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 . 1
Status of Claims Response to Arguments
Claims 31-39 are under examination.
Response to Arguments
Applicant’s cancellation of claim 1, filed Nov 14 2025, with respect to the rejection of claim 1 under 35 USC 112 as lacking antecedent basis has necessitated the withdrawal of the rejection of said claim.
Applicant’s cancellation of claims 1, 12-17 and 20-25, filed Nov 14 2025, with respect to the rejection of claims 1, 12-17 and 20-25 as being obvious over the cited prior art US 092 as evidenced by Drewes in view of US 973 and Pérez, has necessitated the withdrawal of the rejection of said claims.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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 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.
Claims 31-39 are rejected under 35 U.S.C. 103 as being unpatentable over US 2014/107092 (US 092), Abed et al. Tumor Targeting by Fusobacterium nucleatum: A Pilot Study and Future Perspectives Frontiers in Cellular and Infection Microbiology June 2017 Volume 7 Article 295, pages 1-5; and Fonnes et al. “The Combination of Fosfomycin, Metronidazole, and Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor is Stable in vitro and Has Maintained Antibacterial Activity,” Drug Res 2018; 68: 349–354, Published online: 19.12.2017 as evidenced by Drewes et al. “High-resolution bacterial 16S rRNA gene profile meta-analysis and biofilm status reveal common colorectal cancer consortia,” npj Biofilms and Microbiomes (2017) 3:34 Published online: 29 November 2017 in view of
US 2017/196937 (US 937) and Pérez et al. Fosfomycin: Uses and potentialities in veterinary medicine, Open Veterinary Journal, (2014), Vol. 4(1): 26-43.
US Pub 092 and US Pub 937 are listed on Refs. 1 and 2 on the IDS of July 6 2020 and previously cited by the Examiner. Drewes was cited by the Examiner on the 8/11/2023 PTO-892 form. While Pérez was previously cited by the Examiner, a copy is provided here. Abed is newly cited on the PTO-892.
Claim 31 is directed to a method of inhibiting colorectal tumors selected from adenocarcinomas and adenomas promoted by fusobacterium in a subject's bowel lumen comprising:
selecting a subject that has one or more adenocarcinomas and adenomas and a
bacterial biofilm, the one or more adenocarcinomas and adenomas and the bacterial biofilm promoted by fusobacterium; and
administering a composition locally into the bowel lumen of said selected subject, wherein said local administration is provided to the one or more adenocarcinomas and adenomas and the bacterial biofilm associated with the one or more adenocarcinomas and adenomas via a colonoscope,
wherein the composition comprises a thickening agent and active ingredients
provided in an aqueous solution consisting of fosfomycin in a range of 400 mg to 4 gm and
metronidazole in a range of 100 mg to 1 gm.
The specification notes the association Fusobacteria (such as F. Nucleatum) where such bacteria are detected in colorectal (CRC) tumors by the presence of DNA and RNA; where Fusobacteria are known to enhance and protect cancer cells against natural killer cells and tumor-infiltrating T-cells; and such Fusobacteria are present in the bacterial biofilms of the colorectal tumors, see generally Background of the Invention, pages 2-3.
Thus, prior art directed to the selection of the claimed subject in need, suffering from colon cancer tumors, specifically adenocarcinomas, caused/promoted by fusobacterium and a bacterial biofilm associated with such tumors, including detection of bacteria by presence of RNA, as noted by the Background of the Art, would be relevant to the obviousness analysis. Further, prior art teaching the treatment of a subject with fusobacteria, with an antibiotic effective against fusobacteria (fosfomycin) would also be relevant.
Regarding claim 31 and it’s limitation subject in need (i.e. one with fusobacterium promoted adenocarcinomas and adenomas and/or a biofilm associated with it), US Pub 092 discloses methods of detecting and treating colorectal cancer in a subject (see abstract) in particular, the discovery of Fusobacterium can be a proximal cause of colorectal cancer. See paragraph 5. US Pub 092 discloses an association of fusobacterial with tumors via Linear Discriminant Analysis that identifies Fusobacterium as the most differentially abundant taxon in colon tumor versus normal specimens by DNA sequencing in 95 patients. See Figure 2C. Also note PCR RNA analysis and microbial FISH analysis as per US 092, paragraphs 89-91.
