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 .
Formal Matters
Applicants’ claim amendments and arguments in the reply filed on 10 July 2026 are acknowledged and have been fully considered. Claims 1, 13, 17, 20, and 23-27 are pending. Claims 1, 13, 20, and 23-27 are under consideration in the instant office action. Claim 17 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claim. Claims 2-12, 14-16, 18-19, 21-22, and 28-37 are canceled. Claim1 is amended.
Withdrawn Objections/Rejections
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn as are those rejections and/or objections expressly stated to be withdrawn.
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.
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.
Note: The claims are examined with respect to the elected species wherein Fusobacterium as the specific microbe genera; antimicrobial agent administration as specific type of administration once the subject is determined to have pancreatic cancer; and MUC16 and IL1RL1 as specific gene types.
Claims 1, 13, 20, and 25-27 are rejected under 35 U.S.C. 103 as being unpatentable over Allen-Vercoe et al. (US 20130259899) in view of Muniyan et al. (Genes & Cancer, 7(3-4), 110, 124, 2016) and Schmieder et al. (Cytokine 60 (2012) 514–521).
Note: The claims are examined with respect to the elected species wherein Fusobacterium as the specific microbe genera; antimicrobial agent administration as specific type of administration once the subject is determined to have pancreatic cancer; and MUC16 and IL1RL1 as specific gene types to be targeted.
Applicants’ claims
Applicants claim “A method of treating a subject having or suspected of having pancreatic cancer, comprising: sequencing microbial nucleic acid molecules in individual cells obtained from the subject, wherein the microbes comprise microbes from any of genera Prevotella, Megamonas, Spiroplasma, Bacteroides, Polaribacter, Arcobacter, Acinetobacter, Clostridium, Chryseobacterium, Lactobacillus, Paenibacillus, Flavobacterium, Vibrio, Mycoplasma, Campylobacter, Streptococcus, Fusobacterium, Buchnera, Streptomyces, Bacillus, Kluyveromyces, Sphingobacterium, Saccharomyces, Thermothielavioides, Colletotrichum, Aspergillus, Staphylococcus, Paraccocus, Burkholderia, Klebsiella, Pasteurella, and/or Ralstonia; classifying the subject as having pancreatic cancer when the presence of Prevotella, Megamonas, Spiroplasma, Bacteroides, Polaribacter, Arcobacter, Acinetobacter, Clostridium, Chryseobacterium, Lactobacillus, Paenibacillus, Flavobacterium, Vibrio, Mycoplasma, Campylobacter, Streptococcus, Fusobacterium, Buchnera, Streptomyces, Bacillus, Kluyveromyces, Sphingobacterium, Saccharomyces, Thermothielavioides, Colletotrichum, or Aspergillus microbes is detected in the individual cells; classifying the subject as having a poor or good survival outcome, the classifying comprising measuring expression of a set of genes in the individual cells obtained from the subject, the set of genes comprising one or more of NTHL1, C2CD4B, FMO3, and IL1RL1, and one or more of LYPD2 and MUC16; wherein increased expression of one or more of IL1RL1, C2CD4B, FMO3, and NTHL1 compared to a control, and decreased expression of one or more of LYPD2 and MUC16 compared to the control indicates high microbial diversity and classifies the subject as having a poor survival outcome; or wherein decreased expression of one or more of IL1RL1, C2CD4B, FMO3, and NTHL1 compared to a control, and increased expression of one or more of LYPD2 and MUC16 compared to the control indicates low microbial diversity and classifies the subject as having a good survival outcome; and if the subject is determined to have pancreatic cancer, administering at least one of surgery, radiation therapy, a chemotherapeutic agent, antimicrobial, selective bacteriophage, and palliative care to the subject, thereby treating the subject.” Dependent claims thereof recite other additional features.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
Allen-Vercoe et al. teach in claim 1 a method for prognosing or diagnosing a gastrointestinal cancer in a subject, the method comprising:
a) providing a sample from the subject; and
b) detecting a Fusobacterium sp. in the sample,
wherein a positive detection of the Fusobacterium sp. indicates a prognosis or diagnosis of gastrointestinal cancer. Allen-Vercoe et al. dislose in claim 2 that the method of claim 1 wherein the detecting comprises contacting the sample with:
a) an antibody that specifically binds a Fusobacterium sp. antigen or
b) a nucleotide sequence that hybridizes to a Fusobacterium sp. nucleotide sequence,
wherein the specific binding of the antibody to the Fusobacterium sp. antigen or the hybridization of the nucleotide sequence to the Fusobacterium sp. nucleotide sequence indicates a prognosis or diagnosis of gastrointestinal cancer. The method of claim 2, wherein the Fusobacterium sp. antigen is selected from the group consisting of one or more of the polypeptides set forth in Table 4 (see claim 3). The method of claim 2, wherein the Fusobacterium sp. nucleotide sequence is selected from the group consisting of one or more of the sequences set forth in Tables 2 or 4 (see claim 4). Allen-Vercoe et al. disclose in one aspect, the invention provides a method for prognosing or diagnosing a gastrointestinal cancer in a subject, by providing a sample from the subject; and detecting a Fusobacterium sp. in the sample, where a positive detection of the Fusobacterium sp. indicates a prognosis or diagnosis of gastrointestinal cancer (paragraph 0006). In some embodiments, the methods and compounds described or referenced herein may pertain to a condition or a cancer that is “related” to a GI cancer. Such cancers can include, for example, liver cancer or pancreatic cancer, or a cancer of a tissue or organ to which a colorectal tumour or cell has spread by metastasis (paragraph 0030). A method of treating a gastrointestinal cancer, the method comprising administering a compound or