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 .
Claim Status and Formal Matters
This action is in response to papers filed 12/1/2025.
Claims 1-3, 5, 9, 11-12, 18-19, 21-22, 24 have been amended.
Claims 29-35 have been added by amendment.
Claims 1-3, 5, 9, 11-12, 18-19, 21-22, 24 , 29-35 are being examined.
The previous objection to the claims has been withdrawn.
Priority
The instant application was filed 01/13/2023 is a National Stage entry of PCT/US2021/041638 having an International Filing Date: 07/14/2021 and claims priority from provisional application 63052050 , filed 07/15/2020.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
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 2-3, 5, 22, 24 , 29-35 are 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
Method of determining method of determining methylation of TMEM178, KLHL14 and CPXM1 in an esophagus sample comprising: obtaining an esophagus sample, isolating DNA from the esophagus sample; treating the isolated DNA with bisulfite to convert cytosines without methylation to uracil, amplifying the treated DNA and determining the presence of methylation.
does not reasonably provide enablement for in vivo methylation detection. 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 2 An in vitro method of identifying a human subject with Barrett's esophagus (BE) as having a high risk of progressing to esophageal adenocarcinoma (EAC), comprising: extracting DNA from an esophageal sample obtained from the subject; measuring a methylation level of at least three genes the extracted DNAcomprise the transmembrane protein 178 (TMEM178},kelch-like family member 14(KLHL14} and carboxypeptidase X, M14 family member 1 (CPXM1} genes; comparing the methylation level of the at least three genes human control; identifying the subject as having a high risk of progressing to EAC if the methylation level of the at least three genes with endoscopic mucosal resection (EMR), endoscopic submucosal surgical dissection (ESD), minimally invasive esophageal surgery, cryoablation, or radiofrequency ablation (RFA), or if the subject is not identified as having a high risk of progressing to EAC, treating the subject with endoscopic monitoring about every 5 to 10 years.
Thus the claim are drawn to anything which can be encompassed by three gene loci comprise one loci from each of the TMEM178, KLHL14 and CPXM1 genes.
The claims encompass any human control.
Claim 3 depends from claim 2 and draws the invention to further comprising obtaining the esophageal sample from the subject.
Thus the independent claims encompass determining methylation in vivo.
Claim 5 depends from claim 2 and draws the invention further comprising treating the subject identified as having a high risk of progression to EAC with endoscopic monitoring about every 6 months..
Claim 22 depends from claim 1 and draws the invention to wherein the human control is an esophageal sample from a healthy human subject who does not have BE or EAC, or an esophageal sample from a human subject with BE who did not progress to EAC
Claim 24 depends from claim 22 and draws the invention wherein the esophageal sample of the human control is an esophageal cell sample, an esophageal biopsy, or an esophageal resection.
Claim 29 depends from claim 2 and draws the invention to wherein the control is a historical control or reference standard value based on previously tested human control subjects.
Claim 30 depends from claim 2 and draws the invention to further comprising measuring the methylation level of the ubiquitin-specific protease-44 (USP44) gene.
Claim 31 depends from claim 2 and draws the invention to further comprising measuring the methylation level of one or more additional genes, wherein the one or more additional genes is selected from the group consisting of tripartite motif containing 71 (TRIM71), catenin alpha 2 (CTNNA2), neural cell adhesion molecule 1 (NCAM1), synuclein beta (SNCB), bone morphogenetic protein 3 (BMP3), shisa family member 3 (SHISA3), brain derived neurotrophic factor (BDNF), collagen type II alpha 1 chain (COL2A1), cystathionine beta-synthase (CBS), C-type lectin domain family 4 member G pseudogene 1 (CLEC4GP1), lecithin retinol acyltransferase (LRAT), tweety family member 1 (TTYH1), transmembrane protein 90B (TMEM90B), netrin 1 (NTN1), vasohibin 2 (VASH2) and SKI family transcriptional corepressor 1 (SKOR1).
Claim 32 depends from claim 31 and draws the invention to comprising: (i) measuring the methylation level of each of the SNCB, BMP3, CTNNA2, TRIM71 and NCAM1 genes; (ii) measuring the methylation level of each of the SHISA3, BDNF, COL2A1, CBS, CLEC4GP1, LRAT, TTYH1 and TMEM90B genes; and/or (iii) measuring the methylation level of each of the TRIM71, SNCB, NTN1, VASH2 and SKOR1 genes.
