CTNF 17/279,012 CTNF 76048 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia 1. 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 07-42-04 AIA 2. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 March 4, 2026 has been entered. Claim Amendments 3. The amendments filed March 4, 2026 have been entered. Claims 1, 20 and 67 were amended. Claims 3-7, 9-17, 19, 21-23 and 25-66 are canceled. Claims 1-2, 8, 18, 20, 24 and 67 are under consideration in this Office Action. Priority 02-10 AIA 4. The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc. , 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994). The disclosure of the prior-filed application, Application No ’s. 62/862,397 and 62/739,626 , fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. In this case, neither provisional application 62/862,397 nor 62/739,626 recite that is mast cell stabilizer is the mast stabilizing agents disodium cromoglycate and luteolin. Neither compound appears to be mentioned in either provisional application. Therefore priority is granted to the PCT application filed Oct. 1, 2019 for claim 20 . Withdrawn Grounds of Rejection 5. The following rejections have been withdrawn in view of applicants amendments: a) Claims 1, 18, 20 and 67 rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bluth et al., as evidenced by Bernardino et al., and/or Su et al; and b) Claims 1-2, 18, 20, 24 and 67 rejected under 35 U.S.C. 103 as being unpatentable over Halpern et al., in view of Lea and Girschick et al . 12-256 AIA New Grounds of Rejection Necessitated By Applicants Amendments Claim Rejections - 35 USC § 101 07-04-01 AIA 07-04 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. 6. Claims 1-2, 8, 18, 20, 24 and 67 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without including additional elements that are sufficient to amount to significantly more than the judicial exception itself. Claims 1-2, 8, 18, 20, 24 and 67 are directed to a method of treating inflammation which is a symptom associated with Lyme diseases and Borrelia burgdorferi infection in an individual, the method comprising: collecting at least one antibody-containing sample, optionally a blood sample from the individual; contacting said at least one antibody-containing sample from the individual with a live or fixed diagnostic Borrelia burgdorferi ; contacting the diagnostic Borrelia with IgE, IgA and IgG isotype-specific reagents, which reagents are operably linked to a detectable moiety; analyzing the diagnostic Borrelia for the presence of bound isotype-specific reagents to determine a ratio of IgE, IgA and IgG isotype pathogen-specific antibodies, wherein the ratio is indicative of immune response to the Borrelia; and treating the individual with a mast cell stabilizing agent when pathogen Borrelia burgdorferi-specific IgE antibodies are present. The claims set forth analyzing the diagnostic Borrelia for the presence of bound isotype-specific reagents to determine a ratio of IgE, IgA and IgG isotype pathogen-specific antibodies, wherein the ratio is indicative of immune response to the Borrelia. The courts have clearly established that a method directed essentially to a series of algorithmic/mathematical procedures is not a statutory process: “Without additional limitations, a process that employs mathematical algorithms to manipulate existing information to generate additional information is not patent eligible. “If a claim is directed essentially to a method of calculating, using a mathematical formula, even if the solution is for a specific purpose, the claimed method is nonstatutory.” Parker v. Flook , 437 U.S. 584, 595 (1978) (internal quotations omitted).” ( Precedential CAFC decision: Digitech Image Technologies, LLC. v. Electronics for Imaging, Inc. , decided July 11, 2014). “A claim that directly reads on matter in the three identified categories is outside section 101. Mayo , 132 S. Ct. at 1293. But the provision also excludes the subject matter of certain claims that by their terms read on a human-made physical thing (“machine, manufacture, or composition of matter”) or a human-controlled series of physical acts (“process”) rather than laws of nature, natural phenomena, and abstract ideas. Such a claim falls outside section 101 if (a) it is “directed to” matter in one of the three excluded categories and (b) “the additional elements” do not supply an “inventive concept” in the physical realm of things and acts—a “new and useful application” of the ineligible matter in the physical realm—that ensures that the patent is on something “significantly more than” the ineligible matter itself. Alice , 134 S. Ct. at 2355, 2357 (internal quotation marks omitted); see Mayo , 132 S. Ct. at 1294, 1299, 1300. This two-stage inquiry requires examination of claim elements “both individually and ‘as an ordered combination.’” Alice , 134 S. Ct. at 2355.” (Precedential CAFC decision: Buysafe Inc. v. Google Inc., decided September 3, 2014). The instant claims do recite additional elements beyond the judicial exception set forth above. The claims recite analyzing the diagnostic Borrelia for the presence of bound isotype-specific reagents to determine a ratio of IgE, IgA and IgG isotype pathogen-specific antibodies, wherein the ratio is indicative of immune response to the Borrelia. While calculating a ratio is in fact a mathematical operation, it is noted that thr claims do not actually recite the steps of calculating the claimed ratio. Sure the claims imply that it is done, but the claims do not explicitly recite the steps for calculating the ratio. Therefore, attention is directed to MPEP 2106.04(II)(A)(1). This section of the MPEP notes