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 .
Information Disclosure Statement
The IDS filed 3/11/2025 has been considered by the Examiner.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Priority of US application 62/571,414 filed 10/12/2017 is acknowledged.
Claim Status
Claims 1-18 are pending and are examined on the merits.
Claim Objections
Claims 9-10 are objected to because of the following informalities: claims 9 and 10 both recite the phrases “selected form the group consisting of”, which should read as “selected from the group consisting of.” More importantly, both claims end after a comma. Claim 9 ends after “a replicated associated gene,” and claim 10 ends after “non-homologous end joining gene,”. There may be a typographic error, and both claims should end at a period.
Claim 9 recites “a replicated associated gene”, which should read as “a replication associated gene”.
Claim 16 recites “an enzyme inhibitor, a receptor ligand”, which is grammatically incomplete and does not clearly recite alternatives. There may be a typographic error where it should be “an enzyme inhibitor, OR a receptor ligand”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112—Second Paragraph
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 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 recites the limitation "the plurality of cancer-related genes" in the 4th step (3rd line). There is insufficient antecedent basis for this limitation in the claim. Claim 1 does recite “for a plurality of cancer genes” (2nd step, first line), but these two phrases are not perfectly aligned.
Claim 1 recites the limitation "the majority portion of the digital cancer gene score" in the last step (2nd line). There is insufficient antecedent basis for this limitation in the claim. It is not clear what is considered the majority of the digital cancer gene score, or how “a score” can have a majority.
Claim 13 recites the limitation "the group of genes" in the second line. There is insufficient antecedent basis for this limitation in the claim. It is not clear which genes are included in “the group of genes”.
Claim 13 reference tables by reciting table numbers, the contents of which are disclosed in the specification. USPTO Guidance requires adherence with MPEP 2173.05(s) which states that:
Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993).
Therefore, Applicants are required to incorporate the intended subject matter from the Tables directly into the claims.
Claim 18 depends from claim 1 but says the “treatment option is surgery or radiation therapy.” While claim 1 requires “administering … a therapeutic agent that targets the cancer related gene”, or requires an immune therapy related gene or neoepitope encoding gene as a target, surgery or radiation therapy has no requirement for any target genes. This creates an internal inconsistency and it is unclear what the treatment option will be.
Claim Rejections - 35 USC § 112—Fourth Paragraph
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 18 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 18 depends from claim 1 but says the “treatment option is surgery or radiation therapy,” while claim 1 requires “administering … a therapeutic agent.” This creates an internal inconsistency and in fact, claim 18 failed to further limit claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
Step 1: Process, Machine, Manufacture or Composition
Claims 1-18 are to a method of selecting a treatment option for a cancer patient, with a series functional steps. So a process.
Step 2A Prong One: Identification of Abstract Ideas
The claim(s) recite(s):
Analyzing, in silico, the omics data to generate a digital cancer gene score, wherein the digital cancer gene score is calculated in silico using the omics data; and
This step recites generating a digital cancer gene score through in silico analysis in a general way, which reads on a mathematical operation to generate a score under a Broadest Reasonable Interpretation (BRI). Therefore this step equates to an abstract idea of mathematical concepts.
(Administering,) when (1) the digital cancer gene score exceeds a threshold level and (2) the majority portion of the digital cancer gene score is weighted for the cancer related gene, the immune therapy related gene, or the DNA or RNA sequence encoding a neoepitope,
These parts in the claim 1 last step recite (1) comparing a digital cancer gene score to a threshold level, which reads on mathematical operations; and (2) the digital cancer gene score is weighted for …genes, which reads on the human judgement/opinion (weighted for some genes or not) based on data observation. Therefore, this step is directed to abstract ideas of mathematical concepts and mental processes.
Step 2A Prong Two: Consideration of Practical Application
The claims result in a process of administering a therapeutic agent targeting cancer related genes, the immune therapy related gene, or the DNA or RNA sequence encoding the neoepitope upon the satisfaction of two contingent conditions. The therapeutic agent is broad, which is not a particular treatment. The claims do not recite any additional elements that integrate the abstract idea/judicial exception into a practical application.
