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 .
Status of claims
Claims 1, 3, 4, 6, 10, 11, 16, 16, 23, 26, 29, 31, 35, 44, 104, 105, 107 and 108 as amended on 7/23/2026 are currently pending.
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 as amended remain/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.ovatus (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 (col. 8, line 21-23);
wherein the CFU of transformed cells in the sample from the receiving subject was more than 105 CFU/g 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 6-7 or for 28 days (col. 8, line 22, table 1).
As applied to claim 29: 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, 104, 105, 107 and 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 effect 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, 104, 105, 107 and 108 and 104-108 as amended remain/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 7/23/2026 have been fully considered but they are not all found persuasive.
Rejection of claims under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, has been withdrawn in view of current amendment to the claim and applicants’ arguments (response pages 9-10).
With regard to claim rejection under 35 U.S.C. 102 (a) (1) as being anticipated by US 7,988,961 (Farrar et al) Applicants argued that the cited reference does not teach the claim 1 recited steps a) and b) and that the colonization level of the transformed bacteria is lower than recited in claim 1, last 2 lines (response pages 11-12).
The arguments are not found persuasive.
Although the cited document does not explicitly and literally recite the identical phrases as it is recited in the instant claim 1, the cited disclosure clearly encompasses the same steps of obtained and isolating commensal bacteria Bacteroides from a microbiome of a donating subject (see col. 4, lines 53-60) because it is clearly stated therein that Bacteroides ovatus is a commensal colonic bacteria in humans and rodent and that it is available for further genetic manipulation. Thus, Bacteroides ovatus is obtained from a colonic sample of a doating subject; it is recognized as “commensal” bacteria within the meaning of the claim; and the commensal bacteria is cultured in vitro before transformation.
The colonization level of the transformed bacteria is the same as recited in claim 1, last lines, for being more than 105 CFU/g or 2-8x107 CFU/g after analyzing at 28 days (see col. 8, line 22). This disclosed amount clearly refers to amount of transformed bacteria B.ovatus MuIL2 since it refers to production of MuIL2 which is not produced by other original non-transformed cells. The disclosure of table 1 is not relied upon in the instant office action in the lack of proper description about period of analysis. Nevertheless, a particular mouse #5/T28 is characterized by colonization by transformed bacteria MuIL2 at the level 12x104 CFU/g or 1.2x105CFU which is greater than 105 CFU/g as recited in the claim.
Regarding applicants’ arguments as based on obviousness considerations (response page 12), it is noted that the cited reference clearly teaches and suggests increasing level of colonization by increasing administration dose and by repeated administration (col. 8, lines 26-29).
With regard to claim rejection 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) Applicants argue that the cited method of Joyce does not comprises the use of “commensal” bacteria but a “laboratory adapted” strain (response pages 15-16).
The argument is not persuasive. 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.
The differences between prior art “commensal” and “not laboratory adapted” and the claimed “commensal” and “not laboratory adapted” bacteria as intended for the instant application and claims are not established as argued, as disclosed and as claimed. The strain disclosed in specification is obtained/derived from gut as the cited strain; and the strain disclosed in specification was cultured in laboratory and further transduced with antibiotic resistance (0154-0155). Therefore, meaning of the claim-recited phrases are not specific and/or are not limited for broad reasonable interpretation.
Further, applicants also argue that in the cited reference by Joyce does not clearly state level of gut colonization upon administration of transformed bacteria (response page 16).
Nevertheless, the cited reference by Joyce clearly discloses that the BSH-transformed bacterial cells significantly colonized gastrointestinal tract of mammalian subjects for over 70 days (page 7423, col. 2, par. 2, lines 10-11); and the intended therapeutic effects resulting from delivery of transformed bacterial was obtained (entire document including abstract). Thus, even in the silence about precise level of colonization, one would reasonably conclude that the cited method resulted in a colonization which was high enough to provide for therapeutic effects. Moreover, the final colonization would obviously correlate or depend (modified and/or optimized) by CFU bacterial amounts of initial administration dose; and further improved by repeated administration to receiving subject
Next applicants also argue that in the cited method of Joyce mice were treated with antibiotics, but the claimed method excludes administration of antibiotics (response pages 16-19) and that teaching by Lesser does not remedy teaching by Joyce (pages 19-21).
This argument is not found persuasive because the main concept and/or goal of the cited method of Joyce is the same as in the Applicants’ claimed method which is delivering a therapeutic polypeptide. All additional manipulations in the cited method of Joyce including providing antibiotic to mice and using antibiotic resistant strain for delivery of therapeutic polypeptide (BSH in the method of Joyce) are practiced as a model experiment intended to look closer and specifically into delivery of BSH by the bacteria transformed with BSH and to exclude interfering effects of pre-existing gut bacteria expressing native BSH. One of skill in the art would obviously recognize and acknowledge that the use of antibiotic is not an absolute requirement for delivery of therapeutic polypeptide as taught by Joyce with regard to delivery of therapeutic polypeptide because Joyce proves that bacteria transformed with therapeutic BSH is capable to provide for BSH delivery. One of skill in the art would be motivated to exclude the use of antibiotic because it is well known in the prior art 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. The cited secondary reference clearly teaches so.
For example: US 10,702,559 (Lesser et al) teaches that antibiotics promote detrimental effects, alter normal gut microflora leading to overgrowth of pathogens, undoubtedly promote spread of drug resistance (col. 71, lines 8-19); and that designer probiotics modified to deliver therapeutic polypeptides overcome negative issues associated with wide-spread usage of antibiotics (col. 70, lines 32-35 and lines 51-54). 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. 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.
No claims are allowed.
Conclusion
THIS ACTION IS MADE FINAL. 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 VERA AFREMOVA whose telephone number is (571)272-0914. The examiner can normally be reached Monday-Friday: 8.30am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Vera Afremova
October 13, 2026
/VERA AFREMOVA/ Primary Examiner, Art Unit 1653
