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 .
Status of claims
Applicant’s response field on 05/29/2025 have been entered. Claims 1, 3, 12, and 15 are amended. Claims 21-24 are newly added. Claims 2, 9-11, 13-14 and 16-20 are cancelled. Claims 1, 3-8, 12, 15 and 21-24 are pending and currently under examination.
Priority
This application 17/653,114 claims priority to U.S. Provisional Application Ser. No. 63/155,156 filed on 03/01/2021.
Summary of this Final Office Action
Previous rejection of claims 1-15 and 20 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (preAIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn in view of claim amendments filed on 05/29/2025.
Previous rejection of claim 18 under 35 U.S.C. 112(d) or pre-AlA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends, is moot in view of cancellation of claim 18 in claim amendments filed on 05/29/2025.
Previous rejection of claims 1-10 and 13 under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea, a law of nature and a natural phenomenon without significantly more, is withdrawn in view of claim amendments filed on 05/29/2025.
Previous rejection of claim(s) 1-3 under 35 U.S.C.102(a) as being anticipated by Ferreira et al. (Cell Reports 21, 966-978, 2017) is withdrawn in view of claim amendments filed on 05/29/2025.
Previous rejection of claim(s) 1-5 under 35 U.S.C. 102(a) as being anticipated by Peng et al. (Cell research, 29, 725-738, 2019) is withdrawn in view of claim amendments filed on 05/29/2025.
Previous rejection of Claim(s) 16 and 17 under 35 U.S.C. 102(a) as being anticipated by Shalek (US 2022/0396777 Al) is withdrawn in view of claim amendments filed on 05/29/2025.
Previous rejection of claim(s) 1 - 7, 9, 16-18 and 20 under 35 U.S.C. 102(a) as being
anticipated by Zarei 2019 (Diss. University of British Columbia, 2020) is withdrawn in view of claim amendments filed on 05/29/2025.
Previous rejection of claim(s) 6-10 and 13 under 35 U.S.C. 103 as being unpatentable over Peng (Cell research, 29, 725-738, 2019) in view of Shalek (US 2022/0396777 Al) and further in view of Crawford (Cell Mol Gastroenterol Hepatol., 8(4), 645-646, 2019) is withdrawn in view of claim amendments filed on 05/29/2025.
Previous rejection of claim(s) 11 and 12 under 35 U.S.C. 103 as being unpatentable over Peng in view of Shalek and Crawford as applied to claims 1, 9 and 10 above, and further in view of Yan et al. (bioRxiv 2021.01 .09.425923) is withdrawn in view of claim amendments filed on 05/29/2025.
Previous rejection of claims 14 and 15 under 35 U.S.C. 103 as being unpatentable over Peng in view of Shalek and Crawford as applied to claims 1, 9, 10 and 13 above, and further in view of Mazur et al. (Nature Medicine volume 21, pages 11 63-1171, 2015) and Yap et al. (Cancer Discov 2020;10:1528-43) is withdrawn in view of claim amendments filed on 05/29/2025.
Previous rejection of claim 19 under 35 U.S.C. 103 as being unpatentable over Zarei in view of Cunningham ((Diss. University of Glasgow, 2020) is withdrawn in view of claim amendments filed on 05/29/2025.
Claim Objections
Claim 12 is objected to because of the following informalities: “TDZD-8 and 2-DG” should be recited as chemical name and/or spelt out the abbreviarions. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3-8, 12, 15 and 21-24 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
This reject ion is necessitated by claim amendments filed on field on 05/29/2025.
