CTFR 18/021,625 CTFR 82354 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Claim Status and Formal Matters This action is in response to papers filed 4/6/2026. Claims 1-3, 6, 15-16, 18, 22, 26-27, 29,41-44, 55-56, 59, 62 have been amended. Claims 65-68 have been added by amendment. Claims 1-3, 6, 15-16, 18, 20, 22, 26-29, 35, 37, 41-44, 55—56, 58-60, 62-68 are pending. Applicant's election with traverse of group 1 in the reply filed on 9/29/2025 is acknowledged. The traversal is on the ground(s) that the response asserts the prior art does not teach the programs, signatures or both. This is not found persuasive because group 4 has been rejoined and groups 2 and 3 do not require such limitations. 08-25-01 AIA Applicant’s election without traverse of 1. a malignant cell signature; 2. a squamous program; 3. adhesive, secretory, and neurotropic CAF expression programs; 4. a squamoid-basaloid neighborhood; 5. an Epithelial compartment - CAF compartment pair; 6. a squamous program; 7. Table 2.6; 8. Table 2.4; 9. Table 2.5; 10. matrisomal and classical progenitor malignant program; 11. the single-nucleus RNA sequencing; and 12. the genes of Tables 2.1-2.6 . in the reply filed on 9/29/2025 is acknowledged. 08-05 AIA Claim s 27-29, 35, 37 withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention , there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 9/29/2025 . Claims 1-3, 6, 15-16, 18, 20, 22, 26, 41-44, 55-56, 58-60, 62-68 are being examined. The objection to drawings has been withdrawn in view of the amendment to the specification to no longer reference color in the drawings. The objection to the specification has been withdrawn in view of the amendments to the claims and specification. The objection to the claims has been withdrawn in view of the amendments to the claims . Priority The instant application was filed 07/26/2023 and is a continuation of PCT/US2022/015113 which was filed 02/03/2022 and claims priority from provisional application 63145902 which was filed 02/04/2021. Information Disclosure Statement 06-49-06 AIA The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered. It is noted the examiner has not compared IDS to those in the specification. Claim Objections 07-29-01 AIA Claim s 41-44, 55-56, 58-60, 62-64, 67-68 are objected to because of the following informalities: Claim 41 is objected to as it recites “PDAC, “ “BCL-2,” CXCR4,” “HER2,” “TGFbeta.”” but does not recite the full terminology for the acronym (or abbreviation). Claims are more concise when the first time an acronym (or abbreviation) is presented the full terminology is also presented. Finally an acronym (or abbreviation) may have alternative meanings to an artisan . Appropriate correction is required. Response to Arguments This is a new ground of objection. Claim Rejections - 35 USC § 112 07-30-01 AIA The following is a quotation of the first paragraph of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. 07-31-01 Claims 1-3, 6, 15-16, 18, 20, 22, 26, 41-44, 55-56, 58-60, 62-68 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. New Matter MPEP 2163 IB New or amended claims section II With respect to newly added or amended claims, applicant should show support in the original disclosure for the new or amended claims. See, e.g., Hyatt v. Dudas, 492 F.3d 1365, 1370, n.4 (Fed. Cir. 2007) (citing MPEP § 2163.04 which provides that a "simple statement such as ‘applicant has not pointed out where the new (or amended) claim is supported, nor does there appear to be a written description of the claim limitation ‘___’ in the application as filed’ may be sufficient where the claim is a new or amended claim, the support for the limitation is not apparent, and applicant has not pointed out where the limitation is supported."); see also MPEP §§ 714.02 and 2163.06 ("Applicant should ... specifically point out the support for any amendments made to the disclosure."); and MPEP § 2163.04 Claim 1 on 4/6/2026 was been amended to recite, “ wherein the highly expressed programs have an expression greater than the mean expression of a reference cohort” . The response does not provide an indication of where the amendment is supported. The specification states, “0668] For the malignant only analysis, each tumor for the five untreated malignant lineage cNMF programs (normalized by z-scores) were scored, and identified the top scoring program (primary program) as well as the number of highly-expressed programs defined as expression greater than the mean of the cohort (heterogeneity score, H).” Thus the specification does not provide support for the full scope of the claim as amended. Claim 18 has been amended to recite, “primary mesenchymal matrisomal.” The response does not specifically teach where support for the amendment can be found. Searching and review of the specification did not reveal antecedent basis for the claim. Written Description As set forth in In re Alonso 88 USPQ2d 1849 (Fed. Cir. 2008), at 1851: The written description requirement of 35 U.S.C. § 112, ¶ 1, is straightforward: “The specification shall contain a written description of the invention ….” To satisfy this requirement, the specification must describe the invention in sufficient detail so “that one skilled in the art can clearly conclude that the inventor invented the claimed invention as of the filing date sought.” Lockwood v. Am. Airlines, Inc. , 107 F.3d 1565, 1572 [41 USPQ2d 1961] (Fed. Cir. 1997); see also LizardTech, Inc. v. Earth Res. Mapping, Inc ., 424 F.3d 1336, 1345 [76 USPQ2d 1724] (Fed. Cir. 2005); Eiselstein v. Frank , 52 F.3d 1035, 1039 [34 USPQ2d 1467] (Fed. Cir. 1995). Alonso at 1852: A genus can be described by disclosing: (1) a representative number of species in that genus; or (2) its “relevant identifying characteristics,” such as “complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.” Enzo , 323 F.3d at 964. Claim 1 on 4/6/2026 was been amended to recite, “A method of stratifying pancreatic ductal adenocarcinoma (PDAC) patients into treatment groups and/or prognosing PDAC or treatment outcome and/or survival in a human patient comprising:(i) performing single-cell or single-nucleus RNA sequencing to obtain gene expression levels of one or more PDAC tumor cells from a PDAC tumor, and identifying from the gene expression levels a plurality of programs in the one or more PDAC tumor cells, including (a}a malignant cell program; and b}a cancer-associated fibroblast (CAF) program ; (ii) generating a tumor heterogeneity score for the PDAC tumor, wherein the tumor heterogeneity score is calculated by determining a number of highly expressed programs of the plurality of programs , in the one or more PDAC cells, wherein the highly expressed programs have an expression greater than the mean expression of a reference cohort, and wherei n the tumor heterogeneity score is used to assign the PDAC tumor to a risk group for prognosing treatment outcome and/or survival.. Claim 41 has been amended to recite, “A method of treating a subject having PDAC, the method comprising: (i) performing single-cell or single-nucleus RNA sequencing to obtain gene expression levels in one or more PDAC tumor cells, and identifying from the gene expression levels a plurality of programs in the one or more PDAC tumor cells, including (a ) a malignant cell program , a cancer-associated fibroblast (CAF) , program ,; (ii) generating a tumor heterogeneity score for the PDAC tumor, wherein the tumor heterogeneity score is calculated by determining a number of highly expressed programs , of the plurality of programs , in the one or more PDAC cells, and administering or applying a PDAC treatment to the human subject , wherein the PDAC treatment is selected based on the tumor heterogeneity score, wherein the treatment is a tumor resection, a chemotherapy, a radiation therapy, a neoadjuvant, a malignant cell signature and/or program modulating agent, a BCL-2 inhibitor, a tyrosine kinase inhibitor, a TGFbeta modulator, a myeloid cell agonist, a CXCR4 inhibitor, a HER2 inhibitor, or any combination thereof.. Claim 1 has been limited to human subjects. However, claim 41 encompass cells or nucleic from any subject of any species that can be encompassed by a PDAC tumor. The specification teaches, “[0122] The terms “subject,” “individual,” and “patient” are used interchangeably herein to refer to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets. Tissues, cells and their progeny of a biological entity obtained in vivo or cultured in