composition that induces an immunological response against a Fusobacterium sp. to a subject diagnosed with or suspected of having a gastrointestinal cancer (see claim 11). The method of claim 1, wherein the subject is a human (see claim 12). In alternative aspects, a GI cancer or related condition or cancer may be treated by administering an effective amount of a compound (e.g., an antibiotic) or a composition (e.g., a vaccine) effective against a Fusobacterium, such as a F. nucleatum. In some embodiments, a vaccine may include a Fusobacterium or antigen thereof (e.g., a polypeptide encoded by one or more of the Fusobacterium sequences described or referenced herein, or known in the art, or a whole bacterium, such as a killed Fusobacterium bacterin). In the case of vaccine formulations, an immunogenically effective amount of a compound of the invention can be provided, alone or in combination with other compounds, with an immunological adjuvant, for example, Freund's incomplete adjuvant, dimethyldioctadecylammonium hydroxide, or aluminum hydroxide. The compound may also be linked with a carrier molecule, such as bovine serum albumin or keyhole limpet hemocyanin to enhance immunogenicity (see paragraph 0043). Fusobacterium is a genus of gram-negative, filamentous, anaerobic bacteria found as normal flora in the mouth and large bowel, and often in necrotic tissue. A comparison of microbial ribonucleic acids (RNA) between colorectal carcinoma (CRC) tissue and adjacent normal control tissue found the over-representation of F. nucleatum in CRC tissue. RNA abundance was measured by polymerase chain reaction (PCR)-amplifying RNA from the tissue, constructing libraries, sequencing the RNA in the libraries, pairing sequences from CRC and normal tissue, and quantifying RNA abundance. Detection of Fusobacterium in a gastrointestinal sample is indicative of gastrointestinal cancer (see abstract). A “sample” can be any organ, tissue, cell, or cell extract isolated from a subject, such as a sample isolated from a mammal having a gastrointestinal cancer or suspected of having a gastrointestinal cancer. For example, a sample can include, without limitation, cells or tissue (e.g., from a biopsy or autopsy) from any part of the gastrointestinal tract (including without limitation, colon, stomach, stool, anus, rectum, duodenum), a gastrointestinal cell lysate, cell culture or culture medium, or any other specimen, or any extract thereof, obtained from a patient (human or animal), test subject, or experimental animal. A sample may also include, without limitation, products produced in cell culture by normal or transformed cells (e.g., via recombinant DNA or monoclonal antibody technology). A sample may also include, without limitation, any organ, tissue, cell, or cell extract isolated from a non-mammalian subject, such as an insect or a worm. A “sample” may also be a cell or cell line created under experimental conditions, that is not directly isolated from a subject. A sample can also be cell-free, artificially derived or synthesized. A sample may be from a gastrointestinal cell or tissue known to be cancerous, suspected of being cancerous, or believed not be cancerous (e.g., normal or control) (paragraph 0040).
To summarize, Allen-Vercoe et al. disclose treating a human subject diagnosed with or suspected of having a GI cancer or related conditions, explicitly including pancreatic cancer (see paragraph 0030); wherein the subject is a human (see claim 12); wherein treating a subject “diagnosed with or suspected of having a gastrointestinal cancer”. Pancreatic cancer is expressly listed as a treatable related cancer via the same Fusobacterium based approach. Allen-Vercoe et al. discloses sequencing microbial nucleic acid molecules (RNA-Seq of Fusobacterium RNA/DNA after host subtraction) from cell(s)/tissues obtained from the subject (frozen sections of tumor tissue (paragraphs 0047-0052). Fusobacterium sp. (specifically F.nucleatum) is the identified microbe (see claims 8-9 and paragraph 0026). The tissue sections consist of cells from the subject and Allen-Vercoe et al. further shows intracellular Fusobacterium in epithelial cells (see paragraphs 0071-0073) meeting the sequencing of microbial nucleic acids from the cells. Regarding “classifying” Allen-Vercoe et al. disclose the positive detection of Fusobacterium in the sample “indicates a prognosis or diagnosis of gastrointestinal cancer (see claim 1 and paragraph 0006), with pancreatic cancer included as an embodiment (see paragraph 0030). Detection/classification is based on sequencing the microbial nucleic acids in the obtained cell(s)/tissue. Regarding administering an antimicrobial, Allen-Vercoe et al. disclose administering an effective amount of a compound (e.g., an antibiotic/antimicrobial) effective against Fusobacterium to treat the cancer (see paragraph 0043 and see also claim 10 screening inhibitors of growth/activity for treating GI/related cancer).
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
Allen-Vercoe et al. do not specifically teach further comprising classifying the subject as having a poor or good survival outcome, the classifying comprising measuring expression of a set of genes in the individual cells obtained from the subject, the set of genes comprising one or more of NTHL1, C2CD4B, FMO3, and IL1RL1 and one or more of LYPD2 and MUC16; and wherein increased expression of one or more of IL1RL1, C2CD4B, FMO3, or NTHL1 compared to a control, and decreased expression of one or more of LYPD2 or MUC16 compared to the control indicates high microbial diversity and classifies the subject as having a poor survival outcome; or wherein decreased expression of one or more of IL1RL1, C2CD4B, FMO3, and NTHL1 compared to a control, and increased expression of one or more of LYPD2 or MUC16 compared to the control indicates low microbial diversity and classifies the subject as having a good survival outcome. These deficiencies are cured by the teachings of Muniyan et al. and Anderson et al.
