DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The present application was filed on 07/28/2022. This application is a 371 of PCT/US21/19801 filed on 02/26/2021 which claims benefit of U.S. Provisional Patent Application 62/982,273 filed on 02/27/2020.
Claim status
Claims 2 and 4-10 are amended. Claims 1 and 3 are cancelled. Claims 2, and 4-10 are pending and examined herein.
Withdrawn Objections/Rejections
The corrections of the drawings are accepted. The objection of the drawings is withdrawn.
The rejections of claims 3 and 5-10 under 35 USC 112(b) as being indefinite are withdrawn in view of the cancelation of claim 3 and the amendment of claims 5-10.
The rejection of claims 1-2 and 4-10 under 35 USC 101 is withdrawn in view of the amendment of the claims.
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.
Claim(s) 2, 4-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bischoff et al. (Gastrointestinal Food Allergy: New Insights Into Pathophysiology and Clinical Perspectives, Gastroenterology 2005;128:1089–1113, IDS filed 05/20/2024) in view of Kamekura et al. (Inflammation-induced desmoglein-2 ectodomain shedding compromises the mucosal barrier, MBoC vol.26 Sept 2015, PTO-892 06/20/2025) as supported by Zuckerman et al. (Pathophysiology of nasal polyposis: The role of desmosomal Junctions, Am J Rhinol 22, 589–597, 2008).
Regarding claim 2, Bischoff teaches a method of treating a food allergy in a subject comprising administering an antihistamine and epinephrine (see Abstract, see page 1105 Medical therapy: patients with a history of an anaphylactic reaction should be instructed to carry an epinephrine-containing syringe for emergency administration along with corticosteroids and antihistamines), oral immunotherapy, sublingual immunotherapy, and/or epicutaneous immunotherapy to the subject (see page 1106 Site-directed immunotherapy: classic immunotherapy and oral immunotherapy are still considered for the treatment of food allergy).
Bischoff teaches food allergy can involve different organ systems such as the oral cavity and digestive tract, the skin, the respiratory tract, and the cardiovascular system (see page 1089 col.2 par.2).
Bischoff teaches that food allergy can cause allergic inflammation of the gut after the gut is exposed to a sufficient load of triggering allergen and a hyperresponsive mucosal immune system (see page 1091 col.2 par.3). Bischoff teaches that the elevated levels of inflammatory mediators, e.g., TNF-α have been measured in a sample from patients with food allergy (see page 1093 col.2 par.2).
Bischoff teaches that laboratory methods have also been developed to measure IgE, TNF- α, and eosinophil-derived mediators in stool samples, making them interesting tools for the assessment of food allergy (see page 1103 col.2 par.3). However, the assessment of food allergy based on biomarkers (e.g., IgE, TNF-α…) is not yet established for use in clinical practice (see page 1103 col.2 par.3). Therefore, the diagnosis of food allergy rests primarily on the clinical history and also the exclusion of other conditions (see page 1103 col.2 par.3).
Bischoff does not teach determining the presence of one or more fragments of the desmoglein-2 (DSG-2) protein in a sample obtained from the subject using an immunoassay; wherein the presence of one or more fragments of the DSG-2 protein indicates that the subject has a food allergy.
Kamekura teaches a method comprising determining the presence of one or more fragments of the desmoglein-2 (DSG-2) protein in a sample obtained from the subject using an immunoassay. (See Fig.5 and page 3175 section Human colon samples and page 3173 section Cell and organ culture: Kamekura teaches that ulcerative colitis and normal colonic tissue specimens from human and mice were obtained. See Fig.5: Kamekura teaches the detection of full-length and fragments Dsg2 in the tissue samples from human and mice, wherein the detection method was immunoblotting.)
Kamekura teaches that the shedding of DSG-2 of the mucosal barrier (e.g., in intestinal epithelial cells) is induced by inflammation (e.g., proinflammatory cytokines) (see Title and Abstract). Particularly, IL-1β and TNF-α induce Dsg2 cleavage in intestinal epithelial cells (IECs), generating 25- and 100-kDa extra-cellular domain (EC) fragments (see page 3166 column 1 paragraph 2). Kamekura teaches that the shedding of sDsg2, and sE-cadherin increased with proinflammatory cytokines, e.g., TNF-α (see 3171 col.2 par.3 and Fig.5C).
