DETAILED ACTION
Applicant’s amendment submitted 2/27/2026 is acknowledged. Claims 16, 19, 25, and 26-27 are currently amended. Claim 32 is newly added. Claims 1-15, 17-18, 22-24, and 28-30 are canceled.
Claims 16, 19-21, 25-27, and 31-32 are pending in the instant application and the subject of this office 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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 2/27/2026 has been entered.
Priority
The instant application is a U.S. National Phase of PCT/EP2021/051858, filed on 1/27/2021, and claims foreign priority to DE102020101864.9, filed on 1/27/2020.
Response to Amendment
Applicant’s amendment to claim 26 overcomes the objection previously set forth in the Final Rejection mailed on 10/27/2025.
Applicant’s amendment to claim 25 to be in independent form overcomes the 35 U.S.C. 112(d) rejection previously set forth. Accordingly, the rejection is withdrawn.
Applicant’s cancelation of claim 28 renders moot the 35 U.S.C. 112(a) and 112(b) rejections previously set forth. Accordingly, the rejections are withdrawn.
Applicant’s cancelation of claim 29 renders moot the objections and 35 U.S.C. 112(b) rejections previously set forth. Accordingly, the rejection is withdrawn.
Claim Objections
Claim 27 is objected to because of the following informalities:
The “and” recited before abdominal distension in the penultimate line of claim 27 is inappropriate and should be deleted.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 16, 19-21 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.
The term “substantially” in line 7 of claim 16 is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Claim 16 recites “determining the concentration of γ-tryptase present in the fecal protein extract using an immunological method that employs at least one antibody that selectively binds and does not substantially cross-react with α-tryptase or β-tryptase.” It is not clear what is considered to be unsubstantial binding of α-tryptase or β-tryptase. Absent clearly defined parameters for what is considered substantial and unsubstantial, the metes and bounds of the claim limitations cannot be determined. Claim 19 similarly recites “does not substantially bind α- or β-tryptase” and is rejected for similar reasons.
Claim 16 recites the limitation "the antibody" in line 8. There is insufficient antecedent basis for this limitation in the claim. Claim 16 recites “at least one antibody” in line 7. It is not clear if “the antibody” is intended to refer to the at least one antibody previously recited or if it is intended to refer to a separate antibody. Therefore, the metes and bounds of the claim cannot be determined. Applicant may overcome this rejection by amending claim 16 to replace “the antibody” with “the at least one antibody.”
Claims 19-21, 26-27, and 31 are also rejected for being dependent on a rejected base claim and failing to remedy the issues set forth above.
Claim 19 recites the limitation "the immunological methods" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 19 depends from claim 16. Claim 16 recites “an immunological method.” It is not clear if “the immunological methods” recited in claim 19 refers to a separate set of immunological methods or to the immunological method recited in claim 16. Thus, the metes and bounds of the claim are unclear.
The term “substantially” in line 8 of claim 25 is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Claim 25 recites “at least one antibody raised against human γ-tryptase isolated from lung tissue, wherein the antibody selectively binds γ-tryptase and does not substantially bind α-tryptase or β-tryptase.” It is not clear what is considered to be unsubstantial binding of α-tryptase or β-tryptase. Absent clearly defined parameters for what is considered substantial and unsubstantial, the metes and bounds of the claim limitations cannot be determined.
Claim 25 recites the limitation "the antibody" in line 8. There is insufficient antecedent basis for this limitation in the claim. Claim 25 recites “at least one antibody” in line 7. It is not clear if “the antibody” is intended to refer to the at least one antibody previously recited or if it is intended to refer to a separate antibody. Therefore, the metes and bounds of the claim cannot be determined. Applicant may overcome this rejection by amending claim 25 to replace “the antibody” with “the at least one antibody.”
Claim 31 is also rejected for being dependent on a rejected base claim and failing to remedy the issues set forth above.
Claim Rejections - 35 USC § 101
Claims 16, 19-21, 25-27, and 31-32 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more.