Thus, as noted by Applicant’s specification (pages 2-3) and its detection methods related to the claimed invention’s method of treatment, results for treating and detecting Fusobacteria associated with colorectal cancer tumors are taught by the prior art US Pub 092.
With regard to the limitation of a bacterial biofilm associated with colon cancer cells, it is known that said biofilm is associated with colorectal (CRC) tumors as the “biofilm associated with CRC tumors is characteristically thick and continuous, invading the deeper mucous layer and lying in contact with colonic epithelial cells both over the tumor and in adjacent normal epithelium.,” See page 2, lines 7-10 of the specification.
U.S. Pub 092 discloses the selection of such colon cancer patients in need, where it notes the detection of Fusobacterium sequences in colon cancer DNA, where experiments were performed to determine whether Fusobacterium could be detected in histological sections of colon cancer, and if so, where, see paragraph 99. US Pub 092 discloses Fusobacterium probes detected bacteria in the colorectal cancer and normal tissue sections and were quantitated within the lamina propria and mucus. Id at paragraph 99. Accordingly, the selection of colon rectal cancer patients by US Pub 092 would necessarily entail selection of colorectal cancer tumors promoted by fusobacterium and a bacterial biofilm associated with such tumors.
U.S. Pub 092 discloses the selection of such colon cancer patients in need, where it notes the detection of Fusobacterium sequences in colon cancer DNA, where experiments were performed to determine whether Fusobacterium could be detected in histological sections of colon cancer, and if so, where, see paragraph 99. US Pub 092 discloses Fusobacterium probes detected bacteria in the colorectal cancer and normal tissue sections and were quantitated within the lamina propria and mucus. Id at paragraph 99.
Further, with regard to the limitation that the particular colorectal patient suffering from adenocarcinomas associated with fusobacterium, Abed teaches
Colorectal adenocarcinoma (CRC) is a common tumor with high mortality rates.
Interestingly, CRC was found to be colonized by the oral anaerobic bacteria
Fusobacterium nucleatum, which accelerates tumor progression and enables immune Evasion. . . . Here, we show high Gal-GalNAc levels in additional adenocarcinomas including those found in the stomach, prostate, ovary, colon, uterus, pancreas, breast, lung, and esophagus. This observation coincides with recent reports that found fusobacterial DNA in some of these tumors. Given the tumorigenic role of fusobacteria and its immune evasion properties, we suggest that fusobacterial elimination might improve treatment outcome of the above tumors. See Abstract.
Accordingly, the selection of colon rectal adenocarcinoma patients by US Pub 092 and Abed would necessarily entail selection of colorectal cancer tumors promoted by fusobacterium and a bacterial biofilm associated with such tumors.
Per the selection limitation of claim 31, US Pub 092 discloses predicting a risk of colon cancer via a comparison of Fusobacterium in a potential colon cancer patient compared to a reference (non-cancer) level of Fusobacterium; levels above said reference level indicates an increased risk of having or developing colorectal cancer. See paragraph 7. See also Figures 6-7 and paragraphs 31 and 33. Similarly, US Pub 092 that discloses diagnosing colorectal cancer in a subject (paragraph 7) and selecting a subject for treatment of colon cancer (see paragraph 9) via the same comparison of Fusobacterium levels in a subject versus a reference level in a normal sample.
The association of fusobacteria, biofilms and cancer is further evidenced by Drewes (2017) that discloses (title)” High-resolution bacterial 16S rRNA gene profile meta-analysis and biofilm status reveal common colorectal cancer [CRC] consortia.”
