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 the Application
Applicant’s arguments and amendment submitted on 03/13/2026 and 10/12/2023 are acknowledged.
Claims 1-12 are pending.
Claims 3-10 are amended.
Claims 11-12 are new.
Claims 4 and 8-10 are withdrawn (as indicated below).
Claims 1-3, 5-7 and 11-12 have been examined on the merits.
Applicant’s election with traverse of Group I, claims 1-7, 11, and 12, drawn to a prokaryotic carrier, in response to the restriction requirement filed on 03/13/2026, is acknowledged.
Claims 8-10 are withdrawn from further consideration by the Examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Applicant’s election of the species, DNA, in response to the species election requirement set forth in the prior office action is acknowledged.
Claim 4 is withdrawn from further consideration by the Examiner, 37 CFR 1.142(b), as being drawn to a non-elected species.
Applicant’s traverse is on the grounds that Examiner has not established the Loeffler reference teaches all the features of the claim 1. Applicant’s arguments have been fully considered but are not deemed persuasive. As indicated in the previous office action, the Loeffler reference teaches all of the structural features of the claimed prokaryotic delivery carrier in the claim 1, specifically: a chassis bacterium Salmonella typhimurium comprising a DNA polynucleotide for expressing a cytokine interleukin 18.
Thus, the product of Group I and the method of Groups II in the instant application do not form a single general inventive concept.
The requirement is deemed proper and therefore is made FINAL.
Priority
This application, U.S. Application number 18/022051, is a national stage entry of International Application Number PCT/CN2020/110159 filed on 08/20/2020, which claims for foreign priority under 35 U.S.C. 119(a)-(d) to CN202010830264.5 filed on 08/18/2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/11/2023, 08/06/2024, and 03/13/2026 are acknowledged. The reference where lined through has not been considered since its document is not in English-translated version. The remainder of the submissions is in compliance with the provisions of 37 CFR 1.97 and has been considered by the examiner.
Drawings
According to MPEP 608.02, part VIII, Color drawings and color photographs are not accepted in utility applications filed under 35 U.S.C. 111 unless a petition filed under 37 CFR 1.84(a)(2) or (b)(2) is granted. Color drawings and color photographs are not permitted in international applications (see PCT Rule 11.13 ). Unless a petition is filed and granted, color drawings or color photographs will not be accepted in a utility patent application filed under 35 U.S.C. 111.
The drawings submitted on 10/12/2023 have been reviewed. The color drawings (Figs. 1-2 and 4-8) are objected to, because color drawings are not accepted in utility applications unless a petition is filed under 37 CFR 1.84(a)(2) and granted.
Unless Applicant submits a petition and it is granted, Applicant is required to either cancel the drawings or to provide substitute black and white drawings.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see page 9 of the specification). References to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code.
Claim Objections
Claim 1 is objected to due to the recitation of “interleukin8”. The term should be corrected to “interleukin 8”. Appropriate correction is required.
Claim 3 is objected to due to the recitation of “the carrier … comprises signal peptides pelB and OmpF fused to the DNA expressing the cytokine”. Examiner notes that the recited “DNA” is fused to a DNA fragment encoding the signal peptides, not to the signal peptides per se. The recited “signal peptides” should be changed to “a DNA fragment encoding signal peptides”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b), or 112, Second Paragraph
The following is a quotation of 35 U.S.C. 112(b):
(B) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3, 5-7, and 11-12 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 pre-AIA the applicant regards as the invention.
Claim 1 is indefinite due to the recitation of “targeting the anaerobic area of a solid tumor”. The claim does not previously define any anaerobic area in the tumor. It is unclear which specific anaerobic area the recited term of “the anaerobic area” refers to.
Claim 5 is indefinite due to the recitation of “a promoter which is sensitive to tumor environment”. The term “tumor environment” is not defined in the specification. It is not clear which specific environment can be considered as a tumor environment, and how the recited tumor environment is different from a normal-tissue environment. As such, one of ordinary skill in the art would not be reasonably apprised of the metes and bounds of the claimed subject matter. Furthermore, the recited term “sensitive” is a relative term, given whether a promoter can be considered to be sensitive depends on standards/benchmarks used for determining its level of sensitivity. It is unclear based on which specific benchmark or standard a promoter can be considered as being sensitive or not sensitive. For the purpose of examination, the recited limitation is not examined because its true meaning cannot be determined.
