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 .
Applicants filed response on 12/17/2025 has been received and entered.
Claims 16-18, 21-23, 25-26 and 28-53 have been canceled.
Claims 1-15, 19-20, 24 and 27 are pending and under examination.
The objection on claim 24 is withdrawn because of amendment.
The rejection of claims 1-15, 19-20, 24, 27 and 46-47 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second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter is withdrawn because of amendment.
The rejection of claims 46--47 under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Kokkotou (US 10458996) is withdrawn because of cancelation. Accordingly, the rejection on claim 46 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for biopsy samples from active disease site from gastrointestinal disease, does not reasonably provide enablement for any other tissue site is also withdrawan.
A new ground of rejection is set forth below.
A telephonic call was made on 12/30/2025 to applicants’ attorney Dr. Allengorph concerning examiner’s amendment. Examiner indicated claims 13-15 are free of prior art and suggested incorporation into main claim for condition of allowance. But applicants requested an office action for the record.
Claim Rejections - 35 USC § 101
Claims 1-12, 19-20, 24 and 27 are rejected under 35 U.S.C. 101 because the claimed invention is directed to correlation of changes of histone biomarkers in response to candidate therapeutic ex vivo without significantly more. First, the ex vivo culturing of active site tissues of gastrointestinal diseases is resembling in vivo, albeit with lesser degree (Mayo vs. Prometheus, USPQ2d 1961 (2012) Supreme Court Case). Under Mayo vs. Prometheus where a treatment was administered to the patient followed by measuring related drug-metabolite. This administering step does not provide a significant weight to the claim amounting more than law of nature. It is because this step is not one that applies, relies on, or uses the judicial exception (Vanda Pharmaceuticals Inc. v. West-Ward Pharmaceuticals (2018)). The step of treating the cultured tissue is merely part of data-gathering process. In another word, the initial treatment testing here is not the step one clinician does in response to the law of nature, i.e. identified changes of histone modification biomarkers and treating the identified patient accordingly (See Vanda holding) (MPEP 2106.05(a)). Overall, the law of nature is at the end of the instant claim, i.e. correlating the significant levels of changes in biomarkers to the potential efficacy of administered candidate therapeutic. The claim(s) recite(s) judicial exception. This judicial exception is not integrated into a practical application because No additional element adds to the claim amounting significantly more than mere judicial exception.. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because it is well-known and routinely used in the art to measure histone modification biomarker changes in identifying of modulating chemical compounds, such as Dertinger teaches measuring histone 2AX in identifying therapeutic compound (claims 1 and 12)(US 20210132081), Amigorena teaches identifying compounds in inhibiting methylation histone H3 (claim 12)(US 20200157225), Boison teaches identifying compounds in inhibiting methylation histone (section 0015-0016, 0039)(US 20170219562 ) and Kaestner teaches identifying compounds in inhibiting methylation histone (section 0166 and 0176 )(US 20170056524).
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.
Claims 1-3, 6-11, 19-20, 24 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Kolta (WO2017158609; IDS reference) in view of Kelly (JCIinsight 2018 3:e122104).
Kolta teaches an ex vivo cellular model for selecting a suitable therapeutic agent in treating gastrointestinal disease, such as Crohn’ disease (page 2-3). Main claim 1 in Kolta patent recites an ex vivo model preparation, claim 21 and 22 for selecting therapeutic agent using the ex vivo model for culturing the tissue with and without the potential candidate therapeutic agent. The ex vivo model is taking tissues from active sites of the gastrointestinal disease, i.e. intestinal pathological or inflamed tissue (claims 8-9). Kolta does not teach histone modification as markers for gastrointestinal diseases, rather Kolta measuring and comparing cytokines instead (claim 30).
The reference of Kelly is in an analogous field, i.e. study gastrointestinal disease (e.g. Crohn’s disease). Kelly teaches use of histone modification (e.g. H3K4me3) as markers for one ordinary skilled person in evaluating for gastrointestinal disease (see abstract). The measurements are from intestinal epithelial cell (IECs) as active sites of gastrointestinal disease (abstract; Materials and Methods).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the method taught by Kelly to evaluate potential therapeutic for gastrointestinal disease, e.g. Crohn’s disease, by histone modification biomarkers, such as H3K4me3 in the ex vivo model. One ordinary skilled person would have been motivated to look into these gastrointestinal related biomarkers in assessing the potential effectiveness of a potential drug in treating gastrointestinal disease with reasonable expectation of success because the availability of the ex vivo model for screening drug for GI disease, and the known biomarkers (histone modification) for Crohn’s disease.
