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 .
DETAILED ACTION
The response to a further election of species requirement on January 13, 2026 and amendment of the claims after Non-Final filed October 15, 2025 is acknowledged. Claims 1, 4, 10-11, 14 were amended, claim 13 was canceled, claims 19-22 were newly added and claims 1-12, 14-22 are pending in the instant application.
Applicant further elected Clostridiales species and the subspecies of Lachnospiraceae in the response filed January 13, 2026. The restriction is deemed proper and made FINAL in this office action. Claims 6-9 and 15-18 remain withdrawn as being drawn to a non-elected species/invention. Claims 1-5, 10-12, 14, 19-22 are examined on the merits of this office action.
Withdrawn Rejections/Objections
The rejection of claim 11 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in view of amendment of the claims filed October 15, 2025.
The rejection of claim 11 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends is withdrawn in view of amendment of the claims filed October 15, 2025.
The rejection of claim(s) 1-3, 5, 10-12, 14 under 35 U.S.C. 103 as being unpatentable over Abbas (AU2016259423, cited in Applicant’s IDS) in view of Vercoe (WO2013037068 A1), Chitolie (WO2017042568 A1) and Seegert (WO2015124637 A1, cited previously) is withdrawn in view of amendment of the claims filed October 15, 2025.
The rejection of claims 1-3, 5, 10-12 and 14 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-11, 14-18 of copending Application No. 17/573913(reference application) in view of Vercoe (WO2013037068 A1, cited previously), Chitolie (WO2017042568 A1) is withdrawn in view of filing and approval of the terminal disclaimer on October 15, 2025.
The rejection of claims 1-3, 5, 10-12 and 14 on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No.11484569 in view of Vercoe (WO2013037068 A1), Chitolie (WO2017042568 A1) is withdrawn in view of filing and approval of the terminal disclaimer on October 15, 2025.
*Please note the claim 4 is no longer considered allowable due to the amendment and the new grounds of rejection set forth in this office action, which render the claim indefinite and unpatentable over the applied prior art.
Terminal Disclaimer
The terminal disclaimer filed on October 15, 2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of US Patent NO. 11484569 and AN17573913 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Maintained/Revised Rejections
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 1-3, 5, 10-12, 14, 19-22 are rejected under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter. Based upon an analysis with respect to the claim as a whole, claim(s) Claims 1-3, 5, 10-12, 14, 19-22 do not recite something significantly different than a judicial exception. The rationale for this determination is explained below and is based on the analysis presented in the USPTO’s 2019 Revised Patent subject matter Eligibility Guidance (referred to as 2019 PEG) published January 2019 and the “PEG update” in October 2019.
Claim Interpretation
Claims 1 claims “A pharmaceutical composition comprising a Reg3a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO:3, and SEQ ID NO: 4 in combination with at least one oxygen sensitive gram positive bacteria species, cultured ex vivo in the presence of recombinant Reg3a, from fecal microbiota from a human or from a transgenic animal engineered to expresses the Reg3a polypeptide and at least one pharmaceutically acceptable excipient.” Claims 19-20 are drawn to naturally occurring gram positive bacteria such as Lachnospiraceae. Claims 21-22 claim the formulation as a food product or dietary supplement.
Subject Matter Eligibility Test for Products and Processes
Step 1: Is the claim to a process, machine, manufacture, or composition of matter (see, e.g., 79 FR 74621)?
Yes, the instant claims are directed to a statutory patent-eligible subject matter category, namely a composition of matter.
Step 2A (1): Is the claim directed to a law of nature, a natural phenomenon, or an abstract idea (see MPEP 2106.04)?
