link the use of the judicial exception to the technological field of treatment of inflammatory disorders (such as skin disorders). Any downstream processing of the fermentates (i.e., actively drying, etc.) does not impart any markedly different characteristics to the fermentates themselves because any of the components of the fermentate (other than any water) that is beneficial (i.e., biochemical/functional characteristics) is still present in the fermentate. Because there is no indication in the record that drying the fermentates has resulted in a marked difference in structure, function, or other properties as compared to its counterpart, the fermentates are a product of nature.
Furthermore, any effects that administration has (such as the effects on AHR/inhibition of inflammatory cytokines as discussed by Applicant) is a natural effect of the fermentate itself and not due to any manipulations by Applicant because, as discussed by Zhao, tryptophan metabolite ligands (such as IAld and ILA) inhibit the production of inflammatory cytokines in the skin and intestine through AHR signaling to decrease the inflammatory response (see Zhao above). Thus, the rejection is maintained as set forth above.
Modified Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
First rejection
Claims 1, 4, 7-11, and 13-19 are rejected under 35 U.S.C. 103 as being unpatentable over Venkataraman et al (US 20200316023 A1; published 10/08/2020; hereinafter “Venkataraman”; prior art of record) in view of Zhao et al (From gut to skin: exploring the potential of natural products targeting microorganisms for atopic dermatitis treatment. Food Funct. 2023 Aug 29;14(17):7825-7852), Henn et al (US 8906668 B2; published 12/09/2014; hereinafter “Henn”; prior art of record) and Singh et al (Strategies for Fermentation Medium Optimization: An In-Depth Review. Front Microbiol. 2017 Jan 6;7:2087; hereinafter “Singh”; prior art of record).
Venkataraman teaches a composition comprising a fermentate comprising bacterially derived indole-3-propionic acid (IPA) and other indole derivatives; and an excipient, carrier, and/or diluent (see claim 1). Venkataraman teaches that the composition includes indole derivatives including indole-3-acetic acid, indole-3-acrylic acid, and indole-3-lactic acid (a first fermentate as in claim 1) (see claim 5; see also paragraph 0011). Venkataraman teaches including amino acids such as tryptophan in amounts ranging from 8 to about 10,000 μg/mL (i.e., 0.0008 g/L to 10 g/L tryptophan) (fermentate produced by incubating the strain in a fermentation medium comprising tryptophan as in claim 1; see paragraph 0035) and using anaerobic conditions for fermentation (see paragraph 0043-44). Venkataraman also teaches that level of IPA and other derivatives production could be increased by changing the fermentation mediums, such as by increasing the amount of glucose during fermentation (see paragraph 0106 and 0110). Venkataraman also teaches that the fermentate can be used for treating, ameliorating, or preventing a disorder in a subject including inflammatory disorders, and can be incorporated into food bars, shakes, juices, beverages, frozen food products, fermented food products (nutritional supplement or food product as in claim 1; see paragraph 0079 and 0097). Venkataraman teaches concentrating the bacteria solution by reducing the water content (e.g. via reverse osmosis, tray drying, microfiltration, nanofiltration, and combinations thereof), adding a dehydrating agent, and dehydrating to obtain a fermentate powder comprising indole-3-propionic acid and other indole derivatives (i.e., actively dried as in claim 1; paragraph 0023). Venkataraman further teaches that the bacteria can be inactivated or physically removed (e.g., via passing through a membrane filter; the composition is substantially free of viable microbial cells as in claim 1; see paragraph 0046).
Venkataraman does not explicitly teach a second fermentate comprising indole-3-carboxaldehyde.
