DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/09/2025 has been entered.
Status of claims
Claims 1, 3, 4, 6, 10, 11, 16, 23, 26, 29, 31, 35, 44 and 104-108 as amended on 12/09/2025 are currently pending.
Claim Rejections - 35 USC § 112
Indefinite
Claims 1, 3, 4, 6, 10, 11, 16, 23, 26, 29, 31, 35, 44 and 104-108 as amended are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 as amended is indefinite because it is not clear as written whether “CFU/gram” refers to a weight of a sample collected from a receiving subject after treatment or to a weight of a population of the transformed bacterial cells (product) administered to the receiving subject.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3, 4, 6, 10, 11, 23, 26, 29, 31, 35, 44 and 105 are rejected under 35 U.S.C. 102 (a) (1) as being anticipated by US 7,988,961 (Farrar et al).
US 7,988,961 (Farrar et al) teaches a method of delivering a therapeutic polypeptide including cytokines to a mammalian subject in need thereof or in need (see entire document including abstract).
In particular, the cited method comprises following steps:
Steps a), b) and c): obtaining/isolating gut commensal bacteria Bacteroides from a microbiome of a donating subject (col. 4, lines 53-60) and culturing the bacteria (col. 5, lines 56-57);
Step d): transforming in the commensal bacteria with heterologous polypeptide including growth factors and cytokines including IL-2 and IL-10 (col. 3, lines 32-60; col. 6, lines 7-31), wherein the heterologous polypeptide is integrated into genome of host cell B.ovatis (col. 6, lines 30-31), thus, into chromosome of the cell as encompassed by the claims;
Step e): administering to the mammalian subject (mice) the transformed cells that are capable to express a therapeutic polypeptide such as enzyme IL-2 (col. 8, lines 8-11);
wherein the transformed cells colonize mammalian subject for at least 28 days as it was evaluated (table 1);
wherein the CFU of transformed cells in the sample from the receiving subject was more than 104 CFU/g (table 1) or 2-8x107 CFU/g (col. 8, line 22) after more than 2 weeks or after 28 days.
Thus, the cited method comprises same active steps and same structural elements as required by the claimed method (claim 1).
As applied to claim 3: the “commensal” bacterial cells are obtained from gut or from bodily excretion, biopsy within the broadest meaning of the claims.
As applied to claims 4, 6, 23: the bacterial cells are non-pathogenic and non-toxin producing microbiota including Bacteroides.
As applied to clams 10-11: the heterologous polypeptides are growth factors and cytokines including IL-2 and IL-10 (col. 3, lines 32-60; col. 6, lines 7-31),
As applied to claim 26: the transformed cells stable colonize the recipient for at least 6-7or for 28 days (table 1).
As applied to claim 26: the cells of Bacteroides are non-motile.
As applied to claims 31 and 35: about 108 CFU of transformed Bacteroides is administered orally (col. 8, line 9).
As applied to claim 44: the cited document does not disclose side effects; and, thus, administration of transformed cells do not alter microbiome of receiving subject within the broadest meaning of the claims.
As applied to claim 105: the bacterial cells colonize recipient tissues after administration for 28 days, CFU counts remain at the level of about 108 CFU, and, thus, do not decline by a factor of 10 for at least 2 weeks within the broadest meaning of the claims.
Thus, the cited document US 7,988,961 (Farrar et al) is considered to anticipate the claimed invention.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 3, 4, 6, 10, 11, 23, 26, 29, 31, 35, 44 and 104-108 as amended are/remain rejected under 35 U.S.C. 103 as being unpatentable over Joyce et al (PNAS 2014, vol. 111, no. 20, pages 7421-7426), US 10,702,559 (Lesser et al), Kuhnert et al (“Rapid Identification of Escherichia coli K-12 strains”. Applied and Environmental Microbiology, 1995, vol. 61, no. 11, pages 4135-4139) and Autieri et al (Infection and Immunity, 2007, vol. 75, no. 11, pages 5465-5475).
The cited reference by Joyce teaches a method of delivering a therapeutic polypeptide such as BSH (bile salt hydrolase) to a mammalian subject in need thereof or in need of regulation of lipid metabolism (see entire document including abstract).
In particular, the cited method comprises following steps:
Steps a), b) and c): obtaining/isolating an original bacteria from a microbiome of a donating subject and culturing the bacteria; wherein the original bacterial cells of wild type strain E.coli K-12 (page 7422, col.1, last par) are derived or were isolated from a patient (see Kuhnert at page 4135, col.1, par. 2); and thus, the bacterial cells of E.coli are isolated from microbiome of a donating subject, thereby, being “commensal” and/or “not from a laboratory adapted” strain at least before step c) of culturing in vitro to yield a cultured population as encompassed by the claimed method.
