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 .
Priority
The instant application was filed 07/14/2023 and is a national stage entry of PCT/US2022/70208 with an international filing date: 01/14/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 7/14/2023 and 11/20/2024 is being considered by the examiner.
Drawings
There does not appear to be a petition in the file wrapper. . Color 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).
Claim Objections
Claims 2-9 objected to because of the following informalities:
Claims 2-9 recite, “Claim.” However “claim” is not the first word of the claim or a proper noun and thus does not need to be capitalized.
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 1-10 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for
, does not reasonably provide enablement for any individual and means of determining REASON score and selecting treatment. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is undue. These factors have been described by the court in re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in the Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
The nature of the invention and the breadth of the claims:
. Independent claim 1 is drawn to a method of providing decision support for a treatment regimen based on prognosis for an individual having oral squamous cell carcinoma (OSCC), the method comprising: determining a high-Risk Epigenetic And clinicopathologic Score for Oral caNcer (REASON) score from a biological sample from the individual having OSCC; and selecting a treatment regimen in response to the REASON score, the treatment regimen being one or more of an elective neck dissection, radiation, immunotherapy, or chemotherapy.
Thus the claims encompass any individuals of any species with OSCC.
The claims encompass any biological sample from any species having OSCC. Thus including muscle, brain, hair, liver, etc. samples.
The claims encompass anything which can broadly be interpreted as determining a high-Risk Epigenetic And clinicopathologic Score for Oral caNcer (REASON) score. Further the claims encompass any means of calculating the
Further the claims encompass selecting a therapy “based on” by any means the REASON score.
Claim 2 depends from claim 1 and draws the invention to wherein the individual has early-stage (I/II) OSCC.
Claim 2 depends from claim 1 and draws the invention to wherein the REASON score is determined based on a plurality of non-molecular variables and a plurality of methylation patterns of a plurality of genes.
Thus the claim encompass any non-molecular variables by any standard.
The claims also encompass anything which can broadly be encompassed by methylation patterns.
Claim 4 depends from claim 3 and draws the invention to wherein the plurality of non-molecular variables includes one or more of age of the individual, sex of the individual, race of the individual, tobacco use by the individual, alcohol use by the individual, histologic grade of the OSCC, stage of the OSCC, perineural invasion, lymphovascular invasion, and margin status of the OSCC.
Claim 5 depends from claim 3 and draws the invention to wherein the plurality of genes whose methylation patterns are determinative of the REASON score include two or more of ABCA2 (ATP-binding cassette sub-family A member 2), CACNAIH (Calcium Voltage-Gated Channel Subunit Alphal H), CCNJL (Cyclin-J-Like), GPR133 (Adhesion G-Protein-Coupled Receptor 133), HGFAC (hepatocyte growth factor activator), HORMAD2 (HORMA domain containing protein 2), MCPHI (Microcephalin 1), MYLK (Myosin Light Chain Kinase),RNF216 (Ring finger protein 216), SOX8 (SRY-box transcription factor 8), TRPAI(Transient Receptor Potential Cation Channel Subfamily A Member 1), and WDR86 (WD Repeat Domain 86).
Claim 6 depends from claim 1 and draws the invention to wherein the biological sample is acquired using a brush swab.
Claim 7 depends from claim 1 and draws the invention to , wherein a poor prognosis is indicated for the individual with OSCC when the REASON score for the individual with OSCC is above a reference REASON score from a healthy individual.
Claim 8 depends from claim 7 and draws the invention to wherein the REASON score ranges from zero to thirty-five.
Claim 9 depends from claim8 and draws the invention to wherein the reference REASON score is 17.
Independent claim 10 is drawn to method of risk stratification of an individual having oral squamous cell carcinoma (OSCC), the method comprising: determining a high-Risk Epigenetic And clinicopathologic Score for Oral caNcer (REASON) score from a biological sample from the individual; and classifying the individual as having a high risk of OSCC-related mortality in response to the REASON score for the individual with OSCC being above a reference REASON score from a healthy individual.
Thus the claims encompass any individuals of any species with OSCC.
The claims encompass any biological sample from any species having OSCC. Thus including muscle, brain, hair, liver, etc. samples.