Muniyan et al. teach in the abstract that MUC16, a heavily glycosylated type-I transmembrane mucin is overexpressed in several cancers including pancreatic ductal adenocarcinoma (PDAC). Previously, we have shown that MUC16 is significantly overexpressed in human PDAC tissues. However, the functional consequences and its role in PDAC is poorly understood. Here, we show that MUC16 knockdown decreases PDAC cell proliferation, colony formation and migration in vitro. Also, MUC16 knockdown decreases the tumor formation and metastasis in orthotopic xenograft mouse model. Mechanistically, immunoprecipitation and immunofluorescence analyses confirms MUC16 interaction with galectin-3 and mesothelin in PDAC cells. Adhesion assay displayed decreased cell attachment of MUC16 knockdown cells with recombinant galectin-1 and galectin-3 protein. Further, CRISPR/Cas9-mediated MUC16 knockout cells show decreased tumor-associated carbohydrate antigens (T and Tn) in PDAC cells. Importantly, carbohydrate antigens were decreased in the region that corresponds to MUC16 and suggests for the decreased MUC16-galectin interactions. Co-immunoprecipitation also revealed a novel interaction between MUC16 and FAK in PDAC cells. Interestingly, we observed decreased expression of mesenchymal and increased expression of epithelial markers in MUC16-silenced cells. Additionally, MUC16 loss showed a decreased FAK mediated Akt and ERK/MAPK activation. Altogether, these findings suggest that MUC16-focal adhesion signaling may play a critical role in facilitating PDAC growth and metastasis.
Muniyan et al. teach recently, we and others have shown that MUC16 is overexpressed in PDAC, and the expression increases as cancer progresses from precursor invasive lesions (Pancreatic Intraepithelial Neoplasia (PanIN)) to metastatic PDAC, while it is not detected in the normal pancreas. Further, we have also shown that MUC16 expression can be utilized in classifying atypical/suspicious fine needle aspirates as pancreatic adenocarcinoma with 100% specificity (see page 111). qRT-PCR and Western Blot on patient derived samples/cells is performed (see page 115).
Schmieder et al. teach in the abstract human pancreatic cancer is one of the most fatal of all solid tissue malignancies. Pancreatic inflammation plays a key role in the development of pancreatic malignancy mediated by pro-inflammatory signaling cascades. Despite advances in surgery and radiation oncology, no significant improvements in overall survival have yet been achieved. Recent investigations suggest a crucial role of interleukin-33 (IL-33), a novel IL-1 family cytokine, in the pathogenesis of chronic pancreatitis and possibly pancreatic cancer. However, the precise role of IL-33 in pancreatic carcinogenesis is poorly understood. As IL-33 mediates its effects via the heterodimeric ST2L/IL-1 receptor accessory protein (IL-1RAcP) receptor complex, we investigated the influence of IL-33 alone, IL-33 combined with IL-1 and other inflammatory cytokines on IL-33 receptor/ligand mRNA expression and production of tumorigenic factors in the highly metastatic human pancreatic adenocarcinoma cell line Colo357. Our results demonstrated that IL-1 and IL-3 up-regulated IL-33 mRNA while IL-12 showed the opposite effect. We also detected a counter-regulatory effect of IL-33 and IL-1 on the mRNA expression of soluble IL-33 receptor ST2 and membrane-bound receptor ST2L. Furthermore, IL-33 and IL-1 acted synergistically in up-regulating secretion of pro-inflammatory IL-6. IL-33 alone stimulated spontaneous release of pro-angiogenic IL-8, but it did not affect IL-1-induced IL-8 secretion. IL-33/IL-1 effects on cytokine production appear to be mediated via NF-jB activation. These data argue for the pro-inflammatory role of IL-33 in Colo357 cells implying that IL-33 might act as a crucial mediator in inflammation-associated pancreatic carcinogenesis.
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of Allen-Vercoe et al. by further comprising classifying the subject as having a poor or good survival outcome, the classifying comprising measuring expression of a set of genes in the individual cells obtained from the subject, the set of genes comprising MUC16 and IL1RL1 as recited in claim 18 and wherein increased expression of one or more of IL1RL1 compared to a control, and/or decreased expression of MUC16 compared to the control indicates high microbial diversity and classifies the subject as having a poor survival outcome; and/or wherein decreased expression of IL1RL1 compared to a control, and/or increased expression of one or more of MUC16 compared to the control indicates low microbial diversity and classifies the subject as having a good survival outcome because with regard to MUC16 Muniyan et al. teach in the abstract that MUC16, a heavily glycosylated type-I transmembrane mucin is overexpressed in several cancers including pancreatic ductal adenocarcinoma (PDAC). Previously, we have shown that MUC16 is significantly overexpressed in human PDAC tissues. However, the functional consequences and its role in PDAC is poorly understood. Here, we show that MUC16 knockdown decreases PDAC cell proliferation, colony formation and migration in vitro. Also, MUC16 knockdown decreases the tumor formation and metastasis in orthotopic xenograft mouse model. Mechanistically, immunoprecipitation and immunofluorescence analyses confirms MUC16 interaction with galectin-3 and mesothelin in PDAC cells. Adhesion assay displayed decreased cell attachment of MUC16 knockdown cells with recombinant galectin-1 and galectin-3 protein. Further, CRISPR/Cas9-mediated