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 .
Application Status
This action is written in response to applicant’s correspondence received 02/06/2026. Claims 1-19 and 24 are currently pending.
Election/Restrictions
Applicant's election without traverse of the species of CAB964 in the reply filed on 02/06/2026 is acknowledged. The requirement is still deemed proper and is therefore made FINAL. Claim 3 is withdrawn from prosecution pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species.
Claim Rejections - 35 USC § 112(a) – Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(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.
Claims 1-4, 7-8, 11-19 and 24 are 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 1 recites, “an agent that alters expression of a gene”. The issue stems from the breadth of the claimed agent. The specification states, “The present disclosure is not limited to particular agents.” (p. 4 ln 2). The broadest reasonable interpretation of “agent” encompasses anything which is capable of either activating or repressing expression of a gene. The term “expression of a gene” is further interpreted as encompassing transcription as well as translation and protein turnover. Additionally, claim 1 merely recites that the alteration of gene expression may occur in a bacterium. This encompasses any bacterium, including both well-characterized models such as E. coli as well as uncharacterized or undiscovered bacteria.
Bervoets & Charlier review bacterial gene regulation mechanisms, stating, “it has become increasingly clear that the expression of a single bacterial gene or operon is generally controlled not by one but by a combination of diverse mechanisms, potentially operating at different levels (transcription, translation) and stages (initiation, elongation, termination) of gene expression. Furthermore, and to add to the complexity and versatility of bacterial regulatory systems, the effect of a single regulatory molecule, regardless whether it is a DNA- or RNA binding protein, a cis-or trans-acting small regulatory RNA, may vary depending on the specific target, its interaction with a small effector molecule or associated protein(s) and/or its interference/cooperation with other regulatory processes.” (Diversity, versatility and complexity of bacterial gene regulation mechanisms: opportunities and drawbacks for applications in synthetic biology. FEMS Microbiology Reviews, Volume 43, Issue 3, 2019, Pages 304–339.). Even when only considering transcription factors, Figure 4 makes clear that various activator and repressor proteins can act by a wide variety of mechanisms, and the authors note (p. 317):
The affinity of DNA-binding TFs (repressors and activators) for particular target sequences is frequently modulated by reversible interaction with one or more small molecules or chemical modifications. They are allosteric proteins that bind inducers and/or co-repressors, or undergo reversible covalent modifications including phosphorylation-dephosphorylation (two-component and phospho-relay systems) or oxidation reduction (disulfide bond formation) that affect their DNA binding potential. As an example, binding of allolactose or the artificial inducer IPTG to the C-terminal domain of tetrameric E. coli LacI (lactose operon regulator) or of uracil to dimeric RutR (regulator of pyrimidine utilization) triggers a conformational change that lowers the DNA-binding affinity of the N-terminal domain of the repressor…some allosteric regulators bind more than one effector molecule and these may exert opposite effects on the regulatory outcome (transforming a repressor into an activator and vice versa) on the same or distinct promoters, as observed for instance for E. coli TyrR (tyrosine repressor) and ArgP (regulator of arginine export and other genes)
Other agents that may regulate bacterial gene expression are agents which alter DNA methylation (p. 320), small molecules which regulate RNAP activity, such as guanosine 3-diphosphate, 5-diphosphate (Id.), regulation via other RNA-bindnig proteins (p. 322-323). Overall, what this indicates is that regulation of bacterial gene expression is an extremely variable, complex process.
While Bervoets & Charlier primarily focus on native regulatory mechanisms, Kent & Dixon review several synthetic tools for regulating gene expression in bacteria, encompassing such diverse approaches as engineered split T7 RNA polymerases for regulating transcription (p. 320), allosteric regulation of RNA polymerase activity using T7 inhibitors (p. 325), dual protease systems to alter protein turnover rates (p. 325), etc. (Ross Kent, Neil Dixon, Contemporary Tools for Regulating Gene Expression in Bacteria, Trends in Biotechnology, Volume 38, Issue 3, 2020, Pages 316-333.).
