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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 5/19/2025 has been entered.
Status of claims
Claims 9 and 11-20 as amended on 5/19/2025 are pending and under examination in the instant office action.
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 9, 11-14 and 16-20 as amended are rejected under 35 U.S.C. 103 as being unpatentable over Carmen et al (European Journal of Inflammation, 2013, Vol.11, No. 3, pages 641-654), Terzic et al (“Inflammation and Colon Cancer”. Gastroenterology. 2010, Vol. 138, No. 2, pages 2101-2114), Dennis et al (“Current status of IL-10 and regulatory T-cells in cancer”. Curr Opin Oncol. 2013, 15(6): 637-645), Png et al (IDS reference; “DUSP10 regulates intestinal epithelial cell growth and suppress colorectal tumorigenesis”. Oncogene 2016, 35, pages 206-217), Yang et al (“Construction of recombinant adenovirus encoding PTEN cDNA”, Accession Number: 2005:1330192 CAPLUS; Source: Dier Junyi Daxue Xuebao (2004), 25(5), 556-558), US 2003/01388449 (Langermann et al) and Kim et al (“Two-promoter vector is highly efficient for overproduction of protein complexes”. Protein Science. 2004, 13:1698-1703).
The cited reference by Carmen teaches a method for treating intestinal inflammation by orally administering to the gastrointestinal tract a pharmaceutically effective amount of a recombinant probiotic lactic acid bacterium Lactococcus lactis carrying a plasmid vector with a mammalian gene IL-10 that provides for anti-inflammatory effects and lowering intestinal damage (see abstract; see page 645, col. last par.). The connection between intestinal inflammation and colorectal cancer is well established (see abstract of Terzic); and Interleukin-10 (IL-10) is a key cytokine against cancer in view of teaching by Dennis (see abstract). Thus, the therapeutic agent IL-10 in the plasmid vector of recombinant Lactococcus lactis of the reference by Carmen is a generic “tumor suppressor gene” in the method for treating intestinal inflammation including colon cancer.
In particular, in the method of Carmen the recombinant probiotic lactic acid bacterium Lactococcus lactis is capable: 1) to produce foreign procaryotic adhesin that is a fibronectin binding protein (FnBPA) from Staphylococcus; and 2) to deliver to eukaryotic cells or to mammalian cells a plasmid vector “pValac:il-10” with gene coding for IL-10 (see abstract). The pValac:il-10 plasmid harbors an eukaryotic region containing the Cyto Megalo Virus promoter or CMV (page 646, col. 2, lines 6-8 ), which is a promoter from mammalian virus, and, thus, is capable to drive expression of the mammalian gene in mammalian cells but not in bacterial cells as encompassed by the claims and in view of definitions of the as-filed specification (see published application par. 0040-0041, see par. 0041, line 9). The cited reference by Carmen clearly states that recombinant probiotic lactic acid bacterium Lactococcus lactis produces foreign procaryotic adhesin (see abstract and whole document); and, thus, in the recombinant probiotic lactic acid bacterium Lactococcus lactis the expression of recombinant prokaryotic gene adhesin is inherently driven a prokaryotic promoter.
The cited reference by Carmen is silent about claim-recited specific tumor suppressor genes including DUSP10 and PTEN.
However, the prior art teaches the claim-recited specific tumor suppressor genes including DUSP10 and PTEN as therapeutic genes associated with colorectal cancer; and prior art suggests development of therapy based on the use of theses genes.
For example: the reference by Png teaches that DUSP10 regulates intestinal epithelial cell growth and suppress colorectal tumorigenesis and that DUSP10 is a target for the development of therapies for intestinal inflammation and colorectal cancer (see abstract).
For example: the reference by Yang teaches and suggests construction of a recombinant vector encoding for PTEN in recombinant bacteria for therapy of malignant tumors (see abstract).
Therefore, it would have been obvious to one having ordinary skill in the art at the time the claimed invention was filed to substitute specific tumor suppressor genes DUSP10 and/or PTEN or the generic tumor suppressor gene IL-10 in the recombinant vector of the recombinant bacteria of Carmen with a reasonable expectation of success in treating gastrointestinal cancer by administering the recombinant bacteria because the Carmen’s recombinant probiotic lactic acid bacterium Lactococcus lactis carrying recombinant genes including prokaryotic adhesin gene and mammalian therapeutic gene is capable to adhere to mammalian cells and to deliver mammalian therapeutic genes including anti-inflammatory and/or anti-cancer genes, thereby, enabling cancer treatment and because the tumor suppressor genes including DUSP10 and PTEN have been taught/suggested as therapeutic genes associated with colorectal cancer for delivery as recombinant products including recombination in bacteria.