Claim 16 recites “[a] method for diagnosing irritable bowel syndrome (IBS) and determining its severity in a patient suffering from gastrointestinal disorders, comprising the steps of:…iii) comparing the determined concentration of γ-tryptase to a predetermined reference value; and iv) assessing the patient based on the comparison: (a) a concentration >20 ng/g and <30 ng/g indicates an increased likelihood of IBS-Constipation (IBS-C) or IBS-Mixed (IBS-M); (b) a concentration >30 ng/g and <300 ng/g indicates an increased likelihood of IBS-Diarrhoea (IBS-D); and (c) a concentration >300 ng/g indicates a likelihood of allergic reaction or food intolerance…” Claim 25 recites ““[a] method for diagnosing irritable bowel syndrome (IBS) and determining its severity in a patient suffering from gastrointestinal disorders, comprising the steps of:…iii) comparing the determined concentration of γ-tryptase to predetermined reference values; wherein the predetermined reference values are: (a) 10 ng γ-tryptase per gram of feces for healthy subjects; (b) 20 ng γ-tryptase per gram of feces for subjects having an increased likelihood of IBS-Constipation or IBS-Mixed; (c) 30 ng γ-tryptase per gram of feces for subjects having an increased likelihood of IBS-Diarrhoae; and (d) 300 ng γ-tryptase per gram of feces for subjects suffering from allergic reactions and/or food intolerances…” The claimed inventions are directed to the judicial exception of a natural process in which a concentration of γ-tryptase in a fecal protein extract provided from a stool sample of a patient suffering from gastrointestinal disorders is correlated to a likelihood of the patient having irritable bowel syndrome. This judicial exception is not integrated into a practical application because claim 16 recites elements that are considered to be insignificant extra-solution activity for data gathering and abstract mental steps. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements recited are directed to insignificant extra-solution data gathering activity, abstract mental steps, or the natural phenomenon.
Claim 16 recites the step of “preparing an extract of fecal proteins from a stool sample of the patient having a predetermined mass;” which is insignificant extra-solution data gathering activity. Lettesjo et al. (Scandinav. J. Gastroenterol., 2006, Vol. 41, p.54-59; of record) discloses preparing fecal supernatants for tryptase measurement from stool samples collected from patients with irritable bowel syndrome and colitis and dilutes 0.5 g of the feces in extraction buffer before homogenization and centrifugation (see Abstract, p. 55, passage bridging left and right columns, right column, 2nd passage, 2nd paragraph). Furthermore, Roka et al. (Clin. Gastroenterol. Hepatol., 2007, Vol. 5, p.550-555; of record in the IDS filed 7/26/2022) discloses a step of preparing an extract of fecal proteins from stools of IBS patients to study serine protease activity in patients with diarrhea-predominant irritable bowel syndrome (see Abstract, p.551, left column, 1st-3rd paragraphs), and therefore this step is well-understood, routine, and conventional activity in the relevant field. Claim 16 additionally recites the step of “determining the concentration of γ-tryptase present in the fecal protein extract using an immunological method that employs at least one antibody that selectively binds and does not substantially cross-react with α-tryptase or β-tryptase, wherein the antibody is raised against and binds γ-tryptase isolated from human lung tissue;” which is insignificant extra-solution data gathering activity. Furthermore, Walls et al. (Clin. Experim. Allergy, 1990, Vol. 20, p.581-589; of record) discloses monoclonal antibodies raised against human mast cell tryptase purified from lung tissue that can detect epitopes of tryptase in additive and competitive ELISA (see Abstract, p.582, left column, 2nd passage, and right column, last passage, and p.583, left column, 1st passage-right column, 1st paragraph). According to the specification, human γ-tryptase is isolated from the lung tissue, and thus, the monoclonal antibodies raised against human mast cell tryptase purified from lung tissue is expected to be specific to human γ-tryptase. Thus, the step of detecting only γ-tryptase by antibodies raised against human γ-tryptase isolated from lung tissue is well-understood, routine, and conventional activity in the relevant field. Moreover, the level of γ-tryptase in stool is a result of a natural process related to irritable bowel syndrome, as admitted in the