DETAILED ACTION
Applicant’s amendment submitted 2/17/2026 is acknowledged. Claims 15-16, 20, 24-25, and 29 are currently amended. Claims 1-14, 18-19, and 22 are canceled. Claims 15-17, 20-21, and 23-29 remain pending are the subject of the instant application.
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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 3/20/2026 has been entered.
Priority
The instant application is a U.S. national phase of PCT/EP2021/053246, filed on 2/10/2021, and claims foreign priority to DE10 2020 132 668.8, filed on 12/8/2020, and DE10 2020 103 325.7, filed on 2/10/2020.
Claims 15, 17, and 29 find support in DE10 2020 132 668.8, and therefore have an effective filing date of 12/8/2020.
Claims 16, 20-21, and 23-28 do not find support in the foreign priority documents, and therefore have an effective filing date of that of the international application, 2/10/2021.
Response to Amendment
Applicant’s amendment to claims 15 and 16 overcomes the objections previously set forth in the Final Rejection mailed on 11/17/2025.
Applicant’s amendment to the claims overcomes each and every 112(a) rejection previously set forth in the Final Rejection. Accordingly, the rejections are withdrawn.
Applicant’s cancelation of claims 18 and 22 renders moot the objections, 112(a), and 112(b) rejections set forth in the Final Rejection. Accordingly, the rejections are withdrawn.
Applicant’s amendment to claims 15, 20, and 29 overcomes the 112(b) rejections previously set forth in the Final Rejection. Accordingly, the rejections are withdrawn.
Claim Objections
Claims 15, 20, 24, and 29 are objected to because of the following informalities:
Claims 15, 20, 24, and 29 inconsistently recite “milliliter” and “normalized” in British English spelling and American English spelling.
Claim 24 recites the abbreviation “DAO” without spelling it out in its first instance in the claim.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 24-28 are 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.
Claim 24 is directed to a method for diagnosing histamine intolerance syndrome in a subject and recites “administering to said subject a composition from a kit” in lines 1-2. It is not clear how administering a composition from the kit comprising the ingredients recited in lines 3-13 thereby diagnoses histamine intolerance syndrome. Moreover, it is further unclear what composition components are administered to the subject that are comprised in the kit and how they are administered to the subject. Therefore, one of ordinary skill in the art would not be able to determine the metes and bounds of the claimed invention, and claim 24 is indefinite.
Claim 24 recites the limitation "the immunoassay" in the penultimate line. There is insufficient antecedent basis for this limitation in the claim. It is not clear what immunoassay is being referenced because no other immunoassay has been set forth in claim 24. Thus, the metes and bounds of the limitation “the immunoassay” cannot be determined, and claim 24 is indefinite.
Claims 25-28 depend from claim 24 which is directed to a method. However, each of claims 25-28 do not recite active method steps and instead appear to be directed to products. Therefore, claims 25-28 are also rejected for being dependent on a rejected base claim and failing to remedy the issues set forth above.
Closest Prior Art
The closest prior art to claim 15 is to Missbichler et al. (US2008/0227116; of record in IDS filed 12/9/2022). Missbichler discloses a method for determining histaminase (DAO) activity in a sample (see Abstract). The method comprises the steps of: providing a given amount of a diamine, mixing and incubating the diamine with the sample for a fixed period under conditions at which the diamine can be reacted by a DAO possibly present in the sample, derivatizing the amount of derivatized diamine, and comparing the given amount of diamine with the amount of derivatized diamine and determining the activity of possibly present diamine oxidase (see paragraphs [0027-[0032]). Missbichler teaches the disclosure can be used to diagnose a histamine intolerance (see paragraph [0037]). Missbichler further suggests that radioactively labeled substrates such as histamine and putrescine and the measurement of formed hydrogen peroxide are to be avoided (see paragraph [0026]). Regarding claim 15, the prior art does not disclose administering orally to the subject a preparation, solution or suspension containing a known amount of stable isotope-labeled histamine; obtaining from the subject a sample of bodily fluid selected from blood, serum, plasma, urine, or saliva after a predefined period of time from 10 minutes to 24 hours after administration, followed by removal of proteins prior to derivatization; combining a derivatization agent, which reacts with imidazole acetic acid and N-methyl-imidazole acetic acid compounds, with the bodily fluid obtained to produce derivatized isotope-labeled histamine metabolites; measuring derivatized isotope-labeled histamine metabolites contained in said sample of bodily fluid using mass spectrometry, using liquid chromatography tandem mass spectrometry (LC-MS/MS); calculating the subject’s DAO activity and/or the subject’s histamine degradation capacity based on the amount of isotope-labeled imidazole acetic acid compounds and methyl imidazole acetic acid contained in said sample of bodily fluid; and determining, using the measured