This judicial exception is not integrated into a practical application because the claims do not meet any of the following criteria:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
an additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
an additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
an additional element effects a transformation or reduction of a particular article to a different state or thing; and
an additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than
a drafting effort designed to monopolize the exception.
Step 2B: Consideration of Additional Elements and Significantly More
The claimed method also recites "additional elements" that are not limitations drawn to an abstract idea. The recited additional elements are drawn to:
obtaining blood from a patient having a cancer;
obtaining from the blood omics data of the cancer patient for a plurality of cancer genes, wherein the omics data comprise at least one of DNA sequence data, RNA sequence data, and RNA expression level;
wherein the omics data comprise an expression level of a cancer related gene, an expression level of an immune therapy related gene, and an expression level of a DNA or RNA sequence encoding a neoepitope;
providing an omics record computer system that includes at least one processor and at least one computer readable memory coupled to the processor and configured to digitally store the omics data for the plurality of cancer-related genes in the at least one memory;
Administering, … a therapeutic agent that targets the cancer related gene, the immune therapy related gene, or the DNA or RNA sequence encoding the neoepitope.
The claims do not include additional elements that are sufficient to amount of significantly more than the judicial exception because it is routine and conventional to perform the acts of treating a cancer subject with “a therapeutic agent” that targets cancer related genes. Other elements of the method include “providing an omics record computer system that includes at least one processor and at least one computer readable memory coupled to the processor”, which is a recitation of generic computer structure that serves to perform generic computer functions that are well-understood, routine, and conventional activities previously known to the pertinent industry. Obtaining patient blood sample and blood omics data are insignificant extra-solution activities to acquire data for further analysis. Viewed as a whole, these additional claim element(s) do not provide meaningful limitation(s) to transform the abstract idea recited in the instantly presented claims into a patent eligible application of the abstract idea such that the claim(s) amounts to significantly more than the abstract idea itself. Therefore, the claim(s) are rejected under 35 U.S.C. 101 as being directed to non-statutory subject matter.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. US11810672B2. Although the claims at issue are not identical, they are not patentably distinct from each other because US11810672B2 claim 1 already claims a method of obtaining blood, obtaining omics data, storing data in an omics record computer system, calculating a digital score from mutations/methylation/RNA expression/neoepitope/splice/poly-A-tail counts, applying a threshold and majority-weighting condition, generating a personalized treatment option comprising recombinant nucleic acid encoding tumor- and patient-specific neoepitopes, and treating by administering that option.
Claim 1 of US20240021314A1 is broader/different in wording but not patentably distinct in substance: it obtains blood omics data, stores the data in an omics record computer system, calculates a digital cancer gene score, applies a threshold and majority-weighting rule, and administers a targeted therapeutic agent. Claims 2-8 recite subject matter that substantially overlaps with issued dependent claims 2-7 or with obvious variants of the issued scoring/treatment method.
A terminal disclaimer may overcome nonstatutory ODP if common ownership and term conditions are satisfied.
A side-by-side claim mapping is provided here:
Clm
Instant Claims
US20240021314A1
1
A method of selecting a treatment option for a cancer patient, comprising:
obtaining blood from a patient having a cancer;
obtaining from the blood omics data of the cancer patient for a plurality of cancer genes, wherein the omics data comprise at least one of DNA sequence data, RNA sequence
data, and RNA expression level; wherein the omics data comprise an expression level of a cancer related gene,
an expression level of an immune therapy related gene,
and an expression level of a DNA or RNA sequence encoding a neoepitope;
providing an omics record computer system that includes at least one processor and at least one computer readable memory coupled to the processor and configured to digitally store the omics data for the plurality of cancer-related genes in the at least one memory;
analyzing, in silico, the omics data to generate a digital cancer gene score, wherein the digital cancer gene score is calculated in silico using the omics data; and
administering, when (1) the digital cancer gene score exceeds a threshold level and (2) the majority portion of the digital cancer gene score is weighted for the cancer related gene, the immune therapy related gene, or the DNA or RNA sequence encoding a neoepitope, a therapeutic agent that targets the cancer related gene, the immune therapy related gene, or the DNA or RNA sequence encoding the neoepitope.