The claims encompass anything which can broadly be interpreted as determining a high-Risk Epigenetic And clinicopathologic Score for Oral caNcer (REASON) score. Further the claims encompass any means of calculating the REASON score.
The amount of direction or guidance and the Presence and absence of working examples.
The specification teaches, “[0018] Disclosed here are methods wherein gene methylation signatures are combined with clinicopathologic factors to form a composite molecular and non-molecular signature with high prognostic performance in determining risk of 5-year mortality in early stage (I/II) OSCC patients. Clinicopathologic data were analyzed from an internal retrospective cohort of 515 OSCC patients as well as a cohort of 58 patients from TCGA. The top clinicopathologic factors that were highly predictive of 5-year mortality in these two cohorts were determined. Available methylation array data in the TCGA cohort were analyzed and twelve genes were identified that were differentially methylated between the OSCC patients who died by 5 years and those who survived. The relevant clinicopathologic factors with the twelve-gene methylation signature were combined into a risk score-the REASON score. Its predictive performance was evaluated to identify early-stage OSCC patients who died within five years of diagnosis.”
The specification teaches, “[0023] Embodiments include methods for risk stratification of a OSCC subject using brush swab samples and MC-Seq to noninvasively determine the methylation signature of an OSCC patient at the time of diagnosis.”
The specification teaches, “[0034] The DNA methylation-based, molecular component of the REASON score was developed according to a methylation state transition matrix. For each of the CpG sites, a
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of <0.3 indicated an unmethylated state, 0.33-0.75 a hemi-methylated state, and >0.75 a fully methylated state. A gene was considered to be hypermethylated if the methylation level moved from a less methylated state to a more methylated state. Conversely, a gene was considered hypomethylated if there was a state change to a lower level.”
The specification teaches, “Genes were annotated using Homer annotatePeaks.pl. With this software, the promoter region is defined as 1 kilobase from the transcription start site (TSS).” (0038) The specification teaches, “Separate scatterplots were rendered showing the concordance of these CpG sites between tissues and brush swabs for the cancer sites and the normal sites. Student t-tests were performed to compare R values between cancer and normal groups or tissue and brush swab groups. The most significant 1,000 CpGs features in cancer vs. normal groups were selected. Based on these results, the -log10(t-test p-value) was calculated for each of the 1,000 CpG sites to compare the degree of divergence in the significance of the test statistics for these 1,000 CpG between (1) cancer vs. normal and (2) tissue vs. brush swabs. Statistical analyses were performed in R environment (v. 4.1.0).
Methylation array analysis reveals differentially methylated genes in early stage OSCC patients who did not survive to 5 years.” (0038)
The specification teaches, “[0040] Of the 4,544 genes harboring CpG sites meeting criteria for analysis, 12 genes showed an adjusted p-value of <0.1 (Table 2). Gene position and methylation fold-change values are shown. The methylation trends for each gene that are predictive of poor survival here are shown, in comparison to the gene expression trends that are predictive of poor survival in previous studies. The PMID of the referenced study is included. They included ABCA2, CACNAH, CCNJL, GPR133, HGFAC, HORMAD2, MCPH], MYLK, RNF216, SOX8, TRPA], and WDR86.”