However, Zhao teaches use of microbiota metabolites for the treatment of inflammatory skin disorders, specifically atopic dermatitis (see title and abstract; pg. 7828, col 2). Zhao teaches that tryptophan, an essential amino acid, and its metabolite ligands inhibit the production of inflammatory cytokines in the skin and intestine through AHR signaling to decrease the inflammatory response (pg. 7829, col 1, paragraph 2). Zhao teaches various microbiota in fermented foods that are useful in the treatment of atopic dermatitis, including Pediococcus acidilactici (pg. 7833, Table 2). Zhao further teaches that administration of indole-3-carbaldehyde (i.e., indole-3-carboxaldehyde), both topically and orally, effectively alleviated symptoms such as skin thickness and itch, induced a significant decrease in the expression of IL-4, IL-5, IL-6, IL-13, IL-22, and TSLP in skin cells (see pg. 7829, col 1, paragraph 2).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the bacterial fermentate composition of Venkataraman and include the indole-3-carboxaldehyde derivative as taught by Zhao to arrive at the claimed invention. As Venkataraman teaches bacterial fermentates containing indole metabolites including indole-3-lactic acid for treatment of inflammatory disorders, and Zhao teaches microbial-derived tryptophan metabolites like indole-3-carbaldehyde from lactic acid bacteria effectively alleviated symptoms such as inflammatory skin thickness and itch in subjects, one of ordinary skill would have been motivated to make the modification with a reasonable expectation of success. One of ordinary skill would have been motivated to make the modification because Zhao teaches indole-3-carbaldehyde (i.e., indole-3-carboxaldehyde), both topically and orally, effectively alleviated symptoms such as skin thickness and itch. Furthermore, “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (see MPEP 2144.06(I)).
While none of the references explicitly teach that the first fermentate comprises more indole-3-lactic acid than indole-3-carboxyaldehyde (and vice versa), it would have been prima facie obvious to one of ordinary skill to optimize the amount of indole metabolites produced by the bacterial strain using standard laboratory techniques available at the time of filing (see MPEP 2144.05). One of ordinary skill would have been motivated to do so because Venkataraman teaches that changes in the fermentation conditions (such as increasing the amount of glucose during fermentation) can increase the levels of derivatives produced by the bacteria (see paragraph 0106 and 0110).
Neither Venkataraman nor Zhao explicitly teaches a bacterial strain of P. acidilactici comprising a 16S rDNA sequence with at least 99% sequence identity to the nucleotide sequence of SEQ ID NO: 1.
However, Henn teaches therapeutic bacterial compositions useful for treating and reducing dysbiosis in a subject (title, abstract). Henn teaches various purified compositions consisting of bacteria comprising 16S rDNA sequences 97% identical to SEQ ID NO: 1 (see claim 1), for use in food products, beverages, snacks, capsules containing lyophilized powder, etc. (see col 6, lines 35-46). Henn further teaches a suitable bacterial strain of Pediococcus acidilactici, which has 99.7% identity with SEQ ID NO: 1 (see alignment below):
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Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the bacterial fermentate composition of Venkataraman and Zhao by using the P. acidilactici 16S rDNA sequence as taught by Henn to arrive at the claimed invention. As Venkataraman and Zhao teach bacterial fermentates in food products useful for treating inflammatory disorders, and Henn teaches a 16S rDNA sequence of P. acidilactici useful for the creation of probiotic food products, one of ordinary skill would have been motivated to make the modification with a reasonable expectation of success because Henn teaches bacterial strain nucleotide sequences useful for the creation of probiotic food compositions, including P. acidilactici.
None of the references explicitly teach the first fermentation medium has more glucose than the second medium and the second fermentation medium has more nitrogen source concentration than the first fermentation medium (as in claim 1).