1
A method of analyzing omics data and treating a patient having a cancer, the method comprising:
obtaining blood from the patient having or suspected to have the cancer;
obtaining, from the blood, omics data for a plurality of cancer-related genes, wherein the omics data comprise at least one of DNA sequence data, RNA sequence data, and RNA expression level data;
providing an omics record computer system that includes at least one processor and at least one computer readable memory coupled to the processor and configured to digitally store the omics data for the plurality of cancer-related genes in the at least one memory;
calculating, in silico, a digital score from the digital omics data, wherein the digital score is calculated in silico by the sum of (i) counting the number of mutations of cancer-related genes, inflammation-related genes, and DNA-repair genes, (ii) counting changes in methylation or modifications in DNA of cancer-related genes and DNA-repair genes, (iii) counting upregulation or downregulation in expression levels of RNA of cancer-related genes, inflammation-related genes, and DNA-repair genes, (iv) counting the number of tumor- and patient-specific neoepitopes, (v) counting splice variants of cancer-related genes and DNA-repair genes, and (vi) counting changes in length of poly A tail of any cancer-related genes, inflammation-related genes, and DNA-repair genes;
associating the digital score with at least one of a health status, an omics error status, a cancer prognosis, a therapeutic recommendation, an effectiveness of a treatment; and
upon the digital score reaching a threshold value and a majority portion of the digital score is highly weighted as an overexpression of a specific neoepitope;
generating a personalized treatment option for the patient, wherein the personalized treatment option comprises a recombinant nucleic acid encoding one or more tumor- and patient-specific neoepitopes; and
treating the cancer by administering the personalized treatment option to the patient.
2
The method of claim 1, wherein the blood omics data are obtained from DNA/RNA that is enclosed in a vesicular structure or bound to non-nucleotide molecule.
2
The method of claim 1, wherein the plurality of cancer-related genes comprises at least one of a cancer-related gene, a cancer-specific gene, a DNA-repair gene, a neoepitope, and a gene not associated with a disease.
4
The method of claim 1, wherein the DNA sequence data are selected from the group consisting of mutation data, copy number data duplication, loss of heterozygosity data, and epigenetic status.
3
The method of claim 1, wherein the DNA sequence data is selected from the group consisting of mutation data, copy number data duplication, loss of heterozygosity data, and epigenetic status.
5
The method of claim 1, wherein the RNA sequence data are selected from the group consisting of mRNA sequence data and splice variant data.
4
The method of claim 1, wherein the RNA sequence data is selected from the group consisting of mRNA sequence data and splice variant data.
6
The method of claim 1, wherein the RNA expression level data are selected from the group consisting of a quantity of RNA transcript and a quantity of a small noncoding RNA.
5
The method of claim 1, wherein the RNA expression level data is selected from the group consisting of a quantity of RNA transcript and a quantity of a small noncoding RNA.
7
The method of claim 1, wherein DNA sequence data are obtained from circulating free DNA.
6
The method of claim 1, wherein DNA sequence data is obtained from circulating free DNA.
3
The method of claim 1, wherein the blood omics data are obtained from cell-free DNA or cell-free RNA.
6,
7
The method of claim 1, wherein DNA sequence data is obtained from circulating free DNA.
The method of claim 1, wherein the RNA sequence data is obtained from the group consisting of circulating tumor RNA and circulating free RNA.
8
The method of claim 1, wherein the RNA sequence data are obtained from the group consisting of circulating tumor RNA and circulating free RNA.
7
The method of claim 1, wherein the RNA sequence data is obtained from the group consisting of circulating tumor RNA and circulating free RNA.
Although the “immune related gene” is not recited in the reference claims, it is obvious that a general omics data set encompasses (expression of) immune related genes. As neoepitope/neoantigen is about immune response, it is obvious to stress the existence of immune related genes in the analyzed dataset.
Therefore, instant claims 1-8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. US11810672B2.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 4-6, 9-10 and 13-18 are rejected under 35 U.S.C. 103 as being unpatentable over Basu et. al.: (“Molecular profiling for cancer”, WO2014089241A9, published Jun. 12, 2014; priority Dec. 6, 2012. Newly cited) in view of Karasaki, Takahiro, et al. "An immunogram for the cancer-immunity cycle: towards personalized immunotherapy of lung cancer." Journal of Thoracic Oncology 12.5 (2017): 791-803.