MUC16 knockout cells show decreased tumor-associated carbohydrate antigens (T and Tn) in PDAC cells. Importantly, carbohydrate antigens were decreased in the region that corresponds to MUC16 and suggests for the decreased MUC16-galectin interactions. Co-immunoprecipitation also revealed a novel interaction between MUC16 and FAK in PDAC cells. Interestingly, we observed decreased expression of mesenchymal and increased expression of epithelial markers in MUC16-silenced cells. Additionally, MUC16 loss showed a decreased FAK mediated Akt and ERK/MAPK activation. Altogether, these findings suggest that MUC16-focal adhesion signaling may play a critical role in facilitating PDAC growth and metastasis. Muniyan et al. teach recently, we and others have shown that MUC16 is overexpressed in PDAC, and the expression increases as cancer progresses from precursor invasive lesions (Pancreatic Intraepithelial Neoplasia (PanIN)) to metastatic PDAC, while it is not detected in the normal pancreas. Further, we have also shown that MUC16 expression can be utilized in classifying atypical/suspicious fine needle aspirates as pancreatic adenocarcinoma with 100% specificity (see page 111). qRT-PCR and Western Blot on patient derived samples/cells is performed (see page 115). Regarding IL1RL1, Schmieder et al. teach in the abstract human pancreatic cancer is one of the most fatal of all solid tissue malignancies. Pancreatic inflammation plays a key role in the development of pancreatic malignancy mediated by pro-inflammatory signaling cascades. Despite advances in surgery and radiation oncology, no significant improvements in overall survival have yet been achieved. Recent investigations suggest a crucial role of interleukin-33 (IL-33), a novel IL-1 family cytokine, in the pathogenesis of chronic pancreatitis and possibly pancreatic cancer. However, the precise role of IL-33 in pancreatic carcinogenesis is poorly understood. As IL-33 mediates its effects via the heterodimeric ST2L/IL-1 receptor accessory protein (IL-1RAcP) receptor complex, we investigated the influence of IL-33 alone, IL-33 combined with IL-1 and other inflammatory cytokines on IL-33 receptor/ligand mRNA expression and production of tumorigenic factors in the highly metastatic human pancreatic adenocarcinoma cell line Colo357. Our results demonstrated that IL-1 and IL-3 up-regulated IL-33 mRNA while IL-12 showed the opposite effect. We also detected a counter-regulatory effect of IL-33 and IL-1 on the mRNA expression of soluble IL-33 receptor ST2 and membrane-bound receptor ST2L. Furthermore, IL-33 and IL-1 acted synergistically in up-regulating secretion of pro-inflammatory IL-6. IL-33 alone stimulated spontaneous release of pro-angiogenic IL-8, but it did not affect IL-1-induced IL-8 secretion. IL-33/IL-1 effects on cytokine production appear to be mediated via NF-jB activation. These data argue for the pro-inflammatory role of IL-33 in Colo357 cells implying that IL-33 might act as a crucial mediator in inflammation-associated pancreatic carcinogenesis. Muniyan et al. and Schmieder et al. respectively establish that measuring MUC16 and IL1RL1 expression (via standard transcriptomic methods on cells/tissues from subjects) to classify poor vs good survival was predictable in PDAC. A person of ordinary skill in the art would have been motivated to modify Allen-Vercoe et al. by adding steps of measuring MUC16 and IL1RL1 expression to further stratify the subject into poor or good survival groups, with a reasonable expectation of success as demonstrated by Muniyan et al. and Schmieder et al., respectively.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Allen-Vercoe et al. (US 20130259899) in view of Muniyan et al. (Genes & Cancer, 7(3-4), 110, 124, 2016) and Schmieder et al. (Cytokine 60 (2012) 514–521) as applied to claims 1, 13, 20, and 25-27 above, and further in view of Riquelme et al. (Cell, 178(4): 795–806, 2019).
Applicants’ claims
Applicants claim a method of treating a subject having or suspected of having pancreatic
cancer, comprising: sequencing microbial nucleic acid molecules in individual cells obtained from the subject, wherein the microbes comprise or consist of microbes of genera Fusobacterium; classifying the subject as having pancreatic cancer when the presence of Fusobacterium; and if the subject is determined to have pancreatic cancer, administering antimicrobial, thereby treating the subject. Claim 18 recites “The method of claim 1, further comprising classifying the subject as having a poor or good survival outcome, the classifying comprising measuring expression of a set of genes in the individual cells obtained from the subject, the set of genes comprising NTHL1, LYPD2, MUC16, C2CD4B, FMO3, and/or IL1RL1.” Claim 23 recites “The method of claim 18, wherein classifying the subject as
having a poor or good survival outcome further comprises calculating the Shannon diversity
index for the sample, thereby determining the microbial diversity of the sample.”
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
The teachings Allen-Vercoe et al., Muniyan et al., and Schmieder et al. are described above in detail and are incorporated herein by reference.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
Allen-Vercoe et al., Muniyan et al., and Schmieder et al. do not specifically teach wherein classifying the subject as having a poor or good survival outcome further comprises calculating the Shannon diversity index for the sample, thereby determining the microbial diversity of the sample. These deficiencies are cured by the teachings of Riquelme et al.