Step d): in the cited method of Joyce the bacterial cells are E.coli strain K-12 were transformed to express BSH and are capable to colonize mice at high levels (see page 7422, col.1, last par);
Step e): administering to the mammalian subject (mice) the transformed cells that are capable to express a therapeutic polypeptide such as enzyme BSH or bile salt hydrolase (page 7422, col. 1, last par);
Wherein the transformed cells colonize mammalian subject for over 70 days (page 7423, col. 2, par. 2, lines 10-11). The cited reference discloses that the cells of both starting bacterial E.coli strain (EC) and BSH-transformed E.coli strains (ECBSH1 and ECBSH2) significantly colonized mammalian model for 70 days (page 7423, col. 2, par. 2, lines 10-11) or for at least 5 days as encompassed by the claims.
Thus, the cited method comprises same active steps and same structural elements as required by claim 1 except that some mice (recipients) were given antibiotic in their drinking water to promote stable colonization by the transformed bacteria (see notes under figure 4) as intended to evaluate differences between several treatment recipient models including uncolonized, untreated, antibiotic-treated mice and mice colonized by various engineered E. coli including E.coli expressing BSH.
However, the prior art clearly recognizes that administration of antibiotics has side effects and that probiotics including commensal bacteria transformed with therapeutic polypeptides are used to avoid and to substitute conventional drugs including antibiotics.
For example: US 10,702,559 (Lesser et al) teaches that designer probiotics for targeted delivery of therapeutics directly to sites of diseases overcome issues associated with wide-spread usage of antibiotics (col. 70, lines 32-35) which alter microbial flora leading to overgrowth of pathogens and promoting drug resistance (col. 71, lines 8-19). In the disclosure of US 10,702,559 (Lesser et al) the “designer probiotics” are engineered bacteria obtained/derived from commensal intestinal microbiome (col. 3, lines 42-50) including E. coli Nissle (col. 3, line 44) transformed with heterologous polypeptides (col. 9, lines 50-60). US 10,702,559 (Lesser et al) clearly teaches that engineered “commensal” bacterial probiotics persist in the recipient and provide continued delivery of therapeutic polypeptides (col. 6, lines 34-38).
Therefore, it would have been obvious to one having ordinary skill in the art at the time the claimed invention was filed to avoid step of administering antibiotics in the method for treating mammalians with therapeutic polypeptides delivered by transformed commensal bacteria with a reasonable expectation of success in maximizing effects of therapeutic polypeptides while avoiding side effects of conventional treatment as clearly recognized by the prior art (Lesser). It would have been obvious to one having ordinary skill in the art at the time the claimed invention was to exclude/avoid administration of antibiotics in the method for regulation of lipid metabolas of Joyce as suggested/taught by Lesser because transformed commensal bacteria are capable to colonize mammalian recipient host and to deliver therapeutic polypeptides and because administration of antibiotic can lead to detrimental effects.
Thus, the claimed invention as a whole was clearly prima facie obvious, especially in the absence of evidence to the contrary.
The claimed subject matter fails to patentably distinguish over the state art as represented be the cited references. Therefore, the claims are properly rejected under 35 USC § 103.
With regard to limitation drawn to integration of heterologous polypeptide into chromosome of transformed bacteria (step d in claim 1): although the cited reference by Joyce does not explicitly state so but it appears that heterologous polypeptide is integrated into chromosome of transformed bacteria (fig.1 A) resulting in a stable gene expression and gut colonization, thus, grow/proliferation while expressing recombinant gene (fig. 1 B). Further, the cited US 10,702,559 (Lesser et al) clearly teaches and suggests that beneficial heterologous polypeptide is integrated into chromosome of transformed bacteria (fig. 5); and, thus, the engineered commensal and non-pathogenic microbial cells can persist in a subject and provide for continued delivery of beneficial polypeptide (col. 6, lines 33-36).
Thus, the claimed invention as a whole was clearly prima facie obvious, especially in the absence of evidence to the contrary.
With regard to limitation drawn to detectable amount of transformed bacterial cells in a sample form receiving subject (last wherein clause in claim 1): The cited reference by Joyce discloses that the BSH-transformed bacterial cells colonized gastrointestinal tract of mammalian subjects for over 70 days (page 7423, col. 2, par. 2, lines 10-11) and at high levels (page 7422, col.1, last par., line 9). The detectable amounts of administered cells would obviously correlate or depend (modified and/or optimized) by CFU bacterial amounts and frequency of administration to receiving subject.
Thus, the claimed invention as a whole was clearly prima facie obvious, especially in the absence of evidence to the contrary.
The claimed subject matter fails to patentably distinguish over the state art as represented be the cited references. Therefore, the claims are properly rejected under 35 USC § 103.
Further, as applied to claim 3: in the disclosure by Joyce the original wild type strain K-12 is obtained from a biopsy or swab of a surface and a pathological specimen as evidenced see Kuhnert within the broadest meaning of the claims.
As applied to claims 4 and 6: in the disclosure by Joyce the bacterial cells and/or original bacterial cells do not contain pathogenic toxin(s) and are not antibiotic resistant within the broadest meaning of the claims and as recognized by the cited prior art for this record.
As applied to claims 10 and 11: in the cited method of Joyce the heterologous polypeptide is an enzyme bile salt hydrolase BSH. The cited US 10,702,559 (Lesser et al) clearly teaches and suggests integration of heterologous polypeptides IL-10 and IL-27 (col.10, liens 59-60).