Claim 1 is interpreted as a method for selecting treatment option for cancer patient through omics data studies.
Regarding claim 1, Basu provides ([0030]) “the cancer that is profiled according to the methods of the invention”; and ([0028]) “the sample used to perform molecular profiling in the methods of the invention can include one or more of … a bodily fluid sample. … The bodily fluid … comprises peripheral blood, sera, plasma”. Basu teaches obtaining blood sample from a patient having cancer.
Basu provides ([007]) “the present invention provides methods and system for molecular profiling, using the results from molecular profiling to identify treatments for individuals”; and ([074]) “molecular profiling comprises methods that include but are not limited to, nucleic acid sequencing, such as a DNA sequencing or mRNA sequencing”.
Basu teaches obtaining the blood molecular profiling data of the cancer patients based on DNA/RNA sequence. Because the systematical molecular profiling creates omics data.
Basu’s “molecular profiling for cancer” (Title) is for a panel of selected genes ([008]), not an omics profiling. Karasaki applies “Whole Exome Sequencing and RNA Sequencing” (page 792, col 2, 3rd para) to study cancer patient samples (page 792, col 2, 2nd para). Hence Karasaki teaches generating omics data (page 802, col 1, 3rd para) based on the DNA and RNA sequence.
Basu provides (claim 153) “a system for identifying one or more candidate treatment for a cancer comprising: (a) a host server; (b) a user interface for accessing the host server to access and input data; (c) a processor for processing the inputted data; (d) a memory coupled to the processor for storing the processed data and instructions for: i. accessing a molecular profile generated by the method of any of claims 1-130; ii. identifying one or more candidate treatment that is associated with likely treatment benefit by comparing the molecular profiling results to the one or more rules;” Basu teaches computing system in handing the omics data (in silico analyzing). It is obvious that the profiling data is stored in memory.
Basu provides ([156]) “a gene or gene product can be considered up or down-regulated if the differential expression meets a statistical threshold, a fold-change threshold, or both. For example, the criteria for identifying differential expression can comprise both a p-value of 0.001 and fold change of at least 1.5-fold (up or down). One of skill will understand that such statistical and threshold measures can be adapted to determine differential expression by any molecular profiling technique disclosed herein. Basu teaches identifying cancer genes with an expression change threshold.
Karasaki provides “Expression values were calculated as fragments per kilobase of transcript per million fragments mapped (FPKM)” (page 792, col 2, 3rd para); four-digit human leukocyte antigen (HLA) class I alleles of each patient were identified from whole exome sequencing data of normal lung tissue or peripheral blood mononuclear cells by using Omixon Target HLA Typing (Omixon, Cambridge, MA). The Immune Epitope Database analysis resource tool NetMHCpan (version 2.8) was used to predict binding affinities of 8-mer to 11-mer mutant peptides to the patients’ major histocompatibility complex, class I, A gene (HLA-A); major histocompatibility complex, class I, B gene (HLA-B); and major histocompatibility complex, class I, C gene (HLA-C) alleles.23,24 Peptides derived from somatic mutations with a predicted concentration that inhibits 50% value less than 500 nM were considered candidate neoantigens.” (page 792, col 2, last para); and “The Immune Epitope Database analysis resource tool NetMHCpan (version 2.8) was used to predict binding affinities of 8-mer to 11-mer mutant peptides to the patients’ major histocompatibility complex, class I, A gene (HLA-A); major histocompatibility complex, class I, B gene (HLA-B); and major histocompatibility complex, class I, C gene (HLA-C) alleles.23,24 Peptides derived from somatic mutations with a predicted concentration that inhibits 50% value less than 500 nM were considered candidate neoantigens” (page 793, col 1, 2nd para), which teaches varies in silico analysis to omics data.
Basu does not teaches a cancer gene score. Karasaki provides (page 794, col 1, 2nd para) “To evaluate the dynamic process of antitumor immunity in an individual patient and formulate strategies to manipulate antitumor immunity for cancer treatment, we developed an immunogram for the CIC. In Figure 1, the seven steps of the CIC are depicted by the eight axes of the immunogram score (IGS)”, which teaches a composite cancer gene score in silico using the omics data.