Yes, the claims are directed to a natural phenomenon, a composition comprising naturally occurring peptides. For example, SEQ ID NOs:1, 3-4 are sequences from Q53S56_HUMAN Proliferation-inducing protein 34 (see previously attached handout, Reg3a). SEQ ID Nos:1, 3-4 are fragments of the of the naturally occurring protein. However, the polypeptide of the claims is open and thus not limited to fragments. There is no evidence in the specification that the claimed amino acid sequences have any structural or functional characteristics that are different from the naturally occurring sequences. Reg3a is found naturally in the GI tract (including the small intestine and large intestine) due to secretion from cells in these locations (see paragraph 0011, PGPUB). Furthermore, regarding the peptide in combination with fecal microbiota (bacteria found in stool) and an excipient (e.g., water), all of these components are naturally found in the intestines together and in stool (as evidenced by Jang, see previously attached handout, Figure 1D) and thus, the combination is not markedly different from what is found in nature. Please note that claim 4 (which is being interpreted as the fecal microbiota from transgenic animal) was not included given that fecal microbiota from a transgenic animal expression Reg3a would be markedly different from the animal stool in nature given the stool would include foreign DNA which is inclusive to a different species protein (human) and vector DNA. Although the claims recite that the bacteria are “cultured ex vivo in the presence of recombinant Reg3a”, there is no evidence that such culturing imparts any structural or functional difference to the bacteria. Absent such a difference, the bacteria are reasonably interpreted as indistinguishable from naturally occurring microbiota, which are inherently exposed to Reg3a in vivo in the GI tract. Furthermore, the composition as a whole (Reg3a, fecal microbiota, and excipient) represents a combination of components that coexist in nature (e.g. in the intestinal tract and stool), and thus is not markedly different from what exists in nature.
Step 2A (2): Does the Claim recite additional Elements that integrate the judicial Exception into a Practical Application? NO.
Step 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception? Examiners should answer this question by first identifying whether there are any additional elements (features/limitations/steps) recited in the claim beyond the judicial exception(s), and then evaluating those additional elements individually and in combination to determine whether they contribute an inventive concept (i.e., amount to significantly more than the judicial exception(s)) (MPEP 2106.05)?
No, the claims do not recite additional elements that amount to significantly more than the judicial exception. The peptide being part of a pharmaceutical composition in combination of fecal microbiota (gram positive bacteria) which express naturally the protein does not structurally or functional alter the judicial exception (the naturally occurring peptide). Given the broadest reasonable interpretation of excipient, an excipient could be water which does not amount to significantly more than the judicial exception (water is naturally occurring and within fecal microbiota/stool along with Reg3a). Regarding the limitation of “form suitable for oral or transmucosal”, stool can be considered suitable for oral or transmucosal delivery. Regarding claims 21-22, under the broadest reasonable interpretation, such formulations encompass conventional probiotic compositions, including bacteria mixed with carriers such as water or other ingestible media. The use of water or similar carriers represents a naturally occurring component and a well understood, routine and conventional means of administering bacteria. Accordingly, the recited food product for dietary supplement does not impart any structural or functional difference to the claimed composition and does not render the composition markedly different from what exists in nature.
Factors for determining if the claim directed to a product of nature, as a whole, recites something significantly more than the judicial exception, are provided in the Guidance (74623; see esp. 79 FR 74623 at §I.A.3.b). see also, 79 FR.
In sum, when the relevant considerations are analyzed, they weigh against a significant difference. Accordingly, Claims 1-3, 5, 10-12, 14, 19-22 do not qualify as eligible subject matter.