Claim 33 depends from claim 2 and draws the invention to wherein the esophageal sample is an esophageal cell sample, an esophageal biopsy, or an esophageal resection.
Claim 34 depends from claim 2 and draws the invention to further comprising converting the extracted DNA to bisulfite DNA (bs-DNA).
Claim 35 depends from claim 2 and draws the invention to wherein measuring the methylation level comprises bisulfite sequencing, microarray, bead array, PCR combined with sequencing, pyrosequencing, methylation-specific PCR, or endonuclease digestion.
The amount of direction or guidance and the Presence and absence of working examples.
The specification on page 8 states: “Control: A reference standard. In some embodiments, the control is a healthy subject, such as a healthy subject without BE or EAC. In other embodiments, the control is a subject with a cancer, such as EAC, or a subject with BE. In some embodiments, the control is a subject with BE who does not progress to EAC. In other embodiments, the control is a subject who progresses from BE to EAC. In still other embodiments, the control is a historical control or standard reference value or range of values (e.g., a previously tested control subject with a known prognosis or outcome or group of subjects that represent baseline or normal values). A difference between a test subject and a control can be an increase or a decrease. The difference can be a qualitative difference or a quantitative difference, for example a statistically significant difference.”
The specification in example 1 appears determine methylation in human BE cases using FFPE BE samples. (page 27). The specification teaches treatment of DNA extracted from the BE samples and then hybridized to the Illumina Infinium HD methylation. The specification teaches use of Partek Genomic suits or CHAMP methylation analysis.
The specification teaches the use of Illumina Methylation EPIC array for analysis of FFPE samples from esophagus of BE patients that did or did progress to EAC. The specification teaches, “Of 17 progressing cases, 14 cases showed hypermethylation in these 10 genes: KLHL/ 4, USP 44, TMEM178, TRIM71, CTNNA2-LRRTM1-CTNNA2, NCAM1, CPXM1, SNCB-EIF4E1B- SNCB, TRIM71, and BMP3 (Table 2 and FIG. 4). Of the 15 non-progressing cases, none showed ) hypermethylation in these top 10 genes. The sensitivity, specificity and accuracy of top 10 gene hypermethylation to identify high risk patients to progress to EAC were 82.35%, 100% and 91.18%, respectively. Three BE progressing cases did not have these 10 gene hypermethylation. Negative predictive value and positive predictive value were 83.33% and 100%, respectively. With a receiver operating characteristics (ROC) curve analysis, the area under curve is 0.9118 without ) the adjustment of the incidence of EAC and 0.81 with the adjustment of the incidence of EAC.”
Presence and absence of working examples
The specification provides no teachings with respect to how to detect methylation in vivo.
The specification teaches 3 BE progression did not have hypermethylation.
The specification teaches the analysis model depended on genes which were or were indicative of progression to EAC.
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.”
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, he skilled artisan would further have to determine how to assay the presence or absence of hypermethylation of TMEM178, KLHL14 and CPXM1 relative to any control is in indicative of progression to EAC in an in vivo system. Experimentation would be replete with unpredictable trial and error analysis because the specification provides no specific guidance on how to determine methylation in vivo. Further the skilled artisan would further have to determine how to assay the methylation of nucleic acid sequence of specific cells or groups of cells in vivo , as examining all the cells in vivo would result in considerable heterogeneity, as well as possible issues with nucleic acids of symbiotic bacteria, and nucleic acids present in the digestive tract from food sources. The skilled artisan would further have to determine if the in vivo methylation assay corresponds to in vitro methylation assays. The skilled artisan would also have to determine how amplify the signal of hypermethylation of TMEM178, KLHL14 and CPXM1 relative to any control in genomic DNA in such away as to be able to predictably determine the presence or absence of hypermethylation of TMEM178, KLHL14 and CPXM1 relative to any control in a manner which is specifically detectable. This would require undue experimentation, as systems for in vivo nucleic acid methylation detection are not known in the art and the specific guidance required as outlined above has not been provided in the instant specification or prior art.