The specification teaches, “[0042] A literature search of each of the 12 genes revealed that with the exception of SOX8, none of the genes had previously been linked to OSCC in either human or preclinical studies. In Table 2 each of the genes is linked to the referenced clinical studies demonstrating poor cancer survival. HORMAD2 dysregulation through either SNPs or hypermethylation is attributed to poor survival in non-small cell lung cancer (NSCLC) and thyroid carcinoma. MYLK over-expression is linked to poor survival in bladder carcinoma, colorectal carcinoma, and hepatocellular carcinoma. GPR133 expression is inversely correlated with survival in patients with glioblastoma multiforme. The role of SOX8 has been already been investigated using in vitro models and in vivo models, as well as in clinical samples of OSCC. In a clinical study, SOX8 is over-expressed in chemoresistant patients with tongue SCC and is associated with higher lymph node metastasis, advanced tumor stage, and shorter overall survival. Similarly, higher SOX8 expression is linked to a high tumor histological grade, lymph node metastasis, and shorter overall survival in patients with endometrial carcinoma. TRPA] expression in cancer is controversial, with gene over-expression linked to poor survival in nasopharyngeal carcinoma and gene under-expression linked to poor survival in renal clear cell carcinoma. However, a study using International Cancer Genome Consortium data shows that the TRP family of genes has varying expression across different cancer types, and that some TRP genes have stronger prognostic ability than others. ABCA2, which encodes for a membrane- associated protein of the superfamily of ATP-binding cassette transporters, is over-expressed in epithelial ovarian carcinoma and acute lymphoblastic leukemia patients with poor survival. HGFAC expression is directly correlated to survival in breast ductal carcinoma and ovarian carcinoma. WDR86 expression is linked to poor survival in colorectal carcinoma and breast carcinoma . In a clinical study of solid tumors including gastric, lung and ovarian cancer, expression of T-type calcium channel genes including CACNA]H is used as a prognostic signature for survival. RNF216 expression is associated with poor survival in colorectal cancer and ovarian carcinoma, although whether over- or under-expression decreases survival is unknown. CCNJL expression is inversely correlated with survival in hepatocellular carcinoma. [0043] Of note, differential methylation of the 12 genes has not previously been linked to poor survival in any type of cancer. With the exception of HORMAD2 and HGFAC, published studies on these candidate genes have focused on differential gene expression rather than methylation. “
Presence and absence of working examples
The specification provides no working examples in which the individual is not human.
The specification provides no working examples in which the sample is not from the mouth.
The specification does not provide a specific equation for the calculation of the REASON score.
The state of prior art and the predictability or unpredictability of the art:
MPEP2164.03 teaches, " The scope of the required enablement varies inversely with the degree of predictability involved, but even in unpredictable arts, a disclosure of every operable species is not required. A single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements. In re Vickers, 141 F.2d 522, 526-27, 61 USPQ 122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA 1971). However, in applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In re Soll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). This is because it is not obvious from the disclosure of one species, what other species will work.”
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.
Ehrlich et al. (2002 Oncogene Vol 21 p. 5400) teaches that hypomethylation and hypermethylation of DNA are relative terms and denote less or more methylation than in some standard DNA (p. 5400 last paragraph). Ehrlich et al. teaches that there is considerable differences in the amounts and distribution of DNA methylation among different vertebrate tissues because DNA methylation is not only species-specific but also tissue-specific (p. 5400 last paragraph). Therefore the association in one species of CpG islands to disease type cannot be extrapolated to any species predictably. Because the distribution of DNA methylation varies between species and tissues it is not predictable that the same methylation status differences observed in one species is correlative in another species or tissues.
Cottrell (Clinical Biochemistry 2004 Vol. 37 p. 595) teaches that because methylation-based markers are not routinely used in clinical labs, the methodology has not been fully optimized, validated, and standardized. Cottrell et al. teaches that most of the methylation methods rely on bisulfite treatment protocol which must meet strict requirements for consistency and performance (p. 601 1st column 2nd full paragraph). Cottrell et al. teaches that in order to discover optimal markers and crease successful assays, there will need to be clearly defined clinical questions, sample sets, and methodologies coupled with the current methylation technologies (p. 601 1st column last paragraph).
Walsh et al teaches (Genes & Development (1999) volume 13, pages 26-36), "demonstration that a methylation pattern observed in a nonexpressing tissue can prevent transcription in a cell type normally capable of transcribing the gene of interest" (page 30, 2nd column, last full paragraph). Walsh further teaches, "tissue-specific transcription factors might overcome and then induce erasure of methylation patterns in the vicinity of specific binding sites to produce the impression of regulated tissue- specific methylation. According to this explanation, many of the observed tissue-specific methylation patterns within regulatory regions are a consequence, rather than a cause, of transcriptional activation" (page 31, 1st column, 1st full paragraph). Thus Walsh teaches that methylation in one type of cell is not predictable to other cells of different tissues, as different tissues have different transcription factors and thus methods of activating/inactivating genes.