paragraph [0054] of the specification. Claim 16 further recites the step of “comparing the determined concentration of γ-tryptase to a predetermined reference value;” which is an abstract process that can be practically performed in the human mind. Claim 16 further recites the step of “assessing the patient based on the comparison , wherein: (a) a concentration >20 ng/g and <30 ng/g indicates an increased likelihood of IBS-Constipation (IBS-C) or IBS-Mixed (IBS-M); (b) a concentration >30 ng/g and <300 ng/g indicates an increased likelihood of IBS-Diarrhoea (IBS-D); and (c) a concentration >300 ng/g indicates a likelihood of allergic reaction or food intolerance;” which is an abstract process that can be practically performed in the human mind. Lastly, the step of “administering a therapeutic intervention or a dietary or nutritional counseling to a patient classified as having a γ-tryptase concentration >20 ng/g in stool” does not recite a specific administered treatment therapeutic and is general. Furthermore, the step of dietary or nutritional counseling embraces an abstract process that can be practically performed in the human mind. Thus, claim 16 is directed to the natural phenomenon of correlating a level of γ-tryptase in a fecal protein extract obtained from a patient suffering from gastrointestinal disorders to a likelihood of the patient having IBS, which is a natural process, and the additional elements recited do not add significantly more to the judicial exception.
Claim 19 recites “wherein the immunological methods comprises: i) providing a first antibody raised against an epitope of transmembrane human γ-tryptase isolated from lung tissue and immobilized on a solid phase; ii) contacting the first immobilized antibodies of step i) with the fecal protein extract and allowing formation of a first immune complex; iii) contacting the first immune complex with a second antibody that selectively binds human γ-tryptase from lung and does not substantially bind α- or β-tryptase thereby forming a sandwich immune complex; and iv) determining the amount of sandwich immune complex formed to quantify the concentration of human transmembrane γ-tryptase in the fecal protein extract;” which is directed to insignificant extra-solution data gathering activity.
Claim 20 recites “wherein the immunological method is an enzyme-linked immunosorbent assay (ELISA),” which is directed to insignificant extra-solution data gathering activity.
Claim 21 recites “wherein the immunological method is an immunoturbidimetric or immunonephelometric assay,” which is directed to insignificant extra-solution data gathering activity.
Claim 25 recites the step of “preparing an extract of fecal proteins from a defined stool sample of predetermined mass obtained from the patient;” which is insignificant extra-solution data gathering activity. Lettesjo et al. (Scandinav. J. Gastroenterol., 2006, Vol. 41, p.54-59; of record) discloses preparing fecal supernatants for tryptase measurement from stool samples collected from patients with irritable bowel syndrome and colitis and dilutes 0.5 g of the feces in extraction buffer before homogenization and centrifugation (see Abstract, p. 55, passage bridging left and right columns, right column, 2nd passage, 2nd paragraph). Furthermore, Roka et al. (Clin. Gastroenterol. Hepatol., 2007, Vol. 5, p.550-555; of record in the IDS filed 7/26/2022) discloses a step of preparing an extract of fecal proteins from stools of IBS patients to study serine protease activity in patients with diarrhea-predominant irritable bowel syndrome (see Abstract, p.551, left column, 1st-3rd paragraphs), and therefore this step is well-understood, routine, and conventional activity in the relevant field. Claim 25 additionally recites the step of “determining the concentration of γ-tryptase in the fecal protein extract using an immunological method comprising contacting the extract with at least one antibody raised against human γ-tryptase isolated from lung tissue, wherein the antibody selectively binds γ-tryptase and does not substantially bind α-tryptase or β-tryptase;” which is insignificant extra-solution data gathering activity. Furthermore, Walls et al. (Clin. Experim. Allergy, 1990, Vol. 20, p.581-589; of record) discloses monoclonal antibodies raised against human mast cell tryptase purified from lung tissue that can detect epitopes of tryptase in additive and competitive ELISA (see Abstract, p.582, left column, 2nd passage, and right column, last passage, and p.583, left column, 1st passage-right column, 1st paragraph). According