that a claim is understood to recite a judicial exception if it is either recited, or described, or set forth in the claim. In this case, while the instant claims do not recite the step of calculating the ratio, the instantly rejected claims nonetheless describe the step of analyzing the diagnostic Borrelia for the presence of bound isotype-specific reagents to determine a ratio of IgE, IgA and IgG isotype pathogen-specific antibodies, wherein the ratio is indicative of immune response to the Borrelia. Additionally, the claims do not recite anything special regarding the manner in which data is collected such that the scope of said claims would exclude routine and conventional biological experiments known to produce data required by the instant analysis. As such, this element of the claims only adds a conventional data collection method as the source of the data to be analyzed. This does not amount to something beyond the recitation of routine and conventional data gathering activities. The broadest reasonable interpretation of the claims a method comprising analyzing the diagnostic Borrelia for the presence of bound isotype-specific reagents to determine a ratio of IgE, IgA and IgG isotype pathogen-specific antibodies, wherein the ratio is indicative of immune response to the Borrelia. No particular treatment is recited based upon the determined ratio. Instead the treatment is generic and not based upon the ratio, but based upon the presence of any IgE. For process claims, the general rule is that the claim is not subject to the markedly different analysis for nature-based products used in the process. MPEP 2106.04(c)(I)(C). This part of the eligibility analysis evaluates whether the claim falls within any statutory category. MPEP 2106.03. The claim recites at least one step or act, including calculating a ratio. Thus, the claim is to a process, which is one of the statutory categories of invention ( Step 1: YES ). Limitation in the claim recites indicating a ratio measured in the sample which has a BRI that requires performing an arithmetic calculation (division) in order to obtain the ratio of and then using the ratio as an indicative of immune response to the Borrelia. This limitation therefore recites a mathematical calculation. The grouping of “mathematical concepts” in the 2019 PEG includes “mathematical calculations” as an exemplar of an abstract idea. 2019 PEG Section I, 84 Fed. Reg. at 52. Thus, limitation (a) falls into the “mathematical concept” grouping of abstract ideas. In addition, this type of simple arithmetic calculation (division) can be practically performed in the human mind, and is in fact performed in the human mind on a daily basis, for instance by school-aged children studying mathematics. Note that even if most humans would use a physical aid ( e.g ., pen and paper, a slide rule, or a calculator) to help them complete the recited calculation, the use of such physical aid does not negate the mental nature of this limitation. Thus, the limitation also falls into the “mental process” groupings of abstract ideas. In addition, the claim limitations describes a naturally occurring relationship between the ratio of immunoglobulins present as a result of Borrelia infection and thus may also be considered to recite a law of nature. The claims describes a law of nature or natural correlation, namely when the ratio of the isotypes, that indicates immune response to the Borrelia. Accordingly, the claim limitations recites multiple judicial exceptions (an abstract idea that falls within the mathematical concept and mental process groupings in the 2019 PEG, and a law of nature), and the analysis must therefore proceed to Step 2A Prong Two. Thus, limitation also falls into the “mental process” groupings of abstract ideas. Accordingly, the claim limitations recites judicial exceptions (an abstract idea that falls within the mathematical concept and mental process groupings in the 2019 PEG, and a law of nature), and the analysis must therefore proceed to Step 2A Prong Two. Again, the limitation thus fails to meaningfully limit the claim because it does not require any particular application of the recited calculation, and is at best the equivalent of merely adding the words “apply it” to the judicial exception. Accordingly, the limitation does not integrate the recited judicial exception into a practical application and the claim is therefore directed to the judicial exception ( Step 2A: YES ). Furthermore, the claim limitation falls under several exceptions ( e.g ., a mathematical concept-type abstract idea, a mental process-type abstract idea, and a law of nature), there are no bright lines between the types of exceptions. See, e.g ., MPEP 2106.04(I). Thus, it is sufficient for the examiner to identify that limitation (a) aligns with at least one judicial exception, and to conduct further analysis based on that identification. See October 2019 Update at Section I.B n.7. For purposes of further discussion, this example identifies the recited exception as an abstract idea. The eligibility analysis evaluates whether the claim as a whole integrates the recited judicial exception into a practical application of the exception. This evaluation is performed by (a) identifying whether there are any additional elements recited in the claim beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claim as a whole integrates the exception into a practical application. 