However, Singh teaches strategies for fermentation optimization (title, abstract). Singh teaches that optimization of production medium is required to maximize yield of metabolites (see abstract). Singh teaches that the most suitable fermentation conditions (pH, temperature, agitation speed) and the appropriate medium components (carbon, nitrogen, etc.) must be identified and optimized accordingly, especially in chemical, food, and pharmaceutical industries (pg. 2, col 1, paragraph 1; Fig. 1; pg. 4, col 2-pg. 5, col 1). Singh also teaches that carbon and nitrogen sources present in the medium influences metabolite production through rate of assimilation (pg. 2, col 2). The nature of the carbon source (like glucose) also affects the type and amount of product produced, and microorganisms can use organic and inorganic nitrogen sources (pg. 2, col 2; see Tables 1 and 2). Singh further teaches various optimization strategies including one-factor-at-a-time, statistical, etc. (see pg. 5-12) and that novel approaches of using integrated modes of microbe cultivation include combining aerobic and anaerobic conditions or switching anaerobic/aerobic conditions during cultivation (pg. 13, col 2, paragraph 2).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the bacterial fermentate composition of Venkataraman, Zhao, and Henn by using the medium fermentation optimization techniques as taught by Singh to arrive at the claimed invention. As Singh teaches that that optimization of production medium is required to maximize yield of metabolites, the most suitable fermentation conditions (pH, temperature, agitation speed) and the appropriate medium components (carbon, nitrogen, etc.) must be identified and optimized accordingly, especially in chemical, food, and pharmaceutical industries, one of ordinary skill would have been motivated to make the modification and optimize the medium component concentrations with a reasonable expectation of success.
Regarding claim 4, Venkataraman teaches the fermentation medium has manganese (paragraph 0040).
Regarding claim 7, it would have been prima facie obvious to one of ordinary skill to create a fermentate mixture comprising a first and second fermentate to arrive at the claimed invention. One of ordinary skill would have been motivated to do so because Venkataraman teaches creation of fermentates including indole metabolites, such that one of ordinary skill would have been motivated to make mixtures of fermentates using standard laboratory techniques available at the time of filing. Furthermore, “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (see MPEP 2144.06(I)).
Regarding claim 8, Venkataraman teaches the fermentate having maltodextrin (see paragraph 0112).
Regarding claim 9, Venkataraman teaches the fermentate can be spray dried (paragraph 0120-121).
Regarding claim 10, Venkataraman teaches the fermentate can be incorporated into food bars, shakes, juices, beverages, frozen food products, fermented food products, and water (see paragraph 0079-0080).
Regarding claim 11, Venkataraman teaches the fermentate can include other indole derivatives, including indole-3-propionic acid, indole-3-acetic acid, and indole-3-acrylic acid (see rejection above).
Regarding claim 13, Venkataraman teaches the fermentate can be in dosages ranging from 0.01-1000 mg (see paragraph 0089). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here 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) (see MPEP 2144.05).
Regarding claims 14-17, Venkataraman, Zhao, and Henn in combination teach the claimed invention (see rejection above), including treatment of inflammation, atopic dermatitis, and itching in a subject. As discussed above, the claims have been interpreted under broadest reasonable interpretation to encompass statements of inherent properties of the composition of claim 1. In view of the teachings of Venkataraman, Zhao, and Henn, one of ordinary skill would reasonably understand the composition to be able to treat inflammation, atopic dermatitis, allergy, and itching with a reasonable expectation of success.
Regarding claim 18, please note that as the claim is drawn to a product (i.e., a bacterial fermentate composition), the limitations after the “wherein” clause (“the composition increases diversity of an intestinal microbiome in a subject as measured by Shannon diversity index of zero-radius operational taxonomic units (OTUs) present in a fecal sample of the subject”) has been interpreted under BRI to encompass an intended result of using the composition of claim 1. As such, the composition as taught by the combinations of references would be capable of “increasing diversity of the intestinal microbiome in a subject as measured by Shannon diversity index of zero-radius operational taxonomic units (OTUs) present in a fecal sample of the subject” as claimed.
Regarding claim 19, Venkataraman teaches the subject to be treated can be an animal, including household pets (which encompasses dogs and cats as claimed) (see paragraph 0020).
Accordingly, the claimed invention was prima facie obvious at the time of filing, especially in the absence of evidence to the contrary.
Second rejection
Claim 2-3 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Venkataraman, Zhao, Henn, and Singh as applied to claims 1, 4, 7-11, and 13-19 above, and further in view of Yang et al (Microaerobic Fermentation of Lactobacillus acidophilus within Gut Microbiome Physiological Conditions by BioFlo® Bioprocess Control Stations; September 2019; p. 1-8; hereinafter “Yang”; prior art of record).
As discussed above, claims 1, 4, 7-11, and 13-19 were rendered prima facie obvious by the combination of Venkataraman, Zhao, Henn, and Singh.
