DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant's election with traverse of Group I and the species of sleep disorder, antibodies and tryptophan-beta-alanine hydroxysuccinimidyl ester in the reply filed on 6 February 2026 is acknowledged. It should be noted that Applicant indicates claims 1-29 read upon the species but claims 1-15 were previously cancelled. The traversal is on the ground(s) that, as currently amended, claims 25-29 have been amended and should be included in Group I. This is persuasive, and the Restriction between Groups I and II is withdrawn in view of amendments, and claims 16-26 and 28-29 are examined upon their merits.
Claims 27 and 30 are withdrawn. Claim 27 relies upon an election of a sugar-L-tryptophan adduct in claim 25. Claim 30 recites diagnosis of dietary fructose intolerance or excess fructose consumption, which is directed to a distinct outcome from the method of Claim 16.
The remaining requirement is deemed proper and is therefore made FINAL.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is the national stage entry of PCT/EP2021/074298, filed 2 September 2021.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). This application claims the benefit of Federal Republic of Germany application Nos. DE10 2020 128 969.3 filed 3 November 2020 and DE10 2020 122 984.4 filed 2 September 2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claims 16-29 have an earliest effective US filing date of 2 September 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 1 March 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 16 and 22 are objected to because of the following informalities: The word derivatization should not be italicized. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 19 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 19 recites the method of claim 16, comprising a determination of tryptophan and/or hydrolyzable tryptophan product in a body fluid selected from plasma, serum, blood, and urine; this fails to further limit the method comprising (a) collecting a defined fecal sample of said subject in Claim 16. Therefore, Claim 19 fails to further limit the subject matter of claim 16, or and fails to include all the limitations of Claim 16. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 16-26 and 28-29 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 16 is indefinite wherein it recites the term “strong” acid or base. The term is not defined by the claim, nor does the specification provide a standard for ascertaining the requisite degree. Therefore, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention acids can dissociate up to 100% in an aqueous solution, and it is unclear what relative strength is required.
Claim 16 is further indefinite wherein it states: “(c) separating said extract from insoluble components and preparing aliquots of said extract, one for direct determination of L-tryptophan in said aliquot and one for determination of L-tryptophan in said aliquot after hydrolysis of any glycated tryptophan and any sugar-tryptophan adducts”. It is unclear what processes are encompassed by the limitation “preparing”. Thus, the metes and bounds of what is required for direct infringement of this method are unclear. The italicized limitation recites intended use/effect. However, there are no active method steps whereby hydrolysis and glycated or sugar adducts of tryptophan are detected. This in turn renders the scope of depending claim 24 indefinite because it further limits the temperature and pH at which these glycated or sugar adducts of tryptophan are “hydrolyzed”. Therefore, for purposes of applying prior art, claim 16 step (c) will be interpreted as the active step of separating the extract from insoluble components and aliquoting the extract. This affects the scope of all depending claims.
Claim 16 is indefinite wherein it recites: “(g) comparing … to determine the amount and ratio of tryptophan in the subject's fecal sample that has undergone a condensation reaction with an aldose or ketose in the gastrointestinal tract.” This step recites process steps that precede the first claimed step, step (a). The courts have held that the listing order is important and will be given limiting effect. Thus in process/method claims, whenever possible claim steps should be written in the order in which they should be performed (See Mformation Tech v. Research-in-Motion, Fed. Cir. 2014 and Phillips v. AWH, Fed. Cir. 2005). The elements of a method claim are usually recited in temporal sequence, if one step modifies another, the modifying step should precede the modified step (Altiris, Inc. v. Symantec Corp. (2003)). Claim 16 recites steps that temporally precede the first step, encompass naturally-occurring physiological responses and, therefore, are indefinite when read in light of the specification. This affects the scope of all depending claims.
Claims 16, 22-24, and 25 are indefinite wherein they recite “using an antibody” (claim 16; “Use of the method” (claims 22-24); and “using a kit” (claim 25). MPEP 2173.05(q) states: “Attempts to claim a process without setting forth any steps involved in the process generally raises an issue of indefiniteness under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. For example, a claim which read: ‘[a] process for using monoclonal antibodies of claim 4 to isolate and purify human fibroblast interferon’ was held to be indefinite because it merely recites a use without any active, positive steps delimiting how this use is actually practiced. Ex parte Erlich, 3 USPQ2d 1011 (Bd. Pat. App. & Inter. 1986)”. Although a claim should be interpreted in light of the specification disclosure, it is generally considered improper to read limitations contained in the specification into the claims. See In re Prater, 415 F.2d 1393, 162 USPQ 541 (CCPA 1969) and In re Winkhaus, 527 F.2d 637, 188 USPQ 129 (CCPA 1975), which discuss the premise that one cannot rely on the specification to impart limitations to the claim that are not recited in the claim.”
