DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
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.
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.
Claims 27-29, 35, 37 withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 1-18, 20, 22, 26, 41-44, 53-60, 62-64 are being examined.
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
The information disclosure statement (IDS) submitted on 2/16/2023, 6/6/2024, 2/20/2025 are being considered by the examiner.
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.
Drawings
The specification in 0074 (PGPUB) teaches red, blue, purple with respect to figure 3. Paragraph 0075, 0088-0093, 0096, 0098 , 0101, 0104-0105, 0110-0111, 0640, 0673-0674, teach these figures are also in coloreColor photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Specification
The specification provides an HTTP in 0154, 0477, 0819, 0883, 0886, 0891, 0905, 0907-0908, 1085 (PGPUB)The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: “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.” Review and searching of the specification does not provide antecedent basis for the limitation.
Claim Objections
Claims 1-18, 20, 22, 26, 41-44, 53-60, 62-64 are objected to because of the following informalities:
Claim 1 recites, “ a.” “b.”, “c.”, “d.”, “e.”. MPEP 608.01(m) states: Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v.Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Claim 2 recites, “ a.” “b.”, “c.”, “d.”, “e.”, “f.”, “g.” “h.”, “i.” . MPEP 608.01(m) states: Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v.Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Claim 3 recites, “ a.” “b.”, “c.”, “d.”,. MPEP 608.01(m) states: Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v.Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Claim 4 recites, “ a.” “b.”, “c.”. MPEP 608.01(m) states: Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v.Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Claim 5 recites, “ a.” “b.”, “c.”, “d.”, “e.”. MPEP 608.01(m) states: Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v.Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Claim 6 recites, “ a.” “b.”, , “ a.” “b.”, “c.”, “d.” MPEP 608.01(m) states: Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v.Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Claim 15 recites, “ Figs..” MPEP 608.01(m) states: Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v.Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Claim 16 recites, “ Figs..” MPEP 608.01(m) states: Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v.Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Claim 17 recites, “ Figs..” MPEP 608.01(m) states: Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v.Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Claim 41 recites, “ a.” “b.”, “c.”, “d.”, “e.”. MPEP 608.01(m) states: Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v.Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Claim 42 recites, “ a.” “b.”, “c.”, “d.”, “e.”, “f.”, “g.” “h.”, “i.” . MPEP 608.01(m) states: Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v.Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Claim 43 recites, “ a.” “b.”, “c.”, “d.”,. MPEP 608.01(m) states: Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v.Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Claim 44 recites, “ a.” “b.”, , “ a.” “b.”, “c.”, “d.” MPEP 608.01(m) states: Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v.Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Claim 53 recites, “ a.” “b.”, “c.”,. MPEP 608.01(m) states: Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v.Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Claim 4 recites, “ a.” “b.”, “c.”, “d.” MPEP 608.01(m) states: Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v.Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Claim 55 recites, “ Figs..” MPEP 608.01(m) states: Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v.Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Claim 56 recites, “ Figs..” MPEP 608.01(m) states: Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v.Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Claim 57 recites, “ Figs..” MPEP 608.01(m) states: Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v.Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Claim 59 recites, “ a.” “b.”, “c.”, “d.”, “e.”, “f.”,. MPEP 608.01(m) states: Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v.Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Claim 62 recites, “ a.” “b.”, “c.”. MPEP 608.01(m) states: Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v.Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 1-18, 20, 22, 26, 41-44, 53-60, 62-64 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 9/29/2025 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 patient comprising:(i) measuring ,by single-cell or single-nucleus RNA sequencing a plurality of signatures, programs, and/or states in one or more PDAC tumor cells from a PDAC tumor, including: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; ande. one or more co-expressed receptor-ligand pairs; [[or]](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, and wherein a characteristic regarding a patient's treatment, a patient's response to a treatment, and/or their survival is determined or predicted based on the umor heterogeneity score. The response does not provide an indication of where the amendment is supported. However, review and searching of the application did not reveal support for the amendment.
Claim 41 has been amended to recite, “A method of treating a subject having PDAC, the method comprising:(i) measuring,by single-cell or single-nucleus RNA sequencing a plurality of signatures, programs, and/or states in one or more PDAC tumor cells, including: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; (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, and administering or applying a PDAC treatment to the subject in need thereof based on the tumor heterogeneity score, wherein the treatment is optionally 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 response does not provide an indication of where the amendment is supported. However, review and searching of the application did not reveal support for the amendment.
Further while the specification in paragraphs 0012, 0050, 0184, recite, “tumor heterogeneity score.” However the teachings are limited to, “is calculated by determining a number of highly expressed programs in the one or more PDAC cells.” Thus the amendment to encompass any program, any signature, any states appears to provide support for the amendment. Further review and searching of the specification did not reveal basis for “wherein a characteristic regarding a patient's treatment, a patient's response to a treatment, and/or their survival is determined or predicted based on the umor heterogeneity score” or “and administering or applying a PDAC treatment to the subject in need thereof based on the tumor heterogeneity score.”
Claim 26 recites, “generating a tumor heterogeneity score comprises a spatially-resolved transcriptomics technique.” Review and searching of the specification did not reveal antecedent basis for this limitation.