The remaining claims are rejected for depending from an indefinite claim.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
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 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.
Claims 1, 2, 5-7, 11 and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Pohlmann et al. (Journal of Molecular Microbiology and Biotechnology, 2012, 22:1-9, cited in IDS), as evidenced by the printout of pUC19 (retrieved on 4/16/2026 from URL: https://bocascientific.com/v33202-16 detail#:~:text=pUC19%20has%20the%20following%20characteristics:%20*%20**High,pUC18%20in%20the%20multiple%20cloning%20site%20orientation, at the website of Boca Scientific Inc).
Pohlmann et al. teach a chassis Escherichia coli bacterium as a delivery carrier for in situ delivery of biologically active lnterleukin-10 via a Sec-dependent signal peptide (title, abstract), wherein the E. coli bacterium is transformed with a DNA construct, i.e. an expression plasmid pAZ1, which is constructed by inserting into pUC19 vector a DNA fragment encoding the signal peptide of E. coli outer membrane protein F (OmpF) fused in frame to an E. coli codon-optimized mature human IL-1 0 gene under control of a T7 promoter (abstract, page 7/left col/paras 2-3, Fig. 1).
Regarding the limitations “targeting a tumor” and “targeting the anaerobic area of a solid tumor” recited in the claim 1, these limitations are not directed to the structure of the claimed chassis bacterium, Rather they are directed to an intended use of the claimed bacterium for treating a subject having a tumor and how the bacterium is used for the treatment. Although Pohlmann et al. do not specifically teach using their chassis bacterium for treating/targeting a tumor, they teach a chassis bacterium having all the structural limitations recited in the instant claims 1 and 2. The chassis bacterium taught by Pohlmann et al. appears to be suturally same as the claimed chassis bacterium in the claims; and it is capable of being delivered/targeted into an anaerobic area of a tumor (e.g. by injection). Therefore, the teachings of Pohlmann et al. read on the claims 1 and 2.
Regarding the claims 5 and 11, the expression plasmid pAZ1 of Pohlmann et al. comprises constitutive promoters, such as the promoter of bla gene, i.e. Amp gene (encoding a protein product that provides resistance to ampicillin/Amp), as evidenced by teachings of Pohlmann et al. (see Fig. 1 and page 7/left col/para 3/lines 1-3), and as evidenced by the attached printout of pUC19 (see the map in page 2). In addition, the pAZ1 derived from pUC19 plasmid also comprises a lacZ gene (see Fig. 1), which inherently comprises an IPTG-inducible promoter, lac promoter (Plac), as evidenced by the attached printout of pUC19 (see the map and description in page 2).
Regarding the claims 6 and 12, the limitations recited in the claims are directed to the intended use of the claimed bacterium. The teachings of Pohlmann et al. meet the claimed limitations for the reasons indicated above.
Regarding the claim 7, the limitation recited in the claim is directed to the intended use of the claimed bacterium/carrier. The chassis bacterium (delivery carrier) of Pohlmann et al. can be injected, thus meeting the claimed limitation.
Therefore, in view of the teachings of Pohlmann et al., the chassis bacterium (delivery carrier) of Claims 1, 2, 5-7, 11 and 12 is anticipated by the chassis bacterium (delivery carrier) of Pohlmann et al.
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 of this title, 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.
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 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.
Claims 1-3, 5-7, 11, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Pohlmann et al. (Journal of Molecular Microbiology and Biotechnology, 2012, 22:1-9, cited in IDS) in view of Zhang (PhD dissertation, University of Washington, 2015), as evidenced by the printout of pUC19 (retrieved on 4/16/2026 from the website of Boca Scientific Inc).
The teachings of Pohlmann et al. are described above.
Regarding the claim 3, Pohlmann et al. teach fusing a Sec-dependent signal peptide of OmpF to the IL-10 protein for delivery of secretory IL-10 via Sec-dependent pathway in E. coli, as indicated above; and Pohlmann et al. further teach that PelB is a signal peptide that has been employed for efficient secretory production of heterologous proteins in E. coli (page 3, left col, para 2, lines 17-20). Pohlmann et al. do not teach fusing dural signal peptides OmpF and PelB to IL-10 for delivery of the IL-10.