Gottesfeld expands on the genus of agents capable of altering bacterial gene expression, noting that while nucleic acid agents such as antisense oligonucleotides, antisense peptide nucleic acids, circular ODNs, decoys, etc. are all capable of altering expression of a gene in a bacterium, the genus is not limited to those agents and includes further small molecules (p. 77-78)(Gottesfeld et al. Chemical Approaches to Control Gene Expression. Gene Expression, Vol. 9, pp. 77–92, 2000.). For example, various minor groove-binding and intercalating ligands such as adriamycin, which inhibits transcription by E. coli RNA polymerase (p. 79), and calicheamicin oligosaccharides, which block DNA binding by both eukaryotic and prokaryotic transcription factors, play a role in bacterial gene expression (p. 80). Yamaguchi describes some little-known alternatives, such as protein-mediated mRNA interference by an ACA-specific mRNA interferase, which cleaves RNA at a specific seven-base sequence (UUACUCA)(Abstract) and was capable of regulating specific genes in E. coli (p. 4) (Inhibition of specific gene expressions by protein-mediated mRNA interference. Nature Communications volume 3, Article number: 607 (2012).).
In summary, the prior art evidences that the control of bacterial gene expression is an extremely varied and complex process governed by a vast variety of agents. Given the complexity of the processes and the number of possible agents involved, this speaks to a high level of unpredictability. The level of unpredictability within the genus increases when considering the breadth of bacteria encompassed by the claims.
Regarding the scope of the bacteria encompassed by the claims, Lloyd discusses so-called microbial “dark matter”: the uncultured majority of microbes present on Earth (Abstract)(Lloyd et al. Phylogenetically Novel Uncultured Microbial Cells Dominate Earth Microbiomes. mSystems 3:10.1128/msystems.00055-18.). They estimate that uncultured genera could comprise 81% of microbial cells (Id.), and note that, “Given the substantial functional differences that often exist between closely related microbial species or strains, these uncultured lineages are likely to contain many novel metabolic pathways, enzyme functions, cellular structures, and physiologies.” (p. 9). This evidences that there is a high degree of variability and unpredictability within the genus, considering that the majority of microbes (specifically prokaryotes, i.e., archaea and bacteria) are uncultured and uncharacterized.
In contrast with the breadth of the claims and the scope of the claimed genus of agents, the specification only reduces to practice CABs complexed with antisense phosphorothioate gapmers (p. 25-26). Additionally, while the specification states that the agents are not particular limited, the only types of agents it mentions with any specificity are nucleic acid agents. The specification is silent regarding small molecule or protein agents.
Based on the breadth of the claims, the limited amount of guidance provided by the specification and the art, the high degree of variation among members of the claimed genus, and further the unpredictability in the art, one of ordinary skill in the art would conclude that Applicant was not in possession of the invention as broadly claimed.
Claim Rejections - 35 USC § 112(a) – Enablement
Claim 9 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for antisense oligonucleotides, transcription factor decoys, guide RNA, and other oligonucleotides which may reasonable be expected to function in a bacterium, does not reasonably provide enablement for siRNA, mIRNA, or shRNA. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation (United States v. Telectronics., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor but rather is a conclusion reached by weighing many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), and the most relevant factors are indicated below:
Nature of the Invention
Breadth of the Claims
Guidance of the Specification
State of the Art
Experimentation Required
Claim 9 recites wherein the nucleic acid agent is selected from the group consisting of a siRNA, an miRNA, a shRNA, and a guide RNA. While a guide RNA is taught by the prior art and considered enabled, as already discussed in the above rejection under 35 U.S.C. § 103, a search of the prior art did not yield art which taught siRNA, miRNA or shRNA functioning natively in a bacterial cell. In 2025, a post-filing publication by Wang et al. states, “Currently, RNAi cannot be achieved in bacteria due to the lack of RNA-induced silencing complex machinery and the difficulty of small interfering RNA (siRNA) delivery.” (Summary)(siRNA-AGO2 complex inhibits bacterial gene translation: A promising therapeutic strategy for superbug infection. Cell Reports Medicine, Volume 6, Issue 3, 101997.).
The specification does not provide any guidance relating to using RNAi-based technology such as siRNA, miRNA or shRNA to alter gene expression in bacteria. Instead, the specification discloses only the use of single-stranded antisense gapmers, as discussed above. The invention is the class of invention that the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001). The invention as claimed also concerns nascent technology, i.e., siRNA/miRNA/shRNA having the function of altering gene expression in bacteria. Per MPEP 2164.03, “The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art…The law requires an enabling disclosure for nascent technology because a person of ordinary skill in the art has little or no knowledge independent from the patentee’s instruction.”.
In order to practice the claimed invention, an undue amount of experimentation would be required. It would be necessary for one of ordinary skill in the art to design siRNA, miRNA and/or shRNA technology capable of silencing genes in bacteria – something that was, at the time of filing, considered impossible. The ordinary artisan would also need to test the technology throughout the full breadth of all bacteria claimed. Given the high level of variability and unpredictability within the genus of claimed bacteria, as discussed above, this further increases the amount of experimentation required.