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, in particular, in the recombinant Lactococcus lactis of Carmen the adhesin gene (FnBPA gene) and mammalian therapeutic gene are in two separate plasmids, each plasmid containing promoter linked to the respective gene.
But it is known the prior art to deliver different therapeutic polypeptides by providing genes thereof in one recombinant plasmid vector in a host cell.
For example: US 2003/01388449 (Langermann et al) teaches a single plasmid vector comprising an adhesin gene (FimH) with another second gene and 2 promoters preceding both genes (see par. 0100) as intended for administration to be delivered by recombinant host cells (0074) or by a bacterial cell (0082).
For example: the reference by Kim explicitly teaches and states that a single vector with two promoters is highly efficient for expression of two different genes and for overproduction of two recombinant proteins (see title and abstract).
Therefore, it would have been obvious to one having ordinary skill in the art at the time the claimed invention was filed to modify method of Carmen by inserting both genes of therapeutic polypeptides in one plasmid vector in a recombinant bacterial host with a reasonable expectation of success in providing therapeutic effects upon administration of a recombinant bacterial host cell because use of one plasmid vector for expression of several genes is a well-established practice the art.
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 claims 19-20: in the method of Carmen a recombinant bacteria is administered orally to a mammalian model and found effective, thus, suitable for other mammalians including humans.
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 9 and 11-20 are rejected under 35 U.S.C. 103 as being unpatentable over Carmen et al (European Journal of Inflammation, 2013, Vol.11, No. 3, pages 641-654), Terzic et al (“Inflammation and Colon Cancer”. Gastroenterology. 2010, Vol. 138, No. 2, pages 2101-2114), Dennis et al (“Current status of IL-10 and regulatory T-cells in cancer”. Curr Opin Oncol. 2013, 15(6): 637-645), Png et al (IDS reference; “DUSP10 regulates intestinal epithelial cell growth and suppress colorectal tumorigenesis”. Oncogene 2016, 35, pages 206-217), Yang et al (“Construction of recombinant adenovirus encoding PTEN cDNA”, Accession Number: 2005:1330192 CAPLUS; Source: Dier Junyi Daxue Xuebao (2004), 25(5), 556-558), US 2003/01388449 (Langermann et al) and Kim et al (“Two-promoter vector is highly efficient for overproduction of protein complexes”. Protein Science. 2004, 13:1698-1703).
as applied to claims 9, 11-14 and 16-20 above, and further in view of Collins et al (“Combining vaccine and immune checkpoint inhibitors to prime, expand and facilitate effective tumor immunotherapy”. Expert Rev Vaccines, 2018, 17(8): 697-705).
The references by Carmen, Terzic et al., Dennis et al., Png et al., Yang et al US 2003/01388449 (Langermann et al) and Kim et al as above.
The cited references are silent about administration of immune checkpoint inhibitors including anti-programmed death ligand-1 (PDL-1).
However, the prior art teaches and suggests combining administration of immune checkpoint inhibitors including PDL-1 with vaccine platforms including bacterial vaccine platforms to facilitate effective tumor immunotherapy; for example: see Collins at abstract expert opinion, at section introduction and at section 3 therapeutic cancer vaccines.
Therefore, it would have been obvious to one having ordinary skill in the art at the time the claimed invention was filed to combine a bacterial vaccine platform of Carmen with immune checkpoint inhibitors to facilitate effective tumor immunotherapy as suggested by Collins.
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
Applicant's arguments filed on 5/19/2025 with respect to the claims as amended on 5/19/2025 have been fully considered but are moot because the new grounds of rejection.
Some of the arguments are directed to the idea that the use of multiple (or two plasmids) in the method of Carmen for delivery of therapeutic recombinant product carrying 2 genes would have a problem of imbalance in expression of different genes delivered by different plasmids. However, to use of a single dual-promoter vector for co-expression of two target genes is efficient and well-established in the art as evidenced by the cited Kim and US 2003/01388449 (Langermann et al).
Some Applicants’ arguments are based on surprising advantageous effects in tumor load reduction in mice model of the specification example 4 (response page 9)
However, 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 is not commensurate in scope with the degree of protection sought by the claim. The allegation that limited data is sufficient to establish the existence of synergism from other such ingredients is without merit. It is well recognized that synergism is a highly unpredictable result that is very dependent on the ingredients used and conditions. Thus any combination for which synergism is not clearly established would be properly rejected because non-obviousness would not have been established.
No claims are allowed.
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Vera Afremova
September 29, 2025
/VERA AFREMOVA/ Primary Examiner, Art Unit 1653