Brooks et al ( Cancers Causes control (2009) volume 20, pages 1539-1550) teaches, " Though a number of studies have been conducted in subjects with established breast cancer, methylation frequencies of genes measured in different labs and in different sample types have been variable and often not reproducible. This is largely due to 4 factors: 1) Variable methods of methylation analysis are used in different studies, 2) Gene panels are not consistent across studies, 3) If the same genes are used, often different promoter CpG sites are used and 4) sources of DNA are variable from study to study (i.e. serum, plasma, tissue, biopsy etc.).” Brooks further teaches, “Reproducibility of methylation results is an area of great importance, one that has not been sufficiently addressed in the current literature. Methylation frequencies have largely not been reproducible across studies. This variability may be reduced with the standardization of methods and reporting of results. One study designed to specifically examine the reproducibility of the PMR (percent of fully methylated DNA found in a sample), was based on QMSP analysis of DNA from paraffin-embedded colon cancer samples. This study found the PMR to have high inter-assay CVs with an average of 21% (range 10-38%) (78). In a recent study, methylation results using a nested QMSP method (QAMA) on DNA obtained from micro-dissected cells from formalin-fixed and paraffin-embedded tumor tissues (n=13) was found to have a good correlation with sequencing results (R=0.982). To our knowledge no studies have reported the reproducibility of measurements obtained from serum or plasma samples.”
Huehn et al (US PGPub 2007/0269823, 11-2007) teaches, “As a preferred example according to the present invention, a 384-bp stretch that is differentially methylated in the region as covered by amplicons 1 and 2 (as described herein), but not the region covered by amplicons 3 and 4”. Huehn teaches one of skill in the art would not predict every CpG position in a gene is predictive of epigenetic regulation and/or a phenotype associated with such.
The unpredictability of applying methylation results to the prediction of a phenotype is supported by the teachings of Ushijima (Nature Reviews. 2005. 5: 223-231). Ushijima teaches that “interpretation of differential methylation has proven difficult because the significance of methylation alterations depends on the genomic region, and functions of the CpG islands at specific sites have not been fully clarified” (see abstract). Ushijima teaches that both hypermethylation and hypomethylation are associated with the occurrence of cancer (page 223). Ushijima (page 223) also teaches that “it has become recognized that methylation in cancer cells frequently occurs in CGIs outside promoter regions, which do not repress gene transcription, and also in promoter CGIs of genes that cannot be regarded as tumour-suppressor genes. Even in normal cells, methylation of specific CGIs frequently occurs. Therefore, to identify novel tumour suppressor genes silenced in cancer cells by CGI methylation it is necessary to carefully select the particular CGIs to be included in the analysis.”
Sabbioni et al (Mol Diagn 7(3):201-207 [2003]), analyzed promoter methylation of a variety of genes known to be methylated in different cancers in blood from gastrointestinal cancer patients, and report variation in both the extent and timing of aberrant methylation, concluding that even the gene that is the best indicator of colorectal cancer (TPEF) should be combined in a panel with at least 3 other genes for use in diagnosing colorectal cancer (see entire reference, particularly page 204, right column). Thus, the teachings of the prior art do not a support a conclusion that the invention of the instant claims is enabled.
Zhang (PLOS Genetics (2009) volume 5, e1000438) teaches, “We often observed that amplicons next to each other in the same CpG island had different methylation states (see Figure 3 for t an example).
The level of skill in the art:
The level of skill in the art is deemed to be high
Quantity of experimentation necessary:
In order to practice the invention as claimed, one would first have to establish that a predicative relationship exists between any determining a high-Risk Epigenetic And clinicopathologic Score for Oral caNcer (REASON) score from a biological sample from the individual having OSCC in any sample from any species Experimentation would be replete with unpredictable trial and error analysis because the specification teaches not all genes provided methylation consistent with risk of OSCC, The art demonstrates methylation is different in different tissues and different samples as well as species, one of skill in the art would have to recruit an enormous population of ethnically diverse patients of the recited diseases and disease-free controls and determine the association of the mutation with the recited diseases. . One of skill in the art would thus have to determine if methylation in any gene or anywhere in the genes recited is indicative of high risk OSCC.
