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
Applicant’s response filed on 11/17/2025 is duly acknowledged.
Claims 12, 15-18, and 22-25 were previously canceled by the applicants.
Claims 2 and 9 have been canceled by applicant’s current claim amendments.
Claims 27-29 have been newly presented (taken under elected group I) for examination.
Claims 1, 3-8, 10, 11, 13, 14, 19-21 and 26-29, as currently amended/presented are pending in this application.
Claims 13, 14, 19-21 and 26 (non-elected groups II and III, without traverse) remain withdrawn.
Claims 1, 3-8, 10, 11 and 27-29 (elected invention of group I, without traverse; “An engineered non-pathogenic bacteria comprising at least one essential gene under the control of an inducible promoter…”) have been examined on their merits in this action hereinafter.
Priority
This application is a CON of PCT/US2020/059035 (filed on 11/05/2020), which claims domestic benefit from US PRO 62/930,665 filed 11/05/2019.
Claim Objections -Withdrawn
In view of cancellation of claim 2, the objection as previously made by the examiner, has been withdrawn.
Claim Rejection – 35 USC 102- Withdrawn
In view of current claim amendments to claim 1, the rejection under 102(a)(1) as previously made over the cited reference of Huang et al-2017, has now been withdrawn.
The following contains new grounds of objection/rejection necessitated by applicant’s current amendment to pending claims.
Claim Objections
1. Claim 1 (as amended) is objected to because of the following informalities: Claim 1 as amended recites several names with short notations for genes in brackets, wherein the genes need to be italicized, for instance “L-aspartate semialdehyde dehydrogenase (asd)”, in order to conform to normal recitations of genes in literature. Similar correction for all recited genes should be made in claim 1 (and wherever they appear in claims). Appropriate correction is required.
2. Claim 27 (New) is objected to because of the following informalities: Claim 27 recites the biological names of bacteria which are neither italicized nor underlined. Applicants are suggested to italicize the name of the bacterial genus-species in order to conform to the normal standards for reciting biological names of microorganisms (for instance “Escherichia coli Nissle 1917”). Appropriate correction is required.
Claim Rejections - 35 USC § 112 – WD- Made/Maintained
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
1. Claims 1, 3-8, 10, 11 and 27-28 (as amended/newly presented) are/remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
Claim 1 (as currently amended) has been reproduced as follows:
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The instant disclosure of record broadly defines the term “non-pathogenic bacteria” (see page 11, last full paragraph), partly reproduced as follows:
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It is to be noted that as disclosed (specification, pages 11-12, and 17, section “Bacteria”), the term “non-pathogenic bacteria” encompasses any type of gram negative, gram positive, commensal, or probiotic bacteria (see section “Bacteria’ on page 17), because the relationship to the “host” (such as plants, mammal, animals, fungi, etc., for instance) is not defined per se. As evidenced by the fact that various genera of known pathogenic bacteria are listed as exemplary bacteria by the applicants, and the claim does not provide structural features that make them “non-pathogenic” per se, the scope of the claim 1 may encompasses any type of bacterial genus/species, including anaerobic (obligate as well as facultative), aerobic, commensals, etc. It is to be noted that even commensal bacteria are known in the art to cause opportunistic infections in human and animals depending on the immune condition and/or predisposition of the host (see for instance disclosure from Martinez, 2014; NPL previously made of record; see disclosure on page 1, left and right columns, for instance).