isotope-labeled metabolites produced by said administered stable isotope-labeled histamine and said chemical derivatization, whether the subject has histamine intolerance syndrome based on the calculated DAO activity and/or degradation capacity, wherein histamine intolerance is determined when the patient’s DAO activity in said sample is below 3 enzyme units (U) per milliliter of serum as measured by enzymatic activity at physiological conditions of the blood and/or below normalized 10 enzyme units (U) per milliliter, as measured by immunoassay, or the calculated half-life of dietary histamine is above a threshold determined from a reference population of healthy subjects, and wherein the derivatization agent is 2-hydrazinoquinoline, as claimed. Regarding claim 20, the prior art does not disclose adding to said sample a predefined amount of stable isotope-labeled histamine as defined in claim 16 to produce a defined concentration of isotope-labeled histamine substrate in said sample; incubating said sample for a predefined period under physiological conditions to degrade isotope-labeled substrate by the activity of DAO enzyme contained in said sample of plasma or serum; determining by mass spectrometry which comprises an LC-MS/MS technique, the concentration of isotope-labeled metabolites of histamine following derivatization, to determine the activity of DAO and a histamine conversion rate per unit time for diagnosis of histamine intolerance syndrome; and determining whether the subject has histamine intolerance syndrome based on the calculated DAO activity and/or degradation capacity, wherein said determination comprises calculating the activity of soluble human DAO enzyme in said sample under defined physiological conditions, based on the amount of DAO substrate converted per unit time; determining the histamine degradation capacity, the half-life of histamine, and/or DAO substrate in said subject, and wherein histamine intolerance syndrome is determined when the patient’s DAO activity is below 3 enzyme units (U) per milliliter of serum or plasma as determined by enzymatic activity, or below an immunologically measured DAO concentration corresponding to normalized 10 enzyme units (U) per milliliter, and/or when the half-life of 13C-labeled histamine in serum is above a threshold determined from a reference population of healthy subjects. Regarding claim 24, the prior art does not disclose administering to a subject a composition from a kit comprising a defined histamine oral load in the form of a solution, dispersion, or tablet, wherein the composition contains a defined amount of stable isotope-labeled histamine selected from 15N-labaled histamine at positions N1 and/or N3 or 13C-labeled histamine at positions C2, C4, C5, C6, or C7 or deuterium labeled histamine at one or more hydrogen positions; 2-hydrazinoquinoline for derivatization of histamine metabolites prior to mass spectrometric analysis; suitable buffers and solutions for sample preparation; and determining whether the subject has histamine intolerance syndrome based on the calculated DAO activity and/or degradation capacity, wherein the histamine intolerance syndrome is determined when the patient’s DAO activity is below 3 enzyme units (U) per milliliter of serum or plasma, or below 10 U per milliliter as measured by the immunoassay, and/or when the half-life of 13C-labeled histamine in serum is above a threshold found in a sample of a healthy subject. Regarding claim 29, the prior art does not disclose administering orally to the subject a preparation, solution, or suspension containing a known amount of stable isotope-labeled histamine; obtaining from the subject a sample of bodily fluid selected from blood, serum, plasma, urine, or saliva after a predefined period of time from 10 minutes to 24 hours, followed by removal of proteins; providing 2-hydrazinoquinoline for chemically derivatizing imidazole acetic acid and N-methyl-imidazole acetic acid metabolites present in the bodily fluid sample; measuring derivatized isotope-labeled histamine metabolites contained in said sample of bodily fluid using mass spectrometry, which comprises LC-MS/MS technique; calculating the subject’s DAO activity and/or the subject’s histamine degradation capacity based on the amount of isotope-labeled imidazole acetic acid compounds and methyl imidazole acetic acid contained in said sample of bodily fluid; and determining whether the subject has histamine intolerance syndrome based on the calculated DAO activity and/or degradation capacity, wherein histamine intolerance syndrome is determined when the patient’s DAO activity in said sample is below 3 enzyme units (U) per milliliter serum or plasma as determined by enzymatic activity, or below an immunologically measured DAO concentration corresponding to normalized 10 enzyme units (U) per milliliter, and/or when the half-life of 13C-labeled histamine in serum is above a threshold determined from a reference population of healthy subjects.
Response to Arguments
Applicant has not presented any arguments with respect to the rejection of claim 24 under 35 U.S.C. 112(b) as being indefinite. Claim 24 remains rejected for being unclear in what components of the kit are administered and how they are administered.
Conclusion
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/J.P.S./Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651
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