Further it would be unpredictable to use methylation anywhere in the gene as Zhang teaches CpG methylation in amplicons next to each other is not predictable.
Due to the scope of the claims, one of skill in the art would be required to further undertake extensive trial and error experimentation to determine how to calculate a REASON score in any sample from any species using any genes and any non-molecular variable by any standard.
Therefore, in light of the breadth of the claims, the lack of guidance in the specification, the high level of unpredictability in the associated technology, the nature of the invention, the negative teachings in the art, and the quantity of unpredictable experimentation necessary to practice the claimed invention, it would require undue experimentation to practice the invention as claimed.
Claims 1-10 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.
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.
In applying the test as set forth in Alonso, it is noted that applicant is claiming Independent claim 1 is drawn to a method of providing decision support for a treatment regimen based on prognosis for an individual having oral squamous cell carcinoma (OSCC), the method comprising: determining a high-Risk Epigenetic And clinicopathologic Score for Oral caNcer (REASON) score from a biological sample from the individual having OSCC; and selecting a treatment regimen in response to the REASON score, the treatment regimen being one or more of an elective neck dissection, radiation, immunotherapy, or chemotherapy.
Thus the claims encompass any individuals of any species with OSCC.
The claims encompass any biological sample from any species having OSCC. Thus including muscle, brain, hair, liver, etc. samples.
Independent claim 10 is drawn to method of risk stratification of an individual having oral squamous cell carcinoma (OSCC), the method comprising: determining a high-Risk Epigenetic And clinicopathologic Score for Oral caNcer (REASON) score from a biological sample from the individual; and classifying the individual as having a high risk of OSCC-related mortality in response to the REASON score for the individual with OSCC being above a reference REASON score from a healthy individual.
Thus the claims encompass any individuals of any species with OSCC.
The claims encompass any biological sample from any species having OSCC. Thus including muscle, brain, hair, liver, etc. samples.
The claims encompass anything which can broadly be interpreted as determining a high-Risk Epigenetic And clinicopathologic Score for Oral caNcer (REASON) score. Further the claims encompass any means of calculating the REASON) score.
The specification teaches, “[0018] Disclosed here are methods wherein gene methylation signatures are combined with clinicopathologic factors to form a composite molecular and non-molecular signature with high prognostic performance in determining risk of 5-year mortality in early stage (I/II) OSCC patients. Clinicopathologic data were analyzed from an internal retrospective cohort of 515 OSCC patients as well as a cohort of 58 patients from TCGA. The top clinicopathologic factors that were highly predictive of 5-year mortality in these two cohorts were determined. Available methylation array data in the TCGA cohort were analyzed and twelve genes were identified that were differentially methylated between the OSCC patients who died by 5 years and those who survived. The relevant clinicopathologic factors with the twelve-gene methylation signature were combined into a risk score-the REASON score. Its predictive performance was evaluated to identify early-stage OSCC patients who died within five years of diagnosis.”
The specification teaches, “[0023] Embodiments include methods for risk stratification of a OSCC subject using brush swab samples and MC-Seq to noninvasively determine the methylation signature of an OSCC patient at the time of diagnosis.”
The specification teaches, “[0034] The DNA methylation-based, molecular component of the REASON score was developed according to a methylation state transition matrix. For each of the CpG sites, a
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of <0.3 indicated an unmethylated state, 0.33-0.75 a hemi-methylated state, and >0.75 a fully methylated state. A gene was considered to be hypermethylated if the methylation level moved from a less methylated state to a more methylated state. Conversely, a gene was considered hypomethylated if there was a state change to a lower level.”
The specification teaches, “Genes were annotated using Homer annotatePeaks.pl. With this software, the promoter region is defined as 1 kilobase from the transcription start site (TSS).” (0038) The specification teaches, “Separate scatterplots were rendered showing the concordance of these CpG sites between tissues and brush swabs for the cancer sites and the normal sites. Student t-tests were performed to compare R values between cancer and normal groups or tissue and brush swab groups. The most significant 1,000 CpGs features in cancer vs. normal groups were selected. Based on these results, the -log10(t-test p-value) was calculated for each of the 1,000 CpG sites to compare the degree of divergence in the significance of the test statistics for these 1,000 CpG between (1) cancer vs. normal and (2) tissue vs. brush swabs. Statistical analyses were performed in R environment (v. 4.1.0).
