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 .
Detailed Action
Summary
This is a Non-Final Office action based on the 16/978638 application response filed 10/03/2025.
Claims 1, 3-11, 14, 24-26, & 34-39 are pending and have been fully considered.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/03/2025 has been entered.
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 ofmatter, or any new and useful improvement thereof, may obtain a patent therefor, subject to theconditions and requirements of this title.
The claimed invention of Claims 1, 3-11, 14, 24-26, & 34-39 are directed to non-statutory subject matter.
The invention of instant claims 1, 3-11, 14, 24-26, & 34-39 are drawn towards a detecting/diagnosing or monitoring progression of esophageal adenocarcinoma.
Through 101, inquiry analysis:
Step 1, Is the claim directed to a statutory category of invention?
Yes, the independent claims 1 & 34 are drawn towards a statutory category method.
Step 2 A, Prong One: Do the claims involve a Judicial Exception?
Yes. The independent claims 1 & 34 involve the judicial exceptions of a natural correlation (natural amount of claimed biomarker or biomarker panels and their association/correlation with esophageal adenocarcinoma; natural correlations are laws of nature).
Monitoring progression as claimed in the preamble- as claimed seems to also be a mental process and determining a biosignature using ANOVA, Turkey or Kruska- Wallis and Dunn tests, are mathematical calculations which are also an abstract idea judicial exception.
Step 2 A, Prong Two: Has the Judicial Exception, which here is a law of nature/natural correlation or abstract idea been integrated into a particular practical application?
After the steps involving the judicial exceptions in claims a & 34 (so the general measurement of the biomarkers and diagnosis of the EAC), and after performance of the ANOVA, Turkey post hoc or Kruska-Wallis and Dunn post hoc test, what is done?
As amended 10/03/2025, it is claimed that an invasive procedure is performed in subjects which are determined to have EAC, wherein the invasive imaging is esophago-gastro duodenoscopy, CT scan, biopsy, and combinations of. With respect to this--- biopsies, CT scans, and gastro duodenoscopy are not treatments, but instead they are all further diagnostic procedures/scans, and therefore they are extra-solution activity, and not particular and specific treatments. This is especially true when it is claimed that only one is needed, and as alternatives to one another.
SeeMPEP 2106.05(g). See Vanda memorandum.
Therefore, nothing in the claims practically apply the judicial exceptions.
Even further, though again claimed general biopsy, CT scan, and duodenoscopy is not treatment, if it were—as claimed would be akin to “administering a suitable medication,” due to the general level at which these are claimed and since they are claimed as alternatives to one another, which amounts to merely instructions to “apply,” the judicial exception in a generic way. See MPEP 2106/04 (d)(2).
It is further claimed that the measuring of certain biomarkers that are more than a reference is done by “phenyl isothiocyanate,” derivatization. Though phenyl isothiocyanate derivatization would seem to point towards the fact that possibly particular detection is performed in the instant claims, as claimed--- the phenyl isothiocyanate is claimed as extra-solution activity and therefore not enough to move past the instant judicial exceptions. This is because it is not claimed that the phenyl isothiocyanate derivatized metabolite is extracted itself, and then this compound is analyzed to determine the metabolic signature. Nor is it claimed what is meant by “metabolite extraction,” which could mean that any metabolite is extracted, using any method known to man, and does not necessarily mean that the phenyl isothiocyanate derivatized amino acids are what is being detected. Also, as claimed, nothing is done with the derivatized sample and not particular detection is claimed, the claimed measuring step seems to only be a data pull for the statistical analysis (ANOVA) performed in the instant claims.
See USPTO Subject Matter Eligibility examples, Example 29 (Julitis claims), Claims 2-4.
Note that data gathering to be used in an abstract idea is insignificant extra-solution activity, and not a particular practical application. See MPEP 2106.05(g).
Step 2B: Does the claim recite any elements which are significantly more than the natural correlation or abstract idea?