2019 PEG Section III(A)(2), 84 Fed. Reg. at 54-55. Besides the abstract idea, the claim provides a detection mechanism. In fact, this limitation is recited at a high level of generality. Like the claims in Mayo Collaborative Servs. v. Prometheus Labs . , Inc. , 566 U.S. 66, 78 (2012), the claims tell the relevant audience (doctors) about the mathematical concepts and at most adds a suggestion that the doctors take those laws into account when treating their patients. Accordingly, the claim limitation does not integrate the recited judicial exception into a practical application and the claim is therefore directed to the judicial exception. Like the claims in Mayo Collaborative Servs. v. Prometheus Labs . , Inc. , 566 U.S. 66, 78 (2012), the claims tells the relevant audience (doctors) about the mathematical concepts and at most adds providing an indication of an immune response to the Borrelia that the doctors take those laws into account when treating their patients. The claims also tell the relevant audience about the natural correlations. This limitation sets forth a judicial exception, because this type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo Collaborative Svcs. v. Prometheus Labs., 566 U.S. __, 132 S. Ct. 1289, 1297 (2012). The comparison limitation sets forth a judicial exception, because this type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo . Furthermore, this step could be performed by a human using mental steps or basic critical thinking, which are types of activities that have been found by the courts to represent abstract ideas (e.g., the mental comparison in Ambry Genetics , or the diagnosing an abnormal condition by performing clinical tests and thinking about the results in Grams ). Thus, the claim is directed to at least one exception (Step 2A: YES), which may be termed a law of nature, an abstract idea, or both. Next, the claim as a whole is analyzed to determine whether any element, or combination of elements, is sufficient to ensure that the claim amounts to significantly more than the exception. Besides the law of nature, the claim recites additional steps of collecting at least one antibody-containing sample, optionally a blood sample from the individual; contacting said at least one antibody-containing sample from the individual with a live or fixed diagnostic Borrelia burgdorferi ; contacting the diagnostic Borrelia with IgE, IgA and IgG isotype-specific reagents, which reagents are operably linked to a detectable moiety; and treating the individual with a mast cell stabilizing agent when pathogen Borrelia burgdorferi-specific IgE antibodies are present. Contact is well-understood, routine and conventional activity for those in the field of diagnostics. Furthermore, the step is recited at a high level of generality such that it amounts to insignificant activity, e.g., a mere data gathering step necessary to use the correlation. While these are elements in addition to the judicial exceptions, they are at such a high level of generality that they seem to be like saying “detect it with some mechanism” from the sample merely instructs a scientist to use any technique with any generic method. Here, the recited correlation is a law of nature because it is a consequence of a natural process in the body, and that the critical thinking step is an abstract idea similar to those found by the courts to be an exception. Regarding the ratio step, it is well established that the mere physical or tangible nature of additional elements such as the comparing data does not automatically confer eligibility on a claim directed to an abstract idea (see, e.g., Alice Corp. v. CLS Bank Int’l, 134 S.Ct. 2347, 2358-59 (2014)). The elements in the claim do not amount to significantly more, in this case, because they merely add data gathering and well-understood, routine and conventional activities that do not impose meaningful limits on the law of nature. When recited at this high level of generality, there is no meaningful limitation, such as a particular or unconventional machine or a transformation of a particular article, in this step that distinguishes it from well-understood, routine, and conventional data gathering activity engaged in by scientists prior to Appellants’ invention, and at the time the application was filed. Consideration of the additional elements as a combination also adds no other meaningful limitations to the exception not already present when the elements are considered separately. Unlike the eligible claim in Diamond v. Diehr, 450 U.S. 175, 188 (1981) in which the elements limiting the exception are individually conventional, but taken together act in concert to improve a technical field, the claims here do not invoke any of the considerations that courts have identified as providing significantly more than an exception. Even when viewed as a combination, the additional elements fail to transform the exceptions into a patent-eligible application. Thus, the claims as a whole does not amount to significantly more than the exceptions themselves (Step 2B: NO). The claims are not eligible. As such, these elements clearly do not provide for subject matter that is significantly more than the judicial exceptions embraced by the claims. For these reasons, the instant claims encompass non-statutory subject matter. Claim Rejections - 35 USC § 102 07-06 AIA 15-10-15 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. 07-07-aia AIA 07-07 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 – 07-08-aia AIA (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. 