As stated by Applicant’s own disclosure (see pages 2-3 of specification) AND TAUGHT BY US Pub 092, see above) Drewes relies upon RNA profiles as well as biofilm status to reveal common colorectal cancers and tumors associated with it. See Tittle, abstract and multiple references throughout Drewes, Results, Figure 1, Meta-analysis of biofilm prevalence in CRC (where Microbial biofilms were detected by 16S rRNA gene probe) and Figure 2 (Microbial associations with biofilm status). It is noted that that similar to US Pub 092, fluorescence in situ hybridization (FISH) staining was used to visualize the invasion and attachment of biofilms to the colonic epithelium. See page 1, column 2.2
Regarding the step of the administration of an antibiotic (to treat fusobacterium) to said selected colon cancer patient, US Pub 092 discloses the use of therapeutically effect amounts antibiotics effective against Fusobacteria (and the manufacture of a medicament for use) in a method of treating, delaying development of, or reducing risk of developing, colorectal cancer in a subject. See paragraphs 12-13 and 49-50. More specifically, the antibiotics includes various penicillin drugs, including carbapenem. See paragraph 14.
Regarding the limitation that the antibiotic is administered in the local lumen of said selected colon cancer patient, US Pub 092 discloses the antibiotic is formulated in an oral composition formulated for delivery to the colon of the subject. See paragraphs 16 and 19. Similarly, US Pub 092 discloses the antibiotic is formulated for rectal administration, which reads upon the limitation of local lumen delivery and targeting colorectal cancer in a subject. See paragraph 20. In fact US Pub 092 discloses presence of Fusobacterium in the colonic mucosa of colorectal tumor samples (providing a person having ordinary skill in the art (PHOSITA) to look towards delivery into the lumen as the mucosa is present in a subject’s intestinal lumen), as per Figure 3 and paragraph 28.
Regarding claim 31 and the limitation of one or more biocompatible thickening agents (for controlled delivery and adhesion), US Pub 092 discloses its therapeutic compounds are prepared with carriers that will protect the therapeutic compounds against rapid elimination from the body, such as a controlled release formulation. . . Biodegradable, biocompatible polymers can be used. See paragraph 75.
Although US Pub 092 and Abed (as evidenced by Drewes) discloses the limitations of selecting a patient for treatment of colon cancer, as well as the bacterial biofilm based on the levels of Fusobacteria in said patient and treating said patient with a therapeutically effective amount of an antibiotic, US Pub 092 and Abed and Drewes do not disclose the 1) use of fosfomycin and metronidazole and doses claimed and 2) local administration via a colon scope.
However, a PHOSITA would have had a reasonable expectation of success in arriving at the claimed invention with regard to the first point of obviousness, 1) use of fosfomycin, because, treatment of fusobacterium infections with fosfomycin and 2) use of colonoscope for local administration of a drug in to the intestinal lumen, are both well known in the art as established by US Pub 937, Pérez and Fonnes.
Regarding the first point of obviousness and the limitation of treating a fusobacterium infection in a subject with fosfomycin, US Pub 937 discloses use of a composition comprising fosfomycin in the treatment, prevention or alleviation of a bowel condition (IBD) by administration of the composition into the intestinal lumen. See abstract, paragraphs 5, 6, 24, 124 and 145. In particular, US Pub 937 discloses that the antibiotic fosfomycin has bactericidal activity against Fusobacterium. See paragraph 94.
A person having ordinary skill in the (PHOSITA) following the teachings of US Pub 092 (as evidenced by Drewes), US Pub 937 and Pérez would have found the claimed method prima facie obvious as follows.
As taught by US Pub 092 (as evidenced by Drewes) teaches the subject in need (colorectal cancer patient with tumors associated with biofilm and fusobacteria to be treated with antibiotics) and US Pub 937 discloses fosfomycin has antibacterial activity against Fosfomycin in the intestinal lumen, delivered locally into the bowel lumen by colonoscope, where it penetrates into biofilm as taught by Perez, as per the claimed invention.