As applied to claims 23, 29, 107 and 108: the bacterial cells belong to Escherichia coli strain K-12 (as stated by Joyce); and cells of K12 stain are capable to utilize ribose (as evidenced by Autieri, see abstract).
As applied to claim 26: in the cited method of Joyce administration of recombinant bacterial cells delivering BSH expression provided a significant therapeutic effects as intended; and, thus, recombinant bacterial cells stably colonized tissue of recipient under administration within the broadest meaning of the claims.
As applied to claim 31: in the cited method of Joyce comprising administration of recombinant bacterial cells delivering BSH expression the donating and receiving subjects different as explained above.
As applied to claims 35, 44 and 104: in the cited method of Joyce administration of recombinant bacterial cells delivering BSH expression is provided orally as edible compositions or as diets (results are seen/evaluated in mice fed diets for comparison of therapeutic effects as disclosed by Joyce) and, thus, “multiple times” and/or on a “daily” basis within the broadest meaning of the claims.
As applied to claim 105: the cited reference by Joyce discloses the BSH-transformed bacterial cells colonized gastrointestinal tract of mammalian subjects for over 70 days (page 7423, col. 2, par. 2, lines 10-11) and at high levels (page 7422, col.1, last par., line 9). The detectable amounts of administered cells would obviously correlate or depend on amounts and frequency of administration.
Thus, the claimed subject matter fails to patentably distinguish over the state art as represented be the cited references. Therefore, the claims are properly rejected under 35 USC § 103.
Claims 1, 3, 4, 6, 10, 11, 16, 23, 26, 29, 31, 35, 44 and 104-108 are rejected under 35 U.S.C. 103 as being unpatentable over Joyce et al (PNAS 2014, vol. 111, no. 20, pages 7421-7426), US 10,702,559 (Lesser et al), Kuhnert et al (“Rapid Identification of Escherichia coli K-12 strains”. Applied and Environmental Microbiology, 1995, vol. 61, no. 11, pages 4135-4139) and Autieri et al (Infection and Immunity, 2007, vol. 75, no. 11, pages 5465-5475) .are rejected under 35 U.S.C. 103 as being unpatentable over as applied to claims 1, 3, 4, 6, 10, 11, 23, 26, 29, 31, 35, 44 and 104-108 above, and further in view of US 5,861,273 (Olson et al).
The cited references as above.
The cited refences by Joyce et al and US 10,702,559 (Lesser et al) teach methods for delivering therapeutic heterologous polypeptides to a mammalian subject by a transformed E.coli commensal strain. The cited references recognize, teach and/or suggest integration of therapeutic heterologous polypeptide into chromosome of E.coli as explained above. But the cited references are silent about a recombination site of integration such as attB gene as a site of integration into bacterial genome.
However, the prior art clearly teaches that for E.coli, as a host cells, chromosomal transfer of DNA comprising recombination site attP is efficient and results in integrated heterologous polypeptide sequences having a greater stability; for example: see US 5,861,273 (Olson et al) at col.7, lines 25-50.
Therefore, it would have been obvious to one having ordinary skill in the art at the time the claimed invention was filed to integrate heterologous therapeutic polypeptide into the attB gene of bacterial genome of commensal E.coli in the methods of Joyce and Lesser for delivering a therapeutic heterologous polypeptide to a mammalian subject by a transformed E.coli commensal bacteria with a reasonable expectation of success in maximizing effects of heterologous therapeutic polypeptides because prior art recognizes that for E.coli, as a host cells, chromosomal transfer of DNA comprising recombination site attB is efficient and results in integrated heterologous polypeptide sequences having a greater stability.
Thus, the claimed invention as a whole was clearly prima facie obvious, especially in the absence of evidence to the contrary.
The claimed subject matter fails to patentably distinguish over the state art as represented be the cited references. Therefore, the claims are properly rejected under 35 USC § 103.
Response to Arguments
Applicants’ arguments filed on 12/09/2025 have been fully considered but they are not found persuasive.
Claim rejection under 35 U.S.C. 102 (a) (1), (a) (2) as being anticipated by US 10,357,521 (Dominguez-Bello) has been withdrawn because the cited reference does not explicitly teach integration of heterologous polypeptide into chromosome of bacterial cells in the method for delivery of a therapeutic polypeptide by a recombinant probiotic bacterial host to a receiving mammalian. However, the cited document clearly teaches the use of common recombinant techniques.
Claim rejection under 35 U.S.C. 102 (a) (1), (a) (2) as being anticipated by US 2017/0067065 (Falb et al) has been withdrawn because the cited reference does not explicitly teach a value of detectable amount of transformed bacterial cells being greater than 104 CFU for 2 weeks and more in a sample form receiving subject.
With regard to claim rejection under 35 USC § 103 Applicants’ arguments were considered but moot but mott in view of new grounds of rejections necessitated by claim amendments.
No claims are allowed.
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Vera Afremova
February 19, 2026
/VERA AFREMOVA/ Primary Examiner, Art Unit 1653