vitro are also encompassed.” Burgin (Journal of Mammalogy, 99(1):1–14, 2018) teaches, “We found 6,495 species of currently recognized mammals.” Thus the claims encompass an enormous genus. The teachings of the specification are limited to a single species human PDAC samples. The claims encompass any that can broadly be viewed to encompass . a malignant cell program,; b. a cancer-associated fibroblast (CAF) program, or both; c. The specification does not provide a limiting definition of these signatures, programs or states. The specification merely provides lists of genes in Markus groups of what can be encompassed. Benner et al (Trends in Genetics (2001) volume 17, pages 414-418) teaches that, “Here, the ‘homology-implies-equivalency’ assumption is restricted to a subset of homologs that diverged in the most-recent common ancestor of the species sharing the homologs. This strategy is useful, of course. But it is likely to be far less general than is widely thought. Two species living in the same space, almost by axiom, cannot have identical strategies for survival. This, in turn, implies that two orthologous proteins might not contribute to fitness in exactly the same way in two species” (see page 414, 3 rd column last full paragraph). Benner specifically describes that although the leptin gene homologs have been found in mice and humans, their affect is different (see page 414, 3 rd column last paragraph-3 rd column page 415). Benner specifically teaches that the leptin gene in mice plays a major role in obesity, but no such effect has been demonstrated in humans due perhaps to the different evolutionary forces. Benner thus teaches that the activity and function of genes in different species is unpredictable. Modrek (Nucleic Acid Research (2001) volume 29, pages 2850-2859) teaches they assayed more than 2.1 million mRNA and EST transcripts. This is an enormous genus which encompass any gene expression pattern which is enormous genus. The claims encompass anything which can be considered generating a tumor heterogeneity score by any means. The only teachings of the specification with respect to a tumor heterogeneity score are, “0050] In certain example embodiments, the method further comprises determining a tumor heterogeneity score for the PDAC tumor, wherein the tumor heterogeneity score is calculated by determining a number of highly expressed programs in the one or more PDAC cells.” Thus this is an enormous genus. Further claim 41 requires, “ wherein the PDAC treatment is selected based on the tumor heterogeneity score, wherein the treatment is a tumor resection, a chemotherapy, a radiation therapy, a neoadjuvant, a malignant cell signature and/or program modulating agent, a BCL-2 inhibitor, a tyrosine kinase inhibitor, a TGFbeta modulator, a myeloid cell agonist, a CXCR4 inhibitor, a HER2 inhibitor, or any combination thereof.” Review and searching of the specification did not reveal any specific guidance on how the tumor heterogeneity score is used for determining PDAC treatment. Thus while the claims encompass a genus of PDAC cells from any species. The claims encompass anything that broadly can be encompassed by programs encompassed by the claims, which are not specifically defined or limited. The claims encompass anything that can be broadly be encompassed by highly expressed programs recited in the claims. The claims encompass anything which can be considered a tumor heterogeneity score in a single nucleus or single cells. Thus the claims lack adequate written description. Response to Arguments The previous new matter rejections have been withdrawn. However the amendment has introduced new matter. The response begins traversing the written description in view of the amendment to limit claim 1 to humans. This argument is not persuasive as claim 41 still encompasses any species. The response continues by arguing the specific programs by asserting the specification defines the programs in the tables 3 and 4. This argument has been thoroughly reviewed but is not considered persuasive table 3 does not specifically define any program. Table 3 appears to merely provide 200 genes and IFN signaling number. Table 4 provides Topics (which may be programs), but fails to provide which genes are encompassed for each topic and provides no indication of increased or decreased expression of each gene. The response further cites paragraphs 0627-0628 [0627] Despite substantial inter-tumor heterogeneity (FIG. 1C; FIGS. 5A-5C), recurrent gene expression programs were learned across malignant cells of different tumors by consensus non-negative matrix factorization (cNMF). cNMF was performed separately for the untreated and treated malignant cells and focused on the programs shared between patients that were biologically distinct (FIGS. 3A-3B; Tables 3,4; Methods) Each program was annotated based on its top 200 weighted genes (Methods). In both untreated and treated tumors, nine malignant programs were identified that reflected either their lineage or cell state, though there was partial overlap among them (FIGS. 3A-3B). [0628] In untreated tumors, there were five lineage-specific programs: three spanned basal- like phenotypes involving the epithelial-mesenchymal transition87,88 (squamous, mesenchymal cytoskeletal, mesenchymal matrisomal), with the squamous program closely overlapping the basal-like A subtype⁷⁸; two spanned classical-like phenotypes (classical progenitor, classical activated) (FIG 3A) with the classical progenitor program containing transcription factors (TFs) involved in endoderm lineage development (HNFIA, DLX2, PRDM6, and FOXO4) and the classical activated program also containing genes involved in secretion, cell polarization, and cytoskeletal remodeling. The remaining four cell state programs were cycling, hypoxic, TNF-NFkB signaling, and interferon signaling. In treated tumors, there were six lineage- specific programs (squamous, mesenchymal, induced basal-like, classical progenitor, classical acinar-like, classical neuroendocrine-like) and three cell state programs (cycling, TNF-NFkB signaling, interferon signaling) (FIG. 3B). However these do not address these issues. The response further alleges, “The specification teaches a concrete method for computing the heterogeneity score: scoring each tumor by program expression, identifying programs with expression greater than the mean of the cohort as "highly expressed," and then assigning a heterogeneity score H (H=0 for 0-1 highly expressed programs, H=1 for 2 highly expressed programs, H=2 for 3+ highly expressed programs for malignant cells).” This argument has been thoroughly reviewed but is not considered persuasive as the claims are not limited to this. This at best is a preferred embodiment, but not an explicit requirement of the claim. 07-30-02 AIA 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, 6, 15-16, 18, 20, 22, 26, 41-44, 55-56, 58-60, 62-68 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. Claim 1 is indefinite because it lacks a positive active step relating back to the preamble. The preamble recites a method of stratifying pancreatic ductal adenocarcinoma (PDAC) patients into treatment groups and/or prognosing PDAC or treatment outcome and/or survival in a patient, however the last positive active step is drawn to generating a tumor heterogeneity score for the PDAC tumor,. Therefore it is unclear as to whether the method is drawn to method of stratifying pancreatic ductal adenocarcinoma (PDAC) patients into treatment groups and/or prognosing PDAC or treatment outcome and/or survival in a patient or generating a tumor heterogeneity score for the PDAC tumor,. Further claim 1 has been amended to recite, “ performing single-cell or single-nucleus RNA sequencing to obtain gene expression levels of one or more PDAC tumor cells from a PDAC tumor, identifying from the gene expression levels a plurality of programs in the one or more PDAC tumor cells, including:[[a.]]