With regard to the 400 mg to 1g amounts of fosfomycin and 100 mg to 1g metronidazole in a single dose unit, Fonnes discloses amounts of 2 grams of fosfomycin was mixed with water for injection, resulting in 300 ml of fosfomycin solution, see page 350, column 2. Fonnes also discloses 200 ml metronidazole solution 5 mg/ml (1 gram) and mixed with the fosfomycin solution to form a 500 ml combination solution as required claim 31. See also teachings to provide a suggestion of combining fosfomycin with another antibiotic effective against fusobacterium, Pérez noting fosfomycin “Bactericidal activity is evident against Gram positive and Gram negative bacteria (fusobacterium as per Table 1) and can also act synergistically with other antibiotics.” See abstract. Note that it would be routine for a PHOSITA to optimize the doses and concentrations of fosfomycin and metronidazole to fall within the broad ranges claimed, as it would be routine for a PHOSITA to optimize doses to cater to treatment of individual subjects in need.
Prior to the filing of the present patent application, it would have been prima facie obvious to a PHOSITA following the teachings of US Pub 092 and Abed, as evidenced by Drewes the association of biofilm, fusobacterium, DNA/RNA probes to identify patient with adenocarcinoma colorectal cancer with antibiotic, in view of US Pub 937, Pérez and Fonnes (noting the activity of fosfomycin and metronidazole against fusobacteria to penetrate bacterial biofilm in taught doses). Per MPEP 2143, the rationale to support the finding of obviousness are the prior art elements according to known methods (per US Pub 092 and Abed, evidenced by Drewes, US Pub 937, Fonnes and Pérez) to predictably arrive at the claimed invention.
As required by claim 32, US Pub 937 discloses fosfomycin trometamol. See paragraphs 96 and 99.
As required by claim 33, US Pub 937 discloses the fosfomycin disodium salt. See paragraphs 96 and 99.
As required by claim 34, US Pub 937 discloses the safety of fosfomycin in combination with [neoadjuvant] chemotherapy, as it works to exert a protective effect against the toxic action of chemotherapeutic compounds such as cyclosporine and cisplatin, which would be administered to a subject with cancer tumors. See paragraph 96. Accordingly, in the colorectal cancer subject, a PHOSITA would have a motivation to combine chemotherapeutic agents with fosfomycin due its protective effects upon said agents, as per US Pub 937.
As required by claim 35 and the limitation of a combination of a systemic administration of an antibiotic, that reduces fusobacterial or other live microorganisms from tumor cells or metastases remote from the bowel wall, US Pub 092 discloses the systemic administration of an antibiotic to treat colorectal cancer in a subject. See paragraphs 18 and claim 6. Additionally, US Pub 092 discloses the metastases of surgically resected colorectal cancers, where Fusobacterial was detected in 2 out of 11 cases. See paragraph 98.
As required by claim 36, US Pub 092 discloses F. nucleatum (in said subject) is to be detected and treated in a colorectal cancer patient. See paragraph 70. See also paragraphs 100, 104, 116-120 (Example 4); and 121-125 (Example 5).
Claim 37 is directed to the method according to claim 1, wherein a bacterial biofilm associated with said tumor or tumors is reduced or eliminated after administration of said composition.
Regarding claim 37, as noted above, the rationale to combine the cited references is the combination of prior art teachings according to known methods to predictably arrive at the claimed invention. Accordingly, the teachings of US Pub 092 (subjects inflicted with a fusobacterial infection in the bowel (intestinal lumen) and known method of US Pub 937 (treating colorectal cancer patients in need with an antibiotic, where said cancer is caused by or linked to fusobacterium), renders claim 23 obvious. See also above rejection of claim 1, regarding the detection of said biofilm associated with colon cancers as per US Pub 092 as evidenced by De Weirdt and Van de Wiele
Regarding claim 38 and the limitation of evaluating an inhibition of said biofilm post administration, US Pub 092, as evidenced by De Weirdt and Van de Wiele, discloses the detection and known association of a Fusobacterium biofilm with colon cancer tumors, see above rejection of claim 1. Accordingly, a PHOSITA would have found the claim obvious, as per the detection of Fusobacterium with the probes of US Pub 092, where Fusobacterium known to have a biofilm associated with all gut biomes, to be detected in the cells and mucus of a subject’s colon.