(i) Claim 1 recites the limitations “the tumor is of acinar cell origin” and “the tumor is of ductal origin” in the two wherein clauses, lines 9-14 of amended claim 1. It is unclear what assays, criteria, references, and thresholds are utilized to determine the cell origin of a given pancreatic ductal adenocarcinoma (PDAC) being acinar cell origin or ductal cell origin. In this regard, instant specification discloses that “In additional embodiments, the method may
include one or more of the following: the cell origin is elected from an acinar cell-derived tumor and a ductal cell-derived tumor (See [0007] of specification filed on 03/01/2022), and that “In further embodiments, the method may include one or more of the following: the cells in the culture of cancer cells are derived from PDAC tumor; the cells in the culture of cancer cells are derived from an acinar cell-derived tumor or a ductal cell-derived tumor; determining a response to the treatment comprises performing a cell viability assay selected from manual cell counting, flow cytometry, or performing a methyltransferase assay; the method further includes transcriptionally profiling the culture of cancer cells to identify the cell of origin of the cells (See [0009] of specification filed on 03/01/2022). Instant specification also discloses in Example 5 that “Acinar cell-derived and ductal cell-derived tumor signatures were defined based on the highest confidence differentially-expressed mouse genes, using a log fold change > 1.5 and p-adjusted value <0.01. We thus identified 640 genes as differentially-expressed between
acinar cell-derived and ductal cell-derived tumors, 573 of which had human orthologs (FIG. 2A). Of these, 496 genes were more highly expressed in acinar cell-derived tumors in than ductal cell-derived tumors and 77 genes were more in highly expressed ductal cell-derived tumors than in acinar cell-derived tumors (See [0065] of specification filed on 03/01/2022). The relationship between the limitation “the tumor is of acinar cell origin” / “the tumor is of ductal cell origin” recited in claim 1 and the phrase “acinar cell-derived” / “ductal cell-derived” disclosed in the specification is unclear. It is noted that the scope of claim 1 is not limited to mouse, and how the disclosed “differentially-expressed mouse genes” in Example 5 could be directly applied, or applied with undisclosed modifications, to various mammals in terms of determination of pancreatic ductal adenocarcinoma (PDAC) subtype being “the tumor is of acinar cell origin” or “the tumor is of ductal origin” based on “transcript expression data derived from a tumor from an individual affected with PDAC” recited in instant claim 1 are unclear.
Claims 3-8, 12, 15 and 21-24 depend from claim 1.
(ii) Claims 21-23 recites “the genes listed in Table 1", it is unclear what scope “the genes listed in Table 1” encompasses as the claim should be complete and clear by limitations recited in the claims without referring to any tables or drawings disclosed in the specification. See MPEP § 2173.05(s).
Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).
Instant specification discloses that “In FIG. 2A, gene enrichment profiles of human genes for acinar and ductal cell derived tumors are illustrated. Table 1 further lists genes associated with acinar and ductal cell derived tumors” (See [0029] of specification filed on 03/01/2022). The Table disclosed on pages 32-41 is Table 1 based on the amendments of the specification filed on 05/29/2025. The genes listed in Table 1 include, for instance, HNF4F being “Acinar cell-derived” and GATA3 being “Ductal cell-derived”. The specification appears to loosely equate the phrase “Acinar cell-derived” disclosed in the specification to “the tumor is of acinar cell origin” recited in amended claim 1 based on certain undefined thresholds for determination of genes being “associated with” acinar or ductal cell derived tumors.
Improper Markush Grouping Rejection
Claims 21-23 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
Claims 21-23 recite the following Markush group: “the genes listed in Table 1”.
This Markush grouping is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
MPEP 2117(II) states that “A Markush claim may be rejected under judicially approved “improper Markush grouping” principles when the claim contains an improper grouping of alternatively useable members. A Markush claim contains an “improper Markush grouping” if either: (1) the members of the Markush group do not share a “single structural similarity” or (2) the members do not share a common use. Supplementary Guidelines at 7166 (citing In re Harnisch, 631 F.2d 716, 721-22, 206 USPQ 300, 305 (CCPA 1980)).
MPEP 2117(II) further state that alternatives (1) share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class and (2) share a common function or use when they are disclosed in the specification or known in the art to be functionally equivalent in the context of the claimed invention.