Riquelme et al. teach most patients diagnosed with resected pancreatic adenocarcinoma (PDAC) survive less than 5 years, but a minor subset survives longer. Here, we dissect the role of the tumor microbiota and the immune system in influencing long-term survival. Using 16S rRNA gene sequencing, we analyzed the tumor microbiome composition in PDAC patients with short and long-term survival (STS, LTS). We found higher alpha-diversity in the tumor microbiome of LTS patients and identified an intra-tumoral microbiome signature (Pseudoxanthomonas/Streptomyces/Saccharopolyspora/ Bacillus clausii) highly predictive of long term survivorship in both discovery and validation cohorts. Through human-into-mice Fecal Microbiota Transplantation (FMT) experiments from STS, LTS or control donors, we were able to differentially modulate the tumor microbiome and affect tumor growth as well as tumor immune infiltration. Our study demonstrates that PDAC microbiome composition, which cross-talks to the gut microbiome, influences the host immune response and natural history of the disease (see summary). To explore the role of the human tumor microbiome composition in mediating clinical outcomes of PDAC patients, we used a discovery cohort to compare surgically resected patients who survived more than 5 years post-surgery, or long-term survivors (LTS, median survival 10.1 years), to stage-matched short-term survivors who survived less than 5 years post-surgery (STS, median survival 1.6 years) from UT MD Anderson Cancer Center (MDACC) in Houston, Texas (Figure 1A and Table 1). Patients in LTS and STS groups were matched with respect to age, gender, stage and prior therapies, including antibiotics use, neadjuvant or adjuvant treatments (Table 1). We then used a validation cohort with similar survival characteristics from Johns Hopkins Hospital (JHH) in Baltimore, Maryland. Bacterial DNA was extracted from 68 surgically resected PDAC tumor (36 LTS and 32 STS) and taxonomic profiling via 16S rRNA gene sequencing was performed. We first measured the tumor microbial diversity using different methodologies (Observed Taxonomic Units, Shannon and Simpson Indices) and found that alpha-diversity of the tumor microbiome, defined as the number of species present within each tumor sample (Kurilshikov et al., 2017), was significantly higher in the LTS patients compared to STS on both the MDACC discovery cohort (p < 0.0005, p < 0.0005 and p < 0.05, for each alpha-diversity indice, respectively) and the JHH validation cohort (p < 0.005, p < 0.005 and p < 0.005, for each alpha-diversity indice, respectively) (Figure 1B). Based on these results, we then tested the relationship between PDAC tumor microbial diversity and overall survival (OS) in the MDACC cohort by stratifying the patients in two groups based on median diversity obtained by Shannon index. As expected, we found that patients with high alpha diversity had significantly prolonged overall survival (median survival: 9.66 years) than those with low alpha diversity (median survival: 1.66 years) using univariate Cox proportional hazard models (Figure 1C). The relationship between tumoral microbial diversity and survival actually allowed for the stratification and redistribution of PDAC patients according to alpha diversity value (high or low) (Figure 1C). Importantly, we assessed for potential contributors to microbial diversity, including clinico-pathological features, body mass index, sex, smoking, neoadjuvant/adjuvant therapies as well as antibiotics use, and were not able to find any significant association (Figure S1). Recent studies have proposed that a high microbial diversity in the gut microbiome is associated with favorable outcomes to treatment (Gopalakrishnan et al., 2018). On the contrary, an imbalance in the gut microbiome or dysbiosis, is associated with poor responses to these therapies, and associated with chronic diseases and cancer development. Our findings indicate that the tumor alpha diversity could serve as a predictor of survival outcome in resected PDAC patients, suggesting the potential relevance of the microbiome composition in mediating pancreatic cancer progression (see Results section).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of Allen-Vercoe et al., Muniyan et al., and Schmieder et al. by classifying the subject as having a poor or good survival outcome further comprising calculating the Shannon diversity index for the sample, thereby determining the microbial diversity of the sample because Riquelme et al. teach Most patients diagnosed with resected pancreatic adenocarcinoma (PDAC) survive less than 5 years, but a minor subset survives longer. Here, we dissect the role of the tumor microbiota and the immune system in influencing long-term survival. Using 16S rRNA gene sequencing, we analyzed the tumor microbiome composition in PDAC patients with short and long-term survival (STS, LTS). We found higher alpha-diversity in the tumor microbiome of LTS patients and identified an intra-tumoral microbiome signature (Pseudoxanthomonas/Streptomyces/Saccharopolyspora/ Bacillus clausii) highly predictive of long term survivorship in both discovery and validation cohorts. Through human-into-mice Fecal Microbiota Transplantation (FMT) experiments from STS, LTS or control donors, we were able to differentially modulate the tumor microbiome and affect tumor growth as well as tumor immune infiltration. Our study demonstrates that PDAC microbiome composition, which cross-talks to the gut microbiome, influences the host immune response and natural history of the disease (see summary). To explore the role of the human tumor microbiome composition in mediating clinical outcomes of PDAC patients, we used a discovery cohort to compare surgically resected patients who survived more than 5 years post-surgery, or long-term survivors (LTS, median survival 10.1 years), to stage-matched short-term survivors who survived less than 5 years post-surgery (STS, median survival 1.6 years) from UT MD Anderson Cancer Center (MDACC) in Houston, Texas (Figure 1A and Table 1). Patients in LTS and STS groups were matched with respect to age, gender, stage and prior therapies, including antibiotics use, neadjuvant or adjuvant treatments (Table 1). We then used a validation cohort with similar survival characteristics from Johns Hopkins Hospital (JHH) in Baltimore, Maryland. Bacterial DNA was extracted from 68 surgically resected PDAC tumor (36 LTS and 32 STS) and taxonomic profiling via 16S rRNA gene sequencing was performed. We