As further discussed above, Venkataraman teaches including amino acids such as tryptophan in amounts ranging from 8 to about 10,000 μg/mL (0.0008 g/L to 10 g/L tryptophan) (1-50 g/L tryptophan as in claim 2; see paragraph 0035) and using anaerobic conditions for fermentation.
The difference between the references and the instant claims is that none of the references explicitly teach culturing under microaerobic conditions (as in claim 2).
However, Yang teaches microaerobic fermentation of lactic acid bacteria like L. acidophilus (title, abstract). Yang teaches that there is growing interest across the food and feed and biofuel industries in microaerobic fermentation, a process occurring at close to anaerobic conditions, but still requiring small amounts of oxygen at concentrations of less than 5% (abstract). Yang teaches that many probiotics are bacteria that naturally thrive in the human gut microbiome, which is microaerobic (abstract); pg. 1, col 2). Yang teaches successful and robust growth of lactic acid bacteria using microaerobic fermentation (see Fig. 6-8 and 10). Yang further teaches that better control of the microaerobic bioprocess is critical and urgent, shows a detailed example of precisely controlling the DO at 4 % to support microaerobic fermentation (pg. 7, col 2).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the bacterial fermentate composition of Venkataraman, Zhao, Henn, and Singh by using the microaerobic fermentation as taught by Yang to arrive at the claimed invention. One of ordinary skill would have been motivated to make the modification because Yang teaches successful fermentation of lactic acid bacteria under microaerobic conditions that mimic the gut microbiome that advantageously allowed for robust growth of the bacteria.
Further regarding claims 2 and 3, none of the references explicitly teaches using aerobic conditions (as in claim 2), the first fermentation medium comprising 100-200g/L glucose and 10-125 g/L of one or more nitrogen sources (as in claim 3) or the second fermentation medium having 1-100 g/L glucose and 125-200 g/L nitrogen sources (as in claim 3).
However, Singh (as discussed above) teaches various optimization strategies including one-factor-at-a-time, statistical, etc. (see pg. 5-12) and that novel approaches of using integrated modes of microbe cultivation include combining aerobic and anaerobic conditions or switching anaerobic/aerobic conditions during cultivation (aerobic conditions as in claim 2; pg. 13, col 2, paragraph 2). It would have been prima facie obvious to one of ordinary skill to use aerobic conditions during fermentation as taught by Singh because Singh teaches that combining aerobic and anaerobic conditions or switching anaerobic/aerobic conditions during cultivation is an optimization strategy for microbe cultivation.
Furthermore, the concentrations of glucose and nitrogen (as well as the amount present in one medium relative to the other) would have been the result of routine optimization using standard laboratory techniques available at the time of filing, as Singh explicitly teaches that glucose and nitrogen within a fermentation medium can be successfully optimized to affect type and amount of bacterial metabolite products. Furthermore, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here 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) (MPEP 2144.05).
Regarding claim 20, Venkataraman, Zhao, Henn, and Singh teach, in combination, the “bacterial fermentate mixture comprising a first fermentate and a second fermentate of a bacterial strain belonging to the species Pediococcus acidilactici and comprising a 16S rDNA sequence with at least 99% sequence identity to the nucleotide sequence of SEQ ID NO: 1” (see first rejection under 35 U.S.C. 103), Yang teaches using microaerobic conditions for fermentation that mimic the gut microbiome that advantageously allowed for robust growth of the bacteria (see Fig. 6-8 and 10), and Singh teaches optimization of production medium is required to maximize yield of metabolites, the most suitable fermentation conditions (pH, temperature, agitation speed) and the appropriate medium components (carbon, nitrogen, etc.) must be identified and optimized accordingly, especially in chemical, food, and pharmaceutical industries (pg. 2, col 1, paragraph 1; Fig. 1; pg. 4, col 2-pg. 5, col 1). As such, the combination of Venkataraman, Zhao, Henn, Yang, and Singh render prima facie obvious claim 20.
Accordingly, the claimed invention was prima facie obvious at the time of filing, especially in the absence of evidence to the contrary.