Examiner notes that Bischoff teaches a relationship between food allergy, gut inflammation, and the increased level of TNF-α. Kamekura teaches a relationship between gut inflammation, the increased level of TNF-α, and the increased shedding of sDsg2 induced by TNF-α. Therefore, it would be obvious to link food allergy, inflammation of the gut, increased level of TNF-α, and increased shedding of Dsg2 together from the teachings of Bischoff and Kamekura because the food allergy can involve different organ systems such as digestive tract and can cause gut inflammation as taught by Bischoff above.
The relationship between food allergy, inflammation of the related tissue, increased level of TNF-α, and increased shedding of Dsg2 is also supported by Zuckerman.
Zuckerman teaches the pathophysiology of nasal polyposis (see Title, Abstract), wherein the nasal polyps are caused by mucosal reactions including allergic inflammation (see page 589 col.1, and page 591 col.1 par.1 “One patient had a diagnosis of Samter’s triad (aspirin insensitivity, asthma, and nasal polyps), two patients had diagnosis of cystic fibrosis, and the remaining eight patients had allergic fungal sinusitis.”).
Zuckerman teaches determining the presence of the desmoglein-2 (DSG-2) protein in a sample obtained from the subject using an immunoassay (see page 591 col.1 Subjects and Immunofluorescence, Fig.1: “in polyp mucosa, there was a significantly diminished staining intensity for proteins DSG2 and DSG3”). Zuckerman teaches that TNF-a induces the cleavage of Dsg2, thereby causing the down-regulation of full-length 150-kDa Dsg2 on epithelium and a very weak expression of the 50-kDa band (page 591 col.2 pars.1-2, page 594 col.2 par.2, see at least Figs.1-2, and 5-6).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method treating a food allergy in a subject taught by Bischoff with the method of detecting one or more fragments of the Dsg2 protein in the sample using immunoassay taught by Kamekura for indicating a subject with food allergy and treat the subject because:
Bischoff teaches that food allergy can involve different organ systems such as digestive tract, the respiratory tract etc., e.g., food allergy causes allergic inflammation of the gut and the increased level of proinflammatory mediator TNF-α (Bischoff page 1091 col.2 par.3 and 1093 col.2 par.2); Bischoff also teaches TNF-α is a potential tool for the assessment of food allergy (Bischoff page 1103 col.2 par.3), and the need of assessing food allergy based on biomarkers (Bischoff page 1103 col.2 par.3) because the diagnosis of food allergy currently rests primarily on the clinical history and also the exclusion of other conditions (Bischoff page 1103 col.2 par.3);
Kamekura teaches, in the inflamed gut, the increased shedding of sDsg2 is induced by proinflammatory cytokines, e.g., TNF-α (Kamekura page 3171 col.2 par.3 and Fig.5C); therefore, the teaching of Bischoff and Kamekura depicts a relationship between food allergy, inflammation of the gut, increased level of TNF-α, and increased shedding of Dsg2;
Zuckerman supports the relationship taught by Bischoff and Kamekura by teaching a relationship between allergy, inflammation of the nasal mucosa, increased level of TNF-α, and increased shedding of Dsg2 (Zuckerman page 591 col.2 pars.1-2, page 594 col.2 par.2, see at least Figs.1-2, and 5-6).
Since Bischoff teaches that TNF-α is a potential tool for the assessment of food allergy, Dsg2 fragments can be substituted for TNF-α as a tool for the assessment of food allergy because there is a relationship between the presence of TNF-α and the increased shedding of Dsg2 in allergic inflammation.
A person of ordinary skill in the art would have been motivated to combine these teachings for establishing a reliable food allergy test because currently the diagnosis of food allergy rests primarily on the clinical history and also the exclusion of other conditions as taught by Bischoff (see Bischoff page 1103 col.2 Other laboratory tests section).
One having an ordinary skill in the art would have had a reasonable expectation of success in combining Bischoff, Kamekura and Zuckerman because they are directed to the pathophysiology of allergic inflammation. While Kamekura and Zuckerman teach the allergic inflammation in different organs (e.g., digestive tract and nasal mucosa), Bischoff teaches that the allergic inflammation in these organs can be related to food allergy. The combined teaching also supports the relationship of allergy, inflammation of mucosal tissues, the increased level of proinflammatory mediator TNF-α, and the shedding of sDsg2. Therefore, the one or more fragments of Dsg2 would be possible a marker for food allergy.
Regarding claim 4, Bischoff and Kamekura as supported by Zuckerman teach the method of claim 2. Bischoff does not teach determining the presence of full-length DSG-2 protein.