first measured the tumor microbial diversity using different methodologies (Observed Taxonomic Units, Shannon and Simpson Indices) and found that alpha-diversity of the tumor microbiome, defined as the number of species present within each tumor sample (Kurilshikov et al., 2017), was significantly higher in the LTS patients compared to STS on both the MDACC discovery cohort (p < 0.0005, p < 0.0005 and p < 0.05, for each alpha-diversity indice, respectively) and the JHH validation cohort (p < 0.005, p < 0.005 and p < 0.005, for each alpha-diversity indice, respectively) (Figure 1B). Based on these results, we then tested the relationship between PDAC tumor microbial diversity and overall survival (OS) in the MDACC cohort by stratifying the patients in two groups based on median diversity obtained by Shannon index. As expected, we found that patients with high alpha diversity had significantly prolonged overall survival (median survival: 9.66 years) than those with low alpha diversity (median survival: 1.66 years) using univariate Cox proportional hazard models (Figure 1C). The relationship between tumoral microbial diversity and survival actually allowed for the stratification and redistribution of PDAC patients according to alpha diversity value (high or low) (Figure 1C). Importantly, we assessed for potential contributors to microbial diversity, including clinico-pathological features, body mass index, sex, smoking, neoadjuvant/adjuvant therapies as well as antibiotics use, and were not able to find any significant association (Figure S1). Recent studies have proposed that a high microbial diversity in the gut microbiome is associated with favorable outcomes to treatment (Gopalakrishnan et al., 2018). On the contrary, an imbalance in the gut microbiome or dysbiosis, is associated with poor responses to these therapies, and associated with chronic diseases and cancer development. Our findings indicate that the tumor alpha diversity could serve as a predictor of survival outcome in resected PDAC patients, suggesting the potential relevance of the microbiome composition in mediating pancreatic cancer progression (see Results section). One of ordinary skilled in the art would have been motivated to add the Shannon Index calculation as a further step in survival classification because the microbial sequencing data is already generated in the base method as described by Allen-Vercoe et al. and Shannon Index is the most common alpha diversity metric as demonstrated by Riquelme et al. providing independent prognostic value in the exact disease (PDAC) and sample type. Combining a host-gene expression panel (MUC16/IL1RL1) with a microbiome-derived metric (Shannon Index) is a predictable improvement that adds orthogonal prognostic information. One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of Allen-Vercoe et al., Muniyan et al., Schmieder et al., and Riquelme et al. because all of the references deal with pancreatic cancer.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Allen-Vercoe et al. (US 20130259899) in view of Muniyan et al. (Genes & Cancer, 7(3-4), 110, 124, 2016) and Schmieder et al. (Cytokine 60 (2012) 514–521) as applied to claims 1, 13, 20, and 25-27 above, and further in view of Williams et al. (US 2012/0040861).
Note: The claims are examined with respect to the elected species wherein Fusobacterium as the specific microbe genera; antimicrobial agent administration as specific type of administration once the subject is determined to have pancreatic cancer; and MUC16 and IL1RL1 as specific gene types to be targeted.
Applicants’ claims
Applicants claim “A method of treating a subject having or suspected of having pancreatic cancer, comprising: sequencing microbial nucleic acid molecules in individual cells obtained from the subject, wherein the microbes comprise microbes from any of genera Prevotella, Megamonas, Spiroplasma, Bacteroides, Polaribacter, Arcobacter, Acinetobacter, Clostridium, Chryseobacterium, Lactobacillus, Paenibacillus, Flavobacterium, Vibrio, Mycoplasma, Campylobacter, Streptococcus, Fusobacterium, Buchnera, Streptomyces, Bacillus, Kluyveromyces, Sphingobacterium, Saccharomyces, Thermothielavioides, Colletotrichum, Aspergillus, Staphylococcus, Paraccocus, Burkholderia, Klebsiella, Pasteurella, and/or Ralstonia; classifying the subject as having pancreatic cancer when the presence of Prevotella, Megamonas, Spiroplasma, Bacteroides, Polaribacter, Arcobacter, Acinetobacter, Clostridium, Chryseobacterium, Lactobacillus, Paenibacillus, Flavobacterium, Vibrio, Mycoplasma, Campylobacter, Streptococcus, Fusobacterium, Buchnera, Streptomyces, Bacillus, Kluyveromyces, Sphingobacterium, Saccharomyces, Thermothielavioides, Colletotrichum, or Aspergillus microbes is detected in the individual cells; classifying the subject as having a poor or good survival outcome, the classifying comprising measuring expression of a set of genes in the individual cells obtained from the subject, the set of genes comprising one or more of NTHL1, C2CD4B, FMO3, and IL1RL1, and one or more of LYPD2 and MUC16; wherein increased expression of one or more of IL1RL1, C2CD4B, FMO3, and NTHL1 compared to a control, and decreased expression of one or more of LYPD2 and MUC16 compared to the control indicates high microbial diversity and classifies the subject as having a poor survival outcome; or wherein decreased expression of one or more of IL1RL1, C2CD4B, FMO3, and NTHL1 compared to a control, and increased expression of one or more of LYPD2 and MUC16 compared to the control indicates low microbial diversity and classifies the subject as having a good survival outcome; and if the subject is determined to have pancreatic cancer, administering at least one of surgery, radiation therapy, a chemotherapeutic agent, antimicrobial, selective bacteriophage, and palliative care to the subject, thereby treating the subject.” Dependent claims thereof recite other additional features. Claim 24 recites “The method of claim 1, wherein the subject does not exhibit symptoms of pancreatic cancer.”
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
The teachings of Allen-Vercoe et al., Muniyan et al., and Schmieder et al. are described in detail above and are incorporated by reference herein.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
Allen-Vercoe et al., Muniyan et al., and Schmieder et al. do not specifically teach wherein the subject does not exhibit symptoms of pancreatic cancer. This deficiency is cured by the teachings of Williams et al.