MPEP § 2117(II)(A) states that “A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved”. Herein the members of the Markush grouping are all gene/proteins. These do not belong to the same recognized physical or chemical class or to the same art-recognized class because there is no expectation from the art that each of the recited genes/proteins would function in the same way in the claimed method. It is only in the context of this specification that it was disclosed that all members of this group may behave in the same way in the context of the claimed invention.
MPEP § 2117(II)(B) states that “Where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as explained in subsection IIA above, the members of the Markush grouping may still be considered to be proper where the alternatives share a substantial structure feature that is essential to a common use. Again, the members of the Markush grouping are all gene/proteins. While they are all made up of nucleic acids or amino acids, the structure of comprising nucleic acids or amino acids is not essential to any asserted common use.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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.
Claims 1, 3-8, and 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over Bailey et al. (2016) (Bailey et al., Genomic analyses identify molecular subtypes of pancreatic cancer, Nature 2016 Mar 3;531(7592):47-52. doi: 10.1038/nature16965. Epub 2016 Feb 24) in view of Brunton et al. (2020) (Brunton et al., HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer, Cell Rep., 2020 May 12;31(6):107625. doi: 10.1016/j.celrep. 2020.107625).
This reject ion is necessitated by claim amendments filed on field on 05/29/2025.
Regarding claims 1, 3-5, and 21-23, Bailey et al. (2016) teaches “Genomic analyses identify molecular subtypes of pancreatic cancer (See title), and that “Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signaling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumors are enriched for TP53 and KDM6A mutations, upregulation of the TP63ΔN transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumors preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumors displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumors contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development (See Abstract, page 47).
Furthermore, Bailey et al. (2016) teaches more details that “We used bulk tumor tissue to better understand the transcriptional networks and molecular mechanisms that underpin the tumor microenvironment. Initial unsupervised clustering of RNA-seq data for 96 tumors with high epithelial content (≥40%) to balance stromal gene expression resolved four stable classes (Fig. 1a and Extended Data Fig. 3). These four subtypes were also present in the extended set of 232 PCs using array-based mRNA expression profiles encompassing the full range of tumor cellularity (from 12–100%) (Extended Data Fig. 4). We named these subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) on the basis of the differential expression of transcription factors and downstream targets important in lineage specification and differentiation during pancreas development and regeneration. Transcriptional network analysis identified 26 coordinately expressed gene programs representing distinct biological processes, 10 of which discriminated the 4 PC classes (Fig. 1b, Extended Data Fig. 5 and Supplementary Tables 14–16). These 4 subtypes were associated with specific histological characteristics: (1) squamous with adeno-squamous carcinomas (6/25 in squamous versus 1/71 in the rest, P = 0.0011 Fisher’s exact test); (2) pancreatic progenitor and (3) immunogenic with mucinous non-cystic (colloid) adenocarcinomas and carcinomas arising from IPMN, which are mucinous (P = 0.0005); and (4) ADEX with rare acinar cell carcinomas (although numbers were small, both cases clustered with the ADEX class) (Fig. 1a). Squamous subtype was an independent poor prognostic factor (Fig. 1c and Supplementary Table 21). (See right column of page 48, under “Transcriptional networks and subtypes of PC”).
Regarding the limitation “wherein when the molecular signature enrichment score indicates that the tumor is of acinar cell origin, treating the individual comprises inhibiting AKT kinase” recited in instant claim 1, Bailey et al. (2016) teaches that “Extended Data Figure 6 | Core gene programs (GP) defining the squamous class. Each panel shows from left to right: (i) a heatmap representing the genes in the specified gene program most correlated with the indicated PC class with tumors ranked according to their gene program module eigengene values (MEs) (PC classes are designated by color as follows: ADEX (brown); pancreatic progenitor (orange); immunogenic (red); and squamous (blue)); (ii) Kaplan–Meier analysis comparing survival of patients having either high or low gene program MEs; (iii) pathways significantly enriched in a given GP functional interaction (FI) sub-network defined by the ReactomeFI Cytoscape plugin. P values represent FDR < 0.05”; and that Pl3K-Akt signaling pathway is significantly enriched in GP 2 and GP3.