Zhang teaches that secretory proteins translocate across the inner membrane of gram-negative bacteria/E.coli by using a cleavable N-terminal signal peptide that is recognized by a translocation system known as the Sec-dependent pathway; and Zhang investigates whether dural Sec-dependent signal peptides (PelB and OmpA) benefit secretory protein production (abstract in page 3). Zhang further teach that dural signal peptides support Sec-dependent protein translocation and reduce the accumulation of misfolded forms of precursor and mature secretory protein (abstract, lines 11-18).
It would have been obvious to try fusing a DNA fragment encoding dural Sec-dependent signal peptides PelB and OmpF to the DNA fragment encoding IL-10, thus obtaining a modified chassis E. coli bacterium of Pohlmann et al., expressing a fusion protein comprising the dural signal peptides and the IL-10, for determining how the dural signal peptides benefits the delivery of IL-10 via the Sec-dependent pathway. This is because Pohlmann et al. teach both PelB and OmpF signal peptides are effective at delivering heterologous proteins through secretary pathway in E. coli. Furthermore, it is known in the art that dural Sec-dependent signal peptides including PelB are effective at Sec-dependent protein translocation and benefit secretory protein production by reducing accumulation of misfolded secretory proteins, as supported by Zhang. Moreover, there is a limited number of Sec-dependent signal peptides known in the art. See MPEP 2143 I.E., the rationale “obvious to try” supports a conclusion of obviousness when there is a finite number of identified and predictable solutions in the prior art, and choosing from such a finite number of identified and predictable solutions would have a reasonable expectation of success. Thus, the claim would have been obvious over the combined teachings of Pohlmann et al. and Zhang.
Examiner notes that Pohlmann et al. further teach using probiotic E. coli Nissle 1917 as an ideal carrier chassis for delivering intestinal delivery of IL-10 (page 2/left col/last 7 lines). As such, a chassis E. coli Nissle 1917 delivery carrier for in situ delivery of IL-10 would have been obvious over the teachings of the cited prior art.
Therefore, the invention 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 claimed invention.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 1, 2, 6, 7, and 12 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1, 3-12, and 14-21 of copending Application No. 19/145642. Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons.
The claims of the ‘642 application are directed to a modified bacterium for treating a malignant tumor, comprising a polynucleotide or an expression vector (i.e. DNA) encoding a fusion polypeptide, wherein the fusion polypeptide comprises a signal peptide and an interleukin 10 (IL-10) polypeptide, wherein the modified bacterium is capable of expressing and secreting the IL-10 polypeptide; wherein the signal peptide comprises an amino acid sequence of SEQ ID NO: 16 (Note: this is the sequence of pelB signal peptide, as evidenced by disclosure of the specification of the copending ‘642 application, see page 72); wherein the bacterium further comprises one or more expression cassettes for expressing an essential gene, controlled by a strictly hypoxia inducible promoter, i.e. ssbp1 promoter; wherein the bacterium further comprises a pH regulated expression cassette comprising genes under control of a promoter that is active under acid pH condition, i.e. sseA promoter; wherein the unmodified starting strain is a facultative anaerobic bacterium; wherein the bacterium is a bacterium of E. coli or Salmonella typhimurium; and wherein the bacterium is comprised in a pharmaceutical composition for treating a malignant tumor.
Regarding the limitations “targeting a tumor” and “targeting the anaerobic area of a solid tumor” recited in the claim 1, they are directed to the intended use of the claimed bacterium. Furthermore, the claims of the ‘642 application teach that the modified bacterium is used for treating a malignant tumor, the bacterium is an anaerobic bacterium, and it comprises genes under control of strictly hypoxia inducible promoter. Thus, it would have been obvious to target the modified bacterium to a tumor or an anaerobic area of a solid tumor.
Regarding the claims 6 and 12, the limitations recited in the claims are directed to the intended use of the claimed bacterium and they do not further limit the bacterium of the claim 1. As such, the modified bacterium of the claims of the ‘642 application meet the claimed limitations.