Further it would be unpredictable to practice the invention with respect to any human control. The specification teaches the control can be a subject with EAC. Further the specification teach teaches not all subject with EAC had increased methylation of all the recited genes. The art demonstrates methylation based diagnostics are generally not reproducible, 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 hypermethylation of TMEM178, KLHL14 and CPXM1 relative to any control is in indicative of progression to EAC relative to any human control sample .The art teaches genes are differentially methylated in different tissues. Further the art demonstrates is different in different species.
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 if methylation of MEM178, KLHL14 and CPXM1 in any esophagus sample relative to any human control from any sample is correlated with progression to EAC. The specification is limited to only human FFPE esophagus samples relative to human FFPE esophagus.
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.
Response to Arguments
The response begins traversing the rejection by asserting, “Solely in an effort to advance prosecution, independent claims 1 and 2 are amended herein to clarify that the methods are in vitro methods, to specify that the sample is an esophageal sample, to add the step of extracting DNA from the esophageal sample, to specify detecting methylation of the TMEM178, KLHL14 and CPXM1 genes (rather than gene loci), to specify that subject is a human subject, and (in claim 2) to specify the control is a human control. As discussed during the telephone interview of November 4, 2025, these amendments render moot the majority of points raised in the Office Action. With respect to the specific method for detecting methylation, Applicant disagrees that the amended claims lack enablement. Specifically, Applicant asserts that it is not necessary to require treating DNA with bisulfite and amplifying DNA to determine the presence of methylation.” This argument has been thoroughly reviewed but is not considered persuasive as claim 3 recites, “further comprising obtaining the esophageal sample from the subject.” Thus for claim 3 to properly limit independent claim 2, claim 2 must encompass the esophageal sample is not obtained from a subject or is in vivo.
The response continues by asserting, “As taught in Applicant's specification, methods for detecting methylation of a gene were well-known as of the priority date of the application. A number of exemplary methods for detecting DNA methylation are described in section IV of the specification (starting on page 20). Although Applicant's specification teaches that DNA methylation can be detected using bisulfite sequencing or bisulfite treatment of DNA followed by PCR, several alternative methods are described, including methylation-specific PCR, pyrosequencing (for which commercial kits are available), and endonuclease assays (which do not require bisulfite conversion of DNA). The specification also references US patent application publications (e.g., US 2016/0201113 and US 2010/0267021) that disclose a number of different methods for detecting DNA methylation, providing further evidence that such methods were well-known in the art as of the priority date. Moreover, the specification (at page 20) cites the publication Kurdyukov and Bullock (Biology 5:3, 2016), a copy of which was provided with the Information Disclosure Statement filed on January 13, 2023. This reference provides a review of several different exemplary methods for detecting DNA methylation (such as in Table 2) and provides guidance on how to select an appropriate method. Thus, more than sufficient information was available to a skilled person as of the priority date to enable multiple different methods for detecting methylation of a gene.” This argument has been thoroughly reviewed but is not considered persuasive as the specification teaches, “Control: A reference standard. In some embodiments, the control is a healthy subject, such as a healthy subject without BE or EAC. In other embodiments, the control is a subject with a cancer, such as EAC, or a subject with BE. In some embodiments, the control is a subject with BE who does not progress to EAC. In other embodiments, the control is a subject who progresses from BE to EAC. In still other embodiments, the control is a historical control or standard reference value or range of values (e.g., a previously tested control subject with a known prognosis or outcome or group of subjects that represent baseline or normal values). A difference between a test subject and a control can be an increase or a decrease. The difference can be a qualitative difference or a quantitative difference, for example a statistically significant difference.”” Thus using a cancer subject as a control would not allow one of skill in the art to predictably practice the invention.
Claims 2-3, 5, 22, 24 , 29-35 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.
Independent claim 2 is drawn to An in vitro method of identifying a human subject with Barrett's esophagus (BE) as having a high risk of progressing to esophageal adenocarcinoma (EAC), comprising: extracting DNA from an esophageal sample obtained from the subject; measuring a methylation level of at least three genes the extracted DNAcomprise the transmembrane protein 178 (TMEM178},kelch-like family member 14(KLHL14} and carboxypeptidase X, M14 family member 1 (CPXM1} genes; comparing the methylation level of the at least three genes human control; identifying the subject as having a high risk of progressing to EAC if the methylation level of the at least three genes with endoscopic mucosal resection (EMR), endoscopic submucosal surgical dissection (ESD), minimally invasive esophageal surgery, cryoablation, or radiofrequency ablation (RFA), or if the subject is not identified as having a high risk of progressing to EAC, treating the subject with endoscopic monitoring about every 5 to 10 years.