Basu provides ([008]) “(b) identifying one or more treatment that is beneficially associated with the molecular profile of the subject, and optionally one or more treatment associated with lack of benefit, according to the determining in (a) and one or more rules in Table 22, thereby identifying the one or more candidate treatment. The panel of gene or gene products may comprise … AKTl , ALK, APC, AR, ATM, BRAF, CDH1 , cKIT, cMET, CSF1R, CTN B 1 , EGFR, ER, ERBB2, ERBB4, FBXW7, FGFR1 , FGFR2, FLT3, GNA1 1, GNAQ, GNAS, HER2, HNF1A, HRAS, IDH1, JAK2, JAK3, KDR (VEGFR2), KRAS, MGMT, MLH1 , MPL, NOTCH1 , NPM1, NRAS, PDGFRA, PGP, PIK3CA, PR, PTEN, PTPN11 , RB I, RET, RRM1, SMAD4, … TP53, TS, TUBB3 and VHL”. Basu teaches guided therapy weighted by cancer genes.
Basu provides ([005]) “more particularly, additional targets or specific therapeutic agents can be identified assessment of a comprehensive number of targets or molecular findings examining molecular mechanisms, genes, gene expressed proteins, and/or combinations of such in a patient's tumor. Identifying multiple agents that can treat multiple targets or underlying mechanisms would provide cancer patients with a viable therapeutic alternative on a personalized basis”, which teaches treatment with therapeutic agent.
Basu teaches the basic personalized oncology decision engine. It discloses molecular profiling of cancer, including expression and mutation profiling; comparing profiles against a rules database; using differential expression/mutation results to guide selection of therapeutic agents; using thresholds indicative of response/non-response; and selecting pathway/targeted therapies. Basu therefore teaches or suggests: obtaining omics data for cancer-related genes; using computer/rules-based analysis; generating a kind cancer gene score; generating treatment-relevant molecular findings; thresholding/comparison; and selecting/administering therapeutic agents matched to molecular aberrations.
Regarding claim 2, Basu provides ([0028]) “the sample used to perform molecular profiling in the methods of the invention can include one or more of … a bodily fluid sample. … The bodily fluid … comprises peripheral blood, sera, plasma”; and ([112]) “The sample can comprise vesicles… multivesicular body”. Basu suggests the blood omics data are obtained from vesicular DNA/RNA.
Regarding claim 4, Basu teaches ([019]) mutation profiles, ([087]) gene copy number changes, and ([074]) differential expression.
Regarding claim 5, Basu provides ([074]) “molecular profiling comprises methods that include but are not limited to, nucleic acid sequencing, such as a DNA sequencing or mRNA sequencing”; and ([079]) “A particular nucleic acid sequence may implicitly encompass the particular sequence and ‘splice variants’ and nucleic acid sequences encoding truncated forms.” Basu teaches mRNA sequence data and splice variant data.
Regarding claim 6: Basu provides ([136]) “RT-PCR can be used to determine RNA levels, e.g., mRNA or miRNA levels, of the biomarkers of the invention”, which teaches RNA transcript quantity and small noncoding RNA quantity.
Regarding claim 9, claim 9 is indefinite because incomplete. If corrected to include known cancer-related gene classes, Basu teaches ([008]) kinase (“JAK2, ALK2, JAK3)/cancer-associated genes (TP53, VHL, ERBB2, PTEN), DNA polymerase/repair-related genes (ATM, TP53,MLH1), copy-number and mutation profiling (ERBB2, EGFR, KRAS), and therapy mapping (EGFR, ALK, RET).
Regarding claim 10, claim 10 is indefinite because incomplete. If corrected, Basu provides ([387]) “c-Kit is a cytokine receptor expressed on the surface of hematopoietic stem cells as well as other cell types. This receptor binds to stem cell factor (SCF, a cell growth factor). As c-Kit is a receptor tyrosine kinase, ligand binding causes receptor dimerization and initiates a phosphorylation cascade resulting in changes in gene expression. These changes affect cell proliferation, apoptosis, chemotaxis and adhesion. c-Kit is inhibited by multi-targeted agents including imatinib, sunitinib and sorafenib”, which teaches a cytokine receptor gene.
Basu provides ([258]) “CHEMOTACTIC PROTEIN 1 (GCP1)”, which teaches a chemokine gene.