There are no features instantly claimed which result in significantly more than the claimed judicial exceptions in independent claims 1 & 34.
It is claimed that the measuring of certain biomarkers that are more than a reference is done by “phenyl isothiocyanate,” derivatization. Though phenyl isothiocyanate derivatization would seem to point towards the fact that possibly particular detection is performed in the instant claims, as claimed--- the phenyl isothiocyanate is claimed as extra-solution activity and therefore not enough to move past the instant judicial exceptions. This is because it is not claimed that the phenyl isothiocyanate derivatized metabolite is extracted itself, and then this compound is analyzed to determine the metabolic signature. Nor is it claimed what is meant by “metabolite extraction,” which could mean that any metabolite is extracted, using any method known to man, and does not necessarily mean that the phenyl isothiocyanate derivatized amino acids are what is being detected. General metabolite extraction is routine and conventional in the art and not enough to make the claims significantly more than the claimed judicial exceptions.
See MPEP 2106.05(d) which deals with what is considered “Well-Understood, Routine and Conventional.”
Also, see USPTO Subject Matter Eligibility examples, Example 29 (Julitis claims), Claims 2-4.
The independent claim further includes mention that the threshold for needing therapy is “1.5 times less” than what is found in a reference. Though this adds detail to the claim- this recognition is merely part of the recognized natural correlation judicial exception and does not change matters.
Further, as amended 10/03/2025, it is claimed that an invasive procedure is performed in subjects which are determined to have EAC (a type of cancer), wherein the invasive procedure is esophago-gastro duodenoscopy, CT scan, biopsy, and combinations of. With respect to this--- CT scans, biopsies, and duodenoscopies are not treatments, but instead are further diagnostic procedures/tests.
Further- with respect to the CT scan, this is very general imaging. Biopsies are performed for any/every cancer or when one wants to determine if a patient has cancer. CT scans are performed in many cancers, but also for many non-cancerous conditions. Duodenoscopies are also performed for many conditions. Therefore, as claimed the invasive procedures at the level of generality claimed are routine and conventional imaging in the art, and therefore not enough to make the claims significantly more than the claimed judicial exceptions.
See MPEP 2106.05(d) which deals with what is considered “Well-Understood, Routine and Conventional”:
The dependent claims undergo a similar analysis. Nothing in any of the dependent claims change the matters above.
Claims 3-4 & 14 & 24-26, 35-36 specify biomarkers that may be assayed for/that are on the panel. These biomarkers are part of the judicial exception (law of nature/natural correlation) itself.
Claim 5, specifies biomarkers that may be assayed for/that are on the panel and the level they are measured at for indication of a result. These biomarkers are part of the judicial exception (law of nature/natural correlation) itself.
Dependent claims 6-8 specify that variations of MS- HPLC are used for detection. This is also not enough to make the instant method significantly more than the judicial exception as these methods are all routine and conventional in the art.
With respect to Claims 9-11, they specify where the sample is from and what disease the patient has. This is all part of the claimed judicial exception/law of nature/natural correlation and therefore does not change the matters above.
With respect to Claim 37, clustering and computation on ROC, especially at the level of generality claimed is routine and conventional in the art and therefore does not change the matters above.
With respect to Claims 38-39, they specify the treatment which could occur, however list broad treatments including palliative care, radiation, endoscopy to name a few. Especially at the level of generality claimed and since these treatments also do not seem to be particular or specific with respect to EAC, and not enough to overcome the 101 rejection. See Vanda memorandum. And further-- this treatment is akin to “administering a suitable medication,” which is merely instructions to “apply,” the judicial exception in a generic way so not particular practical application. See MPEP 2106.04 (d)(2).
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
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.