Response to Applicant’s Arguments
Applicants argue “Independent claims 1 and 10 are amended herein to identify the fecal microbiota element as at least one oxygen sensitive gram-positive bacteria species, cultured ex vivo in the presence of recombinant Reg3a, from fecal microbiota. With this limitation, one of ordinary skill in the art would recognize that the claimed is distinguishable from fecal matter, such as that found naturally in the intestines together and in stool. Because the oxygen sensitive gram-positive bacteria are cultured ex vivo, the fecal microbiota of the claims is enriched in particular species of interest, which are identified and therefore limited in claims 10 and 11 and new claims 19 and 20. These limitations provide addition distinctions from naturally occurring products such as fecal matter, stool, and the microbiota found naturally in the intestines. In addition, new claims 21 and 22 limit the bacteria species as being formulated as a food product and/or dietary supplement. While the fecal microbiota as now claimed in claims 1, 10, 19 and 20 are isolated from fecal matter and substantially purified, they are naturally occurring species, albeit reduced in some conditions or diseases. However, one objective of the claimed invention to provide a composition enabled to correct an imbalance between gram negative and gram positive bacteria by increasing the amount of beneficial microbiota within the intestine of a subject, since this is unlikely to occur without pharmaceutical intervention. Indeed, the inventors were the first to identify (see page 4, lines 5-9) that "Reg3a polypeptides permit to protect oxygen sensitive gram-positive bacteria. The present invention thus relies in the fact that the polypeptide Reg3a has a protective role for oxygen sensitive gram-positive bacteria and in particular for the beneficial symbionts of the gut microbiota." Thus, Applicant respectfully asserts that the present claims may also be compared to Example 3, claim 5 of the USPTO subject matter eligibility examples. Indeed, the USPTO analysis indicates that the claimed composition of two naturally occurring substances is structurally different from the naturally occurring substances, and this structural difference results in the claimed composition having different functional characteristics in vivo than the naturally occurring substances by themselves. In this instant application, the composition differs from the naturally occurring substances by themselves due to the enrichment of gram-positive species, which are additionally protected and promoted by co-administration of Reg3a. As disclosed on page 21, lines 3-11, "...a modulation of the intraluminal concentration of Reg3a, for instance via
a colon-targeted delivery of a recombinant Reg3a, may be a valuable approach to attenuate intestinal inflammation through a gut microbiota reshaping. Regarding the potential benefits to patients, such an approach would be a more physiological and nontoxic strategy for the treatment of inflammatory outbreaks than the available therapies, including fecal transplantation. Moreover, it might be most successful in the early stages of the inflammatory process or even before the onset of inflammation and could therefore be useful for the maintenance of medically- or surgically-induced remission and even the prevention of IBD in high-risk individuals." As now claimed, the presently claimed composition is markedly different from a natural product and therefore not directed to a judicial exception. Reconsideration and withdrawal of this rejection is thus respectfully requested.
Applicant’s arguments have been fully considered but not found persuasive. Applicant argues that the claimed composition is markedly different from naturally occurring fecal microbiota because the oxygen sensitive gram positive bacteria are cultured ex vivo in the presence of Reg3a, resulting in enrichment and protection of specific bacterial species. This argument is not persuasive. While the claims recite culturing the bacteria ex vivo in the presence of Reg3a, the claims do not require that such culturing results in any structural or functional modification of the bacteria. In the absence of any recited or demonstrated change, the bacteria are reasonably interpreted as being indistinguishable from naturally occurring microbiota. See MPEP2106.04. Furthermore, the alleged “enrichment” of certain bacterial species does not render the claimed composition markedly different from what exists in nature. Variations in the relative abundance of microbial species are inherent in naturally occurring microbiota and do not constitute a structural or functional difference sufficient to confer eligibility.
Applicant’s argument that Reg3a provides a protective effect on oxygen-sensitive gram positive bacteria is also unpersuasive. The claims do not require that the bacteria retain any altered property or enhanced survival as a result of the ex vivo exposure of Reg3a, nor do they recite any measurable or structural change resulting from such exposure. As such, the claimed composition remains a combination of naturally occurring components that do not exhibit markedly different characteristics from their natural counterparts. Accordingly, the claims remain directed to a judicial exception and do not recite additional elements that amount to significantly more than the exception.
Applicant’s reliance on Example 3 of the USPTO subject matter eligibility examples is not persuasive. In Example 3, the claimed composition was found eligible because the combination of natural products results in a composition having a demonstrated structural and functional difference from the naturally occurring substances. In contrast, the present claims do no recite and the specification does not demonstrate any structural or functional modification of the bacteria resulting from culturing ex vivo in the presence of Reg3a. The alleged enrichment or protection of certain bacterial species reflects a different in relative abundance or environment, which is inherent in naturally occurring microbiota and does not rise to the level of a marked difference. Accordingly, unlike Example 3, the claimed composition does not exhibit characteristics markedly different from what exists in nature.