Regarding the limitation “wherein when the molecular signature enrichment score indicates that the tumor is of ductal cell origin, treating the individual comprises targeting the
glycolysis pathway” recited in claim 1, Bailey et al. (2016) teaches “Study participants were recruited and consent for genomic sequencing obtained through the Australian Pancreatic Cancer Genome Initiative (APGI; http://www.pancreaticcancer.net.au) as part of the International Cancer Genome Consortium (ICGC; http://www.icgc.org). The 382 APGI group consisted of participants with primarily treatment-naïve resected PC, which were pancreatic ductal adenocarcinoma (PDAC) and its variants (adenosquamous, colloid, PDAC associated with intraductal papillary mucinous neoplasm (IPMN)) and a small number of rare acinar cell carcinomas (Supplementary Table 1) (See left column of page 48, under “Mutational landscape of PC”).
Bailey et al. (2016) does not explicitly teach (i) the limitation “treating the individual comprises targeting the glycolysis pathway” recited in lines 13-14 of claim 1, and (ii) the limitation “treatment response recited in claims 6-8.
(i) Regarding the limitation “wherein when the molecular signature enrichment score indicates that the tumor is of ductal cell origin, treating the individual comprises targeting the glycolysis pathway” recited in claim 1, Brunton et al. (2020) teaches “HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer” (See Title), and “GSK3b targeting inhibits glycolysis in squamous patient derived cell lines (PDCLs)” (See Highlights). Brunton et al. (2020) further teaches that “Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3b) a key regulator of glycolysis. Pharmacological inhibition of GSK3b results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3b inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC (See Summary).
(ii) Regarding limitation “treatment response” recited in claims 6-8, Brunton et al. (2020) teaches that “we used a set of 48 early-passage PDAC patient-derived cell lines (PDCLs) that provide an isogenic and experimentally tractable system for developing and validating subtype-dependent therapeutic vulnerabilities. We show that PDCLs recapitulate major metabolic transcriptional profiles observed in bulk PDAC tissue, and that plasticity exists between PDAC subtypes. Specifically, HNF4A and GATA6 loss in a classical (progenitor) background can drive a switch toward squamous-associated metabolic reprograming events and identify GSK3b as a driver of glycolysis. Pharmacological inhibition of GSK3b showed selective sensitivity in the squamous subtype; however, a subset of these squamous PDCLs acquire rapid drug tolerance. Using assay for transposase- accessible chromatin sequencing (ATAC-seq) analysis, we show that the squamous subtype separates into two distinct chromatin subgroups with unique chromatin accessibility and promoter usage. We demonstrate that the drug-tolerant squamous subgroup has access to an amplified WNT signaling program via application of both intronic and distal promoter usage. Using both transcriptomic and chromatin landscape profiles, we provide a model system to predict PDAC responders and non-responders to subtype-specific therapeutic vulnerabilities (See right column, page 2).
It would have been prima facia obvious for a skilled artisan to incorporate the teachings of Brunton et al. (2020) into the teachings of Bailey et al. (2016) with reasonable expectation of success because the teachings of Brunton et al. (2020) focus on “Genomic analyses identify molecular subtypes of pancreatic cancer” whereas teachings of Bailey et al. (2016) clearly indicates that “Comparative analysis of bulk tumor and PDCL transcriptomes demonstrated that PDCLs faithfully recapitulate the two broad PDAC transcriptomic subtypes observed in bulk tumor samples” (See right column, page 2) and that “GSK3b targeting inhibits glycolysis in squamous patient derived cell lines (PDCLs)” (See Highlights).