Methylation array analysis reveals differentially methylated genes in early stage OSCC patients who did not survive to 5 years.” (0038)
The specification teaches, “[0040] Of the 4,544 genes harboring CpG sites meeting criteria for analysis, 12 genes showed an adjusted p-value of <0.1 (Table 2). Gene position and methylation fold-change values are shown. The methylation trends for each gene that are predictive of poor survival here are shown, in comparison to the gene expression trends that are predictive of poor survival in previous studies. The PMID of the referenced study is included. They included ABCA2, CACNAH, CCNJL, GPR133, HGFAC, HORMAD2, MCPH], MYLK, RNF216, SOX8, TRPA], and WDR86.”
The specification teaches, “[0042] A literature search of each of the 12 genes revealed that with the exception of SOX8, none of the genes had previously been linked to OSCC in either human or preclinical studies. In Table 2 each of the genes is linked to the referenced clinical studies demonstrating poor cancer survival. HORMAD2 dysregulation through either SNPs or hypermethylation is attributed to poor survival in non-small cell lung cancer (NSCLC) and thyroid carcinoma. MYLK over-expression is linked to poor survival in bladder carcinoma, colorectal carcinoma, and hepatocellular carcinoma. GPR133 expression is inversely correlated with survival in patients with glioblastoma multiforme. The role of SOX8 has been already been investigated using in vitro models and in vivo models, as well as in clinical samples of OSCC. In a clinical study, SOX8 is over-expressed in chemoresistant patients with tongue SCC and is associated with higher lymph node metastasis, advanced tumor stage, and shorter overall survival. Similarly, higher SOX8 expression is linked to a high tumor histological grade, lymph node metastasis, and shorter overall survival in patients with endometrial carcinoma. TRPA] expression in cancer is controversial, with gene over-expression linked to poor survival in nasopharyngeal carcinoma and gene under-expression linked to poor survival in renal clear cell carcinoma. However, a study using International Cancer Genome Consortium data shows that the TRP family of genes has varying expression across different cancer types, and that some TRP genes have stronger prognostic ability than others. ABCA2, which encodes for a membrane- associated protein of the superfamily of ATP-binding cassette transporters, is over-expressed in epithelial ovarian carcinoma and acute lymphoblastic leukemia patients with poor survival. HGFAC expression is directly correlated to survival in breast ductal carcinoma and ovarian carcinoma. WDR86 expression is linked to poor survival in colorectal carcinoma and breast carcinoma . In a clinical study of solid tumors including gastric, lung and ovarian cancer, expression of T-type calcium channel genes including CACNA]H is used as a prognostic signature for survival. RNF216 expression is associated with poor survival in colorectal cancer and ovarian carcinoma, although whether over- or under-expression decreases survival is unknown. CCNJL expression is inversely correlated with survival in hepatocellular carcinoma. [0043] Of note, differential methylation of the 12 genes has not previously been linked to poor survival in any type of cancer. With the exception of HORMAD2 and HGFAC, published studies on these candidate genes have focused on differential gene expression rather than methylation. “
Thus the claim lack adequate written description for the breadth of the claims.
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 1-10 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.
The preamble of claim 1 recites, “method of providing decision support for a treatment regimen based on prognosis for an individual having oral squamous cell carcinoma (OSCC).” However the last active step of the claim is “selecting a treatment regimen in response to the REASON score, the treatment regimen being one or more of an elective neck dissection, radiation, immunotherapy, or chemotherapy.” Thus it is unclear as the claim does not provide a prognosis step. Further it is unclear how “selecting a treatment regimen in response to the REASON score” as the claim provides no specific guidance.