{a}a malignant cell program ; and b}a cancer-associated fibroblast (CAF).” The metes and bounds are unclear what the RNA sequencing requires as the specification and claims do not define what is required of recited programs. Thus it is unclear how the a and b are identified. Claim 1 further recites, generating a tumor heterogeneity score for the PDAC tumor, wherein the tumor heterogeneity score is calculated by determining a number of highly expressed programs of the plurality of programs in the one or more PDAC cells, wherein the highly expressed programs have an expression greater than the mean expression of a reference cohort, and where the tumor heterogeneity score is used to assign the PDAC tumor to a risk group for prognosing treatment outcome and/or survival..” Thus the recitation is vague, unclear and incomplete as the specification provides no specific guidance on how this is done consistent with the claims or the amended performing step.. Further the claim is vague, unclear and incomplete how the tumor heterogeneity score is used to assign the PDAC tumor to a risk group for prognosing treatment outcome and/or survival . Claim 2 has been amended to recite, “wherein the malignant cell signature and/or program comprises:[[a.]]{a}a lineage specific expression program selected from: a squamous program, a mesenchymal cytoskeletal program, mesenchymal matrisomal program, a classical progenitor program, a classical activated program, or any combination thereof; [[b.]](b) a lineage specific expression program selected from: a squamous program, a mesenchymal program, an induced basal-like program, a classical progenitor program, a classical acinar-like program, a classical neuroendocrine-like program, or any combination thereof; [[c.]]c a cell state specific expression program selected from: a cycling program, a hypoxic program, TNF-NFkB signaling program, an interferon signaling program, or any combination thereof; [[d.]]d a cell state specific expression program selected from: a cycling program, a TNF-NFkB signaling program, or an interferon signaling program, or any combination thereof; [[e.]]e a neoadjuvant treated malignant cell expression program; [[f.]]{f an untreated malignant cell expression program; [[g.]](g) a cell state expression program selected from: a neuronal-like program, a neuroendocrine like program, a mesenchymal program, a squamoid program, a MYC signaling program, a cycling (G2M) program, a cycling (S) program, or any combination thereof; [[h.]](h) a lineage specific expression program selected from: an acinar-like program, a classical-like program, a basaloid program, a squamoid program, a mesenchymal program, a neuroendocrine like program, a neuronal like program, or any combination thereof; [[i.]]{ or any combination thereof.” Thus the recitation is vague, unclear and incomplete as the specification provides no specific guidance on what is required of these recitation and what is required.. Claim 3 has been amended to recite, “wherein the CAF signature and/or program:[[a.]](a comprises a myofibroblast program; a neurotropic program; a secretory program; a mesodermal progenitor program a neuromuscular program; or any combination thereof;[[b.]](b) comprises a neoadjuvant treated CAF signature and/or program selected from: a neuromuscular program, a secretory program, a neurotropic program, or any combination thereof; [[c.]]{c} comprises an untreated CAF signature and/or program selected from: a mesodermal progenitor program, a myofibroblast program, a neurotropic program, a secretory program, or any combination thereof; or [[d.]](d) comprises an adhesive expression program, an immunomodulatory expression program, a myofibroblastic progenitor expression program, or a neurotropic expression program.” Thus the recitation is vague, unclear and incomplete as the specification provides no specific guidance on what is required of these recitation and what is required.. Claim 6 has been amended to recite, “wherein the method plurality of programs further comprises, measuring by single-cell or single-nucleus RNA sequencing, in one or more PDAC tumor cells, an untreated tumor malignant cell signature and/or program and an untreated CAF signature and/or program, wherein:[[a.]]{a the untreated tumor malignant cell signature and/or program comprises a lineage specific expression program selected from: a squamous program, a mesenchymal cytoskeletal program, mesenchymal matrisomal program, a classical progenitor program, a classical activated program, or any combination thereof; and[[b.]](b) the untreated tumor CAF signature and/or program is selected from: a mesodermal progenitor program, a myofibroblast program, a neurotropic program, a secretory program, or any combination thereof optionally further comprising determining a tumor heterogeneity score for the PDAC tumor, wherein the tumor heterogeneity score is calculated by determining a number of highly expressed programs in the one or more PDAC cells..” Thus the recitation is vague, unclear and incomplete as the specification provides no specific guidance on what is required of these recitation and what is required. The claim 15 refers to tables. MPEP 2173.05(s) states: 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.” The metes and bounds are unclear how these markers or genes relate to the states, programs or signatures of the independent claim. The claim 16 refers to tables. MPEP 2173.05(s) states: 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.” The metes and bounds are unclear how these markers or genes relate to the states, programs or signatures of the independent claim. The claim 17 refers to tables. MPEP 2173.05(s) states: 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.” The metes and bounds are unclear how these markers or genes relate to the states, programs or signatures of the independent claim. Claim 18 has been amended to recite, “wherein there is a greater likelihood of longer survival when a primary mesenchymal matrisomal and/or a classical progenitor malignant program is detected as compared to detection of a primary classical activated, a squamous, or a mesenchymal cytoskeletal program.” The recitations of greater, longer, and predominant are relative terms. The specification does not provide a standard to differentiate greater from not greater, longer from shorter, and predominant from less predominant. Further it is unclear how these programs relate to the programs of the independent claims. Claim 22 has been amended to recite, “wherein the single-nucleus RNA sequencing technique is optimized for pancreatic tissue; wherein the single-nucleus RNA sequencing technique is optimized for frozen samples; and/or wherein the single-nucleus RNA sequencing technique comprises screening a sample for an RNA integrity number and performing single-nucleus RNA sequencing only on samples with an RNA integrity number of 6 or more.” The recitation of “optimized” is relative term. The specification and claims do not provide a standard to differentiate non-optimized from optimized. Thus the metes and bounds are unclear. Claim 41 has been amended to recite, “administering or applying a PDAC treatment to the human subject , wherein the PDAC treatment is selected based on the tumor heterogeneity score, wherein the treatment is a tumor resection, a chemotherapy, a radiation therapy, a neoadjuvant, a malignant cell signature and/or program modulating agent, a BCL-2 inhibitor, a tyrosine kinase inhibitor, a TGFbeta modulator, a myeloid cell agonist, a CXCR4 inhibitor, a HER2 inhibitor, or any combination thereof.” The metes and bounds are unclear as the claim does not previously recite, “human subject. Further it is unclear how PDAC treatment is selected based on tumor heterogeneity score, as based on is not an art accepted term and thus it is vague unclear and incomplete. Further claim 41 has been amended to recite,” performing single-cell or single-nucleus RNA sequencing to obtain gene expression levels in one or more PDAC tumor cells, and identifying from the gene expression levels a plurality of programs in the one or more PDAC tumor cells, including a malignant cell program a cancer-associated fibroblast (CAF) program , ; and ; (ii) generating a tumor heterogeneity score for the PDAC tumor, wherein the tumor heterogeneity score is calculated by determining a number of highly expressed programs , of the plurality of programs in the one or more PDAC cells, and administering or applying a PDAC treatment to the human subject , .” The metes and bounds are unclear what measuring as the claim required detecting the recited signature probes, neighborhood, or receptor ligand pairs. Thus it is unclear how the a, b, c, d, and e are measured Further review of the specification did not reveal a specific definition of a. a malignant cell signature, program, or both;b. a cancer-associated fibroblast (CAF) signature, program, or both; c. an immune microniche signature, program, or both; d. a tumor spatial neighborhood; and e. one or more co-expressed receptor-ligand pairs. It is further unclear how analyzing a single cell or nucleus provides a heterogeneity score. Thus the metes and bounds are unclear what is required by the recitation. Claim 41 further recites, (ii) generating a tumor heterogeneity score for the PDAC tumor,wherein the tumor heterogeneity score is calculated by determining a number of highly expressed signatures, programs, and/or states of the plurality of signatures, programs, and/or states in the one or more PDAC cells.” Thus the recitation is vague, unclear and incomplete as the specification provides no specific guidance on how this is done consistent with the claims or the amended performing step.. The specification provides no specific guidance on how to differentiate the highly expressed signatures from less than highly expressed signatures. Claim 42 recites, “wherein the wherein the malignant cell signature and/or program comprises [[a.]]