A skilled artisan would have been motivated to incorporate the teachings of Brunton et al. (2020) into the teachings of Bailey et al. (2016) because the patients with pancreatic cancer subtypes identified by Brunton et al. (2020) via genomic analyses of gene expression can clearly benefit from the teachings of Brunton et al. (2020) pertaining to HNF4A and GATA6 loss reveals therapeutically actionable subtypes in pancreatic cancer, and the combined teachings of Brunton et al. (2020) and Bailey et al. (2016) readily reach the claimed methods of instant application for the identification and the treatment of pancreatic cancer subtypes.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Bailey et al. (2016) (Bailey et al., Genomic analyses identify molecular subtypes of pancreatic cancer, Nature 2016 Mar 3;531(7592):47-52. doi: 10.1038/nature16965. Epub 2016 Feb 24) in view of Brunton et al. (2020) (Brunton et al., HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer, Cell Rep., 2020 May 12;31(6):107625. doi: 10.1016/j.celrep. 2020.107625) as applied to claims 1, 3-8, and 21-23 above, and further in view of Grandjean et al. (2016) (Grandjean et al., Definition of a Novel Feed-Forward Mechanism for Glycolysis-HIF1α Signaling in Hypoxic Tumors Highlights Aldolase A as a Therapeutic Target, Cancer Res., 2016 Jul 15;76(14):4259-4269. doi: 10.1158/0008-5472.CAN-16-0401. Epub 2016 Jun 3).
The teachings of Bailey et al. (2016) and Brunton et al. (2020) have been documented above in the rejection of Claims 1, 3-8, and 21-23 under 35 U.S.C. 103 as being unpatentable over Bailey et al. (2016) in view of Brunton et al. (2020).
The combined teachings of Bailey et al. (2016) and Brunton et al. (2020) do not explicitly teach the limitation “targeting the glycolysis pathway comprising administering at least one of TDZD-8 and 2-DG to the individual affected with PDAC” recited in claim 12.
Grandjean et al. (2016) teaches that “The hypoxia-inducible transcription factor HIF1a drives expression of many glycolytic enzymes. Here, we show that hypoxic glycolysis, in turn, increases HIF1a transcriptional activity and stimulates tumor growth, revealing a novel feed-forward mechanism of glycolysis-HIF1a signaling. Negative regulation of HIF1a by AMPK1 is bypassed in hypoxic cells, due to ATP elevation by increased glycolysis, thereby preventing phosphorylation and inactivation of the HIF1a transcriptional coactivator p300. Notably, of the HIF1a-activated glycolytic enzymes we evaluated by gene silencing, aldolase A (ALDOA) blockade produced the most robust decrease in glycolysis, HIF-1 activity, and cancer cell proliferation. Furthermore, either RNAi-mediated silencing of ALDOA or systemic treatment with a specific small molecule inhibitor of aldolase A was sufficient to increase overall
survival in a xenograft model of metastatic breast cancer. In establishing a novel glycolysis–HIF-1a feed-forward mechanism in hypoxic tumor cells, our results also provide a preclinical
rationale to develop aldolase A inhibitors as a generalized strategy to treat intractable hypoxic cancer cells found widely in most solid (See Abstract). Grandjean et al. (2016) further teaches the chemical structure of
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, and TDZD-8 or 2-deoxyglucose (2-DG) are ALDOA inhibitor with antitumor activity (See Fig. 5 on page 4266 and Fig. 6 on page 4267)
It would have been prima facia obvious for a skilled artisan to incorporate the teachings of Grandjean et al. (2016) into the combined teachings of Brunton et al. (2020) and Bailey et al. (2016) with reasonable expectation of success because the Grandjean et al. (2016) clearly demonstrate antitumor activity of TDZD-8 or 2-deoxyglucose (2-DG) as ALDOA inhibitor in glycolysis pathway.
A skilled artisan would have been motivated to incorporate the teachings of Grandjean et al. (2016) into the combined teachings of Brunton et al. (2020) and Bailey et al. (2016) because Grandjean et al. (2016) explicitly teaches that “In summary, we have shown that a feed-forward loop in tumors, simultaneously promoting increased HIF-1 activity and increased glycolysis, offers a target, ALDOA, with which to block tumor energy/metabolite production pathways and the HIF-1a survival response. Our HIF-1 activity-oriented RNAi screen and subsequent mechanism-based analysis expand our understanding of known and novel regulators of the HIF-1 transcription factor, and point to a previously uncharacterized regulation of HIF-1 activity by increased glycolytic enzyme activity (See right column, page 4268).