Kamekura teaches determining the presence of full-length DSG-2 protein (see Kamekura Fig.5 and page 3171 col.2 Increased levels of Dsg2 extracellular fragments in inflamed intestinal mucosa section: teaching that Dsg2 extracellular cleavage fragments and full-length protein are investigated to support the increasing level of Dsg2 extracellular cleavage fragments in inflamed intestinal mucosa compared to the control tissues).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method treating a food allergy in a subject taught by Bischoff with the method of detecting one or more fragments of the Dsg2 protein in the sample using immunoassay taught by Kamekura for indicating a subject with food allergy and treat the subject because of the reasons discussed above in claim 2. A person of ordinary skill in the art would have been motivated to determine the presence of full-length and fragments of DSG-2 protein in the sample to show the difference of DSG-2 cleavage between the test subject and the control subject.
Regarding claim 5, Bischoff and Kamekura as supported by Zuckerman teach the method of claim 2. Bischoff does not teach determining the presence of a 22 kDa DSG-2 protein fragment, a 30 kDa DSG-2 protein fragment, and/or a 75 kDa DSG-2 protein fragment.
Kamekura teaches that TNF-α promoted shed-ding of the soluble 25- and 100-kDa ectodomain fragments of Dsg2 (see Kamekura page 3166 col.1 pars.2-3, Fig(s).1-2 and 5). Zuckerman supports that TNF-α induced the down-regulation of the main 150-kDa fragment of DSG2. A very weak expression of the 50-kDa cleavage band is shown. (see Zuckerman page 591 col.2 par.1, page 594 col.2 par.2)
While the prior arts does not teach determining the presence of DSG-2 fragments having the same size kDa as recited in the claim, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to arrive at the claimed fragment by using the detecting method taught by Kamekura (e.g., Immunoblotting) because Kamekura shows that immunoblotting can detect the fragments of a protein within the claimed size (Kamekura Fig.5A).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method treating a food allergy in a subject taught by Bischoff with the method of detecting one or more fragments of the Dsg2 protein in the sample using immunoassay taught by Kamekura for indicating a subject with food allergy and treat the subject because of the reasons discussed above in claim 2.
Regarding claim 6, Bischoff and Kamekura as supported by Zuckerman teach the method of claim 2. Bischoff does not teach wherein the immunoassay is selected from Western blot, radioimmunoassay, fluoroimmunoassay, enzyme-linked immunosorbent assay (ELISA), and chemiluminescent immunoassay.
Kamekura teaches that the immunoassay is Western blot and enzyme-linked immunosorbent assay (ELISA) (see Kamekura page 3175 col.1 ELISA section, Fig(s).1-2 and 5 for Immunoblot analysis of Dsg2 fragments).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method treating a food allergy in a subject taught by Bischoff with the method of detecting one or more fragments of the Dsg2 protein in the sample using immunoassay taught by Kamekura for indicating a subject with food allergy and treat the subject because of the reasons discussed above in claim 2.
Regarding claims 7-8, Bischoff and Kamekura as supported by Zuckerman teach the method of claim 2. Bischoff does not teach the method further comprising determining the presence of one or more fragments of an adherent junction (AJ) protein in the sample as in claim 7, or one or more fragments of E-cadherin protein in the sample as in claim 8.
Kamekura teaches that the shedding of sDsg2, and sE-cadherin increased with proinflammatory cytokines, e.g., TNF-α (see page 3171 col.2 par.3 and Fig.5C) (see Kamekura page 3166 Proinflammatory cytokines promote cleavage and shedding of cadherins in intestinal epithelial cells section, Fig(s).1-2 and 5: teaching one or more E-cadherin proteins are also detected).
Kamekura teaches that sDsg2 in addition to sE-cadherin are generated in the intestinal mucosa during inflammation. Kamekura suggests that sE-cadherin could also serve as a biomarker of active inflammation in the mucosa.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method treating a food allergy in a subject taught by Bischoff with the method of detecting one or more fragments of the Dsg2 protein in the sample using immunoassay taught by Kamekura for indicating a subject with food allergy and treat the subject because of the reasons discussed above in claim 2.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to further comprise determining the presence of one or more fragments of sE-cadherin in addition to Dsg2 because Kamekura teaches that like Dsg2, the shedding of E-cadherin is increased by the induction of proinflammatory cytokines, e.g., TNF-α in the inflammatory tissue (see Kamekura page 3171 col.2 par.3 and Fig.5C), wherein the inflammatory tissue could be caused by food allergy (Bischoff page 1089 col.2 par.2). Moreover, Kamekura suggests that sE-cadherin could also serve as a biomarker of active inflammation in the mucosa.