However, applicant’s disclosure on record mainly pertains to two specific bacterial species/strains that are namely Escherichia coli Nissle 1917 (an EcN strain; a probiotic strain; see instant specification, page 12, 2nd paragraph, for instance) and Salmonella typhimurium ELH1301 strain (see Table 3 on page 57, for instance). In addition, the “essential” genes that have been deleted from said bacteria specifically include asd and glms genes (see Table 3 on page 57; page 19, last paragraph, and Example 3, for instance) that can be rescued for growth by supplementation with diaminopimelic acid (DAP) and D-glucosamine, respectively. No other bacterial species/strains and “deficient” essential genes have been disclosed and/or described in any relevant details that would provide guidance as to how an artisan in the art would be able to perform the same “more than one” essential gene deletion(s) and/or expression thereof under a given inducible promoter in any bacterial species/strain (as required by instantly amended claim 1). Since, as disclosed by the applicants themselves, the critical design feature for the “biosensor circuit” would variously depend from the components used (that includes specific species/strain of “non-pathogenic” bacteria, specific deletion of “essential” genes, in combination with a given “inducible” promoter; see instant specification, entire page 15), the appropriate amount of guidance appears to be sorely lacking for the current scope (i.e. any bacterial genus-species for any combination of “essential” gene deletions/deficiencies, as recited in instant claim 1) of the product invention as claimed. Given the vast amount of variations in the physiological and biochemical features of different bacterial species/strains (starting from anaerobic, aerobic, gram negative, gram positive, commensals, probiotic bacteria, etc.) in combination with deletion of variety of essential gene(s) along with conditional expression for survival under a given promoter, it is clearly apparent that the disclosure of record does not provide adequate guidance for reasonable number of bacterial genus-species and/or strains, for the essential genes as currently recited in instant claim 1, in order to meet the written description requirement under 112(a). Appropriate correction is required.
NOTE: 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.
Claim Rejections - 35 USC § 103- New Grounds
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.
1. Claims 1, 3-8, 10, 11, 27 and 28 (as amended/presented) are rejected under 35 U.S.C. 103 as being unpatentable over HUANG et al (2017; CN 104471057 B; English machine translation previously made of record) taken with TEMPLETON (US 2013/0129813 A1; US-PGPUB cited in IDS dated 05/05/2022; citation NO. 2) and FALB ET AL (CA 2 996 535 A1; FOR cited as ref. [N] on PTO 892 form).
Claim 1 as currently amended has been reproduced as follows:
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See also limitations of claim 3-7, 11, 27 and 28 as currently presented. Note that the terms used in instant claim 7, i.e. “low copy, medium copy, and high copy” do not specify any copy number, or range(s) thereof.
Claims 8 and 10 (as currently presented/amended) are as follows:
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HUANG et al (2017; citations per English translation of record) disclose an engineered Salmonella typhimurium mutant bacterial strain YB1 (see Title, entire section 5 starting on page 11; sections 5.1 and 5.2, in particular) that is deficient in expression of endogenous essential asd gene (aspartate semialdehyde dehydrogenase gene; see translation, entire page 3, for instance), and is replaced on a plasmid (a high copy number plasmid pBluescript IISK; pBSK with ColE1 origin compatible with E. coli plasmids) under control of a low-oxygen or hypoxia-inducible promoter (PpepT; see translation page 4, 2nd paragraph; and section 5.1, for instance), and a kit/composition comprising a pharmaceutically acceptable carrier (such as a diluent, excipient, mixture thereof; see translation, Abstract, and page 3, 6th paragraph; page 14, section 6.1, for instance); wherein the modified bacterial strain does not grow under aerobic conditions (in animal tissues, for instance; i.e. “non-pathogenic” strain; see translation, page 5, 2nd paragraph, for instance), and requires diaminopimelic acid (DAP; an essential component of bacterial cell wall) for normal growth (and to avoid lysis) under aerobic culture conditions (i.e. converting it into a conditional, obligate anaerobe from a facultative anaerobic bacterial strain; see Abstract, and page 2, section “1. Technical field”, 1st paragraph, for instance); wherein the modified bacteria further comprises additional gene expression regulators such as antisense promoter such as a negative antisense promoter kat regulated by FNR, blocking any leakage from asd gene (see translation, page 3, 3rd paragraph; page 8, section “Salmonella strain 4.1 (YB1) preparing low oxygen targeting method”; and page 29, Claims 1-7, for instances); wherein the composition comprising said modified bacteria can be administered for treatment of solid tumor cancers in combination with radiation therapy, or with other chemotherapeutic agents (see translation, Abstract, and page 30, claims 8-13, for instance), and provides better alternative to conventional methods that employ attenuated bacterial systems that are not as efficient in killing hypoxic tumor cells (see translation, page 5, 2nd-5th paragraphs, for instance).