Claim(s) 1, 6-7, 11, 14, 34, & 37 is/are rejected under pre-AIA 35 U.S.C. 103 as obvious over GOIX in US 20090234202 in view of PETERS in “Dose-dependent effects of leucine supplementation on preservation of muscle mass in cancer cachectic mice” (as shown on the IDS dated 09/04/2020) and further in view of RATHMAN in US 9546994.
With respect to Claims 1, 14, & 34, GOIX teaches of methods for the detection and monitoring of a condition in a subject using highly sensitive detection of molecules (abstract). GOIX further teaches of detecting panels of markers/biomarkers (paragraph 0088-0089, 0341, 0432-0433). GOIX teaches of detecting the markers in gastric fluid (paragraph 0005, 0197) and detecting esophageal cancer and adenocarcinoma cells (paragraph 0132, 0131). GOIX further teaches of detecting methionine (paragraph 0146) and tyrosine kinases (paragraph 0144, 0418), and creatinine (paragraph 011) as biomarkers/markers for the cancer (paragraph 0442). GOIX teaches that the biomarker levels can be determined using analytical methods/instruments of high sensitivity (paragraph 0245-0248), and further teaches of comparison to a reference (paragraph 0342, 0441).
GOIX further teaches that statistical analytical methods are employed to determine when the biomarkers are present (paragraph 0261) and to determine from the measurements if cancer is present (paragraph 0438, 0452).
GOIX further teaches of performing an invasive imaging procedure (paragraph 0349,).
GOIX does not disclose wherein the quantity of the metabolite in the sample from the subject is at least 1.5 times greater than that found in the at least one reference sample or of analysis using ANOVA and post hoc testing.
PETERS is used to remedy this and discloses wherein the quantity of the metabolite in the sample from the subject is at least 1.5 times greater than that found in the at least one reference sample (as shown in table II, the level of tyrosine in tumor-bearing TB mice was found to be 101+8 vs. 68+5 in control C mice, which is equal to about 50 percent increase, where confidence interval +8 indicates that in some mice the level of tyrosine was increased by more than by 50 percent; abstract; page 250, table III), specifically for adenocarcinomas (Page 248, column 1, paragraph 2).
PETERS further teaches of using ANOVA and post hoc analysis to compare the data and measurements of the different groups (Page 249, column 2, paragraph 6).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the instant invention, to have modified the method of GOIX in order to have provided for wherein the quantity of the metabolite in the sample from the subject is at least 1.5 times greater than that found in the at least one reference sample, as disclosed by Peters (Peters; abstract; page 250, table III), for improving effectiveness of monitoring of the progression of cancer. Further, provided that GOIX and PETERS both disclose methods of monitoring cancer progression in mammals by measurement of the level of tyrosine(as shown above), the modification to GOIX’s method, of providing for wherein the quantity of the metabolite in the sample from the subject is at least 1.5 times greater than that found in the at least one reference sample would have been obvious to one of ordinary skill in the art to use ANOVA and the threshold in PETERS in the method of GOIX, due to the advantages both threshold levels and ANOVA offers for comparing groups (PETERS, Page 249, column 2, paragraph 6).
GOIX and PETERS do not teach of derivatization with phenyl isothiocyanate.
RATHMAN et al. is used to remedy this. RATHMAN teach of a method of analyzing samples for diseases(abstract) and more particularly teaches of derivatization of amino acids including histidine with 5% phenylisothiocyanate reagent (PITC), (d) drying of samples, (e ) extraction of metabolites and internal standards with 5 mM ammonium acetate in methanol, (f) centrifugation through filter membrane, (g) dilution with MS running solvent and more specifically that this derivatization works well with mass spectrometry (Column 19, lines 30-31). It would have been obvious to one of ordinary skill before the effective filing date of the instant invention in the art to derivatize samples as is done in RATHMAN in the methods of GOIX and PETERS due to the known success it has for derivatizing amino acids for mass spectrometry and due to common knowledge in the art of methods for derivatization (Column 12, line 25-50, Column 19, line 20-55).