Applicant’s argument that the claimed composition is patent eligible because it is formulated as a food product and or dietary supplement is not persuasive. Under the broadest reasonable interpretation, such formulations encompass conventional probiotic compositions, including bacteria mixed with carriers such as water or other ingestible media. The use of water or similar carriers represents a naturally occurring component and a well understood, routine and conventional means of administering bacteria. Accordingly, the recited food product for dietary supplement does not impart any structural or functional difference to the claimed composition and does not render the composition markedly different from what exists in nature. Rather, these limitations merely reflect conventional preparation and administration of naturally occurring components and therefore do not amount to significantly more than the judicial exception. The rejection under 35 U.S.C. 101 is therefore maintained.
New Objection
Claims 10 and 19 are objected for the following informality: the limitation of “is selected from the group consisting of a Bifidobacteria genera, a lactic acid producing species, a gram positive probiotic bacteria and a Clostridiales species…” should be replaced with -is selected from the group consisting of a bacterium of the genus Bifidobacteria bacterium, a gram positive probiotic bacterium and a bacterium of the order Clostridiales
Claim 11 is objected to for the following informality: the limitation of “wherein the at least one oxygen sensitive gram positive bacteria is a Clostridiales species…” should be replaced with - wherein the at least one oxygen sensitive gram positive bacteria is a bacterium of the order Clostridiales the bacterium of the order Clostridiales belongs to the family of i
Claim 20 is objected to for the following informality: the limitation of “wherein Clostridiales species is at least one of Ruminococcaceae and/or Lachnospiraceae” should be replaced with – wherein the bacterium of the order Clostridiales belongs to the family of i
New Rejection
Claim Rejections - 35 USC § 112
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 4, 10-12, 14, 19-20 and 22 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 4 claims “…in combination with fecal microbiota from a human or from a transgenic animal engineered to express a human Reg3a polypeptide…” but then further recites “wherein the fecal microbiota is from the transgenic animal engineered to express hReg3a”. It is therefore unclear whether the claim is directed to compositions comprising microbiota from a human, a transgenic animal, or only a transgenic animal. The scope of the claim is thus ambiguous.
Claim 10 recites that “the at least one oxygen sensitive gram positive bacteria species is selected from the group consisting of Bifidobacteria genera, a lactic acid producing species, a gram positive probiotic bacteria and a Clostridiales species”. The term “Bifidobacteria genera” is not consistent with standard taxonomic nomenclature and renders the scope of the claim unclear. Additionally, the recitation “Clostridiales species” is improper, as Clostridiales is an order rather than a species. Further, the limitation mixes inconsistent categories, including taxonomic ranks (e.g. genus and order) and functional classifications (e.g. lactic acid producing species and gram positive probiotic bacteria), within a single markush group defining a “species”. As a result, it is unclear what constitutes the claimed “oxygen sensitive gram positive bacteria species” and the metes and bounds of the claim cannot be reasonably determined. Claim 11 is dependent on claim 10 and is also rejected due to the same reasons listed above and not clarifying these points of confusion.
Claim 19 recites similar language and therefore has the same deficiencies as discussed above with regards to claim 10 including the improper and unclear recitations of “Bifidobacteria genera” and “Clostridiales species”, as well as the mixing of inconsistent taxonomic and functional classifications. Claim 20 is dependent on claim 19 and is also rejected due to the same reasons listed above and not clarifying these points of confusion. In particular, claim 20 relies on the unclear recitation of “Clostridiales species”, which lacks proper taxonomic meaning. A suggested amendment to claims 10-11, 19-20 to overcome this rejection is presented above under “claim objections”.