07-15 AIA 7. Claim s 1, 18 and 67 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Bluth et al., (Immunology. Vol.65, Issue 4, April 2007; pages 376-382) as evidenced by Su et al., (Biochemical Pharmacology. Vol. 91, Issue 3, Oct. 2014, pages 359-368) . The claims are drawn to a method of treating inflammation which is a symptom associated with Lyme diseases and Borrelia burgdorferi infection in an individual, the method comprising: analyzing a blood sample from the individual for the presence of IgE isotype Borrelia burgdorferi-specific antibodies; and treating the individual with a mast cell stabilizing agent when Borrelia burgdorferi-specific IgE antibodies are present. Bluth et al., teach IgE anti- Borrelia burgdorferi components and increased blood T cells in children with Lyme disease. Bluth et al., investigated the presence and persistence of IgE anti- B. burgdorferi antibodies (Abs) in pediatric patients infected with Lyme disease over time. For studies of serum immunoglobulins, blood was collected [Blood]. Serum immunoglobulin levels, presence of IgG and IgE anti- B. burgdorferi components, and distributions of blood T, B and natural killer lymphocyte subsets were studied in B. burgdorferi -infected and -uninfected children (nephelometry, UniCAP Total IgE Fluoroenzymeimmunoassay, Western blot, flow cytometry) [abstract]. These results demonstrate that specific IgE anti- B. burgdorferi Abs are generated and persist in children with Lyme disease [abstract]. Peripheral blood was obtained from pediatric patients with Lyme disease [Materials and Methods]. Thus teach the collection of an antibody-containing blood sample from the individual. Bluth et al., teach Mouse anti-human monoclonal antibodies (MoAbs) directly conjugated to fluorescein isothiocyanate (FITC) [Antibodies]. Thus teaching antibodies operably linked to a detectable moiety. Flow cytometric analysis was performed on a Coulter Epics XL/MCL Flow Cytometer [Immunofluorescence assay].. Total serum immunoglobulins (IgM, IgE, IgG and IgA) were measured by nephelometric quantitation, using the Beckman array protein system [Total serum immunoglobulins]. See also Table 1. Table 1. Immunoglobulin levels in serum of Borrelia burgdorferi patients. Subject IgM (mg/dl) IgG (mg/dl) IgA (mg/dl) IgE (IU/ml) Lyme infected 82 ± 11 788 ± 128 85 ± 21 49 ± 40 Normal 73 ± 10 729 ± 55 78 ± 15 46 ± 23 Patients’ serum also contained antigen-specific IgE directed against B. burgdorferi [IgE anti- B.burgdorferi ]. Patients were treated with a 3-week course of doxycycline antibiotics. Treatment was consistent with published recommendations [Materials and Methods]. Thus, Bluth et al., teach analysis for the presence of bound isotype-specific reagents to determine the ratio of IgE, IgA and IgG isotype Borrelia-specific antibodies, wherein the ratio is indicative of a immune response to Borrelia. It is noted that doxycycline acts as a mast cell stabilizer. Su et al., tech doxycycline exerts multiple anti-allergy effects to attenuate murine allergic conjunctivitis and systemic anaphylaxis. Su et al., reported that treatment with doxycycline significantly reduced IgE release from mouse B cells and the degranulation and inflammatory cytokines production of mouse mast cells (MCs) activated by IgE-dependent way. Furthermore, doxycycline treatment significantly inhibited histamine-induced vascular hyperpermeability in vitro. Mechanistically, the doxycycline-mediated inhibition of B cells, MCs and histamine may occur via modulation of the PI3K/Akt pathway. Su et al., further confirmed anti-allergy effects of doxycycline and doxycycline-mediated inhibitory effects on MCs. Therefore, doxycycline acts as a mast cell stabilizer. While primarily a tetracycline antibiotic, research shows it has non-antibiotic properties that help manage allergies and mast cell-related issues. While it is not a traditional medication used exclusively for mast cell stabilization (like cromolyn sodium or ketotifen), doctors occasionally repurpose it for conditions involving mast cell hyperactivity, such as Mast Cell Activation Syndrome (MCAS). Therefore, Bluth et al., as evidenced by Su et al., anticipates the instantly rejected claims . Response to Arguments 07-37 AIA 8. Applicant's arguments filed March 4, 2026 have been fully considered but they are not persuasive. Applicants point to amended claim 1’s recitation of the mast stabilizing agents to overcome the teaching of Bluth’s administration of doxycycline. However, doxycycline acts as a mast cell stabilizer. While primarily a tetracycline antibiotic, research shows it has non-antibiotic properties that help manage allergies and mast cell-related issues. While it is not a traditional medication used exclusively for mast cell stabilization (like cromolyn sodium or ketotifen), doctors occasionally repurpose it for conditions involving mast cell hyperactivity, such as Mast Cell Activation Syndrome (MCAS). Thus, doxycycline as a mast cell stabilizer thereby meeting the instant limitation. Applicants argue that the method of claim 1 requires a whole cell pathogen. However, Applicants attention is directed to the instantly rejected claims. Claim 2 , which is not rejected by Bluth recites an intact pathogen, whereas claim 1 does not. Instead, claim 1 only requires “diagnostic Borrelia”. The instant claims do not limit “diagnostic Borrelia” to an intact whole cell pathogen. Therefore, the teaching of Bluth et al., is sufficient to meet the instantly recited diagnostic Borrelia. Thus, this argument is not persuasive. Applicants argue that treatment is only administered if IgE antibodies against the pathogen are present. Again Applicants attention is directed to the specific claim language. Claim 1 recites “…analyzing a blood sample from the individual for the presence of IgE isotype Borrelia burgdorferi-specific antibodies; and treating the individual with a mast cell stabilizing agent when Borrelia burgdorferi-specific IgE antibodies are present.” Analysis