to the specification, human γ-tryptase is isolated from the lung tissue, and thus, the monoclonal antibodies raised against human mast cell tryptase purified from lung tissue is expected to be specific to human γ-tryptase. Thus, the step of detecting only γ-tryptase by antibodies raised against human γ-tryptase isolated from lung tissue is well-understood, routine, and conventional activity in the relevant field. Moreover, the level of γ-tryptase in stool is a result of a natural process related to irritable bowel syndrome, as admitted in the paragraph [0054] of the specification. Claim 25 further recites the step of “comparing the determined concentration of γ-tryptase to predetermined reference values; wherein the predetermined reference values are: (a) 10 ng γ-tryptase per gram of feces for healthy subjects; (b) 20 ng γ-tryptase per gram of feces for subject having an increased likelihood of IBS-Constipation or IBS-Mixed; (c) 30 ng γ-tryptase per gram of feces for subjects having an increased likelihood of IBS-Diarrhoea; and (d) 300 ng γ-tryptase per gram of feces for subjects suffering from allergic reactions and/or food intolerances;” which is an abstract process that can be practically performed in the human mind. Claim 25 further recites the step of “further comprising determining the concentration of total tryptase in the fecal protein extract, wherein total tryptase includes α-, β-, and γ-tryptase;” which is further directed to the natural phenomenon of correlating a level of α, β-, and γ-tryptase to the likelihood of a patient having IBS. Claim 25 further recites “initiating a therapeutic intervention and/or implementing a dietary counselling program for subjects identified as having an elevated γ-tryptase;” does not recite a specific administered treatment therapeutic and is general. Furthermore, the step of dietary or nutritional counseling embraces an abstract process that can be practically performed in the human mind. Thus, claim 25 is directed to the natural phenomenon of correlating a level of γ-tryptase in a fecal protein extract obtained from a patient suffering from gastrointestinal disorders to a likelihood of the patient having IBS, which is a natural process, and the additional elements recited do not add significantly more to the judicial exception.
Claim 26 recites “wherein the fecal protein extract is further examined for the presence of one or more additional fecal biomarkers selected from: calprotectin, pancreatic elastase, chymotrypsin, lactoferrin, hemoglobin, hemoglobin-haptoglobin-complex, anti-transglutaminase antibodies, anti-gliadin-antibodies, secretory IgA, α-1-antitrypsin, albumin, eosinophil derived neurotoxin (EDN), lysozyme, β-defensin, bile acids, fecal fat, acid steatocrit, fecal sugars,” which seeks to further correlate a fecal biomarker to the likelihood of a patient having IBS and is directed to the natural phenomenon. Claim 31 depends from claim 26 and recites “wherein the pancreatic elastase is fecal elastase-1,” which seeks to further correlate a fecal elastase-1 to the likelihood of a patient having IBS and is directed to the natural phenomenon. Furthermore, Roka teaches determining the presence of pancreatic elastase-1 in fecal samples from patients with IBS (see Abstract), and thus this step is well-understood, routine, and conventional activity in the relevant field.
Claim 27 recites “which further comprises assessing the patient for at least one symptom and/or a condition in said subject suspected of suffering from IBS, wherein said at least one symptom selected from abdominal pain, abdominal discomfort, constipation, diarrhea, bloating, and abdominal distension, rectal bleeding, vomiting, and fever” which is directed to an abstract process that can be performed in the human mind by asking said subject if they suffer from any of the recited symptoms.
Claim 32 recites “wherein the patient is further evaluated for exclusionary conditions selected from weight loss, lactose intolerance, drug-induced diarrhea, post cholecystectomy syndrome, laxative abuse, parasitic disease, eosinophilic gastritis, eosinophilic enteritis, microscopic colitis, small-bowel bacterial overgrowth, celiac disease, and early inflammatory bowel disease;” which does not require any specific evaluation method and embraces asking a patient if they have these conditions or checking a patient’s medical history records. Thus, the claim is directed to an abstract process that can be performed in the human mind by asking said subject if they suffer from any of the recited symptoms.