Williams et al. teach two clinical applications for a blood based pancreatic cancer test are for preclinical diagnosis in the asymptomatic, high-risk population and differential diagnosis in the symptomatic population. The clinical utility for both of these indications is outlined below (paragraph 0007). In the asymptomatic but at-risk population in the absence of an effective screening paradigm the cancer is simply detected at the time of symptomatic presentation. This is likely to be late. The existence of an early detection test would increase the proportion of patients eligible for curative surgery. The current cure rate of 20% in the 20% of early detection subjects is only 4% of the total population. If the eligibility for curative surgery increased—by early detection in the asymptomatic population—from the current 20%, then the curable total would increase, as would the number of lives saved per year. Since pancreatic cancer is a low prevalence disease, even in this high-risk population, high specificity is an important attribute of a screening test. A low false positive rate is essential to reduce the cost incurred by unnecessary follow-up procedures and reduce anxiety for the patient (paragraph 0014). A method for screening an asymptomatic high risk individual for pancreatic cancer, the method comprising: detecting, in a biological sample from an individual, biomarker values that each correspond to one of at least N biomarkers selected from Table 1, wherein said individual is classified as having or not having pancreatic cancer, or the likelihood of the individual having pancreatic cancer is determined, based on said biomarker values, and wherein N=2-65 (see claim 25). Thus, in one aspect of the instant application, one or more biomarkers are provided for use either alone or in various combinations to diagnose pancreatic cancer or permit the differential diagnosis of pancreatic cancer from benign gastrointestinal (GI) conditions such as acute or chronic pancreatitis (or both), pancreatic obstruction, GERD, gallstones, or abnormal imaging later found to be benign. Exemplary embodiments include the biomarkers provided in Table 1, Col. 2, which as noted above, were identified using a multiplex aptamer-based assay, as described generally in Example 1 and more specifically in Example 2. The markers provided in Table 1 are useful in diagnosing pancreatic cancer in a high risk, asymptomatic population and for distinguishing acute or chronic pancreatitis (or both), pancreatic obstruction, GERD, gallstones, or abnormal imaging later found to be benign from pancreatic cancer (paragraph 0037).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of Allen-Vercoe et al., Muniyan et al., and Schmieder et al. utilizing the method as claimed wherein the subject does not exhibit symptoms of pancreatic cancer because Williams et al. teach two clinical applications for a blood based pancreatic cancer test are for preclinical diagnosis in the asymptomatic, high-risk population and differential diagnosis in the symptomatic population. The clinical utility for both of these indications is outlined below (paragraph 0007). One of ordinary skill in the art would have been motivated to apply the method of Allen-Vercoe et al., Muniyan et al., and Schmieder et al. wherein the subject does not exhibit symptoms of pancreatic cancer because Williams et al. teach that in the asymptomatic but at-risk population in the absence of an effective screening paradigm the cancer is simply detected at the time of symptomatic presentation. This is likely to be late. The existence of an early detection test would increase the proportion of patients eligible for curative surgery. The current cure rate of 20% in the 20% of early detection subjects is only 4% of the total population. If the eligibility for curative surgery increased—by early detection in the asymptomatic population—from the current 20%, then the curable total would increase, as would the number of lives saved per year. Since pancreatic cancer is a low prevalence disease, even in this high-risk population, high specificity is an important attribute of a screening test. A low false positive rate is essential to reduce the cost incurred by unnecessary follow-up procedures and reduce anxiety for the patient (paragraph 0014). A method for screening an asymptomatic high risk individual for pancreatic cancer, the method comprising: detecting, in a biological sample from an individual, biomarker values that each correspond to one of at least N biomarkers selected from Table 1, wherein said individual is classified as having or not having pancreatic cancer, or the likelihood of the individual having pancreatic cancer is determined, based on said biomarker values, and wherein N=2-65 (see claim 25). Thus, in one aspect of the instant application, one or more biomarkers are provided for use either alone or in various combinations to diagnose pancreatic cancer or permit the differential diagnosis of pancreatic cancer from benign gastrointestinal (GI) conditions such as acute or chronic pancreatitis (or both), pancreatic obstruction, GERD, gallstones, or abnormal imaging later found to be benign. Exemplary embodiments include the biomarkers provided in Table 1, Col. 2, which as noted above, were identified using a multiplex aptamer-based assay, as described generally in Example 1 and more specifically in Example 2. The markers provided in Table 1 are useful in diagnosing pancreatic cancer in a high risk, asymptomatic population and for distinguishing acute or chronic pancreatitis (or both), pancreatic obstruction, GERD, gallstones, or abnormal imaging later found to be benign from pancreatic cancer (paragraph 0037). One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of Allen-Vercoe et al., Muniyan et al., Schmieder et al., and Williams et al. because all of the references deal with pancreatic cancer.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicants’ arguments filed 10 July 2026 have been fully considered but they are not persuasive.
Applicants argue Muniyan “teaches away.” Muniyan reports that MUC16 is overexpressed in PDAC, that knockdown reduces proliferation, colony formation, migration, orthotopic tumor burden, metastasis, vimentin, and MMP-9, and that MUC16–FAK signaling promotes tumorigenesis and metastasis. From that, Applicants argue one of ordinary skill in the art would expect decreased MUC16 to mean a good survival outcome. Amended claim 1 instead uses decreased MUC16 (with increased IL1RL1/C2CD4B/FMO3/NTHL1) to indicate high microbial diversity and a poor survival outcome. That is said to be “contrary to the expectation created by Muniyan,” so Muniyan cannot supply the MUC16 limitation, and Schmieder/Riquelme do not mention MUC16 at all. Therefore the combination does not teach every element and there is no reasonable expectation of success. Applicants regarding the rejection based on Allen-Vercoe and Williams: did not traverse the merits. Applicant says claim 1 was amended to incorporate former claim 20 (the gene-signature / survival-classifying step), which was not in that ground, so the Williams ground is moot. The examiner rearranged the rejections to address the claimed limitations as currently amended.
