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 .
Response to Amendment
The amendment received on 04/28/2026 is acknowledged. Claims 1 and 16 have been amended. Claims 1-14, 16, 28, 30 and 33-34 are currently pending. Claims 8-12, 28, 30, 33-34 are currently withdrawn. Claims 1-7, 13-14, 16 have been treated on the merits.
Response to Arguments
Applicant’s arguments have been fully considered but they are not persuasive.
Applicant argues that the one of ordinary skill in the art would expect the strain to survive and exhibit toxicity in normal organs that are rich in macrophages. This is not found persuasive as the modification to the strain by deleting SPI-I and SPI-II are to improve properties such as reducing fitness in normal tissue, thus one would expect reduced survival in normal tissue, while they would be present in phagocytes or macrophages. Applicant further argues that the strain would have limitations in directly targeting and killing tumor cells of epithelial cell origin, but this argument is not persuasive as the claims are not limited to such cells and further Liang teaches that modification of SPI-I and SPI-2 have been used in the bacteria while targeting cancer (Table 2, Page 171 Last paragraph).
Applicant further argues that the currently claimed quadruple mutant exhibited the smallest increase in spleen size indicating the unexpected effect of minimizing the hyperinflammatory response of the strain. This argument has been fully considered and is not persuasive. The figures provided show that the double strain has the highest measured size at low dose and has a size within the error bars of a mutant containing neither deletion, and no comparison is made to a strain with the SPI-2 deletion. It thus cannot be determined if an unexpected result occurs, and if so at what dosages. Further the results indicate the claims are not commensurate in showing of any unexpected result for this one cancer model in mice.
Applicant argues that the quadruple mutant has reduced levels in macrophage rich organ liver while maintain high levels in tumors. This argument has been full considered and is not unexpected as Liang directly teaches “Mutations such as htrA, SPI-2 and STM3120 are also potential candidates to reduce bacterial fitness in normal tissues while retaining fitness in tumors( Page 171)”. Strain CNC18 is the only strain tested with the mutation in SPI-2. One of ordinary skill in the art would not find it unexpected for it to have reduced fitness and levels in normal tissue as this loci is specifically taught to be of interest to achieve such a result.
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.
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.
Claim(s) 1-7, 13-14, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Liang (“Genetically engineered Salmonella Typhimurium: Recent advances in cancer therapy”, Cancer Letters, 448 (2019), 168-181/IDS submitted) in view of Thanos (WO2020176809, filing date 02/27/2020).
Regarding claim 1 and the limitation “A Salmonella sp. mutant strain…and wherein the ppGpp synthase-encoding genes are inactivated, wherein the ppGpp synthase encoding genes are Salmonella-relA gene and Salmonella-spoT, wherein the Salmonella sp. mutant strain has a specific and selective targeting ability to cancer by inhibiting tumor growth while having reduced viability in normal organs.” Liang teaches that there are a number of well-known genetically engineered S. Typhimurium strains, including SHJ2037, that preferentially target tumors over the liver that have inhibitory effects on tumor growth (Introduction, Page 168-169). Liang teaches that strain SHJ2037 is a well-known strain and that it is a relA spoT double mutant deficient in ppGpp (Page 171, right column, last paragraph).
Laing further teaches that modifications to SPI-1 are known in Salmonella bacteria used for cancer treatment (Table 2), and further suggests that SPI-2 may be a good candidate for reducing bacterial fitness in normal tissue (Page 171 right column, last paragraph)
Liang does not teach strains in which Salmonella pathogenicity island-I (SPI-1) and Salmonella pathogenicity island-2 (SPI-2) have been deleted, this difference however would have been obvious to one of ordinary skill in the art as it is taught in the same field of endeavor as engineered Salmonella strains for treatment of tumors.
In the same field of endeavor, Thanos teaches that therapeutic Salmonella strains may be developed with one or more genes or operons of SPI-1 and/or SPI-2 deleted (Page 8, Ln 15-Page 9 Ln 30, Page 99 Ln 26-Page 107 Ln 22), to limit its uptake into unintended cells.
One of ordinary skill in the art would have found it obvious that the known anti-cancer therapeutic bacteria known in the art, such as SHJ2037, could be further modified to reduce pathogenicity or ability to infect healthy tissue as such modification are taught in the art by Thanos., such as the deletion or interruption of SPI-1and SPI-2 One of ordinary skill in the art would be motivated to do so to create a strain which targeted tumor at a higher rate relative to healthy tissue. One of ordinary skill in the art would further have a reasonable expectation of success in doing so as methods of genetically engineering Salmonella are well known as demonstrated by the presence of multiple well-known strains as described by Liang (Introduction, Table 2), as well as descriptions of techniques throughout Thanos.