As to claim 2, 27 and 24, the biopsy samples are from gastrointestinal diseases, such as Crohn’s disease, or ulcerative colitis or irritable bowel syndrome (see Kolta page 2-3; or Kelly Abstract).
As to claim 3, 6, and 11, Kolta teaches using ELISA for measuring analytes in the sample (See Materials and Methods).
As to claim 6 and 19, Kelly teaches measuring methylated H3K4me3 which involving methylase action (see Abstract).
As to claims 7-11, Kolta teaches measuring cytokines, such as IL-6, 8, 10, 12, 17 or 27 and TNF-α in assessing the effect of the potential candidate therapeutic (see Example 1).
Claim(s) 4, 20 are rejected under 35 U.S.C. 103 as being unpatentable over Kolta in view of Kelly as applied to claims 1-3, 6-11, 19, 24 and 27 above, and further in view of Chen (Molecular Immunology 2020 118:191- available online 12/30/2019).
Both Kolta and Kelly references have been discussed but none teaches measuring histone H3K27me3.
Chen teaches that the H3K27me3 (mediated by METLL3 methyltransferase) is associated with the pathological development in ulcerative colitis (See abstract; Figure 7, page 198 left column) where the H3K27me3 is decreased by TNBS (inducer for ulcerative colitis)(also read on claim 20).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the method taught by Chen to measure H3K27me3 in order for a broader and more thorough gastrointestinal diseases analysis and to assess the impact of the potential candidate therapeutic in the test subject.
Claim(s) 5 is rejected under 35 U.S.C. 103 as being unpatentable over Kolta in view of Kelly as applied to claims 1-3, 6-11, 19, 24 and 27 above, and further in view of Lawrence (US 20140213475).
Both Kolta and Kelly references have been discussed but none teaches measuring histone H3K9me2.
Lawrence teaches that use antibody to detect H3K9me2 marker for diagnosis of gastrointestinal stromal tumor (GIST)(see section 0013).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the method taught by Lawrence to measure H3K9me2 in order for a broader and more thorough gastrointestinal diseases analysis, i.e. including potential gastrointestinal stromal tumor, and to evaluate the efficacy of the potential screened therapeutics in treating gastrointestinal tumor.
Claim(s) 12 is rejected under 35 U.S.C. 103 as being unpatentable over Kolta in view of Kelly, Chen and Lawrence as applied to claims 1-11, 19, 24 and 27 above, and further in view of Bauer (Gut 2010 vol. 59:1192).
The current claim directs to measure all TNFα, IL1B, H3K9me2 and H3K27me3 biomarkers in evaluating the potential therapeutic. The only deficiency is IL1B that none of Kolta, Kelly, Chen and Lawrence has disclosed this marker.
Bauer teaches that inflammatory cytokines IL1B and IL-18, are central for the pathogenesis of IBD. Moreover, the secretion of IL1B, IL-6, IL-18, TNFα are correlated with the severity of IBD (See Introduction).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to measure IL1B as taught by Bauer for a broader and more thorough gastrointestinal diseases analysis and to assess the impact of the potential candidate therapeutic in the test subject.
Using L-alanyl-L-glutamine dipeptide as an ex vivo active sites of a gastrointestinal disease tissues culturing medium is free of prior art. The closest prior art is the reference of Jo (US 20190169576) where Jo found out culturing midbrain neurological tissues in 0.5-3% of L-alanyl-L-glutamine dipeptide for optimal maintaining tissues (see section 0065 and 0067). However the tissues in the current invention is not neurological tissues and one ordinary skilled would need to experiment to determine its suitability because of different anatomical, physiological and pathological functionalities among different organs. Therefore claims 13-15 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claim is allowed.
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CHANGHWA J. CHEU
Primary Examiner
Art Unit 1678
/CHANGHWA J CHEU/Primary Examiner, Art Unit 1678