The above assertions are not found persuasive because Muniyan does not teach away from the claimed method. A reference teaches away when it criticizes, discredits, or otherwise discourages the path the applicant took. In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004); In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994); MPEP 2145(X)(D). Disclosure of a different purpose, a preferred embodiment, or even an opposite standalone correlation for one analyte is not teaching away from a different use of that analyte in a multi-parameter method. Muniyan teaches that MUC16 protein promotes PDAC cell growth and metastasis, and that experimental knockdown of MUC16 reduces those phenotypes. That is a mechanistic statement about MUC16 as an oncogenic driver in PDAC cell lines and xenografts. It does not: criticize measuring MUC16 transcript levels in individual cells; criticize combining a MUC16 measurement with microbial sequencing; criticize using MUC16 as one component of a multi-gene pattern; address microbial diversity at all; address NTHL1, C2CD4B, FMO3, IL1RL1, or LYPD2; address survival classification based on a reciprocal host-gene signature used as a surrogate of microbial diversity.
Applicant equates “MUC16 drives metastasis, so low MUC16 should mean good prognosis” with the claimed limitation.
The above assertions are not found persuasive because those are not the same proposition. Claim 1 does not recite “decreased MUC16, standing alone, indicates poor survival.” It recites a conjunction: increased expression of one or more of IL1RL1, C2CD4B, FMO3, and NTHL1 and decreased expression of one or more of LYPD2 and MUC16, which the claim itself defines as indicating high microbial diversity, which the claim then maps to poor survival. Muniyan never considers that pattern, that biological meaning (diversity), or that use. A reference cannot teach away from a combination it does not contemplate. In re Fulton, 391 F.3d at 1201. The examiner noted that Applicant’s “expectation” is the wrong comparison. Even if Muniyan would lead one of ordinary skill in the art to expect that isolated low MUC16 tracks less aggressive PDAC, that expectation does not control a method in which MUC16 is only one optional member of a two-arm signature tied to microbial diversity, not to MUC16-driven metastasis. The claimed poor-survival call also requires the increased arm (IL1RL1/C2CD4B/FMO3/NTHL1). Schmieder supplies IL1RL1 (ST2) expression and proinflammatory signaling in metastatic PDAC cells. The combination is not “use Muniyan’s MUC16 direction as a standalone prognostic.” It is “measure host genes known to be dysregulated in PDAC (Muniyan; Schmieder) in the same individual cells in which Allen Vercoe-type oncomicrobes are detected, and use the resulting pattern to stratify.” That is a different question from whether knocking down MUC16 shrinks a xenograft. Additionally, a closer look of the claimed recitation confirm that MUC16 is not even required. Amended claim 1 recites “one or more of LYPD2 and MUC16.” The decreased-expression arm is satisfied by LYPD2 alone. Applicant’s entire teaching-away theory is directed at MUC16. It does not address LYPD2, which Muniyan does not discuss. A teaching-away argument that can be avoided by reading the claim on LYPD2 cannot defeat the rejection of the claim as written. The examiner maintains that Muniyan still supplies the MUC16 measuring step. The Office relied on Muniyan to show that MUC16 expression is measured in PDAC and is clinically relevant to PDAC biology and outcome-related phenotypes. That teaching remains intact. Whether Muniyan’s direction for standalone MUC16 matches the claim’s direction inside a diversity signature goes to motivation and expectation of success for the pattern, not to whether MUC16 is an obvious PDAC analyte to measure. Measuring a known PDAC-associated gene in cells already being profiled is the predictable use of a known technique. Furthermore, the combination teachings is not required to show Applicant’s biological theory. Obviousness does not require the prior art to explain the invention in the applicant’s terms (here, “decreased MUC16 indicates high microbial diversity”). Allen-Vercoe teaches detecting a recited oncomicrobe (Fusobacterium) and using that detection to diagnose/prognose GI cancer and to treat. Muniyan and Schmieder teach measuring MUC16 and IL1RL1 in PDAC in connection with aggressive disease. One of ordinary skill in the art already profiling microbes and host transcripts in tumor-derived cells would have combined those readouts to refine diagnosis and prognosis, with a reasonable expectation of obtaining some clinically usable pattern. The precise signs Applicant later assigned to each gene are the product of routine correlation on datasets of the type already in the art (PDAC transcriptomes; tumor microbiome surveys). Unexpected results, if any, must be shown with evidence commensurate with the claim—not by pointing out that one reference’s knockdown phenotype points the other way for one optional gene. Applicant’s statement that Schmieder and Riquelme “do not concern MUC16” is correct and irrelevant. They were not cited to teach MUC16. Schmieder teaches IL1RL1/ST2 in PDAC cells. Riquelme (as used in the action) teaches intra-pancreatic taxa and survival associations. Each reference is cited for what it actually contains. The test is what the combination would have suggested, not whether every secondary reference repeats every limitation. MPEP 2145(IV). The examiner takes the position that reasonable expectation of success is not defeated by a conflicting standalone correlation.Reasonable expectation of success is measured against the claimed process succeeding in its claimed result (classifying and treating), not against Muniyan’s xenograft result. Detecting Fusobacterium (Allen-Vercoe), measuring PDAC-associated host genes in pancreatic cells (Muniyan; Schmieder), and administering specific therapy if cancer is called, are each conventional. Combining diagnostic assays already used in the same disease is predictable. One of ordinary skill in the art would have expected the combined assay to classify patients; the fact that one gene’s mechanistic literature points opposite to one optional clause of a multi-gene rule does not establish unpredictability of the method as a whole. Based on the above reasons the examiner concludes that Muniyan’s teaching that MUC16 promotes PDAC metastasis does not criticize or discourage measuring MUC16 (or LYPD2) as part of a multi-gene, microbe-linked survival classifier. It does not teach away. Applicants have not shown that any limitation of amended claim 1 is absent from the combination, and has not shown a lack of reasonable expectation of success in performing the recited sequencing, measuring, classifying, and treating steps. Therefore, the rejections under 35 USC 103 are still applicable.
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.
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/TIGABU KASSA/Primary Examiner, Art Unit 1619
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