However, the engineered, non-pathogenic bacteria - wherein the bacteria further comprises one or more plasmids encoding a nucleic acid which encodes a therapeutic agent and/or a diagnostic agent (see instant claim 8); or comprises “more than one” essential gene under control of an inducible promoter (see instant claims 1 and 10, as currently amended), have not been explicitly disclosed by the teachings of Huang et al, as discussed above.
Templeton (2013), while teaching targeted delivery of therapeutic agents employing tissue-specific peptidomimetic ligands (see Title, Abstract), disclose bacterial vectors that comprise one or more plasmids with nucleic acid which encodes an anti-angiogenic agent such as human thrombospondin ( such as hTSP-1 and TSP-1 mimetic ABT-510; see [0065]-[0068], and claim 36, for instance) that are suitable for use in effective cancer therapies that are specifically directed towards the tumor vasculature, for instance. Thus, it would have been obvious to an artisan of ordinary skill in the art to modify the bacteria as disclosed by Huang et al such that it comprises suitable plasmid (or more than one plasmids) containing nucleic acid that encode therapeutic agent(s), such as a therapeutic protein as explicitly disclosed by Templeton for use in cancer/tumor therapy, at least in order to improve the effectiveness of the bacterial vector/delivery system in treatment of solid tumor/cancer as already contemplated by the disclosure from Huang et al, as discussed above.
Although, Templeton does not explicitly disclose engineered bacteria deficient in “more than one” essential genes (as currently recited in instantly amended claim 1) and that are under inducible promoters sensing different physiological conditions, such would have been obvious to an artisan in the art as Falb et al already disclose and/or demonstrate the engineered non-pathogenic probiotic bacterial cells (such as Escherichia coli Nissle strain ; see page 43, [0123], for instance) that can be made deficient in one or more essential genes, including genes such as asd, glmS, acpP, hemA, glnS, nadE, adk, tmk, for instances (see page 35 [099]; page 122, section “Essential Genes and Auxotrophs”, [0346]-[0347]; page 126, [0354]-[0355], for instance), wherein “engineering a bacterial strain with more than one auxotroph may greatly decrease the probability that DNA transfer will occur enough times to rescue the auxotrophy”, and thus avoiding reversal mutants ensuring the fact that engineered bacteria do not survive in the absence of the auxotrophic gene product, for e.g. outside of the gut (see page 125, [0353], for instance), and therefore can be effectively used in pharmaceutical compositions for delivering desired therapeutic genes, or gene products for treatment of various disorders (see page 167, [0469], for instance) in a controlled manner. Alternatively, the bacteria may be engineered to die after the bacteria has spread outside of a disease site, or after the treated subject has experienced the therapeutic effect, by employing various types of kill switches (see page 132, [0371]-[0373], for instance), if needed.
Thus, unless evidence/data provided on record to the contrary, the limitations of engineered bacteria deficient in more than one essential genes, and having more than one essential gene under inducible promoter(s) sensing different physiological conditions, would have been obvious and fully contemplated by an artisan in the art depending on the choice of different host cells and/or downstream applications of the bacterial vector that would be intended to be employed and/or used with different types of therapeutic agent(s), and types of different disorders, such as cancers/tumor or GI treatments, and/or regulation thereof, as per need. Therefore, the product invention as generically claimed fails to distinguish itself over the combined teachings and/or suggestions as discussed above from the cited prior art references of record.
Thus, the claim as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the invention as claimed.
As per MPEP 2111.01, during examination, the claims must be interpreted as broadly as their terms reasonably allow. In re American Academy of Science Tech Center, F.3d, 2004 WL 1067528 (Fed. Cir. May 13, 2004)(The USPTO uses a different standard for construing claims than that used by district courts; during examination the USPTO must give claims their broadest reasonable interpretation.). This means that the words of the claim must be given their plain meaning unless applicant has provided a clear definition in the specification. In re Zletz, 893 F.2d 319, 321, 13 USPQ2d 1320, 1322 (Fed. Cir. 1989).