Basu provides ([387]) “BRCA1, breast cancer type 1 susceptibility gene, is a gene involved in cell growth, cell division, and DNA-damage repair”, which teaches a DNA repair gene.
Basu provides ([258]) “LIF, LOST IN INFLAMMATORY BREAST CANCER (LIBC)”, which teaches an inflammation gene.
Regarding claim 13, to the extent the tables list known cancer/immune/repair genes, Basu ([008, 258, 387]) and routine oncology panels render the limitation obvious.
Regarding claim 14, Basu expressly teaches ([021]) pathway-related treatment rules and pathway inhibitors (“PAM pathway inhibitors”).
Regarding claim 15, Basu provides ([008]) “In an aspect, the invention provides a method of identifying one or more candidate treatment for a cancer in a subject in need thereof, comprising: (a) determining a molecular profile for a sample from the subject by assessing a panel of gene or gene products, wherein the panel of gene or gene products are assessed as indicated in Table 21, FIG. 33A or FIG. 33B; and (b) identifying one or more treatment that is beneficially associated with the molecular profile of the subject, and optionally one or more treatment associated with lack of benefit, according to the determining in (a) and one or more rules in Table 22, thereby identifying the one or more candidate treatment”. Basu teaches composite molecular profiling and treatment rules, which suggests a compound score.
Regarding claim 16, Basu teaches ([021]) targeted agents including kinase/pathway inhibitors and receptor-targeted therapies such as “PAM pathway inhibitors” EGFR/c-Kit/EREG/Her2 related ligand treatment selection ([387]).
Regarding claim 17, Basu provides ([0105]) “A treatment can include administration of a therapeutic agent, which can be an agent that exerts a cytotoxic, cytostatic, or immunomodulatory effect on diseased cells, e.g., cancer cells, or other cells that may promote a diseased state, e.g., activated immune cells”. Basu teaches immune therapy.
Regarding claim 18: Basu provides ([572]) “Standard of care of GBM involves maximal safe surgical resection followed by a combination of radiation and chemotherapy with an oral DNA alkylating agent temozolomide”, which teaches radiation therapy.
It would have been prima facie obvious to one of ordinary skilled person in art, to modify Basu’s method for molecular profiling of cancer using targeted gene panel, with Karasaki’s omics data in silico analysis and a composite cancer gene score. Because the omics data is more systematic and comprehensive than Basu’s targeted cancer gene panel and the composite Immunogram score (IGS) is more comprehensive than Baus’s gene expression fold changes..One would reasonably expect success, because Basu’s already use a molecular profiling of targeted cancer gene panel to identify treatments that have likely benefit for a cancer, under the guidance of gene expression fold change. This would have been a “simple substitution of one known element for another to obtain predictable results” (MPEP 2141.III.(B)) because Karasiki’s omics data is a substitution for Baus’s RNA profiling and Karasiki’s immunogram score is a substitution for Basu’s gene expression fold change. A person of ordinary skill in art would have had a reasonable expectation of success because this is a same field endeavor.
Claims 3 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Basu et al. in view of Karasaki et al., as applied to claims 1-2, 4-6, 9-10 and 13-18 above, and further in view of Newman et al. (“An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage,” Nature Medicine 20, 548-554 (2014). Newly cited).
Regarding claim 3, Basu in view of Karasaki et al. teach claims 1-2, 4-6, 9-10 and 13-18, as set forth above. Basu and Karasaki do not teach Cell-free DNA or cell-free RNA. Newman (page 548, section abstract) expressly teaches circulating tumor DNA/cfDNA quantitation by CAPP-Seq.
Regarding claim 7, Basu and Karasaki do not teach Cell-free DNA. Newman (page 548, section abstract) expressly teaches circulating tumor DNA/cfDNA quantitation by CAPP-Seq.
Newman teaches that blood-derived ctDNA can provide broad tumor genomic information, covering multiple classes of somatic alterations and facilitating personalized cancer therapy. It would have been obvious to a POSA to use blood-derived cfDNA/ctDNA and/or blood RNA as a less invasive source of the molecular data used in the combined Basu’s and Karasaki’s treatment-selection system.