Claims 12, 14 and 22 are also rejected due to their dependence on claim 10 and not further clarifying these points of confusion.
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.
Claim(s) 1-3, 5, 10-12, 14, 19-22 are rejected under 35 U.S.C. 103 as being unpatentable over Abbas (AU2016259423, cited in Applicant’s IDS) in view of Vercoe (WO2013037068 A1, cited previously).
Abbas teaches “A method of treating an infection by a microbial pathogen, in a subject, by modulating an anti-microbial immune response in said subject, comprising administering to said subject an effective amount of an anti-microbial polypeptide (AMP) or modulator thereof, wherein said AMP is selected from a group consisting of: IL-6, IL-18, IL-23, REG I , REG I , HIP/PAP, REG III, REG IV, Reg-related sequence (RS) and LT” (see claim 2). Abbas teaches wherein the AMP is SEQ ID NO:16 which comprises instant SEQ ID NO:4 (see claims 2, 25). Abbas teaches that “The therapeutic methods of the present invention comprise one or more compositions or pharmaceutical formulations of the present invention. Such methods include in vitro, ex vivo, and in vivo therapeutic methods, unless otherwise indicated” (see page 65, lines 3-5). Regarding claims 1 and 10, Abbas teaches including pharmaceutical excipients (see page 18, lines 1-3). Abbas teaches treating bacterial infections and treating microbial disorders of the gut including Crohn’s, IBD or UC (see claims 5-10).
Abbas is silent to including at least one oxygen sensitive gram positive bacteria from a healthy human in combination with the peptide.
However, Vercoe teaches of synthetic stool preparations comprising bacteria isolated from a fecal sample from a healthy donor (see abstract) and for treating dysbiosis, Crohn’s disease, ulcerative colitis, IBS and IBD (see abstract).
Vercoe teaches microbiota based compositions comprising defined bacterial consortia derived from fecal microbiota, including compositions comprising selected bacterial strains. Vercoe further teaches that such compositions may comprise gram positive anaerobic bacteria, including members of the order Clostridiales, such as the family Lachnospiraceae (claim 14, see page 24, paragraph 2, Table 14). Vercoe further teaches that bacterial strains may be cultured ex vivo (e.g. in a chemostat under controlled conditions stimulating the GI tract), purified isolated strains, and combined to form a defined composition (see, e.g., claims 65-66 and related disclosure). Thus, Vercoe teaches microbiota compositions comprising cultured and purified bacteria derived from fecal microbiota, rather than raw fecal material. Vercoe teaches that “Lachnospiraceae family members are part of the core human microbiome and may be important in maintaining stability of the human microbiota. Lachnospiraceae have also been implicated as part of the 'healthy' gut microbiota and may play a role in optimizing immune function in the gut” (see page 25, first paragraph). Regarding claims 2, 5 and 14, Vercoe teaches wherein the fecal microbiota from a healthy human (see Examples 1, 3 for example).
It would have been obvious before the effective filing date of the claimed invention to combine the teachings of Abbas with those of Vercoe. Abbas teaches that Reg3a modulates microbial populations and is useful for treating GI and microbial disorders. Vercoe teaches composition compositions comprising beneficial microbiota derived from fecal samples, including gram positive anaerobic bacteria such as Clostriadiales and Lachnospiraceae, for restoring microbial balance. One of ordinary skill in the art would have been motivated to combined Abbas Reg3a containing compositions with the microbiota compositions of Vercoe because both are directed to modulating microbial populations in the GI tract and treating related disorders, and combining these known therapeutic approaches would have been expected to improve or complement microbial modulation. There would have been a reasonable expectation of success in making such a combination because each component (Reg3a and microbiota compositions) was already known to be effective for its intended purpose, and their combination represents the use of know elements according to their established functions to yield predictable results (see MPEP 2143, I(A), KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007)).