Therefore, E-cadherin fragments and Dsg-2 fragments can be substituted for TNF-α as tools for the assessment of food allergy because there is a relationship between the presence of TNF-α and the increased shedding of Dsg-2 and E-cadherin in the allergic inflammation. A person of ordinary skill in the art would have been motivated to combine these teachings for establishing a reliable food allergy test because currently the diagnosis of food allergy rests primarily on the clinical history and also the exclusion of other conditions as taught by Bischoff (see page 1103 col.2 Other laboratory tests section).
Regarding claim 9, Bischoff and Kamekura as supported by Zuckerman teach the method of claim 2. Bischoff further teaches that food allergy is selected from a peanut allergy, a tree nut allergy, a dairy allergy, a wheat allergy, a soy allergy, an egg allergy, a shellfish allergy, a meat allergy, and a corn allergy (see page 1101 Food Allergens section: teaching the food allergy is triggered by eggs, wheat, nuts, fruits, and milk…etc.).
Regarding claim 10, Bischoff and Kamekura as supported by Zuckerman teach the method of claim 2. Bischoff teaches that inflammatory mediators for allergic inflammation can be detected in serum, urine, gut lavage fluid, and stool from patients with food allergy (Bischoff page 1093 col.2 par.2).
Kamekura teaches that Dsg2 and E-cadherin can be detected in serum (see Kamekura page 3173 col.1 par.2: teaching DSG2 and E-cadherin can be detected in serum).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method treating a food allergy in a subject taught by Bischoff with the method of detecting one or more fragments of the Dsg2 protein in the sample using immunoassay taught by Kamekura for indicating a subject with food allergy and treat the subject because of the reasons discussed above in claim 2.
A person of ordinary skill in the art would have been motivated to determine the presence of one or more fragments of the desmoglein-2 (DSG-2) protein in urine or blood of a subject for diagnosis because it is more convenient to take urine or blood from a subject than to take an intestinal tissue specimen from a subject. One having an ordinary skill in the art would have had a reasonable expectation of success in detecting Dsg2 in blood because: sE-cadherin and Dsg2 are generated in the intestinal mucosa; Kamekura teaches that the change of sE-cadherin level has been observed in the serum of patients compared to healthy subjects (Kamekura page 3173 col.1 par.2), so the change of Dsg2 level in the serum of patients compared to healthy subjects is more likely to be observed.
Response to Arguments
Applicant's arguments filed 09/22/2025 regarding the rejections under 35 USC 103 have been fully considered but they are not persuasive.
Applicant argued that Kamekura in view of Bischoff “fail to teach, disclose or suggest a method of treating a food allergy in a subject as recited in claim 2. Kamekura does not teach, disclose or even remotely reference allergy or allergic disease. Bischoff does not teach, disclose or even remotely suggest the desmoglein-2 (DSG-2) protein or any utility that it may provide. There is no reason or motivation in the cited references or in the art to combine the cited references absent the disclosure of the present disclosure.
Examiner respectfully disagrees. While Kamekura does not teach the association between Dsg2 and allergy or allergic disease and Bischoff does not teach the association between food allergies and Dsg2, Bischoff teaches a relationship between the food allergy (which involves different organ systems, e.g., gut), the inflammation of the mucosal tissues and the increased level of TNF- α and Kamekura teaches the relationship between the gut inflammation, the increased shedding of sDsg2 is induced by proinflammatory cytokines, e.g., TNF-α (Kamekura page 3171 col.2 par.3 and Fig.5C). Therefore, it would be obvious to link food allergy, inflammation of the gut, increased level of TNF-α, and increased shedding of Dsg2 together from the teachings of Bischoff and Kamekura because the food allergy can involve different organ systems such as digestive tract.
However, the rejections of claims 2, 4-10 are updated in view of the amendment of the claims, wherein Examiner adds an additional reference Zuckerman to support the relationship between food allergy, inflammation of the related tissues, increased level of TNF-α, and increased shedding of Dsg2. See discussion in the office action above.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In this case, as Bischoff teaches that the TNF- α level increases in food allergy which makes TNF- α a possible marker for the assessment of food allergy, and Kamekura teaches the correlation of TNF- α with the increased level of Dsg2 extracellular fragments in gut inflammation which can be caused by food allergy. Therefore, it would be obvious to use Dsg2 as a substitute for TNF- α with a reasonable expectation of success in detecting food allergy.
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 CHAU N.B. TRAN whose telephone number is (571)272-3663. The examiner can normally be reached Mon-Fri 8:30-6:30 CT.
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/CHAU N.B. TRAN/ Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/ Supervisory Patent Examiner, Art Unit 1677 February 11, 2026