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
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Based on the filing receipt, the effective filing date of this application is May 30, 2021 which is the filing date of foreign application ISRAEL 283563 from which the benefit of priority is claimed.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-9 and 12-16, in the reply filed on 07/14/2026 is acknowledged. Claims 1-9 and 12-16 are examined herein.
Claims 10-11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected Group II, there being no allowable generic or linking claim.
Information Disclosure Statements
The information disclosure statement (IDS) filed 12/07/2023 has been considered by the examiner.
Claim Objections
Claims 2 and 8-9 are objected to because of the following informalities:
Claim 2 recites, “said stool sample is levels greater than that in stool sample of a subject free of IBD”. The claim should recite, “said stool sample is levels greater than that in- a stool sample of a subject free of IBD”.
Claims 8-9 recite, “AMP binding moieties”. The claims should first define the abbreviation.
Appropriate correction is required.
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 1-9 and 12-16 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more. The claims recite methods for determining the presence of, treating, and monitoring inflammatory bowel disease (IBD) by measuring azurocidin (AZU) in stool samples. This judicial exception is not integrated into a practical application, such as constituting an improvement in the technological field, or including steps recited in addition to the judicial exception that integrates detection of the natural phenomena into a particular treatment/prophylaxis according to MPEP § 2106.04(d)(2). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exceptions because the additional elements fail to provide either an inventive concept or impose meaningful limits upon the method such that the invention does not preempt every observance of the natural phenomenon itself.
Eligibility Step 1:
Claims 1-9 and 12-16 are directed to methods for determining the presence of, treating, and monitoring inflammatory bowel disease (IBD) by measuring azurocidin (AZU) in stool samples. Methods are one of the eligible statutory categories for invention (STEP 1: YES). However, eligibility of the claims is not self-evident, and therefore analysis must proceed to Step 2.
Eligibility Step 2A, Prong One:
The natural relationships to which the claims are directed (i.e. the relations between expression levels of AZU in stool samples and the state of IBD) are laws of nature. Similar concepts have been held by the courts to constitute law of nature/natural phenomena, as in the identification of a correlation between the presence of in a bodily sample (such as blood or plasma) and cardiovascular disease risk in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). In Mayo, the Supreme Court found that a claim was directed to a natural law, where the claim required administering a drug and determining the levels of a metabolite following administration, where the level of metabolite was indicative of a need to increase or decrease the dosage of the drug. See Mayo Collaborative Services v. Prometheus Labs., Inc., 566 U.S. 66, 74 (2012).
The instant claims are similar to those in Mayo as they involve a "relation itself [which] exists in principle apart from any human action" (id. at 77), namely the relationship between the naturally occurring level of the biomarker AZU in stool samples and the state of IBD. Therefore, the claims recite at least one judicial exception (STEP 2A, Prong One: YES).
The claims also recite further judicial exceptions abstract ideas, namely mental steps. For example, claims 12-13 and 15-16 recite “determining” or “determined”. Claims 13 and 16 recite “comparing”. If a claim recites a limitation that can practically be performed in the human mind, with or without the use of a physical aid such as pen and paper, the limitation falls within the mental processes grouping, and the claim recites an abstract idea. See, e.g., Benson, 409 U.S. at 67, 65, 175 USPQ at 674-75, 674 (noting that the claimed “conversion of [binary-coded decimal] numerals to pure binary numerals can be done mentally,” i.e., “as a person would do it by head and hand.”); Synopsys, 839 F.3d at 1139, 120 USPQ2d at 1474 (holding that claims to the mental process of “translating a functional description of a logic circuit into a hardware component description of the logic circuit” are directed to an abstract idea, because the claims “read on an individual performing the claimed steps mentally or with pencil and paper”).
Eligibility Step 2A, Prong Two:
According to Step 2A, Prong Two, set forth in MPEP 2106.04 II A (2), the claims are next evaluated with respect to whether the judicial exception is integrated into a practical application. This analysis turns to the additional steps/elements recited within the claims. In claim 12, the additional step is “treating said IBD in said subject confirmed as having IBD”. Claim 13 recites, “initiating treatment for IBD”. Claim 14 recites, “adjusting said treatment”.
Regarding the additional steps cited in claims 12-14, the treatment is recited at a high level of generality and are not tied, for example to any particular agent. The treatment or prophylaxis limitation must be “particular,” i.e., specifically identified so that it does not encompass all applications of the judicial exception(s). See MPEP 2106.04(d)(2).
Regarding claims 2-9 and 12-13, providing samples and measuring biomarker levels using methods with specific techniques, such as mass spectrometry and sample pre-treatment, are insufficient to integrate the judicial exception because the purpose is merely to obtain data. This does not go beyond insignificant presolution activity, i.e., a mere data gathering step necessary to use the correlation, similar to the fact pattern in In re Grams, 888 F.2d 835 (Fed. Cir. 1989) and Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015). Furthermore, the steps of measuring biomarkers are recited at a high level of generality and are not tied, for example, to any particular machine or apparatus.