Regarding the claim 7, the limitation recited in the claim is directed to the intended use of the claimed bacterium/carrier. The claims of the ‘642 application teach the modified bacterium is used as a pharmaceutical composition for treating a tumor, and the bacterium of the ‘642 application can be injected or orally administered.
Therefore, the chassis bacterium of Claims 1, 2, 6, 7, and 12 of the instant application is deemed obvious over the modified bacterium or composition of claims 1, 3-12, and 14-21 of copending Application No. 19/145642.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Claims 3, 5, and 11 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1, 3-12, and 14-21 of copending Application No. 19/145642, as applied to the claims 1, 2, 6, 7, and 12, further in view of Pohlmann et al. (Journal of Molecular Microbiology and Biotechnology, 2012, 22:1-9, cited in IDS) and Zhang (PhD dissertation, University of Washington, 2015).
The subject matter of the claims 1, 3-12, and 14-21 of the copending ‘642 Application are described above.
Regarding the claim 3, the claims of the ‘642 application teach fusing the signal peptide PelB to the IL-10 polypeptide for secreting/delivery the IL-10 from the modified bacterium/E.coli. But, they do not teach fusing dural signal peptides OmpF and PelB to the IL-10 polypeptide for its secretion/delivery.
The teachings of Pohlmann et al. and Zhang are described above.
It would have been obvious to try fusing a DNA fragment encoding dural signal peptides PelB and OmpF to the DNA fragment encoding IL-10 polypeptide, thus obtaining a modified E. coli bacterium of the ‘642 application, expressing a fusion protein comprising the dural signal peptides and the IL-10 polypeptide, for determining how the dural signal peptides benefits the secretion/delivery of lnterleukin-10. This is because it is well known in the art that PelB and OmpF are Sec-dependent signal peptides effective at secretory production and delivery of heterologous proteins, as supported by Pohlmann et al. and Zhang. Furthermore, it is known in the art that dural Sec-dependent signal peptides comprising PelB are effective at Sec-dependent protein translocation and benefit secretory protein production by reducing accumulation of misfolded secretory proteins, as supported by Zhang. Moreover, there is a limited number of Sec-dependent signal peptides known in the art. See MPEP 2143 I.E., the rationale “obvious to try” supports a conclusion of obviousness when there is a finite number of identified and predictable solutions in the prior art, and choosing from such a finite number of identified and predictable solutions would have a reasonable expectation of success. Thus, the claim would have been obvious over the teachings of the claims of the ‘642 application in combination of the cited prior art.
Regarding the claim 5, the claims of the ‘642 application teach that the modified bacterium (delivery carrier) comprises expression cassettes comprising genes under the control of a strictly hypoxia inducible promoter or a promoter inducible by acid pH condition. The claims of the ‘642 application do not expressively teach that the modified bacterium/delivery carrier comprises a constitutive promoter. However, it would have been obvious for the modified bacterium/delivery carrier to comprise a constitutive promoter for constitutive gene expression, because it is a common practice in the art for bacteria to comprise a constitutive promoter for maintaining constitutive gene expression, as supported by Pohlmann et al.
Regarding the claim 11, the claims of the ‘642 application are silent about whether the modified bacterium/delivery carrier comprises an IPTG inducible promoter. However, it would have been obvious for the modified bacterium/delivery carrier to comprise an IPTG inducible promoter in the expression cassettes or vectors, because it is a common practice in the art to include an IPTG inducible promoter (i.e. lac promoter along with lacZ gene) in an expression cassette or vector for facilitating gene cloning and controlling gene expression, as supported by Pohlmann et al.
Therefore, in view of the cited prior art, the chassis bacterium of Claims 1-3, 5-7, 11, and 12 of the instant application is deemed obvious over the modified bacterium or composition of claims 1, 3-12, and 14-21 of copending Application No. 19/145642.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Conclusion
No claim is in condition for allowance.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PMR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Qing Xu, Ph.D., whose telephone number is (571) 272-3076. The examiner can normally be reached on Monday-Friday from 9:30 AM to 5:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath N. Rao, can be reached at (571) 272-0939. Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to the receptionist whose telephone number is (571) 272-1600.
/Qing Xu/
Patent Examiner
Art Unit 1656
Prosecution Insights