With respect to Claims 6-7, RATHMAN et al. teach of detection by LC-MS (Column 19, lines 30-31).
With respect to Claim 11, GOIX et al. teach of the method detecting dysplasia and cancers (the progression) (paragraph 0131-132).
With respect to Claim 37, GOIX teaches of using ROC analysis (paragraph 0438).
Claim(s) 24-25 is/are rejected under pre-AIA 35 U.S.C. 103 as obvious over GOIX in US 20090234202 in view of PETERS in “Dose-dependent effects of leucine supplementation on preservation of muscle mass in cancer cachectic mice” (as shown on the IDS dated 09/04/2020) in view of RATHMAN in US 9546994 and in further view of QIU in “Mass Spectrometry-Based Quantitative Metabolomics Revealed a Distinct Lipid Profile in Breast Cancer Patients” (as cited on IDS dated 09/04/2020).
With respect to Claims 24-25, GOIX, PETERS, and RATHMAN teach of the claimed invention as shown in the above rejection for Claim 1. GOIX, PETERS, and RATHMAN do not disclose wherein the glycerophospholipid is lysoPC a C26:0.
However, Qiu discloses wherein the glycerophospholipid is lysoPC a C26:0 (as shown in table 1 in line 33, the level of the lysoPC a C26:0 was found to be 1.28 fold decreased in the breast cancer group compared to the controls; page 8051, table 1). Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the instant invention, to have modified the method of GOIX, PETERS and RATHMAN in order to have provided for wherein the glycerophospholipid is lysoPC a C26:0, as previously disclosed by Qiu (Qiu; page 8051, table 1) is used as a marker since it would have improved effectiveness /success in increasing cancer markers for diagnostic purposes (Qiu; abstract; page 8051, table 1).
Claim(s) 8-10, 3-5, 26, & 35-36 is/are rejected under pre-AIA 35 U.S.C. 103 as obvious over GOIX in US 20090234202 in view of in view of PETERS in “Dose-dependent effects of leucine supplementation on preservation of muscle mass in cancer cachectic mice” (as shown on the IDS dated 09/04/2020) in view of RATHMAN in US 9546994 and in further view of RAFTERY2 in US 20160341729.
With respect to Claims 8-10, GOIX, PETERS, and RATHMAN teach of the claimed in invention as shown above in the rejection of Claim 1. GOIX, PETERS, and RATHMAN et al. further disclose conditions ranging from healthy to cancerous and high grade dysplasia which obviously includes metaplasia in the middle and of progressions from healthy to dysplasia to cancer –so including metaplasia (paragraph 0039-0040 & Claim 3). They do not disclose the use of MRM, gastric tissue/fluid and metaplasia.
However, RAFTERY2 is used to remedy this and further teaches of a panel of glycine, phenylalanine, serine, isoleucine, threonine and aspartic acid (a method of detecting cancer by measuring the relative distribution of free amino acids in a serum including phenylalanine 2, isoleucine 4; glycine 8, serine 10, threonine 12 and aspartic acid 14, as shown on figure 3B; figure 3B; paragraph [0019]; claim 8). RAFTERY2 further teaches of measuring in association with gastric conditions and gastric tissue/fluid(paragraph 0005, 0232, 0002, 0042), using MRM(0071, 0156, 0160, 166, table 6, 0219, 0221). Thus, it would have been obvious to a person of ordinary skill in the art, before the effective filing date of the instant invention to have modified the method, as previously disclosed by RAFTERY with the method of RAFTERY2 for improving effectiveness of monitoring of the progression of cancer and to enable efficient monitoring of multiple reactions/compounds at the same time (RAFTERY2; abstract, paragraph 0160).
With respect to Claim 5 & 26, RAFTERY2 teach of one biomarker, proline having over a 2-fold change positive or negative (more or less than controls) (Table 2, 3, paragraph 0077, Table 15, Tables 5, 6, 0225).