is the only step recited before the treatment step. There is no measurement requirement for detecting a specific level of IgE to be detected before deciding if treatment is necessary. Contrary to Applicants assertion, the claim language does not recite conditional treatment after receiving the a specific ratio of results. The claim only recites treating individuals when any amount of IgE is present, which is exactly what Bluth teaches. Bluths’ patients’ serum also contained antigen-specific IgE directed against B. burgdorferi [IgE anti- B.burgdorferi ]. Patients were treated with a 3-week course of doxycycline antibiotics. Peripheral blood was obtained from pediatric patients with Lyme disease [Materials and Methods]. Thus teach the collection of an antibody-containing blood sample from the individual. Bluth et al., teach Mouse anti-human monoclonal antibodies (MoAbs) directly conjugated to fluorescein isothiocyanate (FITC) [Antibodies]. Thus teaching antibodies operably linked to a detectable moiety. Flow cytometric analysis was performed. Total serum immunoglobulins (IgM, IgE, IgG and IgA) were measured by nephelometric quantitation. Thereby teaching the analysis step. Patients were treated with a 3-week course of doxycycline antibiotics. Applicants point out that amended claim 20 recites the mast stabilizing agents disodium cromoglycate and luteolin. However claim 20 is no longer rejected by Bluth et al., as evidenced by Su et al; therefore this argument is misplaced. Finally, Applicants point to the specification at paragraphs 71-73 which recite the functions being that Mast cell stabilizing drugs inhibit the release of allergic mediators from mast cells and are used clinically, e.g. to prevent allergic reactions. Additionally, the paragraphs recite non-limiting examples of mast cell stabilizers. The specification does not excluded doxycycline. Su et al., reported that treatment with doxycycline significantly reduced IgE release from mouse B cells and the degranulation and inflammatory cytokines production of mouse mast cells (MCs). Doxycycline inhibit the release of allergic mediators from mast cells, meeting the definition of a mast cell stabilizer. Therefore, applicants arguments are not found persuasive . Claim Rejections - 35 USC § 103 07-06 AIA 15-10-15 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. 07-20-aia AIA 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. 07-23-aia AIA 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 ord20inary skill in the pertinent art. 4. Considering objective evidence present in the application indicating obviousness or nonobviousness. 07-21-aia AIA 9. Claim s 1-2, 18, 20, 24 and 67 are rejected under 35 U.S.C. 103 as being unpatentable over Halpern et al., (Clinical and Vaccine Immunology. March 2013, Vol. 20, Number 3, p 350-357) in view of Lea (US 20130165335 published June 2016; priority to Dec 2008) and Gerhart et al., (WO2015120389 published 2015-08-13; priority to Feb 10, 2014) . The claims are drawn to a method of treating inflammation which is a symptom associated with Lyme diseases and Borrelia burgdorferi infection in an individual, the method comprising: collecting at least one antibody-containing sample, optionally a blood sample from the individual; contacting said at least one antibody-containing sample from the individual with a live or fixed diagnostic Borrelia burgdorferi ; contacting the diagnostic Borrelia with IgE, IgA and IgG isotype-specific reagents, which reagents are operably linked to a detectable moiety; analyzing the diagnostic Borrelia for the presence of bound isotype-specific reagents to determine a ratio of IgE, IgA and IgG isotype pathogen-specific antibodies, wherein the ratio is indicative of immune response to the Borrelia; and treating the individual with a mast cell stabilizing agent when pathogen Borrelia burgdorferi-specific IgE antibodies are present. Current methods for detection of Lyme disease in a clinical setting approved by the CDC entail a two-tiered approach using a first-tier enzyme immunoassay (EIA) followed by a second-tier immunoblot assay for both IgM and IgG B. burgdorferi -specific antibodies using whole-cell B. burgdorferi lysates, recombinant antigens, or various combinations, depending on the commercial kit used [age 350, col. 1]. Halpern et al., developed an immuno-PCR (iPCR)-based approach employing recombinant in vivo -expressed B. burgdorferi antigens for objective detection of a host immune response to B. burgdorferi infection. iPCR is a liquid-phase protein detection method that combines the sensitivity of PCR with the specificity and versatility of immunoassay-based protocols. Use of magnetic beads coated with intact spirochetes provided effective antigen presentation and allowed detection of host-generated antibodies in experimentally infected mice at day 11 postinoculation, whereas host-generated antibodies were detected at day 14 by enzyme-linked immunosorbent assay (ELISA) and day 21 by immunoblotting [abstract]. FIG 1 Schematic representation of iPCR assay for detection of Lyme disease biomarkers. Intact spirochete (A) was used to capture B. burgdorferi -specific host-generated antibodies. A biotinylated DNA oligonucleotide reporter molecule coupled to a streptavidin-conjugated reporter antibody was amplified by qPCR for detection and quantification. Anti- B. burgdorferi antibody coupled to magnetic beads was used for spirochete capture, with detection accomplished by qPCR amplification of the DNA oligonucleotide-coupled reporter antibody, similar to detection of host antibody [page 352]. Thus teaching a live intact Borrelia diagnostic agent. Human samples consisted