Claim 39 is directed to a method according to claim 31, wherein the composition comprises 800 mg fosfomycin and 200 mg metronidazole in a 100 ml aqueous solution.
Fonnes discloses amounts of 2 grams of fosfomycin was mixed with water for injection, resulting in 300 ml of fosfomycin solution, see page 350, column 2. Fonnes also discloses 200 ml metronidazole solution 5 mg/ml (1 gram) and mixed with the fosfomycin solution to form a 500 ml combination solution.
See also teachings to provide a suggestion of combining fosfomycin with another antibiotic effective against fusobacterium, Pérez noting fosfomycin “Bactericidal activity is evident against Gram positive and Gram negative bacteria (fusobacterium as per Table 1) and can also act synergistically with other antibiotics.” See abstract.
Further note US Pub 937 teaches adjustment of volume of an administered fosfomycin comprising formulation wherein the composition is in a volume of 20 mL to 100 mL, where the claims require a volume of 100 mL. See paragraph 177.
As doses of fosfomycin and metronidazole per Fonnes are taught, and where US Pub 937 discloses the taught volume of 100 ml to formulate fosfomycin with, it would be routine for a PHOSITA to optimize the claimed and known fosfomycin and metronidazole combination doses into a known volume of aqueous solution as claimed.
RESPONSE TO ATTORNEY ARGUMENTS:
The Attorney response states US 092 does not teach therapeutically effective amounts of antibiotics against fusobacteria to treat colorectal tumors or thickening agents. The Attorney response states US' 092 relates to tumorigenesis and not to treatment of established colorectal tumors, via fosfomycin/metronidazole locally applied (not as per claim 31, by diffusion but transport into colon mucosa cells, thus reducing cellular proliferation, tumor favorable conditions to reduce resistance to chemo/radio-therapy) to colon fusobacterium and associated biofilm with low systemic side effects, as in the present application, that the skilled person (PHOSITA) could not have gleaned from US 092.
The Attorney response states Drewes does not cure US 092 as it does not teach/disclose fosfomycin/metronidazole and adenocarcinomas or adenomas.
The Attorney response states Drewes cautions (but not necessarily teaches against) attributing the evolution of carcinogenesis to microbes noting further research is necessary (biofilms/B. fragilis and oral pathogens), (paraphrase of Drewes at page 10, column 1).The Attorney response states differences between established tumors (DNA multiple mutations) are inherently different from tumors that revert back to normal state if the cause of tumor removed.
In response to applicant's arguments against the references individually US '092, Drewes, US '937, Pérez, Da Violante, and Fonnes, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
With regard to the critique of US Pub 092 discloses the use of therapeutically effect amounts antibiotics effective against Fusobacteria (and the manufacture of a medicament for use) in a method of treating, delaying development of, or reducing risk of developing, colorectal cancer in a subject, see paragraphs 12-13 and 49-50; formulated into oral and rectal compositions for delivery into the local lumen, see paragraphs 16, 19 and 20. Fusobacterium are known to infiltrate such local lumen, mucus and cells of the colon per Perez below.
In addressing these points regarding Drewes and the art, the association of fusobacteria, biofilms and cancer is disclosed as above and Drewes (2017) that discloses (title)” High-resolution bacterial 16S rRNA gene profile meta-analysis and biofilm status reveal common colorectal cancer [CRC] consortia.”3 While the Attorney points to the caution statement from Drewes, this not necessarily a true teaching away as it does not expressly state Drewes states there is absolutely no teaching of such an association, but rather cautions the necessity of more research.