Allowable Subject matter
Claim 29 as newly presented is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Examiner’s Response to Arguments
Applicant’s arguments (filed on 11/17/2025; see REM, p. 7-10) with respect to claim(s) 1, 3-8, 10, 11 and 27-29 (as currently amended) have been considered but are moot because the new ground of objection/rejection as made in this office action discussed above, and at least for the reasons of record as discussed below:
Regarding the 112(a)-WD rejection of record, applicants mainly argue that “…Those of ordinary skill in the art would understand that such a disclosure at least implies other non-pathogenic bacteria can be similarly engineered to delete more than one of the other specified essential genes and be rescued, especially in view of the maturity and predictability of the subject art” (see REM, p. 8), is duly note and considered. However, it is not found to be persuasive because as presented, instant claim 1 is not limited to any specific species of bacteria, which may in fact encompass variety of different types of bacterial genera that have distinct physiological and biochemical characteristics, and may not be compatible with the same auxotrophy and rescue system as disclosed by applicants. As evidenced by applicant’s own disclosure, the critical design feature for the “biosensor circuit” would variously depend from the components used (that includes specific species/strain of “non-pathogenic” bacteria, specific deletion of “essential” genes, in combination with a given “inducible” promoter; see instant specification, entire page 15),and therefore, out of the vast amount of different bacterial genera and/or species, the mere two examples from the same bacterial family of Enterobacteriaceae, would not be reasonably sufficient to provide guidance for any non-pathogenic bacteria as claimed (see instant claim 1, in particular). Notwithstanding, applicant’s instant arguments evidencing the cited NPL references of Babu et al, 2014, and Kang et al,2011 (see REM, p. 9-10) for unpredictability already attests to the fact that the disclosure of record with merely two examples of bacteria from the same family of Enterobacteriaceae is not generally sufficient for any and all bacterial gerera and/or species, and/or strains, as encompassed by the product of instant claim 1 as currently amended. Thus, the 112a-WD rejection is still deemed proper.
Regarding the 103(a) rejection of record, applicants appear to argue the superiority of selected “essential genes” as recited in instant claim 1, for example “the combination of asd and glms genes…such combination ensures tight regulation, as the bacteria would need to circumvent both knockouts to restore normal cell wall properties” (see REM, p. 9-10), which is duly noted and considered. However, as discussed in the new grounds of 103a rejection of record above, the cited reference of Falb et al discloses the same advantage of double deletions of essential genes, wherein they state that “…engineering a bacterial strain with more than one auxotroph may greatly decrease the probability that DNA transfer will occur enough times to rescue the auxotrophy”, and thus avoiding reversal mutants ensuring the fact that engineered bacteria do not survive in the absence of the auxotrophic gene product, e.g. outside of the gut (see Falb et al, page 125, [0353]-[0354], for instance). Although, Falb et al do not exemplify the combination of asd and glms genes, such would have been deemed obvious to an artisan in the art given the combined teachings and/or suggestions already provided in the cited prior art references as discussed in the rejection above. It is also noted to applicants that the scope of the showing must be commensurate with the scope of claims to consider evidence probative of unexpected results, for example. In re Dill, 202 USPQ 805 (CCPA, 1979), In re Lindner 173 USPQ 356 (CCPA 1972), In re Hyson, 172 USPQ 399 (CCPA 1972), In re Boesch, 205 USPQ 215, (CCPA 1980), In re Grasselli, 218 USPQ 769 (Fed. Cir. 1983), In re Clemens, 206 USPQ 289 (CCPA 1980). It should be clear that the probative value of the data disclosed on record is not commensurate in scope with the degree of protection sought by the claim (see instant claim 1, in particular).
Thus, the 103(a) rejection as discussed above, is still deemed proper and is therefore made/maintained.
Conclusion
NO claims are currently 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 SATYENDRA K. SINGH whose telephone number is (571)272-8790. The examiner can normally be reached M-F 8:00- 5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, LOUISE W HUMPHREY can be reached at 571-272-5543. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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SATYENDRA K. SINGH
Primary Examiner
Art Unit 1657
/SATYENDRA K SINGH/Primary Examiner, Art Unit 1657