of sera collected from healthy or Lyme disease patients blood donors living in areas where Lyme disease is not endemic [Human Sera]. Over the course of 21 days, sera were analyzed for detection of B. burgdorferi IgG antibodies using iPCR [page 353, col. 2]. Figure 3 shows IgM and IgG antibody detection at different time points. FIG 6 shows iPCR directly detects B. burgdorferi in infected samples. Live spirochetes were serially diluted in HN buffer and tested in triplicate using iPCR to detect organism capture using anti-B. burgdorferi antibody-coated magnetic beads. Spirochetes and blood samples were collected every 24 h for a period of 14 days [page 355, col. 2]. Recombinant antigen iPCR successfully quantified B. burgdorferi antibodies in human serum samples [page 356, col. 1]. Lea et al., teach methods for detecting and quantifying biomarkers, therapeutic proteins and patient derived antibodies; the use of secondary reagents to determine immunoglobulin classes IgG, IgA, IgM, IgE and sub-classes including IgG1, IgG2, IgG3, IgG4 and IgA. The intensity of each fluorescent signal allows measurement of a specific immune response to a therapeutic protein and associated analytes [abstract]. The method for detecting and quantifying biomarkers diagnostic for immunogenicity testing of a therapeutic protein, is taught [para 31]. It is common for several antigenic substances or bio-markers to be associated with detection and diagnosis for any pathological or physiological disorder [para 3]. The method applies a plurality of different fluorescently labeled antibodies that selectively bind to human immunoglobulin classes IgG, IgA, IgM, IgE, IgD and sub-classes including IgG1, IgG2, IgG3, IgG4 and IgA1, IgA2, respectively, the fluorescently labeled antibodies including a first fluorescently labeled anti-antibody that specifically binds to IgA antibodies, a second fluorescently labeled anti-antibody that selectively binds to IgG antibodies, a third fluorescently labeled anti-antibody that selectively binds to IgM antibodies, a fourth fluorescently labeled anti-antibody that selectively binds to IgE antibodies, a fifth fluorescently labeled anti-antibody that selectively binds to IgD antibodies, a sixth fluorescently labeled anti-antibody that selectively binds to sub-class IgG1, a seventh fluorescently labeled anti-antibody that selectively binds to sub-class IgG2, an eighth fluorescently labeled anti-antibody that selectively binds to sub-class IgG3, a ninth fluorescently labeled an anti-antibody that selectively binds to sub-class IgG4,wherein the first, second, third fourth, fifth, sixth, seventh and eighth fluorescently labeled antibodies each comprise a different fluorescent dye having emission and excitation spectra that do not overlap with each other. [para 31]. An analyte capture matrix comprises a plurality of capture spots, each capture spot comprising a predetermined amount of an agent that selectively binds to the target analytes [para 31]. Lea teach measuring a signal intensity value for each immunoglobulin contained within each spot forming the microarray printed in each well of the assay device; generating calibration curves by fitting a curve to the measured signal intensity values for the each of the calibration spots versus the known concentration of the human IgA, IgG, IgE, IgM, IgD and subclass antibodies; and determining the concentration for each of captured human isotype class and subclass immunoglobulins [para 32-49]. Thus claims 1 and 18 are taught. As the antibodies are labeled with different optically excited and emitted fluorescent probes, each of the targets bound to a single capture spot can be detected and quantified using an appropriate calibrator. The use of multi-channel detectors allows for substantially simultaneous detection of multiplex analytes in a single assay [para 55]. Thereby teaching reagents are operably linked to a detectable moiety. The concentration for each target analyte in the test sample is then determined using the appropriate calibration curve and by plotting the measured signal intensity for the target analyte on the calibration curve [para 65]. The methods disclosed herein can be used to detect and quantify multiple clinically relevant biomarkers in a biological sample for diagnostic or prognostic purposes. The measured concentrations for a disease-related biomarker can be compared with established index normal levels for that biomarker. The measured concentrations levels that exceed index normal levels may be identified as being diagnostic of the disease. The method disclosed herein can also be used to monitor the progress of a disease and also the effect of a treatment on the disease. Levels of a clinically relevant biomarker can be quantified using the disclosed method a plurality of times during a period of treatment [para 66]. Thus teaching claim 24. A trending decrease in biomarker levels may be correlated with a positive and/or negative patient response to treatment [para 66]. Thus teaching the ratio is indicative of a immune response to the pathogen. Samples collected from untreated and therapeutic protein-treated patients are incubated with the immobilized microarray components. Samples are most likely to be serum or plasma [para 70]. Thus teaching the samples of claims 1 and 12. Therefore, Lea teach diagnostic method for determining an individual an immune response and disease state, the method comprising: collecting at least one antibody-containing sample, optionally a blood sample from the individual; contacting said at least one antibody-containing sample from the individual with a fixed diagnostic antigen; contacting the diagnostic