With regard to the Attorney arguments to distinguish US Pub 937 (different patient population, effect of fosfomycin with regard to GM-CSF etc.) and to address the arguments regarding choice of antibiotic from US Pub 092 and issues of intraluminal administration, it is noted US Pub 937 discloses use of a composition comprising fosfomycin in the treatment, prevention or alleviation of a bowel condition (IBD) by administration of the composition into the intestinal lumen, see abstract, paragraphs 5, 6, 24, 124 and 145. In particular, US Pub 937 discloses that the antibiotic fosfomycin has bactericidal activity against Fusobacterium, see paragraph 94. Pérez discloses fosfomycin’s, ”Bactericidal activity is evident against . . . . Gram negative bacteria [fusobacteria is gram negative] and can also act synergistically with other antibiotics . . . . Other properties of this drug include . . . exopolysaccharide biofilm penetration . . .”, see abstract. Pérez discloses at Table 1 fosfomycin has activity against Fusobacterium.
A person having ordinary skill in the (PHOSITA) following the teachings of US Pub 092 (as evidenced by Drewes), US Pub 937 and Pérez in further view of Da Violante would have found the claimed method prima facie obvious as follows.
The Attorney response states Perez states does not mention use of fosfomycin for colonoscopic administration of treatment of tumors, adenocarcinomas/adenomas in humans promoted by fusobacterium.
In response to the lack of teaching of Pérez, fosfomycin use for treating adenocarcinoma/tumors promoted by fusobacterium, colonoscopic administration of fosfomycin/ metronidazole in humans, etc., Pérez discloses fosfomycin’s, ”Bactericidal activity is evident against . . . . Gram negative bacteria [fusobacteria is gram negative] and can also act synergistically with other antibiotics . . . . Other properties of this drug include . . . exopolysaccharide biofilm penetration . . .”, see abstract. Pérez discloses at Table 1 fosfomycin has activity against Fusobacterium. While there are certainly deficiencies in the Pérez and US ‘092 references with regard to claim 31, this is to be expected as the current rejection is spelled out above with regard to US '092, Drewes, US '937, Pérez, Da Violante and Fonnes.
The Attorney response states Da Violante does not cure the deficiencies of US 092, Drewes, US 937 and Perez as it notes only that DMSO was tested in vitro for deleterious effects on human colonic adenocarcinoma cell lines.
With regard to the deficiencies of Da Violante (only discloses DMSO tested in vitro), it is not relied upon by the Examiner.
The Attorney response states Fonnes cannot cure the deficiencies of US 092, Drewes, US 937, Pérez and Da Violante as it only discloses fosfomycin and metronidazole drug combination. The Attorney response states Arane also cannot cure the deficiencies of US '092, Drewes, US '937, Pérez, Da Violante and Fonnes as Arane only discloses that metronidazole is known to be effective against anaerobic bacteria.
With regard to the attorney arguments regarding Fonnes, because the underlying prima facie rejection is maintained as detailed above, and Fonnes teach combinations of fosfomycin and metronidazole are known to treat anaerobic bacterial infections such as fusobacterium, the rejection is maintained. Note that Arane is not cited as prior art in the current rejection.
New claim 31 is now directed to treatment of adenocarcinomas in the colon associated with fusobacterium bacterial biofilm, in support of the previously cited prior art, Abed discloses what was already known in the prior art.
Applicant’s claims 31-39 are narrower in scope than previously examined claims 1, 12-17 and 20-25, and were generally discussed in the Interview dated Nov 4 2025. The scope of the claims appear to broadly encompass a particular example from paragraph 4 of the Declaration of Dr. Lars Otto Uttenthal (Uttenthal Declaration) dated Nov 11 2024.
A 100 ml composition containing fosfomycin at 8mg/ml and metronidazole at 2 mg/ml was administered [emphasis added], via a colonoscope, to patients with precancerous lesions comprising adenomas or with adenocarcinomas in the right side of the bowel.
One week after treatment, the precancerous lesions and adenocarcinomas were removed and tested. Id.
The Attorney response filed along with the Uttenthal Declaration, discussed paragraphs 6-7 of the Uttenthal Declaration where the specific example of paragraphs 4-5 demonstrated a 67% decrease of the patient bowel lining biofilm. The tumor periphery biofilm of the adenocarcinoma patients was decreased by about 95%. Id. paragraphs 6-7. Non-treated precancerous lesions were said to have unexpectedly increased by about 50% and the ratios of CD8 to CD3 T-cells was found to increase in treated adenocarcinoma tumors about a factor of about 2. Id.