There are no additional elements that reflect an actual improvement within the technical field. For example, there are no additional elements that apply the natural correlation/phenomena judicial exception to a particular treatment or which utilize a particular machine; there are no additional elements that effect a transformation; and, there are no additional elements that apply the judicial exception in some other meaningful way beyond generally linking it to a field, namely, IBD. In this way the claims, as drafted, do not integrate the judicial exception into a practical application that would overcome monopolizing the exception. (STEP 2A, Prong Two: NO).
Eligibility Step 2B:
Lastly, there are no additional elements in claims 1-9 and 12-16. (STEP 2B: NO).
The claimed steps/elements recited in addition to the judicial exception, alone or in combination, do not make an inventive contribution over the methods that were known in the art prior to filing, and they amount to mere observation of the natural phenomenon itself, by any means known, with the words “apply it” in order to append it to the field of IBD
For all of these reasons, the claimed subject matter is ineligible under 35 U.S.C. 101 because the claims are directed to a natural phenomenon judicial exception without significantly more.
Claim Rejections - 35 USC § 102
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.
Claims 1 and 3-7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Casavant (“Proteomic Discovery of Stool Protein Biomarkers for Distinguishing Pediatric Inflammatory Bowel Disease Flares”, published 2020) as evidenced by Lichtman (“Host-centric Proteomics of Stool: A Novel Strategy Focused on intestinal Responses to the Gut Microbiota”, published 2013-11).
With respect to claim 1, Casavant teaches a method of determining presence of Inflammatory Bowel Disease (IBD) in the gut mucosa of a subject, the method comprising measuring levels of azurocidin (AZU) in a stool sample from said subject, wherein increased levels of AZU in said stool sample compared to normal levels is indicative of IBD (see, e.g., determining presence of IBD – p. 2618, col. 1, para. 1: “To develop an assay with higher specificity in pediatric patients, we identified a panel of multiple proteins that are present in both IBD flare and remission but have distinct abundance ranges between each condition”; measuring levels of azurocidin in a stool sample from subject – p. 2618, col. 1, para. 2: “Stool collection occurred”, and p. 2619, under “Table 1.”, under “Row no./gene ID”: “20/AZU1”; increased levels of AZU in stool sample compared to normal levels – p. 2619, under “Table 1.”, under “Row no./gene ID”: “20/AZU1”, under “Fold change”: “15.98”). It is understood that the “normal levels” are the levels in the remission state.
With respect to claim 3, Casavant teaches determining said levels of AZU is effected
on a protein extract of said stool sample (see, e.g., p. 2618, col. 2, para. 1: “Adjustments to the protocol included purification steps such as protein precipitation (TCA) and an in-gel digestion”).
With respect to claim 4, Casavant teaches the stool sample is depleted of membrane proteins and membrane-bound organelle proteins (see, e.g., p. 2618, col. 1, para. 2: “fecal aliquots were processed in parallel as previously described3”). Lichtman provides evidence that the method of Casavant comprised the depletion of the stool sample (see, e.g., Lichtman, p. 3313, under “Fig. 1.”, under panel “A”).
With respect to claim 5, Casavant teaches wherein said subject is suffering from the IBD symptom, bloody diarrhea (p. 2618, col. 1, para. 2: “Patients’ IBD flare status was determined based on clinical assessment (ie, physician global assessment, Pediatric Ulcerative Colitis Activity Index”, emphasis added). The Pediatric Ulcerative Colitis Activity Index includes assessment of stool consistency and rectal bleeding.
With respect to claim 6, Casavant teaches wherein said AZU is identified by a combination of liquid chromatography and mass spectrometry (see, e.g., p. 2618, col. 2, para. 1: “Peptides were subsequently analyzed by liquid chromatography and tandem mass spectrometry”).
With respect to claim 7, Casavant teaches said AZU is identified by mass spectrometry-based label-free quantification (LFQ) (see, e.g., p. 2618, col. 2, para. 1: “purification steps such as protein precipitation (TCA)and an in-gel digestion. Peptides were subsequently analyzed by liquid chromatography and tandem mass spectrometry with an Eksigent nano-flow (SCIEX, Framingham, MA) high-performance liquid chromatography coupled to an Orbitrap Elite mass spectrometer (Thermo Fisher Scientific, Waltham, MA). Resulting mass spectra were searched against a human proteome sequence database (UniProt) and interpreted in the Proteome Discoverer 2.2 software package”). On p. 30 of the applicant’s specification, the applicant defined “label-free quantitative proteomics” as “protease digestion, mass spectrometry and identification of the peptides by database searching” (see, para. 5).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Casavant, as applied to claims 1 and 3-7 above, and further in view of Bosch (“ES2762403T3”, published 2013).
Casavant teaches as set forth above, but fails to teach AZU is identified by AMP binding moieties immobilized on an array, as in claims 8-9.