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Bailey et al. (2016) (Bailey et al., Genomic analyses identify molecular subtypes of pancreatic cancer, Nature 2016 Mar 3;531(7592):47-52. doi: 10.1038/nature16965. Epub 2016 Feb 24) in view of Brunton et al. (2020) (Brunton et al., HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer, Cell Rep., 2020 May 12;31(6):107625. doi: 10.1016/j.celrep. 2020.107625) as applied to claims 1, 3-8, and 21-23 above, and further in view of Maynard et al. (2013) (Maynard et al., 2-Deoxy-2-[18F] fluoro-D-glucose positron emission tomography demonstrates target inhibition with the potential to predict anti-tumor activity following treatment with the AKT inhibitor AZD5363, Mol Imaging Biol., 2013 Aug;15(4):476-85.doi: 10.1007/s11307-013-0613-3) and Jones et al. (2020) (Jones et al., Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, estrogen receptor-positive breast cancer (FAKTION): a multicenter, randomized, controlled, phase 2 trial, Lancet Oncol., 2020 Mar;21(3):345-357. doi: 10.1016/S1470-2045(19)30817-4. Epub 2020 Feb 5).
The teachings of Bailey et al. (2016) and Brunton et al. (2020) have been documented above in the rejection of Claims 1, 3-8, and 21-23 under 35 U.S.C. 103 as being unpatentable over Bailey et al. (2016) in view of Brunton et al. (2020).
The combined teachings of Bailey et al. (2016) and Brunton et al. (2020) do not explicitly teach the limitation “wherein inhibiting AKT kinase comprises administering Capivasertib to the individual affected with PDAC” recited in claim 15.
Maynard et al. (2013) teaches that “The phosphatidyl inositol 3 kinase, AKT and mammalian target of rapamycin are frequently deregulated in human cancer and are among one of the most promising targets for cancer therapy. AZD5363 (AstraZeneca) is an AKT inhibitor in phase 1 clinical trials” and “Multiple doses of AZD5363 showed an anti-tumor volume effect and a reduction in 18F-FDG uptake (28 % reduction compared to vehicle), highlighting the potential of 18F-FDG PET as an efficacy biomarker” (See Abstract). Maynard et al. (2013) further teaches that “Levels of pGSK3b were 61% lower in the AZD5363-treated group
compared to vehicle (p=0.005), and levels of pPRAS40 were 63 .6 % lower in the AZD5363-treated group compared to vehicle (p=0.0006)” (See right column page 481).
Additionally, Jones et al. (2020) teaches that “Capivasertib (AZD5363) is a potent selective oral inhibitor of all three isoforms of the serine/threonine kinase AKT”.
It would have been prima facia obvious for a skilled artisan to incorporate the teachings of Maynard et al. (2013) and Jones et al. (2020) into the combined teachings of Brunton et al. (2020) and Bailey et al. (2016) with reasonable expectation of success because Maynard et al. (2013) explicitly teaches “AZD5363 (AstraZeneca), a potent inhibitor of AKT with a pharmacological profile consistent with its mechanism of action in vitro and in vivo. Its primary pharmacology has recently been described, and it is currently in phase 1 clinical trials (See left column page 477), whereas Jones et al. (2020) explicitly teaches AZD5363 taught by Maynard et al. (2013) is Capivasertib recited in instant claim 15.
A skilled artisan would have been motivated to incorporate the teachings Maynard et al. (2013) and Jones et al. (2020) into the combined teachings of Brunton et al. (2020) and Bailey et al. (2016) because (i) Maynard et al. (2013) teaches that “Levels of pGSK3b were 61% lower in the AZD5363-treated group compared to vehicle (p=0.005), and levels of pPRAS40 were 63 .6 % lower in the AZD5363-treated group compared to vehicle (p=0.0006)” (See right column page 481), and (ii) Brunton et al. (2020) teaches “HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer” (See Title), and “GSK3b targeting inhibits glycolysis in squamous patient derived cell lines (PDCLs)” (See Highlights).