Claim 1 recites, “determining a high-Risk Epigenetic And clinicopathologic Score for Oral caNcer (REASON) score from a biological sample from the individual having OSCC.” The metes and bounds are unclear as high-risk suggests there is low risk. However, the specification and claims do not provide a basis to differentiate the two. Further the recitation of “determining a high-Risk Epigenetic And clinicopathologic Score for Oral caNcer (REASON) score from a biological sample” is vague, unclear and incomplete as the claims provide specific guidance and the specification fails to disclose a limiting definition. Thus the metes and bounds are unclear.
Claim 3 recites, “the REASON score is determined based on a plurality of non-molecular variables and a plurality of methylation patterns of a plurality of genes.” The metes and bounds are unclear how this is done as the claim provide no specific guidance on how to determine a REASON score. Further based on is not an art accepted term. Thus it is unclear what is included or excluded by the recitation of the claim. Further it is unclear as the individual, histologic grade of the OSCC, stage of the OSCC, perineural invasion, lymphovascular invasion, and margin status of the OSCC do not necessarily provide values nor does methylation status.
Claim 7 recites, “healthy individual.” The specification recites this limitation once. The specification does not define the limitation. Thus it is unclear if a healthy individual requires a subject with no disease including allergies, athletes foot, etc. or if the claim merely requires a subject without OSCC.
Claim 10 recites, “determining a high-Risk Epigenetic And clinicopathologic Score for Oral caNcer (REASON) score from a biological sample from the individual having OSCC.” The metes and bounds are unclear as high-risk suggests there is low risk. However, the specification and claims do not provide a basis to differentiate the two. Further the recitation of “determining a high-Risk Epigenetic And clinicopathologic Score for Oral caNcer (REASON) score from a biological sample” is vague, unclear and incomplete as the claims provide specific guidance and the specification fails to disclose a limiting definition. Thus the metes and bounds are unclear.
Claim 10 recites, “healthy individual.” The specification recites this limitation once. The specification does not define the limitation. Thus it is unclear if a healthy individual requires a subject with no disease including allergies, athletes foot, etc. or if the claim merely requires a subject without OSCC.
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 1-10 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a mental step without significantly more. The claim(s) recite(s) the abstract idea or mental step of determining and selecting. This judicial exception is not integrated into a practical application because the claim fails to provide an active step which cannot be done in the mind. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims provide only mental steps.
Claim analysis
The instant claim 1 is directed towards method of providing decision support for a treatment regimen based on prognosis for an individual having oral squamous cell carcinoma (OSCC), the method comprising: determining a high-Risk Epigenetic And clinicopathologic Score for Oral caNcer (REASON) score from a biological sample from the individual having OSCC; and selecting a treatment regimen in response to the REASON score, the treatment regimen being one or more of an elective neck dissection, radiation, immunotherapy, or chemotherapy.
The determining and selecting step encompass mental steps or abstract ideas which can be practiced in the mind.
Dependent claims set forth further limitations to about individual, non-molecular variable, genes of which methylation was determined, etc.
Claim 10 is drawn to a method of risk stratification of an individual having oral squamous cell carcinoma (OSCC), the method comprising: determining a high-Risk Epigenetic And clinicopathologic Score for Oral caNcer (REASON) score from a biological sample from the individual; and classifying the individual as having a high risk of OSCC-related mortality in response to the REASON score for the individual with OSCC being above a reference REASON score from a healthy individual.
The determining and classifying steps are mental steps or abstract ideas which can be done in the mind.
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/or mental step.
With regards to claim 1, the claim recites, “determining a high-Risk Epigenetic And clinicopathologic Score for Oral caNcer (REASON) score from a biological sample from the individual having OSCC; and selecting a treatment regimen in response to the REASON score, the treatment regimen being one or more of an elective neck dissection, radiation, immunotherapy, or chemotherapy.” The determining step broadly encompasses reading a report comprising the data, while the selecting step is a mental step which can be done in the mind.
Further claim 7 encompasses a comparison to determine the REASON score is above a reference. This is an additional mental step.
Further claim 10 recites, “determining a high-Risk Epigenetic And clinicopathologic Score for Oral caNcer (REASON) score from a biological sample from the individual; and classifying the individual as having a high risk of OSCC-related mortality in response to the REASON score for the individual with OSCC being above a reference REASON score from a healthy individual.” The determining step broadly encompasses reading a report comprising the data, while the classifying step is a mental step or abstract idea which can be done in the mind.