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, it is the conclusion that an undue amount experimentation would be required to make and use the invention as claimed.
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.
Note: In comparing the claims to the prior art, it is noted that while the claims were previously rejected in this Office Action for lack of enablement/written description, the claims are rejected here insofar as the prior art teaches at least some embodiments encompassed by the claims. However, the application as filed is not particularly enabling for, nor does it specifically describe, the invention taught by the prior art where the application does not principally contemplate or describe those elements as provided in the prior art. Additionally, it is noted that the particular embodiments of the prior art are not enabling for the generic breadth of the invention as claimed.
Claims 1-2, 5-8, 10-12, 14-15 and 24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sharma (The Journal of Antibiotics volume 71, pages713–721 (2018).; of record, applicant’s submission), as evidenced by Hegarty (International Journal of Nanomedicine 2016:11 3607–3619.; of record, applicant’s submission).
Regarding claim 1, Sharma teaches a composition comprising:a cationic bolaamphiphile (CAB) complexed with an agent that alters expression of a gene in a bacterium (antisense oligonucleotides targeting dnaE)(Abstract):
Here, three (APDE-8, CODE-9, and CYDE-21) novel cationic amphiphilic bolaamphiphiles (CABs) were synthesized and tested for their ability to form nano-sized vesicles or vesicle-like aggregates (CABVs), which were characterized based on their physiochemical properties, their antibacterial activities, and their toxicity toward colonocyte (Caco-2) cell cultures. The antibacterial activity of empty CABVs was tested against cultures of E. coli, B. fragilis, and E. faecalis, and against C. difficile by “loading” CABVs with 25-mer antisense oligonucleotides (ASO) targeting dnaE.
Regarding claim 2, in Fig. 1 and on pp. 714-715, Sharma teaches the synthesis and structures of N,N′-(Decane-1,10-diyl)bis(9-amino-2,3-dihydro-1H cyclopenta[b]quinolinium)dichloride (CYDE-21), N,N′-(Decane-1,10-diyl)bis(4 aminopyridinium)dichloride (APDE-8), and N,N′-(Decane-1,10-diyl)bis(2,4,6 trimethylpyridinium)dibromide (CODE-9), which comprise 10-carbon alkyl chains, chloride salts, and R groups depicted in the claim.
Regarding claims 5-6, Sharma teaches wherein said agent is an antisense oligonucleotide (see above).
Regarding claims 7-8, Sharma teaches wherein said (target) gene is dnaE, a nucleic acid (DNA) polymerase (see above)
Regarding claims 10-11, Sharma teaches wherein said agent is a modified phosphorothioate gapmer antisense oligonucleotide (p. 714):
Here, we report our data on vesicles formed from novel cationic amphiphilic bolaamphiphiles (CABs) as carriers for chimeric 25-mer 2′-O-methyl phosphorothioate ASO.
Regarding claim 12, Sharma teaches that the ASO used had a sequence identical to one previously described:
As previously described [9], prior whole genome shotgun sequencing of a tissue-banked ribotype 027 C. difficile isolate performed by our group using Illumina MiSeq pro
vided sequences for the 5′-UTR of dnaE, a DNA poly merase III alpha subunit important for DNA replication. Using NCBI BLAST, sequences were selected which were specific toC. difficile and which targeted accessible local secondary mRNA structures near start codons, while also selecting sequences predicted in silico to minimize off target effects. Therefore, this ASO was selected for use in the present study due to its specificity to C. difficile and to due to its previous effectiveness in treating C. difficile in culture. The ASO (Integrated DNA Technologies, Coral ville, IA, USA) sequence was identical to one previously described.
Here, Sharma is citing previous work by the same authors, Hegarty, which evidences that the ASO that Sharma incorporates by reference has the nucleotide sequence of SEQ ID NO: 1 and has the recited modification pattern, as shown below:
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643
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Regarding claims 14-15, Sharma teaches that the bacterium is pathogenic C. difficile (see above).
Regarding claim 24, Sharma teaches a method of killing a pathogenic bacterium by administering the composition:
this proof-of-concept work suggests that CABVs are a promising nanocarrier for ASO targeting C. difficile, with vesicles formed from CYDE-21 delivering 25-mer gapmers in concentrations resulting in growth inhibition of C. difficile at concentrations which left tested non-C. difficile bacteria largely undisturbed.