Therefore, the claimed inventions are directed to the natural phenomenon of correlating a concentration of γ-tryptase in a fecal protein extract provided from a defined stool sample of a patient suffering from gastrointestinal disorders to a likelihood of the patient having irritable bowel syndrome, which is a natural process. The additional elements recited in claims 16 and 25 do not amount to more than the judicial exception because the additional elements are directed to insignificant extra-solution data gathering activities and abstract ideas. The dependent claims do not recite anything that amounts to more than the exception because the additional claims are directed to the natural phenomenon, abstract ideas, or insignificant extra-solution data gathering activity.
Claim Rejections - 35 USC § 103
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.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 16, 19-20, 25, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Lettesjo et al. (Scandinav. J. Gastroenterol., 2006, Vol. 41, p.54-59; of record) in view of Walls et al. (Clin. Experim. Allergy, 1990, Vol. 20, p.581-589; of record), Gong et al. (US2011/0159521; of record), and as evidenced by Caughey (Immunolog. Rev., 2007, Vol. 217, p.141-154; of record).
Regarding claims 16, 20, and 25, Lettesjo teaches preparing fecal supernatants for tryptase measurement from stool samples collected from patients with irritable bowel syndrome and colitis and dilutes 0.5 g of the feces in extraction buffer before homogenization and centrifugation, reading on preparing an extract of fecal proteins from a defined stool sample of a patient having a predetermined mass (see Abstract, p. 55, passage bridging left and right columns, right column, 2nd passage, 2nd paragraph). Lettesjo teaches testing for tryptase in the prepared fecal supernatants using the Pharmacia UniCAP® system immunoassay (see Abstract, p.56, left column, 1st passage, and Fig. 3). Lettesjo teaches that 6 out of 46 samples from IBS patients and 1 out of 19 healthy controls had detectable tryptase levels in the feces collected, and thus compares the levels of tryptase to a predetermined reference value to determine a likelihood of IBS (see p.57, left column, 2nd paragraph, and Fig. 3). Lettesjo further teaches that their findings suggest that a subgroup of IBS patients may have a dysfunctional mast cell regulation that can be detected by tryptase in stools for identification (see p.58, left column, 2nd paragraph). Caughey provides evidence that tryptases are major proteins stored and secreted by mast cells, and teaches that α-, β(I-III)-, γ-, and δ-tryptases are expressed by mast cells (see Abstract, p.142, right column, last paragraph, and Table 1). Thus, the fecal tryptase determination of Lettesjo is expected to have detected α-, β(I-III)-, γ-, and δ-tryptases. Lettesjo further teaches IBS patient stool samples comprise up to over 100 ng tryptase per gram of feces in subjects with constipation or diarrhea IBS (see Fig. 3 and p.56, left column, 4th passage). This is considered to read on the assessing patients recitations in claims 16 and 25. Furthermore, it would have been obvious to provide treatment to IBS patients to reduce symptoms.
Lettesjo does not teach contacting the extract with at least one antibody raised against human γ-tryptase isolated from lung tissue that selectively binds γ-tryptase and does not substantially cross-react with α-tryptase or β-tryptase or wherein the immunological method is an enzyme-linked immunosorbent assay (ELISA).
Walls teaches monoclonal antibodies raised against human mast cell tryptase purified from lung tissue that can detect epitopes of tryptase in additive and competitive ELISA (see Abstract, p.582, left column, 2nd passage, and right column, last passage, and p.583, left column, 1st passage-right column, 1st paragraph). According to the specification, human γ-tryptase is isolated from the lung tissue, and thus, the monoclonal antibodies raised against human mast cell tryptase purified from lung tissue is expected to be specific to human γ-tryptase.