Third rejection
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Venkataraman, Zhao, Henn, and Singh as applied to claims 1, 4, 7-11, and 13-19 above, and further in view of Toutain (Pharmacokinetic/pharmacodynamic integration in drug development and dosage-regimen optimization for veterinary medicine. AAPS J 4, 38 (2002); prior art of record).
As discussed above, claims 1, 4, 7-11, and 13-19 were rendered prima facie obvious by the combination of Venkataraman, Zhao, Henn, and Singh.
The differences between the references and the instant claim is that none of the references teaches the nutritional or food supplement is formulated for administration to a canine subject at an ILA dose of 0.8 ug/kg per day-8 mg/kg per day and an IAld dose of 0.08-800 ug/kg per day (as in claim 12).
However, Toutain teaches pharmacokinetic and pharmacodynamic integration in drug development and dosage regimen optimization for veterinary medicine (see title, abstract). Toutain teaches pharmacokinetic (PK)/pharmacodynamic (PD) modeling is a scientific tool to help developers select a rational dosage regimen for confirmatory clinical testing (pg. 1, col 1). Toutain teaches the 2 most important questions in drug development are "Has the right drug been selected?" and "Has the optimal dosage regimen been established?" (pg. 1, col 2, paragraph 1). Toutain teaches that the PK/PD model helps developers select a rational dosage regimen for confirmatory clinical testing and failure to determine a safe and effective dosage regimen for use in pivotal clinical trials has been acknowledged as a frequent flaw encountered during the development of many drugs, and in veterinary medicine, the situation is even more complex because of potential interspecies differences in kinetics and dynamics (pg. 1, col 2, paragraph 2). Toutain also teaches that using dose-effect relationships versus PK/PD for establishing clinically relevant dosage regimens (see Fig. 3). Toutain further teaches that “whereas dose is merely a nominal mass (with no intrinsic biological information), the concentration versus time profile reflects dose, formulation, and the major physiological processes affecting the distribution and residence of that drug within the animal (clearance, rate constant of absorption, etc). In addition, plasma concentration profiles provide information on temporal changes in response, allowing time to be an independent variable in PK/PD trials. For this reason, a PK/PD trial is the most suitable method for simultaneously determining the 2 main components of a dosage regimen: dose and dosage interval” (pg. 5, col 1).
Toutain does not teach the dosages as claimed in claim 12. However, dosage formulation for administration to a canine subject would have been the result of routine optimization using standard laboratory techniques available at the time of filing, as Toutain explicitly teaches major physiological processes affecting the distribution and residence of drugs within the animal (clearance, rate constant of absorption, etc), which can allow for determining and optimizing the 2 main components of dosage regimen: dose and dose interval.
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the bacterial fermentate composition of Venkataraman, Zhao, and Henn by using the dosage optimization techniques as taught by Toutain to arrive at the claimed invention. As Toutain explicitly teaches that dosage and dosage regimen must be optimized via selection a rational dosage regimen for confirmatory clinical testing, one of ordinary skill would have been motivated to optimize the dose to advantageously determine the major physiological processes affecting the distribution and residence of drugs within the animal (clearance, rate constant of absorption, etc.), leading to determining the 2 main components of dosage regimen: dose and dose interval.
Accordingly, the claimed invention was prima facie obvious at the time of filing, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 08/08/25 have been fully considered but they are not persuasive for the reasons set forth below.
On pg. 13-15, Applicant argues that “a fermentate mixture comprising two fermentates of P. acidilactici produced by separate fermentations with such conditions is not taught or suggested by the references of record.” Specifically, Applicant argues that adding IAld to a single fermentate as the rejection appears to suggest, would have produced the fermentate mixture as recited.” Applicant argues much of the same as in the above arguments to the rejection under 35 USC 101 regarding ILA and IAld not being the only metabolites present, where the claimed fermentate is different from a mixture of pure ILA and IAld. Applicant also argues that the cited Venkataraman, Zhao, and Hann provide no motivation because Venkataraman relates to C. sporogenes and not Pediococcus, such that “species are d