Regarding claims 2 and 3 and the limitations “wherein the Salmonella pathogenicity island-I (SPI-1) consists of the nucleotide sequence set forth in SEQ ID NO: 1“, and “wherein the Salmonella pathogenicity island-2 (SPI-2) consists of the nucleotide sequence set forth in SEQ ID NO: 2”, Thanos makes obvious the deletion of SPI-1 and SPI-2 (Page 8, Ln 15-Page 9 Ln 30, Page 99 Ln 26-Page 107 Ln 22). Applicant claims a sequence which has been removed, this sequence thus is not present in the strain and does not provide additional structure or limit the deleted strains. The strains thus made obvious by Liang and Thanos, such as SHJ2073 with deleted SPI-1 and SPI-2 will lack these islands. It is further noted that SHJ2073 is the strain exemplified in the instant specification and thus prior to having had the islands deleted would have a matching sequence.
Regarding claims 4-6 and the limitation “wherein the Salmonella sp. mutant strain is one into which a gene encoding an anticancer protein has been additionally introduced”, “wherein the anticancer protein is at least one selected from the group consisting of a toxin protein, an antibody specific for a cancer antigen or a fragment of the antibody, a tumor suppressor protein, an angiogenesis inhibitor, a cancer antigen, a prodrug-converting enzyme, and a pro-apoptotic protein”, “wherein the toxin protein is at least one selected from the group consisting of ricin, saporin, gelonin, momordin, debouganin, diphtheria toxin, Pseudomonas toxin, hemolysin (HlyA), FAS ligand (FASL), tumor necrosis factor-a (TNF-a), TNF-related apoptosis-inducing ligand (TRAIL), and cytolysin A (ClyA)” Liang teaches that engineered Salmonella can be used to deliver antitumor agents including toxic proteins like cytolysin A (ClyA) (3.2 Delivery of anti-tumor agents, Page 172 and 3.3 Combination therapy, Page 174). One of ordinary skill in the art would have found it obvious that the strains of Liang and Thanos could be engineered to express cytolysin A through the introduction of the gene ClyA, as it is taught by Liang as an anti-tumor agent which is known to be used in ppGpp deficient strains of Salmonella. One of ordinary skill in the art would further be motivated to do so to deliver anti-tumor therapeutic to the tumor. One of ordinary skill in the art would further have a reasonable expectation of success in doing so as Liang teaches the expression of this protein from ppGpp deficient strains of Salmonell as part of cancer therapeutic.
Regarding claim 7 and the limitation and “wherein the cytolysin A is expressed from a nucleotide consisting of the sequence set forth in SEQ ID NO: 15”, The instant specification states that the sequence of ClyA is known in the prior art and that it’s sequence and gene encoding it are available under accession numbers ABI83833.1 and DQ910780.1. As noted below these sequences were deposited in 2006. One of ordinary skill in the art would find it obvious that the sequences of ClyA known in the prior art referenced in the instant application could be used in the method of Liang and Thanos.
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Regarding claims 13 and 14 and the limitations “wherein the Salmonella sp. mutant strain is derived from at least one selected from the group consisting of Salmonella typhimurium, Salmonella choleraesuis, Salmonella enteritidis, Salmonella infantis, Salmonella paratyphi, Salmonella gallinarum,and Salmonella typhi. ”, and “wherein the Salmonella sp. mutant strain is a mutant strain lacking ability to synthesize guanosine polyphosphate”, LLiang teaches that there are a number of well-known genetically engineered S. Typhimurium strains, including SHJ2037, that preferentially target tumors over the liver that have inhibitory effects on tumor growth (Introduction, Page 168-169). Liang teaches that strain SHJ2037 is a well known strain and that it is a relA spoT double mutant deficient in ppGpp, i.e. guanosine polyphosphate (Page 171, right column, last paragraph).
Regarding claim 16 and the limitation “A method for producing a Salmonella sp. mutant strain, the method comprising (i)removing Salmonella pathogenicity island-I (SPI-1) and Salmonella pathogenicity island-2 (SPI-2) genes from a Salmonella sp. strain to obtain a transformed strain; and(ii) inactivating ppGpp synthase genes, wherein the ppGpp synthase encoding genes are Salmonella-relA gene and Salmonella-spoT gene.”, The deletion of SPI-1 and SPI-2 from strain SHJ2037 will result in these method steps being practiced as no order is imposed.
Conclusion
No claim is allowed.
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 CHARLES Z CONSTANTINE whose telephone number is (571)270-5533. The examiner can normally be reached Mon-Fri 9-5.
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/CHARLES Z CONSTANTINE/Examiner, Art Unit 1657
/ROBERT J YAMASAKI/Primary Examiner, Art Unit 1657
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