@ a lineage specific expression program selected from: a squamous program, a mesenchymal cytoskeletal program, mesenchymal matrisomal program, a classical progenitor program, a classical activated program, or any combination thereof;[[b.]]@ a lineage specific expression program selected from: a squamous program, a mesenchymal program, an induced basal-like program, a classical progenitor program, a classical acinar-like program, a classical neuroendocrine-like program, or any combination thereof; [[c.]]c a cell state specific expression program selected from: a cycling program, a hypoxic program, TNF-NFkB signaling program, an interferon signaling program, or any combination thereof; [[d.]]d a cell state specific expression program selected from: a cycling program, a TNF-NFkB signaling program, or an interferon signaling program, or any combination thereof; [[e.]]e a neoadjuvant treated malignant cell expression program; [[f.]]{f an untreated malignant cell expression program; [[g.]](g) a cell state expression program selected from: a neuronal-like program, a neuroendocrine like program, a mesenchymal program, a squamoid program, a MYC signaling program, a cycling (G2M) program, a cycling (S) program, or any combination thereof; or [[h.]](h) a lineage specific expression program selected from: an acinar-like program, a classical-like program, a basaloid program, a squamoid program, a mesenchymal program, a neuroendocrine like program, a neuronal like program, or any combination thereof; [[i.]]{ or any combination thereof.” Thus the recitation is vague, unclear and incomplete as the specification provides no specific guidance on what is required of these recitation and what is required.. Claim 43 recites, “wherein the CAF signature and/or program:comprises [[a.]]{a comprises a myofibroblast program; a neurotropic program; a secretory program; a mesodermal progenitor program a neuromuscular program; or any combination thereof;[[b.]](b) comprises a neoadjuvant treated CAF signature and/or program selected from: a neuromuscular program, a secretory program, a neurotropic program, or any combination thereof;[[c.]]{c} comprises an untreated CAF signature and/or program selected from: a mesodermal progenitor program, a myofibroblast program, a neurotropic program, a secretory program, or any combination thereof; or [[d.]](d) comprises an adhesive expression program, an immunomodulatory expression program, a myofibroblastic progenitor expression program, or a neurotropic expression program.” Thus the recitation is vague, unclear and incomplete as the specification provides no specific guidance on what is required of these recitation and what is required.. Claim 44 recites, “wherein the method comprises, detecting, in one or more a PDAC tumor cells, an untreated tumor malignant cell signature and/or program and an untreated CAF signature and/or program, wherein [[a.]](a the untreated tumor malignant cell signature and/or program comprises a lineage specific expression program selected from: a squamous program, a mesenchymal cytoskeletal program, mesenchymal matrisomal program, a classical progenitor program, a classical activated program, or any combination thereof; and[[b.]](b) the untreated tumor CAF signature and/or program is selected from: a mesodermal progenitor program, a myofibroblast program, a neurotropic program, a secretory program, or any combination thereof,..” Thus the recitation is vague, unclear and incomplete as the specification provides no specific guidance on what is required of these recitation and what is required. The claim 55 refers to tables. MPEP 2173.05(s) states: 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.” The metes and bounds are unclear how these markers or genes relate to the states, programs or signatures of the independent claim. The claim 56 refers to tables. MPEP 2173.05(s) states: 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.” The metes and bounds are unclear how these markers or genes relate to the states, programs or signatures of the independent claim. The claim 57 refers to tables. MPEP 2173.05(s) states: 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.” The metes and bounds are unclear how these markers or genes relate to the states, programs or signatures of the independent claim. Claim 65 has been amended to recite, “wherein assigning the PDAC tumor to a risk group comprises assigning the PDAC tumor to a single malignant risk group and to a single CAF risk group, wherein the malignant class is selected from A0, A1, A2, SO, Si, S2, CO, C1, C2, MO,M1, M2, P0, P1, or P2, and wherein the CAF class is selected from SO, Si, N0, N1, MO, M1, P0, or P1.” The claim recites, “the malignant class” and “the CAFclass” these recitations lack antecedent basis in the claim. Further the metes and bounds are unclear how assigning PDAC to a tumor risk group and what is require of the A0, A1, A2, SO, Si, S2, CO, C1, C2, MO,M1, M2, P0, P1, or P2, or SO, Si, N0, N1, MO, M1, P0, or P1” requires. Claim 65 has been added by amendment and recites, “further comprising assigning the PDAC tumor to a combined risk class that integrates the malignant risk group and CAF risk group class and is selected from: a low combined risk group, a low-intermediate combined risk group, a high- intermediate risk group, or a high combined risk group, wherein:(a) a PDAC tumor in a low malignant risk group and in a low CAF risk group is classified into the low combined risk group;(b) a PDAC tumor in a high malignant risk and in a high CAF risk is classified into the high combined risk group;(c) a PDAC tumor in an intermediate malignant risk group or in an intermediate CAF risk and in a high malignant risk or in a high CAF risk is classified into the high-intermediate combined risk group; and(d) a PDAC tumor in a low malignant risk group and in a high CAF risk group, a PDAC tumor in a high malignant risk group and in a low CAF risk group, a PDAC tumor in a low malignant risk group and in a low CAF risk group, a PDAC tumor in an intermediate malignant risk group and in an intermediate CAF risk group, a PDAC tumor in a low malignant risk group and in an intermediate CAF risk group is classified into the low-intermediate combined risk group.” The claim recites a low combined risk group, a low-intermediate combined risk group, a high- intermediate risk group, or a high combined risk group. These are relative terms. The claim continues by reciting low, high and intermediate malignant risk group and CAF risk group. However the specification and claims do not provide how to differentiate these or indicate how they are related to tumor heterogeneity score. Thus the claims is vague, unclear and incomplete. Claim 67 has been amended to recite, “assigning the PDAC tumor to a risk group comprises assigning the PDAC tumor to a single malignant risk group and to a single CAF risk group, wherein the malignant class is selected from A0, A1, A2, SO, Si, S2, CO, C1, C2, MO,M1, M2, P0, P1, or P2, and wherein the CAF class is selected from SO, Si, N0, N1, MO, M1, P0, or P1.” The claim recites, “the malignant class” and “the CAFclass” these recitations lack antecedent basis in the claim. Further the metes and bounds are unclear how assigning PDAC to a tumor risk group and what is require of the A0, A1, A2, SO, Si, S2, CO, C1, C2, MO,M1, M2, P0, P1, or P2, or SO, Si, N0, N1, MO, M1, P0, or P1” requires. Claim 68 has been added by amendment and recites, “further comprising assigning the PDAC tumor to a combined risk class that integrates