Thus the claim are drawn to anything which can be encompassed by three gene loci comprise one loci from each of the TMEM178, KLHL14 and CPXM1 genes.
The claims encompass any human control.
Claim 3 depends from claim 2 and draws the invention to further comprising obtaining the esophageal sample from the subject.
Thus the independent claims encompass determining methylation in vivo.
The teachings of the specification are limited to human esophagus samples assayed in vitro. Thus the claims lack adequate written description for detection of hypermethylation in any in vivo esophagus sample.
Thus the claims lack adequate written description.
Response to Arguments
The response traverses the rejection in view of the amendment. This argument has been thoroughly reviewed but is not considered persuasive as claim 3 depends from claim 2 and requires, “further comprising obtaining thesophageal sample from the subject.” Thus claim 2 must encompasses analysis without obtaining the esophageal sample. Thus the independent claim must encompass in vivo analysis. Thus the rejection is maintained.
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 2-3, 5, 22, 24 , 29-35 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.
Independent claim 2 is drawn to An in vitro method of identifying a human subject with Barrett's esophagus (BE) as having a high risk of progressing to esophageal adenocarcinoma (EAC), comprising: extracting DNA from an esophageal sample obtained from the subject; measuring a methylation level of at least three genes the extracted DNAcomprise the transmembrane protein 178 (TMEM178},kelch-like family member 14(KLHL14} and carboxypeptidase X, M14 family member 1 (CPXM1} genes; comparing the methylation level of the at least three genes human control; identifying the subject as having a high risk of progressing to EAC if the methylation level of the at least three genes with endoscopic mucosal resection (EMR), endoscopic submucosal surgical dissection (ESD), minimally invasive esophageal surgery, cryoablation, or radiofrequency ablation (RFA), or if the subject is not identified as having a high risk of progressing to EAC, treating the subject with endoscopic monitoring about every 5 to 10 years. However, claim 3 depends from claim 2 and draws the invention to further comprising obtaining the esophageal sample from the subject. Thus the metes and bounds of the independent claim are confusing and unclear how the method can be an in vitro method, and extracting DNA from the esophageal sample obtained from the subject when dependent claim 3 requires obtaining an esophageal sample from the subject.
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, 9, 11-12, 18-19 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dilworth (Ann Surg 2019;269:479–485)
This is a new grounds of rejection necessitated by amendment as independent claim 1 no longer requires detection of hypermethylation.
With regards to claim 1, Dilworth teaches, “A whole genome methylation interrogation using the Illumina HumanMethylation 450 array of patients with nondysplastic Barrett esophagus who either develop adenocarcinoma or remain static, with validation of findings by bisulfite pyrosequencing.” (methods) Dilworth teaches, “: In all, 12 patients with ‘‘progressive’’ versus 12 with ‘‘nonprogres sive’’ nondysplastic Barrett esophagus were analyzed via methylation array. Forty-four methylation markers were identified that may be able to discriminate between nondysplastic Barrett esophagus that either progress to adeno carcinoma or remain static. Hypomethylation of the recently identified tumor suppressor OR3A4 (probe cg09890332) validated in a separate cohort of samples (median methylation in progressors 67.8% vs 96.7% in nonprogressors; P < 0.0001, z = 3.85, Wilcoxon rank-sum test) and was associated with the progression to adenocarcinoma. There were no differences in copy number between the 2 groups, but a global trend towards hypomethylation in the progressor group was observed.)
With regards to claim 9, 11-12, Dilworth teaches whole genome methylation which encompasses the recited genes.
With regards to claim 18, Dilworth teaches esophageal biopsy (patients and samples).
With regards to claim 19, Dilworth teaches bisulfite conversion (methylation arrays)
With regards to claim 21, Dilworth teaches use of Illumina human methlation 450 arrays. (methylation arrays)
Summary
NO claims are allowed.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEVEN C POHNERT PhD whose telephone number is (571)272-3803. The examiner can normally be reached Monday- Friday about 6:00 AM-5:00 PM, every second Friday off.
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/Steven Pohnert/Primary Examiner, Art Unit 1683
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