The Attorney response states metagenome sequencing of treated lesions and adenocarcinomas indicated an increase in the commensal gut bacterium, genus Bacteroides, in the treated lesions. Id. In the adenocarcinomas, an unexpected reduction or elimination of cancer promoting Fusobacterium was observed. Id. Cancer protecting Lactobacillales was unexpectedly increased in tumor center without reducing mucosa-associated gut microbiota diversity. Id.
While not detailed by the Attorney response, the compositions of the Uttenthal Declaration are specifically detailed as composition (RNX-051) that included two specific components. Component 1 included 50 ml of an aqueous solution containing 0.25% Kelcogel CG-LA Component 2 included 50 ml of an aqueous solution containing 0.25% calcium chloride, 200 mg metronidazole and 800 mg fosfomycin. See para. 4.
Note, the Declaration’s 12 patients were of a specific population suffering from adenocarcinomas in the colon and not necessarily the broader claimed patients also suffering from adenomas.
Further, the method of administration to the subject patient in need was very specific; a two channel colonoscope to administer RNX-051 where when components 1 and 2 were mixed in the colonic lumen by spraying, they formed a muco-adhesive gel due to the action of calcium chloride on the Kelcogel. Id.
In order to overcome the established prima facie case of obviousness, "objective evidence of nonobviousness must be commensurate in scope with the claims [emphasis added] which the evidence is offered to support."4 The examined claims are far broader than the Uttenthal Declaration working example referenced by Attorney.
Note that claim 31 is broader than the Uttenthal Declaration evidence proffered previously by the Attorney. Note that the subject patient in need includes patients suffering from adenoma tumors, where the administering step, and where the doses and composition (thickening agent broadly claimed vs. specific RNX-051 formulation) claimed are both far broader than the step is broader than described by the Uttenthal Declaration. Therefore, the prima facie case of obviousness is maintained.
Conclusion and Correspondence
In conclusion, no claims are 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 WILLIAM LEE whose telephone number is (571)270-3876. The examiner can normally be reached M-F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/WILLIAM Y LEE/
Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
1 This application claims earliest priority to Foreign applications, DENMARK PA201870030 filed 01/17/2018 and DENMARK PA201870392 filed 06/14/2018. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
2 Drewes discloses that that CRC tissues are enriched for invasive biofilms (particularly on right sided tumors), a symbiont with capacity for tumorigenesis (Bacteroides fragilis), and oral pathogens including Fusobacterium nucleatum, see abstract.
Drewes discloses that “Fusobacterium was also detectable in almost all (16/17) tumors with polymicrobial biofilms, ranging from sparse populations (less than 5 bacteria visible in a 200 μm × 200 μm field of view) in the majority of tumors to dense blooms in 4/17 of the biofilm-positive tumors (Fig. 1f),” see page 34 column 1. In fact Drewes teaches that unlike cancerous tumor tissue, “paired normal tissues were largely devoid of Fusobacterium (Fig. 1f).” Id.
3 Further, as stated by Applicant’s own disclosure (see pages 2-3 of specification) AND TAUGHT BY US Pub 092, see above) Drewes relies upon RNA profiles as well as biofilm status to reveal common colorectal cancers and tumors associated with it, see Title, abstract and multiple references throughout Drewes, Results, Figure 1, Meta-analysis of biofilm prevalence in CRC (where Microbial biofilms were detected by 16S rRNA gene probe) and Figure 2 (Microbial associations with biofilm status). Fluorescence in situ hybridization (FISH) staining was used to visualize the invasion and attachment of biofilms to the colonic epithelium, as also relied upon by US Pub 092 see page 1, column 2.
4 MPEP 716.02(d) Unexpected Results Commensurate in Scope With Claimed Invention [R-08.2012]
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)
Prosecution Insights