antigen with IgE, IgA and IgG isotype-specific reagents, which reagents are operably linked to a detectable moiety; and analyzing the diagnostic antigen for the presence of bound isotype-specific reagents to determine the ratio of IgE, IgA and IgG isotype pathogen-specific antibodies, wherein the ratio is indicative of a immune response. Finally, Gerhart et al., teach methods of treating a systemic mast cell related disorder by delivering a systemically effective amount of a mast cell stabilizer to a patient wherein a systemic mast cell disorder is chronic lyme disease [para 6]. In some embodiments, the mast cell stabilizer is cromolyn sodium [para 9]. Methods for the treatment or prophylaxis of systemic mast cell related disorders comprising administering compositions comprising one or more mast cell stabilizers. As used herein, a "systemic mast cell related disorder" is a disease or condition that is caused by or associated with excessive proliferation or activation of mast cells or abnormal release of vasoactive or pro-inflammatory mediators in the body as a whole, and is thus treatable by administration of a systemically effective amount of a mast cell stabilizer, e.g., cromolyn sodium. A systemic mast cell related disorder is distinct from a local mast cell related disorder, in which symptoms of the disease or condition manifest in a particular region of the body. Systemic mast cell related disorders include, but are not limited to chronic lyme disease [para 46]. The utility of mast cell stabilizers in the treatment of systemic mast cell related disorders, such as mastocytosis, has been limited. For example, cromolyn sodium (also known as disodium cromoglycate or DSCG) was first approved in 1973 and is widely considered safe [para 4]. Example 3 teach study treatments, dosage and mode of administering DSCG. It is noted that the inflammation is not correlated with the ratio of IgA, IgE and IgG isotype specific antibodies. Additionally, the treatment is not correlated to either the specific ratio of isotype specific antibodies or the inflammation being treated. Therefore, it would have been prima facie obvious at the time of applicants’ invention to apply Lea et al’s comparisons and ratios of IgG, IgA and IgM antibody titers to the methods of Halpern et al., to contact the diagnostic Borrelia with IgE, IgA and IgG isotype-specific reagents, in order indicate of the isotype specific antibodies in a subject and treat the subject with a mast cell stabilizer as taught by Gerhart et al.. One of ordinary skill in the art would have a reasonable expectation of success by incorporating the diagnostic isotype antibody ratios to detect and quantifying the IgA, IgG and IgE biomarkers for Borrelia over a period of time. Furthermore, no more than routine skill is required to treat lyme disease with a mast cell stabilizer, such as DSCG. Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". It is well known to take a mast cell stabilizer for treating Lyme disease, which is well known and when there is no change in the respective function of DSCG, thus the combination would have yielded a reasonable expectation of success along with predictable results to one of ordinary skill in the art at the time of the invention. Therefore, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary . Response to Arguments 07-37 AIA 10. Applicant's arguments filed March 4, 2026 have been fully considered but they are not persuasive. Applicants state that Halpern teach an intact spirochete; yet argues the Halpern teach away from the whole cell pathogen. Halpern et al., teach a tiered immunoblot assay for both IgM and IgG B. burgdorferi -specific antibodies using whole-cell B. burgdorferi . Furthermore, Halpern et al., teach spirochete capture with detection accomplished by qPCR amplification of the DNA oligonucleotide-coupled reporter antibody, similar to detection of host antibody. Thus teaching a live intact Borrelia diagnostic agent. Applicants argue that the references do not teach the measurement of IgE. Contrary to Applicants assertion, Halpern teach over the course of 21 days, sera were analyzed for detection of B. burgdorferi IgG antibodies from patient infected serum. Lea teach the human immunoglobulin classes IgG, IgA, IgM, IgE, IgD and sub-classes including IgG1, IgG2, IgG3, IgG4 and IgA1, IgA2, as isotype-specific reagents. Applicants argue that Halpern does not teach the importance of the ratio of antibody isotype. However, the importance of antibody ratio is not the standard for determining obviousness. In response to applicant's arguments against the Halpern reference 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). In this case, Halpern in view of Lea et al., teach a ratio method in calibration curves is a way to improve accuracy by normalizing the signal to a reference signal. Lea teach generating calibration curves by fitting a curve to the measured signal intensity values for each analyte contained in each of the calibration spots versus a known concentration of the first target analyte and the second target analyte; thus teach a ratio method just as instantly recited. Therefore, Halpern in view of Lea teach analyzing the diagnostic Borrelia for the presence of bound isotype-specific reagents to determine a ratio of IgE, IgA and IgG isotype pathogen-specific antibodies, Applicants argue that Lea does not teach the use of an intact antigen; however one cannot show nonobviousness by attacking the Lea reference individually where the rejections are based on combinations of Halpern references. As stated above, Halpern in view of Lea teach a live intact spirochete . 