the malignant risk group and CAF risk group class and is selected from: a low combined risk group, a low-intermediate combined risk group, a high- intermediate risk group, or a high combined risk group, wherein:(a) a PDAC tumor in a low malignant risk group and in a low CAF risk group is classified into the low combined risk group;(b) a PDAC tumor in a high malignant risk and in a high CAF risk is classified into the high combined risk group;(c) a PDAC tumor in an intermediate malignant risk group or in an intermediate CAF risk and in a high malignant risk or in a high CAF risk is classified into the high-intermediate combined risk group; and(d) a PDAC tumor in a low malignant risk group and in a high CAF risk group, a PDAC tumor in a high malignant risk group and in a low CAF risk group, a PDAC tumor in a low malignant risk group and in a low CAF risk group, a PDAC tumor in an intermediate malignant risk group and in an intermediate CAF risk group, a PDAC tumor in a low malignant risk group and in an intermediate CAF risk group is classified into the low-intermediate combined risk group.” The claim recites a low combined risk group, a low-intermediate combined risk group, a high- intermediate risk group, or a high combined risk group. These are relative terms. The claim continues by reciting low, high and intermediate malignant risk group and CAF risk group. However the specification and claims do not provide how to differentiate these or indicate how they are related to tumor heterogeneity score. Thus the claims is vague, unclear and incomplete. Response to Arguments The response traverses the rejection with respect to the preamble and last active step in view of the amendment. This argument has been thoroughly reviewed but is not considered persuasive as the preamble recites, “method of stratifying pancreatic ductal adenocarcinoma (PDAC) patients into treatment groups and/or prognosing PDAC or treatment outcome and/or survival in a human patient.” The last active step is “generating a tumor heterogeneity score for the PDAC tumor,.” Thus the rejection is maintained. The response continues arguing the rejection with respect to detecting has been overcome by amendment to measuring gene expression leves. This argument has been thoroughly reviewed but is not considered persuasive as it is unclear what gene expression levels are required or what the malignant cell program and CAF cell program are require. The malignant cell program and CAF cell program are not defined by the specification or claims and thus the claim is vague, unclear and incomplete. The response continues traversing the rejections by stating, “Applicant notes that immune microniche signatures, Tumor spatial neighborhoods, and Co-expressed receptor-ligand pairs are no longer recited in the claims. Malignant cell signatures and programs are defined through cNMF analysis and annotated based on their top 200 weighted genes. The specific programs are enumerated (e.g., squamous, mesenchymal cytoskeletal, mesenchymal matrisomal, classical progenitor, classical activated for untreated tumors), and the gene lists are provided in Tables 3 and 4. See, e.g., Specification, [0628]. Dependent claims 2 and 42 further specify the programs. CAF signatures and programs are similarly identified through cNMF and include myofibroblast, neurotropic, secretory, and mesodermal progenitor programs, each defined by their characteristic gene expression patterns. See, e.g., Specification, [0631] and Tables 3 and 4. Dependent claims 3 and 43 further specify the programs. These definitions are sufficiently clear to one of ordinary skill in the art to understand the metes and bounds of the claims. “This argument has been thoroughly reviewed but is not considered persuasive table 3 does not specifically define any program. Table 3 appears to merely provide 200 genes and IFN signaling number. Table 4 provides Topics (which may be programs), but fails to provide which genes are encompassed for each topic and provides no indication of increased or decreased expression of each gene. The response continues by arguing, “The Office Action additionally questions how analyzing a single cell or nucleus provides a heterogeneity score. Office Action, page 17. Applicant respectfully contends that the claims do not require the heterogeneity score to be derived from a single cell or nucleus. Rather, the claims recite measuring in "one or more PDAC tumor cells," i.e., a population of cells from a PDAC tumor. The heterogeneity score is a tumor-level metric computed across all cells profiled from a given tumor. Each tumor is scored for each program, and the number of programs with expression "greater than the mean of the cohort" constitutes the heterogeneity score. The claim amendments clarify this by specifying the threshold for "highly expressed."” This argument has been thoroughly reviewed but is not considered persuasive as the claims require one or more PDAC tumor cells and thus encompass a single tumor cel. Further the claims and specification provide no specific guidance on how the tumor heterogeneity score is calculated. The response traverses the rejections of claims 15-17 and 55-57 in view of the amendment to no longer recite figures. This argument has been thoroughly reviewed but is not considered persuasive as the claims still recite tables and the rejection states: MPEP 2173.05(s) states: 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.” The metes and bounds are unclear how these markers or genes relate to the states, programs or signatures of the independent claim. The response continues by asserting, “he Office Action states that "greater," "longer," and "predominant" in claim 18 are relative terms without a standard of measure. Office Action, page 22. Applicant respectfully disagrees and submits that these terms are clearly defined in the context of the specification. "Greater likelihood of longer survival" is a comparative statement supported by the Kaplan- Meier survival analyses at FIGS. 13A-13F and paragraphs [0636]-[0637], which demonstrate statistically significant differences in overall survival among patients grouped by primary program. Specifically, "among the malignant programs, mesenchymal matrisomal and classical progenitor were associated with the best OS, classical activated was associated with intermediate OS, and squamous and mesenchymal cytoskeletal were associated with the worst OS." These are objective, measurable differences demonstrated through standard statistical methods (log-rank test). The term "predominant" has been replaced with "primary" in the claim, and refers to the primary (top-scoring) program in a given tumor, as defined in paragraph [0668].” This argument has been thoroughly reviewed but is not considered persuasive as the assertion of a “comparative statement” is a relative term. Further the cited statistical differences are not a limitation of the claim and thus is not defining or limiting the limitation. Further the arguments with respect to, “objective, measurable differences demonstrated through standard statistical methods (log-rank test)” are not limitations of the claims and appear to merely be arguments of counsel. The response continues by asserting, “ Applicant respectfully disagrees. The specification provides the standard for "optimized" in the context of the snRNA-seq technique for pancreatic tissue. Paragraph [0832] states that "Applicant optimized snRNA-seq for banked frozen PDAC specimens stored for up to five years." The specification further teaches that optimization includes, for example, screening samples for an RNA integrity number (RIN) greater than 6 before processing, as well as employing nucleus isolation techniques adapted for the unique tissue requirements of pancreatic tumors. Claim 22 itself further specifies that the optimization optionally includes "screening a sample for an RNA integrity number and performing single-nucleus RNA sequencing only on samples with an RNA integrity number of 6 or more."” This argument has been thoroughly reviewed but is not considered persuasive as the cited portions are not limiting definitions or standard, at best they are preferred embodiments not required of the claims. Thus this argument is not persuasive. The response continues by asserting, “ The Office Action states that the specification provides no specific guidance on how to administer or apply treatment based on the tumor heterogeneity score as recited in claim 41. Office