With respect to Claims 3-4, & 35-36, RAFTERY2 teaches of selected from combinations of histidine, methionine, tyrosine, alanine, valine, leucine, lysine, proline (the panel consists of lysine, leucine, valine, methionine, tyrosine, proline, histidine, alanine, and of comparison to controls wherein the value are less than the reference in some cases (paragraphs 0074, 0075, Table 5 & 6).
Claim(s) 38-39 is/are rejected under pre-AIA 35 U.S.C. 103 as obvious over GOIX in US 20090234202 in view of PETERS in “Dose-dependent effects of leucine supplementation on preservation of muscle mass in cancer cachectic mice” (as shown on the IDS dated 09/04/2020) and further in view of RATHMAN in US 9546994 and further in view of BASS in US 20180238884.
With respect to Claims 38-39, GOIX, PETERS, and RATHMAN teach of the claimed invention as shown above. They do not theca of the claimed treatments.
BASS is used to remedy this. BASS teach of methods of analysis for esophageal cancers (abstract), and further of the pressing need for new EAC therapies (paragraph 0003, 0038). BASS further teach that the therapies can be targeted therapy, chemotherapy, radiation therapy, and/or hormonal therapy (paragraph 0010, 0109, 0119, 0158) and further of using endoscopy as a treatment (paragraph 0072, 0304). It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to use the treatments of BASS in the methods of GOIX, PETERS, and RATHMAN due to the pressing need in the art for new therapies (paragraphs 0003, 0038).
Response to Arguments
Applicant's arguments filed 10/03/2025 have been fully considered but they are not persuasive.
With respect to the 101 rejection, it is maintained as shown above. With respect to the instant amendments and particularly with respect to applicant’s arguments that the claims have been amended to include Vanda style treatment, the examiner disagrees that this is the case.
As shown in the rejection above, what applicant has amended into the claims 10/03/2025 is not actually a treatment, but instead the claimed treatments are other diagnostic tests. Applicant argues that the claimed imaging is “a specific conditional treatment decision.” The examiner disagrees. As shown in the 101 rejection above, the claimed CT imaging is imaging, not treatment. This also holds true for the claimed general biopsies, as they are again further diagnostic tests, and not treatments, Though yes, biopsies are invasive procedures, these are still not “treatments,” but instead are further diagnostic tests performed that are routine and conventional in the art. This also applies to the claimed esopho-gastro duodenoscopies. Specifically, biopsies and CT scans are so widely used in the art, that they are in fact routine and conventional in the art at step 2 B, and at step 2A, they are extra-solution activity to the diagnostic that was already performed. Further analysis for this newly amended claim subject matter is shown in greater detail in the rejection above.
Also, with respect to the 101 rejection, applicant argues that the office action misapplies Step 2 A. Again, the examiner disagrees- however, has made more clarifications in the rejection as shown in the above office action.
With respect to the prior art, applicant argues that the prior art does not teach of “the entirety of the method of detecting esophageal adenocarcinoma (EAC) or of monitoring EAC disease progression in a subject”. The examiner disagrees- and it is shown how these are taught in the rejections above.
The examiner notes that applicant makes no substantive arguments about the prior art used, other than with respect to the singular Peters reference, which was used as the secondary reference. Applicant makes not arguments about the GOIX reference which is the primary reference or the RATHMAN reference which is the third reference.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant’s argument with respect to PETERS is that PETERS does not teach of ALL of the claimed biomarkers. However, the examiner notes that this argument is not commensurate in scope with the claims as the claims only require, “at least one metabolite selected from.” PETERS does in fact teach of at least one of the claimed metabolites, as shown in the above rejections.
All claims remain rejected.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to REBECCA M FRITCHMAN whose telephone number is (303)297-4344. The examiner can normally be reached 9:30-4:30 MT Monday-Friday.
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/REBECCA M FRITCHMAN/Primary Examiner, Art Unit 1758