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 9/29/2025 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 patient comprising:(i) measuring ,by single-cell or single-nucleus RNA sequencing a plurality of signatures, programs, and/or states in one or more PDAC tumor cells from a PDAC tumor, including: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; ande. one or more co-expressed receptor-ligand pairs; [[or]](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, and wherein a characteristic regarding a patient's treatment, a patient's response to a treatment, and/or their survival is determined or predicted based on the umor heterogeneity score.
Claim 41 has been amended to recite, “A method of treating a subject having PDAC, the method comprising:(i) measuring,by single-cell or single-nucleus RNA sequencing a plurality of signatures, programs, and/or states in one or more PDAC tumor cells, including: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; (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, and administering or applying a PDAC treatment to the subject in need thereof based on the tumor heterogeneity score, wherein the treatment is optionally 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 claims 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 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. 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, 3rd 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, 3rd column last paragraph-3rd 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, “administering or applying a PDAC treatment to the subject in need thereof based on the tumor heterogeneity score, wherein the treatment is optionally 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.
Thus while the claims encompass a genus of PDAC cells from any species. The claims encompass anything that broadly can be encompassed by the signatures, programs or states encompassed by the claims. The claims encompass anything that can be broadly be encompassed by highly expressed signatures, programs and states 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.
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 1-18, 20, 22, 26, 41-44, 53-60, 62-64 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, “(i) measuring detecting,by single-cell or single-nucleus RNA sequencing a plurality of signatures, programs, and/or states in one or more PDAC tumor cells from a PDAC tumor, including: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.” 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 1 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 detecting step.. Further it is unclear as highly expressed signatures suggests there are less than highly expressed. The specification provides no specific guidance on how to differentiate the highly expressed signatures from less than highly expressed signatures.
Claim 2 recites, “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. 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. 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. a neoadjuvant treated malignant cell expression program; f. an untreated malignant cell expression program; 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. 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 optionally wherein a subject having a classical-like malignant expression program has the greatest likelihood of time to progression and longest survival; and optionally wherein a subject having a neuronal like malignant expression program or a malignant squamoid expression program has the greatest likelihood of least time to progression.” 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 recites, “wherein the CAF signature and/or program:a. comprises a myofibroblast program; a neurotropic program; a secretory program; a mesodermal progenitor program a neuromuscular program; or any combination thereof,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. 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. comprises an adhesive expression program, an immunomodulatory expression program, a myofibroblastic progenitor expression program, or a neurotropic expressinn program, optionally wherein a subject having an immunomodulatory CAF expression program has the greatest likelihood of time to progression; optionally wherein a subject having an adhesive CAF expression program has the greatest likelihood of shortest survival; and optionally wherein there is a greater likelihood of longer survival when a CAF secretory or neurotropic program is detected as compared to detection of a myofibroblast or mesodermal progenitor program is detected.” 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 4 recites, “the tumor spatial neighborhood is:a. a treatment enriched neighborhood,b. a squamoid-basaloid neighborhood; or [[a]] c. a classical neighborhood.” 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 5 recites, “herein the one or more co-expressed receptor-ligand pairs is selected from:a. an Epithelial compartment - CAF compartment pair;b. an Epithelial compartment - Immune compartment pair;c. a CAF compartment [[and]] -_Immune compartment pair;d. 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 6 recites, “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. 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; optionally further comprising assigning the PDAC tumor to a single malignant class and to a single CAF class, wherein the malignant class is selected from AO, Al, A2, SO, Si, S2, CO, Ci, C2, MO, M1, M2, P0, P1, or P2, and wherein the CAF class is selected from SO, Si, NO, N1, MO, M1, P0, or Pi;optionally wherein the PDAC tumor is assigned 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; andoptionally wherein a subject with a PDAC tumor in low combined risk group has the greatest likelihood of longest survival..” 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. Further it is unclear if the everything after the two optionally steps are required. Further the recitations of “om AO, Al, A2, SO, Si, S2, CO, Ci, C2, MO, M1, M2, P0, P1, or P2, and wherein the CAF class is selected from SO, Si, NO, N1, MO, M1, P0, or Pi” are vague unclear and incomplete
The claim 15 refers to figures. 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 figures. 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 figures. 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 recites, “, wherein there is a greater likelihood of longer survival when a predominant 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 recites, “wherein the single-nucleus RNA sequencing technique is optimized for pancreatic tissue; optionally wherein the single-nucleus RNA sequencing technique is optimized for frozen samples; and
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optionally wherein the single-nucleus RNA sequencing technique comprises screening a sample for an RNA integrity number and performing 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 recites, “applying a PDAC treatment to the subject in need thereof based on the tumor heterogeneity score,” the specification provides no specific guidance on how to administer or apply treatment based on tumor heterogeneity score. Thus the metes and bounds of the claim are vague, unclear, and incomplete.