Furthermore, “It is prima facie obvious to combine two compositions (REGIIIa and gram positive bacteria derived from human fecal microbiota) each of which is taught by the prior art to be useful for the same purpose (treating microbial infections, patients with GI disorders associated with microbial imbalances in the gut (i.e. Crohn’s, IBD etc..), 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) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious). But see In re Geiger, 815 F.2d 686, 2 USPQ2d 1276 (Fed. Cir.1987) (“Based upon the prior art and the fact that each of the three components of the composition used in the claimed method is conventionally employed in the art for treating cooling water systems, the board held that it would have been prima facie obvious, within the meaning of 35 U.S.C. 103, to employ these components in combination for their known functions and to optimize the amount of each additive....Appellant argues... hindsight reconstruction or at best,... obvious to try’.... We agree with appellant.”). One of ordinary skilled in the art would have been motivated to combine the two each known to be useful for the same purpose, with a reasonable expectation that at least here will be an additive effect.
Regarding claims 3, 12, 21-22, Vercoe teaches “The subject may also be treated with a colon cleansing agent before administration of the synthetic stool preparation. In another aspect, administration is oral, e.g., freeze-dried synthetic stool preparation or synthetic stool preparation in capsule or tablet form is administered” (see page 41, second paragraph, and claim 73). Vercoe teaches “In sum, synthetic stool preparations described herein can provide safe, defined, controllable, reproducible, stable, deliverable, palatable and/or available alternatives to fecal transplants” (see page 15, second paragraph, last 3 lines). Vercoe teaches “In an embodiment, the synthetic stool preparation further comprises a prebiotic. Without wishing to be bound by theory, a prebiotic may provide a bolus of nutrients for the strains in the synthetic stool preparation to assist their early growth after administration to the patient. Any prebiotic known in the art may be used” (page 38, paragraph 0004, see also page 41, second to last paragraph). Vercoe teaches formulation of microbiota compositions in oral dosage forms capsules or ingestible preparations, which correspond to food products and or dietary supplements. Therefore, it would have been obvious to formulate the composition of Abbas and Vercoe in such forms.
Regarding the limitation of “at least one oxygen sensitive gram positive bacteria species, cultured ex vivo in the presence of recombinant Reg3a…”, Vercoe teaches that bacteria derived from fecal microbiota are cultured ex vivo and purified into isolated strains prior to formulation, as discussed above. While Vercoe does not explicitly teach culturing in the presence of Reg3a, this limitation is directed to the process by which the bacteria are prepared, rather than to a structural or functional characteristic of the claimed bacteria or composition. The claim does not require that the bacteria possess any structural, compositional or functional difference as a result of being cultured in the presence of Reg3a, nor does it define the bacteria by any measurable property imparted by such exposure. Accordingly, the limitation is treated as a product by process limitation, which does not impart patentable weight unless the applicant demonstrates that the claimed product is structurally or functionally distinct from the prior art product (see MPEP 2113). In the absence of evidence that culturing in the presence of Reg3a results in a structural or functional difference in the claimed bacteria, the claimed composition is not distinguished from the prior art compositions comprising cultured and purified bacteria derived from fecal microbiota as taught by Vercoe.
Regarding claims 10-11, 19-20, Abbas in view of Vercoe teach wherein the gram positive oxygen sensitive bacteria are Lachnospiraceae (see claims 65-66).
Response to Applicant’s Arguments
Applicants argue “As discussed above, the claims are now limited to claim the fecal microbiota element as at least one oxygen sensitive gram-positive bacteria species, cultured ex vivo in the presence of Reg3a, from fecal microbiota. This amendment demonstrates that wording "fecal microbiota" in the claims is different from "fecal matter" and refers to microbiota which has been separated from the other elements from fecal matter. The "purified" microbiota would differ in both composition and function from feces: for example, Reg3a would only be present in negligible amounts after purification, i.e. in reduced amounts compared to fecal matter. Furthermore, while Reg3a is known to interact with the overall microbiota and inflammatory environment in patients, the prior art fails to teach an ex vivo protective effect on oxygen-sensitive gram-positive bacteria during the culturing process, nor does it teach a pharmaceutical composition comprising Reg3a and at least one oxygen sensitive gram-positive bacteria species cultured ex vivo in the presence of Reg3a. This is an important contribution of the present invention. The claimed composition supplements purified microbiota cultured in the presence of Reg3a to ensure protection of oxygen sensitive gram-positive bacteria during sample preparation for administration.