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Bailey et al. (2016) (Bailey et al., Genomic analyses identify molecular subtypes of pancreatic cancer, Nature 2016 Mar 3;531(7592):47-52. doi: 10.1038/nature16965. Epub 2016 Feb 24) in view of Brunton et al. (2020) (Brunton et al., HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer, Cell Rep., 2020 May 12;31(6):107625. doi: 10.1016/j.celrep. 2020.107625) as applied to claims 1, 3-8, and 21-23 above, and further in view of Wöll et al. (2014) (Wöll et al., Claudin 18.2 is a target for IMAB362 antibody in pancreatic neoplasms, Int J Cancer, 2014 Feb 1;134(3):731-9. doi: 10.1002/ijc.28400. Epub 2013 Sep 16).
The teachings of Bailey et al. (2016) and Brunton et al. (2020) have been documented above in the rejection of Claims 1, 3-8, and 21-23 under 35 U.S.C. 103 as being unpatentable over Bailey et al. (2016) in view of Brunton et al. (2020).
The combined teachings of Bailey et al. (2016) and Brunton et al. (2020) do not explicitly teach the limitation “targeting the glycolysis pathway comprising administering at least one of TDZD-8 and 2-DG to the individual affected with PDAC” recited in claim 12.
Wöll et al. (2014) teaches that “The majority of pancreatic neoplasms are characterized by a generally lethal progress within a short period of time after primary diagnosis and the mortality of patients is expected to increase further. Due to lack of efficient screening programs and moderate response to treatments, novel compounds for treatment are needed. We investigated the CLDN18.2 expression in affected patients as in vitro feasibility study for a potential treatment with the novel antibody IMAB362. Therefore, we analyzed the expression of CLDN18.2 in normal pancreatic tissues (N = 24), primary lesions (N = 202), metastases (N = 84) and intra-individually matched samples (N = 48) of patients with pancreatic ductal adenocarcinoma (PDAC), neuroendocrine neoplasia (NEN) and acinar cell carcinoma. A standardized method for evaluation by immunohistochemistry was developed. The specific staining was evaluated by two independent raters and analysis of staining intensities (range 0-3+) and relative proportions of tumor cells were performed. One hundred three (59.2%) samples of primary PDAC were found positive. The vast majority of positive samples were characterized to highly express CLDN18.2: 54.6% (N = 95) with staining intensities of ≥ 2+. NEN were positive in 20% of cases (all ≥ 2+). Metastases of pancreatic neoplasms were also frequently found positive with comparable high rates (69.4% of lymph node and 65.7% of liver metastases). The rate of CLDN18.2 positivity is high in pancreatic neoplasms whereby the expression is not limited to the primaries but is also maintained upon metastasis. Thus, a considerable number of patients with pancreatic neoplasms would be in principle eligible for a CLDN18.2-targeting approach” (See Abstract).
It would have been prima facia obvious for a skilled artisan to incorporate the teachings of Wöll et al. (2014) into the combined teachings of Brunton et al. (2020) and Bailey et al. (2016) with reasonable expectation of success because the Wöll et al. (2014) clearly demonstrate that “The rate of CLDN18.2 positivity is high in pancreatic neoplasms whereby the expression is not limited to the primaries but is also maintained upon metastasis” (See Abstract).
A skilled artisan would have been motivated to incorporate the teachings of Wöll et al. (2014) into the combined teachings of Brunton et al. (2020) and Bailey et al. (2016) because
the patents with pancreatic cancer subtypes identified by Brunton et al. (2020) via genomic analyses of gene expression can be readily supplemented with the well-developed immune-histochemistry assay for increased accuracy using antibody IMAB362 to detect the expression level of Claudin 18.2 in pancreatic neoplasm samples.
Conclusion
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).
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/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682