Walls does not teach only detecting γ-tryptase with said antibodies.
Gong teaches non-invasive methods and assays for diagnosis and classification of irritable bowel syndrome by detecting the presence or concentration level of certain diagnostic markers in a sample alone or in combination with identifying the presence or severity of IBS-related symptoms based upon the individual’s response to one or more questions (see paragraphs [0038]-[0039]). Gong teaches samples include biological specimens obtained from an individual including stool, i.e., feces (see paragraph [0044]). Gong further teaches diagnostic markers encompass serine proteases such as γ-tryptase detected by ELISA immunoassays, and the sample is tested for the presence or level of at least one diagnostic marker, reading on determining only a presence or level of γ-tryptase serine protease in the sample by ELISA (see paragraphs [0045], [0243]-[0244], [0249], and [0252]-[0253]).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have substituted using a monoclonal antibody raised against mast cell tryptase isolated from lung tissue and ELISA to detect mast cell tryptase, as taught by Walls, and providing only a monoclonal antibody raised against human lung γ-tryptase for an ELISA to diagnose IBS, as taught by Gong, for the Pharmacia UniCAP® detection system used to detect tryptase, as taught by Lettesjo, to arrive at the claimed invention. One of ordinary skill in the art would have been substituting known techniques for measuring specific mast cell tryptase according to known methods, yielding predictable results. One of ordinary skill in the art would have been motivated to use only an antibody specific for γ-tryptase since Gong discloses a single serine protease such as γ-tryptase can be detected in a sample to diagnose IBS, yielding predictable results.
With regards to claim 25, the fecal tryptase determination of Lettesjo is expected to have detected α-, β(I-III)-, γ-, and δ-tryptases.
Regarding claim 19, Lettesjo in view of Walls and Gong teach a method of detecting in a fecal extract of proteins from a defined stool sample of a patient suffering from IBS, by an ELISA assay, γ-tryptase using monoclonal antibodies raised against human lung tissue γ-tryptase, as set forth in the rejection of claim 16 above. The ELISA assay is expected to form a first immune complex through the contacting of the antibodies to the fecal protein extract.
Lettesjo and Walls do not teach the antibodies raised against human γ-tryptase isolated from lung tissue is bound to a solid phase, a second antibody specific for human γ-tryptase and providing conditions to allow the formation of a sandwich immune complex; and determining the amount of sandwich immune complex formed to determine the amount of γ-tryptase in said fecal protein extract.
Gong teaches the diagnostic markers, which exemplify γ-tryptase as a serine protease marker, can be determined by sandwich ELISA (see paragraphs [0346]-[0347]). Gong further teaches a sandwich ELISA is a two-antibody sandwich assay, a first antibody is bound to a solid support, and the marker of interest is allowed to bind the first antibody, then the amount of marker is quantified by measuring the amount of a second antibody that binds the marker (see paragraph [0347]).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have implemented a two-antibody sandwich ELISA assay in which a first antibody that binds the marker is bound to a solid support and second antibody that binds the marker is used to further bind the marker, as taught by Gong, as the ELISA assay using a γ-tryptase antibody raised against human γ-tryptase isolated from lung tissue, as taught by Lettesjo in view of Walls and Gong, to arrive at the claimed invention. One of ordinary skill in the art would have been applying known ELISA methods used for detecting markers with a reasonable expectation of success.
Regarding claim 27, Lettesjo teaches 19 of 46 IBS patients had diarrhea-predominant IBS, 16 had constipation-predominant IBS, and 11 had alternating bowel pattern (see p.55, right column, 1st passage).
Regarding claim 32, Lettesjo teaches all patients with diarrhea-predominant IBS had colonic biopsies taken to exclude collagenous colitis, reading on further evaluating for microscopic colitis (see p.55, passage bridging left and right columns).