However, Bosch teaches measuring AZU with binding moieties immobilized on an array, as in claims 8-9 (see, e.g., measuring AZU – p. 2, para. 7: “screening a stool sample obtained from an individual for two or more biomarkers comprising myeloperoxidase (MPO) and one or more biomarkers selected from the group consisting of: azurocidine 1 (AZU1)”; binding moieties – p. 2, para. 11: “the stool sample is screened for the two or more biomarkers using binding agents capable of binding the two or more biomarkers”; immobilized on an array – p. 3, para. 2: “the matrix comprises one or more agents bonding agent”).
Casavant and Bosch are analogous to the field of the claimed invention because they are both in the field of gastrointestinal disease. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to use the binding agents immobilized on a matrix of Bosch in the method of Casavant. An artisan would have been motivated to do so because Bosch discloses, “Matrices by themselves are already well known in the art. Typically, they are formed of a linear or two-dimensional structure that has separate (ie, discrete) regions ("dots"), each with a finite area, formed on the surface of a solid support. An array can also be a bead structure where each bead can be identified by molecular code or
color code or identified in a continuous stream. Analysis can also be performed sequentially when the sample is passed over a series of points, each of which adsorbs the class of molecules in the solution”. An artisan would have understood the benefit that a matrix provides in terms of multiplexing biomarkers. An artisan would have had a reasonable expectation of success based on the given disclosures.
Claims 2, 12-13, and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Casavant, as applied to claims 1 and 3-7 above, and further in view of Boone (WO 2004/037073 A1, published 2004-05-06).
Casavant teaches as set forth above, including the disclosure that “We highlight this proteomic approach for its ability to discover novel stool biomarkers that could increase the overall sensitivity and specificity of stool biomarkers in IBD monitoring” (see p. 2619, para. spanning col. 1 to 2). But, Casavant fails to teach treating IBD in a subject and monitoring response of a subject to treatment for IBD, as in claims 12-13 and 15-16. Casavant also fails to teach the level of the biomarker in the IBD subject being greater than the level of the biomarker in a normal healthy subject, as in claims 2 and 15.
However, Boone teaches treating IBD in a subject and monitoring response of a subject to treatment for IBD, as in claims 12-13 and 15-16 (see, p. 1, under “Abstract”: “IBD patients are further monitored for intestinal inflammation using fecal lactoferrin to evaluate the effectiveness of medical therapy and to predict relapse”, and Boone’s claim 27: “monitoring the person for changing levels of lactoferrin as an indicator for the effectiveness of medical therapy”). Boone teaches levels of a biomarker in a subject with IBD being greater than the levels in a normal healthy subject, as in claims 2 and 15 (see, e.g., p. 35, under “TABLE 32”).
Casavant and Boone are analogous to the field of the claimed invention because they are both in the field of IBD. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to monitor biomarker levels as taught by Boone using the method of Casavant. An artisan would have been motivated to do so because Boone discloses that monitoring biomarkers is useful as an “indicator for the effectiveness of medical therapy” (see, Boone’s claims 27). One of ordinary skill in the art would compare the level of a biomarker of a subject with IBD to the level of a biomarker of a subject free of IBD as taught by Boone using the method of Casavant. An artisan would have been motivated to do so because Boone teaches the comparison can be useful for establishing a positive test result (see, p. 14, para. 2: “A positive test result indicated the specimen contained elevated levels of lactoferrin when compared with a reference value established for healthy control subjects. A negative test result indicated the specimen did not contain elevated levels of lactoferrin relative to samples from healthy control subjects”). An artisan would have had a reasonable expectation of success based on the given disclosures.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Casavant (cited above) and Boone (cited above), as applied to claims 2, 12-13, and 15-16 above, and further in view of Verstockt (“Results of the Seventh Scientific Workshop of ECCO: Precision Medicine in IBD—Disease Outcome and Response to Therapy”, published 2021-03-17).
Casavant and Boone teach as set forth above, but fail to teach adjusting the treatment for IBD according to the response monitored by biomarker measurement, as in claim 14.
However, Verstockt teaches using a biomarker measurement to adjust medical therapy, as in claim 14 (see, e.g., p. 1439, col. 1, under “7. Conclusion”, para. 1: ““the best biomarkers will be those that can effectively guide treatment decisions”).
Casavant, Boone, and Verstockt are analogous to the field of the claimed invention because they are all in the field of IBD. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to use biomarker measurements for guiding treatment as taught by Verstockt with the method of Casavant as modified by Boone. An artisan would have been motivated to do so because Verstockt discloses that effectively guiding treatment decisions with biomarkers will “subsequently change disease course” (see, p. 1439, col. 1, under “7. Conclusion”, para. 1). An artisan would have had a reasonable expectation of success based on the given disclosures.
Conclusion
No claims are allowed.
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/MICHAEL CAMERON SVEIVEN/ Examiner, Art Unit 1678
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678
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