In contrast, nothing in the prior art teaches the ex vivo protective role of Reg3a on the microbiota. Abbas teaches antimicrobial polypeptides that mediate the anti-microbial immune response but does not teach co-administration of oxygen sensitive gram-positive bacterial species. As noted by the Examiner, Abbas is silent regarding fecal microbiota. However, Vercoe teaches preparation of a "synthetic stool" comprising at least 30 bacterial species (see Table 2). Chitolie requires the use of honey or a honey mimetic in combination with microbiota, as taught in the paragraph bridging pages 4-5 and in lines 14-18 on page 5. See also page 4, lines 6- 19, which teaches microbiota stored in honey or a honey mimic as a bacteriostatic storage medium. Seegert teaches "IMEnT", comprising administration of an artificial, synthetic, cultured or fermented stool made by suspending the stool, particularly pig stool, in a liquid and by depletion of the microbiota in the suspension and addition of a "defined panel of microbiota" added back to the stool preparation, however the "defined panel of microbiota" is not disclosed (see claim 1; the paragraph bridging pages 6-7; page 11, lines 9-23; and page 12, lines 13-28). Thus, the combination of Abbas, Vercoe, Chitolie and Seegert would not lead one of ordinary skill in the art to the present invention, and in fact, teaches away from the present combination as now claimed in claims 1 and 10.
Thus, one of ordinary skill would not look to Abbas in combination with any or all of Vercoe, Chitolie and/or Seegert to devise a pharmaceutical composition combining hReg3a and oxygen sensitive gram-positive bacteria cultured ex vivo for preventing or treating microbiota- related diseases and/or disorders, including inflammatory bowel disease (IBD), colitis, gastrointestinal infections, irritable bowel syndrome and other gastrointestinal functional diseases, gastrointestinal tract cancer, metabolic syndrome and obesity, diabetes, liver diseases, allergic diseases, neurodegenerative diseases and psychological disorders, as disclosed in the present application.
Applicant’s arguments have been fully considered but not found persuasive. Applicants argue that the amended claims are distinguishable because they recite at least on oxygen sensitive gram positive bacteria species cultured ex vivo in the presence of Reg3a, and that such compositions are not taught or suggested by the prior art. Applicants further assert that the claimed microbiota is distinct from naturally occurring fecal matter and that Reg3a provides a protective effect during ex vivo culturing. This argument is not found persuasive. As set forth in the rejection, Vercoe teaches microbiota-based compositions comprising defined bacterial consortia derived from fecal microbiota, including gram positive anaerobic bacteria such as members of Clostriadiales and Lachnospiraceae. Vercoe further teaches that such bacteria are isolated, cultured ex vivo, purified into defined strains, and formulated into compositions for administration to a subject. Abbas teaches Reg3a polypeptides and their use in modulating microbial populations in the GI tract including in pharmaceutical compositions. With respect to the limitation that the bacteria are “cultured ex vivo in the presence of Reg3a”, this limitation is directed to the process by which the bacteria are prepared rather than to a structural or functional characteristic of the claimed composition. The claims do no recite any measurable structural or functional difference in the bacteria resulting from such culturing. Accordingly, this limitation is treated as a product-by-process limitation, which does not impart patentable weight unless the claimed product is shown to be structurally or functionally distinct from the prior art (see MPEP 2113).
Applicants have not provided evidence that exposure to Reg3a during ex vivo culturing results in any structural or functional modification of the bacteria. Therefore, the claimed composition encompasses bacteria indistinguishable from those taught by Vercoe (i.e., cultured and purified bacteria derived from fecal microbiota).