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Lettesjo et al. (Scandinav. J. Gastroenterol., 2006, Vol. 41, p.54-59; of record) in view of Walls et al. (Clin. Experim. Allergy, 1990, Vol. 20, p.581-589; of record) and Gong et al. (US2011/0159521; of record), and as evidenced by Caughey (Immunolog. Rev., 2007, Vol. 217, p.141-154; of record), as applied to claims 16, 19-20, 25, and 32 above, and further in view of Mali et al. (Clin, Biochem., 2009, Vol. 42, p.1568-1571; of record).
Lettesjo in view of Walls and Gong, and as evidenced by Caughey, teach the invention of claim 16 as outlined in the rejection above.
Regarding claim 21, Lettesjo in view of Walls and Gong teach testing for γ-tryptase in fecal protein extract using an ELISA assay.
Lettesjo, Walls, and Gong do not teach the immunological method is an immunoturbidometric or immunonephelometric assay.
Mali teaches immunoturbidimetric and immunonephelometric assays are fully automated systems for assaying proteins (see Abstract and p.1568, left column, 1st paragraph). Mali teaches immunonephelometry is a well-recognized and accepted methodology that requires specialized analyzers that performs a limited menu of test (see p.1568, left column, 1st paragraph). Mali teaches a variety of immunoturbidimetric assays are available and can be adapted to general purpose clinical chemistry analyzers that are “open systems,” and the advantages of immunoturbidimetry include random access analysis instead of batch testing, relatively rapid turnaround time, high volume testing capability, cost reduction through consolidation of testing on a single platform, elimination of standalone specialized analyzers and the time and effort required to maintain them (see p.1568, left column, 1st paragraph).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have substituted an immunonephelometric or immunoturbidimetric assay, as taught by Mali, for the ELISA assay used to measure γ-tryptase, as taught by Lettesjo in view of Walls and Gong, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to use immunonephelometry because it is well-recognized and accepted for protein assaying or to have use immunoturbidimetry because it has a relatively rapid turnaround time and a high volume testing capability. One of ordinary skill in the art would have been substituting known protein assaying techniques which would have yielded predictable results. Thus, claim 21 is prima facie obvious.
Claims 26 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Lettesjo et al. (Scandinav. J. Gastroenterol., 2006, Vol. 41, p.54-59; of record) in view of Walls et al. (Clin. Experim. Allergy, 1990, Vol. 20, p.581-589; of record) and Gong et al. (US2011/0159521; of record), and as evidenced by Caughey (Immunolog. Rev., 2007, Vol. 217, p.141-154; of record), as applied to claims 16, 19-20, 25, and 32 above, and further in view of Roka et al. (Clin. Gastroenterol. Hepatol., 2007, Vol. 5, p.550-555; of record in the IDS filed 7/26/2022).
Lettesjo in view of Walls and Gong, and as evidenced by Caughey, teach the invention of claim 16 as outlined in the rejection above.
Regarding claims 26 and 31, Lettesjo, Walls and Gong do not teach wherein the fecal protein extract is further examined for the presence of one or more of the fecal biomarkers recited in claim 26 or wherein the pancreatic elastase is fecal elastase-1.
Roka teaches collecting stool samples from patients with irritable bowel syndrome, ulcerative colitis, and healthy controls, taking one spot (1-2 g) from each stool sample, transferring to a reaction buffer, homogenizing the sample, filtering the sample, and centrifuging the sample (see Abstract and p.551, left column, 3rd paragraph). Roka teaches measuring mast cell tryptase activities as well as serine protease activity, pancreatic elastase-1, and secretory leukocyte protease inhibitor in the fecal samples (see p.551, paragraph bridging left and right columns, right column, 1st-3rd paragraphs, Figs. 1-4 and Table 2).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to additionally test the fecal samples from IBS patients of Lettesjo in view of Walls and Gong for serine protease activity, pancreatic elastase-1, and secretory leukocyte protease inhibitor, as taught by Roka, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to perform known fecal tests for IBS patients according to known methods, yielding predictable results. One of ordinary skill in the art would have had a reasonable expectation of success additionally testing for serine protease activity, pancreatic elastase-1, and secretory leukocyte protease inhibitor since each of Lettesjo and Roka teach their testing measurements in fecal samples. Thus, claims 26 and 31 are prima facie obvious.