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? The answer is no as the claims provide no active step which is not practiced in the mind which integrates the judicial exception.
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No, the claims provide no limitations which require specific reagents which can be considered significantly more.
If the methylation determination of 1 and 10 are considered active steps these are routine and conventional as the specification teaches:
Methylation analysis by Illumina Infinium Methylation 450K Array data analyses
Thus the claim does not provide additional steps which are significantly more.
Further the art of Guerrero-Preston (US20130071842) demonstrates this is routine and conventional.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-4, 6-7, 10 is/are rejected under 35 U.S.C. 102(a)(1)/102 (a)(2) as being anticipated by Guerrero-Preston (US20130071842).
With regards to claims 1-4, 10 Guerrero-Preston discloses a method of providing decision support for treatment regimen based on prognosis for an individual having oral squamous cell carcinoma( OSCC) (Differentially methylated oral squamous cell carcinoma (OSCC) biomarkers, identified in-vitro and validated in well-characterized surgical specimens, have shown poor clinical correlation in cohorts with different risk profiles. To overcome this lack of relevance we used the Human Methylation BeadChip, publicly available methylation and expression array data, and Quantitative Methylation Specific PCR to uncover differential methylation in OSCC clinical samples with heterogeneous risk profiles. A two stage-design consisting of Discovery and Prevalence screens was used to identify differential promoter methylation and deregulated pathways in patients diagnosed with OSCC and head and necks squamous cell carcinoma. This Phase Biomarker Development Trial identified a panel of differentially methylated genes in normal and OSCC clinical samples from patients with heterogeneous risk profiles. Th I s pane! May be useful for early detection and cancer prevention, Abstract; multi-dimensional! Knowledge may provide opportunities for the diagnosis of premalignant squamous lesions, and for the development of novel molecular-targeted strategies for the prevention and treatment of OSCC,[0059]), the method comprising: determining a high-Risk Epigenetic And clinicopathologic Score for Oral cancer (REASON)score (differential methylation in as subset of genes show a progression to hypermethylation in OSCC samples... overlap of significantly hypermethylated genes in cancer when compared to normal tissue,(0014); candidate genes can be used in diagnostic panels for early detection of OSCC and HNSCC in tissue and saliva from patients from countries with different PAR due to tobacco and alcohol use [plurality of non-molecular variables], [0049];OSCC, which are smoking and alcohol related [plurality of non-molecular variables].It might very well be that viral related tumors have different patterns of methylation motifs [plurality of methylation patterns], [0055]; directly modulating the expression of BRCA1, a DNA repair gene[38]. Therefore HOXAQ hypermethylation may lead to diminished DNA repair capacity in OSCC/HNSCC, thus increasing cancer risk particularly in those patients that smoke tobacco,[0057]; [see applicant definition of REASON score [0004)) from a biological sample from the individual having OSCC (Bioinformatics strategies were used for background correction, normalization a data analysis of differentially methylated genomic regions between tumor, leukoplakia and normal tissue. The gene selection from the Illumina Infinium assay data was performed in a stepwise manner. An F-test was performed across all twelve samples to identify genes with a significant difference in values between normal, leukoplakia, and malignant tissue, (0066): focus genes with high specific connectivity (overlap between the initialized network and gene's immediate connections) were added to the growing network until the network reached a default size of 35 nodes. Non-focus genes (those that were not among our differentially methylated input list) that contained a maximum number of links to the growing network were also incorporated. The ranking score for each network was then computed by a right-tailed Fisher's exact test as the negative log of the probability that the number of focus genes in the network is not due to random chance. Similarly, significances for functional enrichment of specific genes were also determined by the right-tailed Fisher's exact test, using all input genes as a reference set, (0069}); and selecting a treatment regimen in response to the REASON score (identifying said human subject as having a head and neck squamous cell cancer when the level of promoter methylation of the one or more genes of interest in the test sample of the subject, is increased relative to the level of promoter methylation of the one or more genes of interest in a referenc