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:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
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.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Sharma, as applied to claims 1-2, 5-8, 10-12, 14-15 and 24, in view of Kang (Nonviral Genome Editing Based on a Polymer-Derivatized CRISPR Nanocomplex for Targeting Bacterial Pathogens and Antibiotic Resistance. Bioconjugate Chem. 2017, 28, 957−967.) and Marín-Menéndez (Sci. Rep. 2017 Jan 25:7:41242.; of record, applicant’s submission).
Sharma teaches the CAB-ASO composition of claims 1 and 5, from which the instantly rejected claim depends, as discussed above.
Sharma does not teach wherein the agent is a guide RNA.
Kang teaches a CRISPR nanocomplex for targeting bacterial pathogens (Title). The nanocomplex comprises CRISPR guide RNAs to target antibiotic resistance gene mecA in Methicillin-resistant Staphylococcus aureus. This shows that CRISPR/Cas9 systems and guide RNAs may be used in bacteria to target bacterial pathogens.
Marín-Menéndez teaches oligonucleotide-based antimicrobial nanoplexes employing cationic bolaamphiphiles that bound oligonucleotides (transcription factor decoys) with high affinity to form self-assembled complexes (Abstract). In Figure 1, Marín-Menéndez shows that the transcription factor decoy is larger than Sharma’s antisense oligonucleotides and has a secondary structure, thereby providing the ordinary artisan with a reasonable expectation that the CABs would predicably form complexes with oligonucleotides of various lengths and secondary structures.
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the CAB-ASO compound for targeting the genes of bacterial pathogens, as taught by Sharma, to comprise a CRISPR guide RNA. Kang teaches that CRISPR systems functioned in bacterial pathogens to knock down bacterial genes. Sharma and Marín-Menéndez teach that CABs are suitable delivery vehicles for a variety of oligonucleotides. Based on those combined teachings, the ordinary artisan would have had a reasonable expectation that a guide RNA could have been substituted in the place of an ASO or TFD and would predictably have formed a complex with the CAB and permitted delivery of the guide RNA to the bacterial cell.
Claims 13, and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Sharma, as applied to claims 1-2, 5-8, 10-12, 14-15 and 24.
Sharma teaches the composition of claim 1, from which the instantly rejected claims depend, as discussed above.
Sharma does not teach wherein said (target) gene is involved in bacterial toxin or spore formation (relevant to claim 13), or wherein the composition comprises two or more distinct agents targeting two or more different genes (claim 18) in the same or different species (claim 19).
Sharma does, however, provide an explicit teaching, suggestion or motivation to target genes involved in sporulation and toxin production, noting that modification of ASO to address variations in genetic targets is easily accomplished and cost-effective (p. 719):
Antisense therapies offer several advantages beyond greater drug specificity. The production of antisense therapies offers a lower-cost pathway for novel drug development, considering the cost of many modified oligonucleotides. Modification of ASO to address variations in genetic targets is easily accomplished, and ASO potentially allow for therapeutic targets previously unapproach able by conventional antibiotics, including interruption of sporulation and toxin production pathways which would address the major disease reservoir and the principal cause of disease symptoms, respectively.
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the composition as taught by Sharma to comprise ASOs targeting genes involved in toxin production or sporulation, either instead of or in addition to the ASO targeting dnaE, as also taught by Sharma. Sharma provides an explicit suggestion to adapt the composition to target different genetic targets and states that this is easily accomplished and cost-effective. Based on that, the ordinary artisan would have had a reasonable expectation that ASOs targeting such genes could be designed which would predictably repress their targets when complexed with a CAB.
Claims 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Sharma, as applied to claims 1-2, 5-8, 10-12, 14-15 and 24, further in view of Marín-Menéndez (Sci. Rep. 2017 Jan 25:7:41242.; of record, applicant’s submission).
Sharma teaches the composition of claim 1, from which the instantly rejected claims depend, as described above.
Sharma does not teach the composition as a pharmaceutical composition formulated for oral or topical delivery.
Marín-Menéndez teaches oligonucleotide-based antimicrobial nanoplexes employing cationic bolaamphiphiles that bound oligonucleotides (transcription factor decoys) with high affinity to form self-assembled complexes (Abstract).