Response to Arguments
Applicant's arguments filed 2/27/2026 have been fully considered but they are not persuasive.
In Applicant’s Remarks, see p.8, 4th paragraph,-p.11, 2nd paragraph, Applicant argues the claims are integrated into a practical application and recite additional elements that not well-understood, routine, or conventional and are not directed to a natural phenomenon. Applicant argues the claims require a human-made antibody specific to γ-tryptase isolated from lung tissue, which cannot be considered a natural phenomenon. Applicant further argues extracting fecal proteins from a defined mass of stool cannot be a natural phenomenon. Applicant further argues the thresholds of γ-tryptase are not a natural phenomenon and provides a diagnostic capability. Applicant further argues the prior art tryptase assays were directed to total tryptase not γ-tryptase. Applicant further argues the claims are directed only to using γ-tryptase as a diagnostic for IBS. This is not found persuasive. The claims as a whole are directed to correlating the level of γ-tryptase in a fecal protein extract from a stool sample of predetermined mass to a type of irritable bowel syndrome. The individual steps directed to preparing the fecal protein extract and detecting the level of γ-tryptase in the fecal protein extract are techniques known in the art. Lettesjo in view of Walls and Gong and demonstrate that it was obvious to detect γ-tryptase using antibodies raised against γ-tryptase from human lung tissue. Walls teaches monoclonal antibodies raised against human mast cell tryptase purified from lung tissue that can detect epitopes of tryptase in additive and competitive ELISA (see Abstract, p.582, left column, 2nd passage, and right column, last passage, and p.583, left column, 1st passage-right column, 1st paragraph). According to the specification, human γ-tryptase is isolated from the lung tissue, and thus, the monoclonal antibodies raised against human mast cell tryptase purified from lung tissue is expected to be specific to human γ-tryptase. Thus, the step of detecting only γ-tryptase by antibodies raised against human γ-tryptase isolated from lung tissue is well-understood, routine, and conventional activity in the relevant field. Thus, the step is related to detecting γ-tryptase and is considered to be well-understood, routine, and conventional activity with regards to data gathering. The concentration of γ-tryptase in the fecal protein extract as it relates to the type of IBS is a result of a natural phenomenon. Furthermore, an antibody specific to γ-tryptase is directed to insignificant extra-solution data gathering activity for determining the concentration of γ-tryptase in the fecal protein extracts. Therefore, the claims as a whole are directed to the natural phenomenon without significantly more.
In Applicant’s Remarks, see p.11, 3rd paragraph,-p.15, 3rd paragraph, Applicant argues that Lettesjo teaches away from the claimed invention and the rejection uses hindsight reconstruction. Applicant further argues Walls is directed to mast cell tryptase purified from human lung tissue and does not teach antibodies specific to γ-tryptase that do not cross-react with α-tryptase and β-tryptase. Applicant argues Caughey, Gong, Mali, and Roka do not teach γ-tryptase as a diagnostic for IBS and that there is no motivation to combine the references. Applicant argues there is no reasonable expectation of success detecting γ-tryptase in a highly degradative fecal matrix while maintaining selectivity over α-tryptase and β-tryptase or to be able to overcome low detection rates reported in Lettesjo. Applicant further teaches the defined fecal specimen of predetermined mass and quantification in nanograms per gram of stool are not taught or suggested. This is not found persuasive. Applicant presents arguments without specifically pointing to why Lettesjo supposedly teaches away from the claimed invention. Attorney arguments cannot take the place of objective evidence where needed. See MPEP § 2145. Applicant’s arguments thus do not provide objective evidence that the references could not be combined or that fecal matrix is degradative. Furthermore, Lettesjo quantifies the tryptase in fecal protein extract in ng/g and measured the concentration in samples taken from patients suffering from constipation IBS and diarrhea IBS. For these reasons, the rejections are maintained.
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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