Action, pages 22-23. Applicant respectfully disagrees. As discussed above, the specification teaches a prognostic risk stratification system based on the heterogeneity score and primary program that assigns patients to low, intermediate, and high-risk categories with significantly different survival outcomes. A person of ordinary skill in the art would understand that prognostic risk stratification informs treatment decisions. For example, a high-risk patient might be treated more aggressively (e.g., with combination therapy), while a low-risk patient might receive less aggressive treatment. The amendment to claim 41 also makes the treatment step affirmative by removing "optionally" and reciting that "the PDAC treatment is selected based on the tumor heterogeneity score," linking the diagnostic step to the therapeutic application.” This argument has been thoroughly reviewed but is not considered persuasive as this does not appear to be supported by the specification as originally filed. Further this is merely arguments of counsel not substantiated by evidence. First, MPEP 716.01(c) makes clear that "The arguments of counsel cannot take the place of evidence in the record. In re Schulze , 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding state of the art, ordinary skill in the art, , understanding of the skilled artisan, etc.." Here, the statements regarding the what an artisan of ordinary skill int eh art would understand must be supported by evidence, not argument. This should not be construed as an invitation for providing evidence. As further stated in the MPEP 716.01 regarding the timely submission of evidence: A) Timeliness. Evidence traversing rejections must be timely or seasonably filed to be entered and entitled to consideration. In re Rothermel, 276 F.2d 393, 125 USPQ 328 (CCPA 1960). Affidavits and declarations submitted under 37 CFR 1.132 and other evidence traversing rejections are considered timely if submitted: (1) prior to a final rejection, (2) before appeal in an application not having a final rejection, or (3) after final rejection and submitted (i) with a first reply after final rejection for the purpose of overcoming a new ground of rejection or requirement made in the final rejection, or (ii) with a satisfactory showing under 37 CFR 1.116(b) or 37 CFR 1.195, or (iii) under 37 CFR 1.129(a). The response continues by asserting, “The Office Action asserts that dependent claims 2-6, 42-44, and 53 are "vague, unclear and incomplete," because the specification does not provide guidance on what is required by the recitations. Office Action, pages 18-21 and 24-27. Applicant respectfully disagrees. Each of the programs, signatures, and classifications recited in these dependent claims is described in detail in the specification: The malignant cell programs in Claims 2 and 42 are defined in paragraph [0047] and described in detail at least at paragraphs [0249], [0259] and [0628]-[0629]. The CAF programs in Claims 3 and 43 are defined in paragraph [0048] and described at paragraphs [0086], [0187], and [0260].” This argument has been thoroughly reviewed but is not considered persuasive as paragraph 0047 states: In certain example embodiments, the malignant cell signature and/or program comprises a lineage specific expression program selected from: a squamous program, a mesenchymal cytoskeletal program, mesenchymal matrisomal program; a classical progenitor program, a classical activated program, or any combination thereof lineage specific expression program selected from: a squamous program, a mesenchymal program, an induced basal-like program, a classical progenitor program, a classical acinar-like program, a classical neuroendocrine-like program, or any combination thereof; a cell state specific expression program selected from: a cycling program, a hypoxic program, TNF-NFkB signaling program, an interferon signaling program, or any combination thereof, a cell state specific expression program selected from: a cycling program, a TNF-NFkB signaling program, or an interferon signaling program, or any combination thereof, a neoadjuvant treated malignant cell expression program; an untreated malignant cell expression program; a cell state expression program selected from: a neuronal-like program, a neuroendocrine like program, a mesenchymal program, a squamoid program, a MYC signaling program, a cycling (G2M) program, a cycling (S) program, or any combination thereof; a lineage specific expression program selected from: an acinar-like program, a classical-like program, a basaloid program, a squamoid program, a mesenchymal program, a neuroendocrine like program, a neuronal like program, or any combination thereof, or any combination thereof. This does not define how to get from gene expression to any of the claimed programs. The response further cites paragraph 0249 which states: [0249] In some embodiments, a malignant cell state is characterized by a malignant cell signature comprising: a lineage specific expression program selected from a squamous program, a mesenchymal cytoskeletal program, mesenchymal matrisomal program, a classical progenitor program, or a classical activated program; a lineage specific expression program selected from a squamous program, a mesenchymal program, an induced basal-like program, a classical progenitor program, a classical acinar-like program, and a classical neuroendocrine- like program; a cell state specific expression program selected from a cycling program, a hypoxic program, TNF-NFkB signaling program, or an interferon signaling program; a cell state specific expression program selected from a cycling program, a TNF-NFkB signaling program, or an interferon signaling program; a neoadjuvant treated malignant cell expression program; an untreated malignant cell expression program; a basal-like malignant cell expression program; a classic-like malignant cell expression program; an immune microniche signature; or a combination thereof. This does not define how to get from gene expression to any of the claimed programs, but may be a preferred embodiment and still does not teach how to get from gene expression to the programs of the claims or tumor heterogeneity score. Paragraph 0259 also provides at best a preferred embodiment, but may be a preferred embodiment and still does not teach how to get from gene expression to the programs of the claims or tumor heterogeneity score. Paragraph 0628-0629 state: [0628] In untreated tumors, there were five lineage-specific programs: three spanned basal- like phenotypes involving the epithelial-mesenchymal transition87,88 (squamous, mesenchymal cytoskeletal, mesenchymal matrisomal), with the squamous program closely overlapping the basal-like A subtype⁷⁸; two spanned classical-like phenotypes (classical progenitor, classical activated) (FIG 3A) with the classical progenitor program containing transcription factors (TFs) involved in endoderm lineage development (HNFIA, DLX2, PRDM6, and FOXO4) and the classical activated program also containing genes involved in secretion, cell polarization, and cytoskeletal remodeling. The remaining four cell state programs were cycling, hypoxic, TNF-NFkB signaling, and interferon signaling. In treated tumors, there were six lineage- specific programs (squamous, mesenchymal, induced basal-like, classical progenitor, classical acinar-like, classical neuroendocrine-like) and three cell state programs (cycling, TNF-NFkB signaling, interferon signaling) (FIG. 3B). [0629] Programs varied in the extent to which they co-occurred within the same cell and associated with one another. In both untreated and treated tumors, IFN signaling and squamous program scores were correlated across nuclei (FIG. 12), as were those of mesenchymal with TNF-NFkB signaling. TNF-NFkB signaling was also correlated with the induced basal-like and classical neuroendocrine-like programs in the post-treatment context. Thus, basal-like cells may be more inflammatory/immunogenic overall than classical-like cells. Taken together, the increase in expression of basal-like genes, interferon signaling, and immune response promoting genes (FIG. 2C) in treated VS. untreated samples may reflect coupled programs in the same individual cells (FIG. 12), which could in turn drive immune cell state changes (FIGS. 9A-9B). One possibility is that these are driven through the effects of p63, especially the Np63 isoform, though this remains an area of controversy in the field 11,89,90 This does