Further claim 41 has been amended to recite, (i) measuring by single-cell or single-nucleus RNA sequencing a plurality of signatures, programs, and/or states in one or more PDAC tumor cells, including: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; ande. one or more co-expressed receptor-ligand pairs; [[or]](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,.” 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 detecting step. Further it is unclear as highly expressed signatures suggests there are less than highly expressed. 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 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. 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. 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. a neoadjuvant treated malignant cell expression program; f. an untreated malignant cell expression program; 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. 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 optionally wherein a subject having a classical-like malignant expression program has the greatest likelihood of time to progression and longest survival; and optionally wherein a subject having a neuronal like malignant expression program or a malignant squamoid expression program has the greatest likelihood of least time to progression.” 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:a. comprises a myofibroblast program; a neurotropic program; a secretory program; a mesodermal progenitor program a neuromuscular program; or any combination thereof,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. 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. comprises an adhesive expression program, an immunomodulatory expression program, a myofibroblastic progenitor expression program, or a neurotropic expressinn program, optionally wherein a subject having an immunomodulatory CAF expression program has the greatest likelihood of time to progression; optionally wherein a subject having an adhesive CAF expression program has the greatest likelihood of shortest survival; and optionally wherein there is a greater likelihood of longer survival when a CAF secretory or neurotropic program is detected as compared to detection of a myofibroblast or mesodermal progenitor program is detected.” 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, “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. 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; optionally further comprising assigning the PDAC tumor to a single malignant class and to a single CAF class, wherein the malignant class is selected from AO, Al, A2, SO, Si, S2, CO, Ci, C2, MO, M1, M2, P0, P1, or P2, and wherein the CAF class is selected from SO, Si, NO, N1, MO, M1, P0, or Pi;optionally wherein the PDAC tumor is assigned 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; andoptionally wherein a subject with a PDAC tumor in low combined risk group has the greatest likelihood of longest survival..” 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. Further it is unclear if the everything after the two optionally steps are required. Further the recitations of “om AO, Al, A2, SO, Si, S2, CO, Ci, C2, MO, M1, M2, P0, P1, or P2, and wherein the CAF class is selected from SO, Si, NO, N1, MO, M1, P0, or Pi” are vague unclear and incomplete
Claim 53 recites, “herein the tumor spatial neighborhood is:a. a treatment enriched neighborhood; a squamoid-basaloid neighborhood; or a c. a classical neighborhood..” 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 figures. 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 figures. 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 figures. 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 Rejections - 35 USC § 101
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 1-18, 20, 22, 26, 41-44, 53-60, 62-64 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 measuring and generating. Further the claim has been amended to recite, “wherein a characteristic regarding a patient's treatment, a patient's response to a treatment, and/or their survival is determined or predicted based on umor heterogeneity score “ which is a natural law or correlation. 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 method of stratifying pancreatic ductal adenocarcinoma (PDAC) patients into treatment groups and/or prognosing PDAC or treatment outcome and/or survival in a patient comprising:(i) measuring detecting,by single-cell or single-nucleus RNA sequencing a plurality of signatures, programs, and/or states in one or more PDAC tumor cells from a PDAC tumor, including: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; ande. one or more co-expressed receptor-ligand pairs; [[or]]and f. any combination thereof,(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, andwherein a characteristic regarding a patient's treatment, a patient's response to a treatment, and/or their survival is determined or predicted based on the detection of one or more of the signatures, programs, and/or or states tumor heterogeneity score. The correlation in the wherein clause in a natural correlation or phenomena. The measuring and generating steps are a mental step or abstract idea.
Claim 41 is directed to A method of treating a subj ect having PDAC, the method comprising:(i) measuring,by single-cell or single-nucleus RNA sequencing a plurality of signatures, programs, and/or states in one or more PDAC tumor cells, including: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; ande. one or more co-expressed receptor-ligand pairs; (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, and administering or applying a PDAC treatment to the subject in need thereof based on the tumor heterogeneity score, wherein the treatment is optionally 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 or phenomena. The measuring and generating steps are a mental step or abstract idea.
The treatment does not integrate the judicial exception as the it is limited to only subject in need thereof. 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 signatures or 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, “(i) measuring,by single-cell or single-nucleus RNA sequencing a plurality of signatures, programs, and/or states in one or more PDAC tumor cells from a PDAC tumor, including: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; ande. one or more co-expressed receptor-ligand pairs; andii) 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,.” This is an abstract idea or mental step..
Further claim 2 recites, “wherein a characteristic regarding a patient's treatment, a patient's response to a treatment, and/or their survival is determined or predicted based on theumor heterogeneity score..” This is a natural correlation.
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, this is limited to a subject in need thereof and thus does not encompass all subjects. The measuring and generating steps are a mental step or abstract idea.
Step 2B. Does the claim recite additional elements that are significantly more then the judicial exceptions? No
While claim 1 and 41 require, “ measuring detecting,by single-cell or single-nucleus RNA sequencing a plurality of signatures, programs, and/or states in one or more PDAC tumor cells from a PDAC tumor.”
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.
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
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/Steven Pohnert/Primary Examiner, Art Unit 1683