Marín-Menéndez further teaches administration of these complexes in vivo with low toxicity (p. 4):
The anti-bacterial efficacy of LNPs loaded with a SigH-targeted TFD to treat C. difficile infections was tested in a severe animal model established in Golden Syrian Hamsters (Fig. 3c,d). Briefly, the intestines of the animals were sterilized by clindamycin treatment prior to inoculation with a potentially lethal dose of spores. One hour later the treatments were started in groups of five animals. The vehicle arm, consisting of the buffer alone (50 mM MES pH 5.6) succumbed to the infection within 2 days as did the LNP containing a scrambled version of the SigH TFD at 2 mg/kg (Fig. 3c). The other two arms were the positive control (25 mg/kg vancomycin) and the SigH LNP (at 2 mg/kg) that both gave full protection until the end of the study and were statistically superior to the vehicle control (Fig. 3d)…SigH LNPs were effective in treating the infection by clearing vegetative bacteria, were well tolerated and showed no signs of toxicity.
Marín-Menéndez further suggests employing the formulation for oral delivery (p. 4).
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the composition as taught by Sharma to be suitable for oral delivery in a pharmaceutical composition for use as an antibiotic to treat infections caused by pathogenic bacteria such as C. difficile, as taught by Marín-Menéndez. The ordinary artisan would have had a reasonable expectation of success based on Marín-Menéndez’s results, which showed that the compound was effective in treating the infection, well tolerated, and showed no signs of toxicity.
Subject matter free of the prior art
A composition comprising CAB964 and the nucleic acid of claim 12 is free of the prior art. While the nucleic acid, a modified ASO gapmer, itself was known in the prior art, the complex combining the CAB with the ASO was not. While the prior art teaches various CABs complexed with oligonucleotides, it does not teach this specific CAB, and the preponderance of evidence suggests that CAB964 is not an obvious variant of the prior art CABs which would have predictably yielded a composition capable of delivering an ASO to a bacterial cell and altering gene expression in the bacterium. This reasoning is based on the combined disclosures of Sharma, Marín-Menéndez, and U.S. PGPUB 2019/0298841 to McArthur (hereinafter ‘McArthur’, of record, applicant’s submission).
Sharma discloses three CABs, designated as CODE-9, CYDE-21, and APDE-8. Their structures are shown in Figure 1. They are all classed as CABs. However, despite belonging to the same class of compounds, their structures vary in terms of the number and type of heterocyclic rings and functional groups such as amine and methyl groups, and their functions also diverge. Figure 4 shows that of the empty CABs, APDE-8 had no effect on C. difficile growth at all, while CODE-9’s effect was minimal and only at higher doses. Figure 6, which shows the outcomes for CABV-ASO complexes, shows similar results: while CYDE-21 was effective at reducing C. difficile growth by at least 60% for the lowest concentration, CODE-9 only slightly reduced growth at similar doses, only reaching the same level as CYDE-21 at the highest dose of 25.6 μM ASO/306.2 μM CAB. APDE-8, instead, had minimal efficacy, only reducing growth by less than 20% at the highest dose. Comparison of the structures shows that APDE-8 and CODE-9 are the closest in structure to CAB964.
Marín-Menéndez confirms the efficacy of a compound which differs only from CYDE-21 in the length of its alkyl chain. While Marín-Menéndez does not compare the CAB to others in the class, McArthur teaches dequalinium (FIG. 1) and an analogue which is identical to CYDE-21, termed Compound 7 (FIG. 2, para [0156]), both for forming complexes with transcription factor decoys. In Example 3, McArthur reduces the delivery of a TFD by Compound 7 to practice, and demonstrates that it kills E. coli (in para [0451]-[0459]). McArthur lists other suitable analogues in paras [0160]-[0250]. However, CAB964 is not among those analogues, and in any case, none of those analogues aside from dequalinium, Compound 7, and Compound 7-12 (a variant with a 12-carbon alkyl chain instead of a 10-carbon chain) were reduced to practice, so their efficacy is unknown.
Based on the preponderance of evidence, the art teaches that there is a certain degree of structural diversity as well as variability and unpredictability in the suitability of CABs for complexing with nucleic acids to alter gene expression in bacteria. Of the three CABs tested by Sharma, one significantly outperformed the other two, and the two poor performers were more structurally similar to CAB964. Marín-Menéndez and McArthur confirm the efficacy of CYDE-21/Compound 7, but are silent as to the efficacy of compounds more structurally similar to CAB964. Given what was known in the prior art, the ordinary artisan would have had no motivation to try CAB964 out of all of the alternatives, and would in fact have been discouraged from doing so by the performance of more structurally-similar CABs in Sharma’s disclosure, which showed that the structurally more similar CABs were less effective.
Conclusion
No claim is allowed at this time.
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/AMANDA M ZAHORIK/Examiner, Art Unit 1636