07-37-04 AIA In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine , 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones , 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc. , 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, it would have been prima facie obvious at the time of applicants’ invention to apply Lea et al’s comparisons and ratios of IgG, IgA and IgM antibody titers to the methods of Halpern et al., to contact the diagnostic Borrelia with IgE, IgA and IgG isotype-specific reagents, in order indicate of the isotype specific antibodies in a Borrelia infected subject treat the Lyme disease infected subject with DSCG as taught by Gerhart et al . It is noted that Gilschick is no longer apart of the rejection. Therefore, Applicants arguments regarding Gilschick will not be addressed. Instead the new rejection incorporate Gerhart which teach treatment of Lyme disease with a mast cell stabilizer such as disodium cromoglycate (DSCG). Pertinent Art 07-96 AIA 11. The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure. Runsewe (Journal of Biosciences and Medicines > Vol.7 No.6, June 2019). It has been established that tetracyclines possess anti-bacterial properties, but recent development has also shown that it also possesses anti-inflammatory properties as well as apoptotic properties which can be applied in the treatment of mastocytosis. This paper focuses on the use of the principle of “Creative synthesis” to formulate a possible treatment to mastocytosis using tetracycline and polyphenols as well as chemically modified tetracyclines (CMTs). In addition to the antibiotic properties of tetracycline, they have also been discovered to exert a number of pleiotropic anti-inflammatory and immunomodulatory activities These include the capacity to inhibit metalloproteinases (MP), which are an enzyme class involved in important cell functions, for example, the shedding of dissolvable mediators and their receptors from the cell surface, and connection with, the remodeling of the extracellular matrix. It was additionally detailed that doxycycline (DOXY) at therapeutic concentrations (1 - 5 ug/ml) suppresses Ig secretion to a significant extent and class switching by in vitro activated murine B cells Miller et al., (Microbial Pathogens. Vol. 41, Issue 1, July 2006, pages 43-47) Detection of Borrelia burgdorferi gene expression during mammalian infection using transcriptional fusions that produce green fluorescent protein Dietrich et al., (J of Microbiol Methods. Vol. 13, Issue 4, August 1991, pages 281-291) Measurement of antibody binding to intact bacteria using flow cytometric techniques Moor et al., (Nature Protocols. Vol. 11, No. 8, 2016, pages 1531-1553) Antibacterial antibody responses that target surfaces of live bacteria or secreted toxins are likely to be relevant in controlling bacterial pathogenesis. The ability to specifically quantify bacterial-surface-binding antibodies is therefore highly attractive as a quantitative correlate of immune protection. Here, binding of antibodies from various body fluids to pure-cultured live bacteria is made visible with fluorophore-conjugated secondary antibodies and measured by flow cytometry. We indicate the necessary controls for excluding nonspecific binding and also demonstrate a cross-adsorption technique for determining the extent of cross-reactivity. This technique has numerous advantages over standard ELISA and western blotting techniques because of its independence from scaffold binding, exclusion of cross-reactive elements from lysed bacteria and ability to visualize bacterial subpopulations . Conclusion 12. It is noted that claim 8 is free of the art. However claim 8 is objected to as being dependent upon rejected claim 1. No claims allowed. 13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JA-NA A HINES whose telephone number is (571)272-0859. The examiner can normally be reached Monday thru Thursday. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor Peter Paras, can be reached on 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). /JANA A HINES/Primary Examiner, Art Unit 1645 Application/Control Number: 17/279,012 Page 2 Art Unit: 1645 Application/Control Number: 17/279,012 Page 3 Art Unit: 1645 Application/Control Number: 17/279,012 Page 4 Art Unit: 1645 Application/Control Number: 17/279,012 Page 5 Art Unit: 1645 Application/Control Number: 17/279,012 Page 6 Art Unit: 1645 Application/Control Number: 17/279,012 Page 7 Art Unit: 1645 Application/Control Number: 17/279,012 Page 8 Art Unit: 1645 Application/Control Number: 17/279,012 Page 9 Art Unit: 1645 Application/Control Number: 17/279,012 Page 10 Art Unit: 1645 Application/Control Number: 17/279,012 Page 11 Art Unit: 1645 Application/Control Number: 17/279,012 Page 12 Art Unit: 1645 Application/Control Number: 17/279,012 Page 13 Art Unit: 1645 Application/Control Number: 17/279,012 Page 14 Art Unit: 1645 Application/Control Number: 17/279,012 Page 15 Art Unit: 1645 Application/Control Number: 17/279,012 Page 16 Art Unit: 1645 Application/Control Number: 17/279,012 Page 17 Art Unit: 1645 Application/Control Number: 17/279,012 Page 18 Art Unit: 1645 Application/Control Number: 17/279,012 Page 19 Art Unit: 1645 Application/Control Number: 17/279,012 Page 20 Art Unit: 1645 Application/Control Number: 17/279,012 Page 21 Art Unit: 1645 Application/Control Number: 17/279,012 Page 22 Art Unit: 1645 Application/Control Number: 17/279,012 Page 23 Art Unit: 1645 Application/Control Number: 17/279,012 Page 24 Art Unit: 1645 Application/Control Number: 17/279,012 Page 25 Art Unit: 1645 Application/Control Number: 17/279,012 Page 26 Art Unit: 1645
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