Applicant’s arguments that the claimed composition is distinct from naturally occurring fecal matter is also not persuasive. Vercoe explicitly teaches compositions comprising isolated and cultured bacterial strains derived from fecal microbiota, rather than raw stool. Thus, the prior art already distinguishes from naturally occurring fecal matter in the same manner as the present claims.
Furthermore, as stated above, It would have been obvious before the effective filing date of the claimed invention to combine the teachings of Abbas with those of Vercoe. Abbas teaches that Reg3a modulates microbial populations and is useful for treating GI and microbial disorders. Vercoe teaches composition compositions comprising beneficial microbiota derived from fecal samples, including gram positive anaerobic bacteria such as Clostriadiales and Lachnospiraceae, for restoring microbial balance. One of ordinary skill in the art would have been motivated to combined Abbas Reg3a containing compositions with the microbiota compositions of Vercoe because both are directed to modulating microbial populations in the GI tract and treating related disorders, and combining these known therapeutic approaches would have been expected to improve or complement microbial modulation. There would have been a reasonable expectation of success in making such a combination because each component (Reg3a and microbiota compositions) was already known to be effective for its intended purpose, and their combination represents the use of know elements according to their established functions to yield predictable results (see MPEP 2143, I(A), KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007)).
Furthermore, “It is prima facie obvious to combine two compositions (REGIIIa and gram positive bacteria derived from human fecal microbiota) each of which is taught by the prior art to be useful for the same purpose (treating microbial infections, patients with GI disorders associated with microbial imbalances in the gut (i.e. Crohn’s, IBD etc..), 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) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious). But see In re Geiger, 815 F.2d 686, 2 USPQ2d 1276 (Fed. Cir.1987) (“Based upon the prior art and the fact that each of the three components of the composition used in the claimed method is conventionally employed in the art for treating cooling water systems, the board held that it would have been prima facie obvious, within the meaning of 35 U.S.C. 103, to employ these components in combination for their known functions and to optimize the amount of each additive....Appellant argues... hindsight reconstruction or at best,... obvious to try’.... We agree with appellant.”). One of ordinary skilled in the art would have been motivated to combine the two each known to be useful for the same purpose, with a reasonable expectation that at least here will be an additive effect.
Regarding Applicant’s arguments that Abbas teaches away because Reg3a is antimicrobial, is not persuasive. Abbas teaches the use of Reg3a for treating microbial related disorders such as Crohn’s disease, IBD, and UC by modulating microbial populations. This teaching is directed to targeting pathogenic or dysbiotic bacteria, not eliminating all bacteria indiscriminately. Notably, these same disease states are also treated in the art using beneficial microbiota or probiotic compositions, as taught by Vercoe. Thus, Abbas does not discourage the presence or administration of beneficial bacteria, but rather is consistent with modulating the microbial environment. One of ordinary skill in the art would have understood that antimicrobial peptides such as Reg3a can be used in conjunction with beneficial microbiota to suppress pathogenic species while supporting restoration of a healthy microbial balance. Accordingly, Abbas does not teach away from combining Reg3a with microbiota based compositions, and instead is consistent with such use.
A reference teaches away only when it criticizes or discourages the claimed combination (see MPEP 2141.02 VI) which is not present in Abbas.
Regarding claims directed to food products or dietary supplements, Vercoe teaches that microbiota compositions may be formulated in oral dosage forms including capsules, tablets or ingestible preparations. Such formulations correspond to food products or dietary supplements. Moreover, probiotic bacterial compositions are conventionally formulated with naturally occurring carriers (e.g., water or other ingestible excipients). Thus, reciting the composition as a food product or dietary supplement does not render the claimed invention nonobvious.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERINNE R DABKOWSKI whose telephone number is (571)272-1829. The examiner can normally be reached Monday-Friday 7:30-5:30 Est.
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/ERINNE R DABKOWSKI/Examiner, Art Unit 1654
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