not define how to get from gene expression to any of the claimed programs, but may be a preferred embodiment and still does not teach how to get from gene expression to the programs of the claims or tumor heterogeneity score. The response asserts claims 2 and 42 are defined by 0048 which states: [0048] In certain example embodiments, the CAF signature and/or program comprises a myofibroblast program; a neurotropic program; a secretory program; a mesodermal progenitor program a neuromuscular program; or any combination thereof; comprises a neoadjuvant treated CAF signature and/or program selected from: a neuromuscular program, a secretory program, a neurotropic program, or any combination thereof; comprises an untreated CAF signature and/or program selected from: a mesodermal progenitor program, a myofibroblast program, a neurotropic program, a secretory program, or any combination thereof; or comprises an adhesive expression program, an immunomodulatory expression program, a myofibroblastic progenitor expression program, or a neurotropic expression program. This does not define how to get from gene expression to any of the claimed programs, but may be a preferred embodiment and still does not teach how to get from gene expression to the programs of the claims or tumor heterogeneity score. The response further alleges 0086, 0187, and 260 describe a CAF program. Paragraph 0086 describes figures 15A-15D and thus does not define what is required. While paragraph 0187 list numerous genes which “in certain example embodiments, the CAF signature and/or program comprises one or more.” This does not define what is required but merely provides possible embodiments and thus is not limiting. While paragraph 0260 appears to merely repeat paragraph 0048. The response continues by asserting, “he risk classification system in Claims 6 and 44 (AO-P2 malignant classes and SO-P1 CAF classes) is described at paragraphs [0051]-[0052] and [0182]-[0183], and in detail at [0668]-[0670], with reference to FIG. 3E.” None of the cited paragraphs define what is required or the gene expression patterns or values which provide for any of the recited classes. Thus the rejection is maintained. Claim Rejections - 35 USC § 101 07-04-01 AIA 07-04 35 U.S.C. 101 reads as follows: Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title. Claims 1-3, 6, 15-16, 18, 20, 22, 26, 41-44, 55-56, 58-60, 62-68 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation and mental step without significantly more. The claim(s) recite(s) the abstract idea or mental step of generating. Further the claim has been amended to recite, “ wherein the highly expressed programs have an expression greater than the mean expression of a reference cohort, and the tumor heterogeneity score is used to assign the PDAC tumor to a risk group for prognosing treatment outcome and/or survival. “ which is a natural law/correlation and/or an abstract idea. This judicial exception is not integrated into a practical application because there is no limitation which depends from or otherwise integrates the judicial exception. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claim provides no specific reagents. Claim analysis The instant claim 1 is directed towards a A method of stratifying pancreatic ductal adenocarcinoma (PDAC) patients into treatment groups and/or prognosing PDAC or treatment outcome and/or survival in a human patient comprising:(i) performing single-cell or single-nucleus RNA sequencing to obtain gene expression levels of one or more PDAC tumor cells from a PDAC tumor, and identifying from the gene expression levels a plurality of programs in the one or more PDAC tumor cells, including a}a malignant cell , program ; and {b}a cancer-associated fibroblast (CAF) program , ; (ii) generating a tumor heterogeneity score for the PDAC tumor, wherein the tumor heterogeneity score is calculated by determining a number of highly expressed programs , of the plurality of programs in the one or more PDAC cells, wherein the highly expressed programs have an expression greater than the mean expression of a reference cohort, and where the tumor heterogeneity score is used to assign the PDAC tumor to a risk group for prognosing treatment outcome and/or survival. The correlation in the wherein clause in a natural correlation/ phenomena and/or an abstract idea. The generating steps are a mental step or abstract idea. Further the identifying step is a mental step or abstract idea. Claim 41 is directed to A method of treating a subject having PDAC, the method comprising: (i) performing single-cell or single-nucleus RNA sequencing to obtain gene expression levels in one or more PDAC tumor cells, and identifying from the gene expression levels a plurality of programs in the one or more PDAC tumor cells, including:[[a.]]@ a malignant cell program , a cancer-associated fibroblast (CAF) program , ; and c (ii) generating a tumor heterogeneity score for the PDAC tumor, wherein the tumor heterogeneity score is calculated by determining a number of highly expressed programs , of the plurality of programs , in the one or more PDAC cells, and administering or applying a PDAC treatment to the human subject , wherein the PDAC treatment is selected based on the tumor heterogeneity score, wherein the treatment is a tumor resection, a chemotherapy, a radiation therapy, a neoadjuvant, a malignant cell signature and/or program modulating agent, a BCL-2 inhibitor, a tyrosine kinase inhibitor, a TGFbeta modulator, a myeloid cell agonist, a CXCR4 inhibitor, a HER2 inhibitor, or any combination thereof.. The correlation in the wherein clause in a natural correlation/ phenomena and/or a mental step or abstract idea.. The generating steps are a mental step or abstract idea. Further the identifying step is a mental step or abstract idea. The treatment does not integrate the judicial exception all subject are treated as the specification provides no guidance on treating based on tumor heterogeneity score. Further the treatment is generic and does not specifically integrate how it is based on tumor heterogeneity.. Dependent claims set forth further limitations to providing program, likelihood of survival, means of generating score, etc. . According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility. Step 1 . Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case the Step 1 requirement is satisfied as the claims are directed towards a process. Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, abstract idea and law of nature or natural phenomena. With regards to claim 1, the claim recites, (ii) generating a tumor heterogeneity score for the PDAC tumor, wherein the tumor heterogeneity score is calculated by determining a number of highly expressed programs , of the plurality of programs in the one or more PDAC cells, wherein the highly expressed programs have an expression greater than the mean expression of a reference cohort, and where the tumor heterogeneity score is used to assign the PDAC tumor to a risk group for prognosing treatment outcome and/or survival. “ This is an abstract idea/mental step and/or natural correlation or phenomenon. Further the wherein clause requires a comparison to determine highly expressed programs which is another judicial exception. Further the identifying step is a mental step or abstract idea. Claim 41 recites, “(ii) generating a tumor heterogeneity score for the PDAC tumor, wherein the tumor heterogeneity score is calculated by determining a number of highly expressed programs , of the plurality of programs , in the one or more PDAC cells, and administering or applying a PDAC treatment to the human subject , wherein the PDAC treatment is selected based on the tumor heterogeneity score, wherein the treatment is a tumor resection, a chemotherapy, a radiation therapy, a neoadjuvant, a malignant cell signature and/or program modulating agent, a BCL-2 inhibitor, a tyrosine kinase inhibitor, a TGFbeta modulator, a myeloid cell agonist, a CXCR4 inhibitor, a HER2 inhibitor, or any combination thereof.” This is an abstract idea/mental step and/or natural correlation or phenomenon. Further the identifying step is a mental step or abstract idea. Step 2A prong two . Does the claim recite additional elements that integrate the judicial exception into a practical application? The answer is no as claim 1 provides no dependent claims or steps which specifically depend from or otherwise integrate the judicial exception. Further while claim 41 recites administering or applying, it requires all subject are treated based on the tumor heterogeneity score ( which the specification does not teach how to do and thus is considered generic.). The generating steps are a mental step or abstract idea and/or natural correlation or phenomenon. Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No as the claims provide no specific reagents or conditions which provide for significantly more. While claim 1 requires, “ performing single-cell or single-nucleus RNA sequencing to obtain gene expression levels of one or more PDAC tumor cells from a PDAC tumor .” Claim 41 requires, “generating a tumor heterogeneity score for the PDAC tumor, wherein the tumor heterogeneity score is calculated by determining a number of highly expressed programs , of the plurality of programs , in the one or more PDAC cells, and administering or applying a PDAC treatment to the human subject.” These can be considered active steps. However, Olsen (Current Protocols in Molecular Biology e57, April 2018 Published online April, pages 1-14) and Haque (Genome Medicine (2017) 9:75) demonstrate single cell sequencing is routine and conventional. Peng (Cell research (2019) pages 726-738) teaches single cell sequencing of PDAC. Response to Arguments The response begins traversing the rejection by asserting, “Single-cell or single-nucleus RNA sequencing is a complex, multi-step laboratory procedure that requires specialized equipment, reagents, and computational infrastructure. It involves physical steps including nucleus isolation from frozen tissue samples, library preparation, sequencing on specialized platforms (e.g., 1 Ox Chromium, Illumina NextSeq), and computational analysis including quality control, dimensionality reduction, and clustering.” This argument has been thoroughly reviewed but is not considered persuasive as the claims have been amended to recite performing single cell or single nucleus RNA sequencing, which the art of Olsen (Current Protocols in Molecular Biology e57, April 2018 Published online April, pages 1-14), Haque (Genome Medicine (2017) 9:75), and Peng (Cell research (2019) pages 726-738) demonstrate are routine and conventional. The response continues by alleging, “Similarly, "generating a tumor heterogeneity score" as defined in the claims requires computational processing of gene expression data from multiple cell profiles across a tumor, scoring each tumor for multiple programs, comparing expression levels to a cohort mean, and computing a numerical score. This is a specific, computational methodology, not a mere mental observation.” This argument has been thoroughly reviewed but is not considered persuasive as the claims require no specific computational methodology as evidence by the 112 rejections of record. Even if it the generating a tumor heterogeneity score is considered a computational methodology it is still a mental step or abstract idea. The response continues by providing the representatives interpretation of the claim 1. This is noted. The response continues by providing arguments to Vanda Pharmaceutical Inc v, West-ward Pharmaceuticals Intl Ld. This argument has been thoroughly reviewed but is not considered persuasive as the Vanda Pharmaceutical Inc v, West-ward Pharmaceuticals Intl Ld provide a different fact pattern as claim 1 does not provide any treatment steps. Thus this argument is not persuasive. The response traverses the rejection of claim 41 in view of the amendment. This argument has been thoroughly reviewed but is not considered persuasive as the administering or applying step is considered generic as the specification and claims provide no guidance on how to select treatment based on tumor heterogeneity. The response continues by asserting the claim require single cell or single nucleus sequencing and identifying malignant cell program and CAF program. This argument has been thoroughly reviewed but is not considered persuasive as the identifying step is a mental step or abstract idea and has numerous 112 issues. The response continues by asserting none of the prior art teach the judicial exceptions of the claims. This argument has been thoroughly reviewed but is not considered persuasive as the art of record demonstrates the only active step of the claim is routine and conventional. Subject matter eligibility is not dependent on the judicial exceptions being known or routine and conventional. The response alleges the ordered combination of steps provides for significantly more. This argument has been thoroughly reviewed but is not considered persuasive as the art of record demonstrates the only active step of the claim is routine and conventional. Subject matter eligibility is not dependent on the judicial exceptions being known or routine and conventional. Summary No claims are allowed. While Olsen (Current Protocols in Molecular Biology e57, April 2018 Published online April, pages 1-14), Haque (Genome Medicine (2017) 9:75), Peng (Cell research (2019) pages 726-738) demonstrate single cell sequencing including PDAC cells, they do not specifically teach the signatures, programs or states or determining a tumor heterogeneity score based on the signatures, programs or states from a single cell or nucleus.. Further US 18/813710 application provides claims which appear to encompass PDAC signatures and programs as well single cell or single nucleus sequencing, but does not teach determining tumor heterogeneity score. Conclusion 07-40 AIA Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL . See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a). A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action. Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEVEN C POHNERT PhD whose telephone number is (571)272-3803. The examiner can normally be reached Monday- Friday about 6:00 AM-5:00 PM, every second Friday off. 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /Steven Pohnert/Primary Examiner, Art Unit 1683 Application/Control Number: 18/021,625 Page 2 Art Unit: 1683 Application/Control Number: 18/021,625 Page 3 Art Unit: 1683 Application/Control Number: 18/021,625 Page 4 Art Unit: 1683 Application/Control Number: 18/021,625 Page 5 Art Unit: 1683 Application/Control Number: 18/021,625 Page 6 Art Unit: 1683 Application/Control Number: 18/021,625 Page 7 Art Unit: 1683 Application/Control Number: 18/021,625 Page 8 Art Unit: 1683 Application/Control Number: 18/021,625 Page 9 Art Unit: 1683 Application/Control Number: 18/021,625 Page 10 Art Unit: 1683 Application/Control Number: 18/021,625 Page 11 Art Unit: 1683 Application/Control Number: 18/021,625 Page 12 Art Unit: 1683 Application/Control Number: 18/021,625 Page 13 Art Unit: 1683 Application/Control Number: 18/021,625 Page 14 Art Unit: 1683 Application/Control Number: 18/021,625 Page 15 Art Unit: 1683 Application/Control Number: 18/021,625 Page 16 Art Unit: 1683 Application/Control Number: 18/021,625 Page 17 Art Unit: 1683 Application/Control Number: 18/021,625 Page 18 Art Unit: 1683 Application/Control Number: 18/021,625 Page 19 Art Unit: 1683 Application/Control Number: 18/021,625 Page 20 Art Unit: 1683 Application/Control Number: 18/021,625 Page 21 Art Unit: 1683 Application/Control Number: 18/021,625 Page 22 Art Unit: 1683 Application/Control Number: 18/021,625 Page 23 Art Unit: 1683 Application/Control Number: 18/021,625 Page 24 Art Unit: 1683 Application/Control Number: 18/021,625 Page 25 Art Unit: 1683 Application/Control Number: 18/021,625 Page 26 Art Unit: 1683 Application/Control Number: 18/021,625 Page 27 Art Unit: 1683 Application/Control Number: 18/021,625 Page 28 Art Unit: 1683 Application/Control Number: 18/021,625 Page 29 Art Unit: 1683 Application/Control Number: 18/021,625 Page 30 Art Unit: 1683 Application/Control Number: 18/021,625 Page 31 Art Unit: 1683 Application/Control Number: 18/021,625 Page 32 Art Unit: 1683 Application/Control Number: 18/021,625 Page 33 Art Unit: 1683 Application/Control Number: 18/021,625 Page 34 Art Unit: 1683 Application/Control Number: 18/021,625 Page 35 Art Unit: 1683 Application/Control Number: 18/021,625 Page 36 Art Unit: 1683 Application/Control Number: 18/021,625 Page 37 Art Unit: 1683 Application/Control Number: 18/021,625 Page 38 Art Unit: 1683 Application/Control Number: 18/021,625 Page 39 Art Unit: 1683 Application/Control Number: 18/021,625 Page 40 Art Unit: 1683 Application/Control Number: 18/021,625 Page 41 Art Unit: 1683
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