The field had a recognized need for personalized, minimally invasive cancer treatment selection. Basu expressly motivates treatment selection from molecular profiles. Newman provides blood-based alternatives to tissue profiling. The combination merely uses known molecular features for their known treatment-selection purpose, with predictable results.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Basu and karasaki, as applied to claims 1-2, 4-6, 9-10 and 13-18 above, and further in view of Best et al. (“RNA-Seq of Tumor-Educated Platelets Enables Blood-Based Pan-Cancer, Multiclass, and Molecular Pathway Cancer Diagnostics,” Cancer Cell 28(5), 666-676 (2015). Newly cited).
Regarding claim 8, Basu and Karasaki teach claims 1-2, 4-6, 9-10 and 13-18, as set forth above. Basu and Karasaki do not teach Cell-free RNA. Best teaches (page 666, Title and section Abstract) blood-based RNA-seq using tumor-educated platelets.
Best teaches blood-derived RNA profiles from tumor-educated platelets, including pan-cancer and pathway/companion diagnostic information. It would have been obvious to a POSA to use blood-derived cell-free RNA as a less invasive source of the molecular data used in the combined Basu’s and Karasaki’s treatment-selection system.
The field had a recognized need for personalized, minimally invasive cancer treatment selection. Basu expressly motivates treatment selection from molecular profiles. Best provide blood-based alternatives to tissue profiling. The combination merely uses known molecular features for their known treatment-selection purpose, with predictable results.
Claims 11 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Basu and Karasaki, as applied to claims 1-2, 4-6, 9-10 and 13-18 above, and further in view of Valiante et al. (“Cancer vaccines,” WO2017070618A1, published Apr. 27, 2017; priority Oct. 22, 2015. Newly cited).
Regarding claim 11, Basu and Karasaki teach claims 1-2, 4-6, 9-10 and 13-18, as set forth above. Basu and Karasaki do not teach neoepitope. Valiante provides (page 13, 3rd para) “A method for treating a subject with a personalized mRNA cancer vaccine, by isolating a sample from a subject, identifying a set of neoepitopes by analyzing a patient transcriptome and/or a patient exome from the sample to produce a patient specific mutanome, selecting a set of neoepitopes for the vaccine from the mutanome based on MHC binding strength, MHC binding diversity, predicted degree of immunogenicity, low self reactivity, and/or T cell reactivity, preparing the mRNA vaccine to encode the set of neoepitopes and administering the mRNA vaccine to the subject within two months of isolating the sample from the subject is provided in other aspects of the invention.” Valiante teaches patient/tumor-specific neoepitopes and personalized mutanome vaccines.
Regarding claim 12, Basu and Karasaki do not teach patient’s HLA type. Valiante provides (page 24, 2nd para) “Methods for generating personalized cancer vaccines generally involve identification of mutations, e.g., using deep nucleic acid or protein sequencing techniques, identification of neoepitopes, e.g., using application of validated peptide-MHC binding prediction algorithms or other analytical techniques to generate a set of candidate T cell epitopes that may bind to patient HLA alleles and are based on mutations present in tumors, optional demonstration of antigen-specific T cells against selected neoepitopes or demonstration that a candidate neoepitope is bound to HLA proteins on the tumor surface and development of the vaccine.” Valiante teaches MHC/HLA binding metrics including HLA type.
Valiante teach tumor/patient-specific neoepitopes, RNA expression confirmation, HLA/MHC binding prediction, and weighted neoepitope selection. It would have been obvious to include immune-therapy-related genes and neoepitope-encoding sequences among the omics features used for treatment selection, and to weigh the score according to the feature driving the combined Basu’s and Karasaki’s therapeutic recommendation.
The field had a recognized need for personalized, minimally invasive cancer treatment selection. Basu expressly motivates treatment selection from molecular profiles. Valiante provides the immune/neoepitope features and scoring/selection rationale. The combination merely uses known molecular features for their known treatment-selection purpose, with predictable results.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GUOZHEN LIU whose telephone number is (571)272-0224. The examiner can normally be reached Monday-Friday 8-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Larry D Riggs can be reached at (571) 270-3062. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/GL/
Patent Examiner
Art Unit 1686
/Anna Skibinsky/
Primary Examiner, AU 1635
Prosecution Insights