Claim 21 is indefinite wherein it recites: “the method according to claim 16, comprising a determination of the effective amount of one of the following, supplementary dietary tryptophan, pharmaceutical composition comprising de- and tri-peptides of tryptophan, supplementary niacin or vitamin B3”. There are no method steps whereby an effective amount of any of these are determined. It is entirely unclear what processes are encompassed by the “determination” of the claim; nor is there an nexus between the determination of L-tryptophan in the parent claim (Claim 16) and this determination of an effective amount. The scope of the claim, and what is required for direct infringement thereof, is entirely unclear.
Claim 24 is further indefinite wherein it recites: “wherein glycated tryptophan or sugar-tryptophan product” and “is hydrolyzed” in claim 16. There is insufficient antecedent basis for the active step of hydrolyzing and glycated tryptophan or sugar-tryptophan products are not positively stated in the parent claim.
Claim 25 is similarly indefinite wherein it recites “the amount of hydrolysable glycated tryptophan or sugar-tryptophan adduct” in claim 16. There is insufficient antecedent basis for this limitation in the parent claim. For purposes of applying prior art the claim will be interpreted as using a kit comprising the instantly-elected antibodies which bind the tryptophan obtained in claim 16 part (b).
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 16-26 and 28-29 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the diagnosis of IBD and UC comprising detecting a statistically significant increase in fecal L-tryptophan levels between IBD and Healthy Controls (HC) or between UC and HC (see Tables 2 and 3 of Bosch et al. cited in art rejection below); the specification provides does not reasonably provide enablement for the detection of the instantly-elected sleep disorder. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure would require undue experimentation include:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims: The broadest reasonable interpretation of the claimed method is that it provides a determination of a disorder selected from digestion disorders, obstipation, diarrhea, gastrointestinal disorders, colitis, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), Crohn's disease, dermatitis, depression, insomnia, sleep disorders, migraine, fatigue syndrome, bulimia nervosa, eating disorders, anxiety, dysphoric disorders, or burn-out syndrome (claim 20) comprising measuring fecal amounts of L-tryptophan and comparing to control levels. A skilled artisan would not know how to use the method with a reasonable expectation of success based solely on what is disclosed in the specification.
The amount of direction provided by the inventor; existence of working examples: Regarding the instantly-elected sleep disorder, the specification states: “a decreased tryptophan absorption can lead to insomnia or poor sleep-wake rhythm (melatonin deficiency)” (paragraph [0056]) and “The fructose content in foods consumed has an impact on mood and sleep as well as on physiological variables such as core body temperature. Small shifts in the ratio of free to blocked tryptophan in the gastrointestinal tract are therefore likely associable to mood state, sleep and sleep phase” (paragraph [0063]) but there is no data to support this declarations. Absent guidance as to how to use the claimed method in the context of diagnosing sleep disorders a person having ordinary skill would rely solely upon what was known in the art before filing.
The state of the prior art: While the prior art at filing demonstrated subjects with IBS have altered plasma tryptophan levels during sleep (Heitkemper et al., Serum Tryptophan Metabolite Levels During Sleep in Patients With and Without Irritable Bowel Syndrome (IBS), Biol Res Nurs. 2015 Jul 7;18(2):193–198) there was nothing to teach or suggest fecal levels could accurately predict sleep disorders.
Level of ordinary skill:
The level of ordinary skill for making a determination of the presence of disease is relatively high, requiring a medical degree.
Nature of the invention and quantity of experimentation needed to make or use the invention based on the content of the disclosure:
The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea and how that idea might be developed into the claimed invention. In the decision of Genentech, Inc, v. Novo Nordisk, 42 USPQ 2d 1001, (CAFC 1997), the court held that:
"[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable" and that "[t]ossing out the mere germ of an idea does not constitute enabling disclosure". The court further stated that "when there is no disclosure of any specific starting material or of any of the conditions under which a process is to be carried out, undue experimentation is required; there is a failure to meet the enablement requirements that cannot be rectified by asserting that all the disclosure related to the process is within the skill of the art", "[i]t is the specification, not the knowledge of one skilled in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement".
The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. Given that the nature of the invention is directed to making a determination of a disorder selected from including digestion disorders, obstipation, diarrhea, gastrointestinal disorders, colitis, dermatitis, depression, insomnia, sleep disorders, migraine, fatigue syndrome, bulimia nervosa, eating disorders, anxiety, dysphoric disorders, or burn-out syndrome (claim 20); a person having ordinary skill in the art would have to perform multiple further experiments, in humans or animal models that are predictive of these disorders, in order to demonstrate use of the method with a reasonable expectation of successfully determining the presence of these diseases. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine’ within the art, and constitutes undue further experimentation in order to use the method with a reasonable expectation of success.
Therefore, Claims 16-26 and 28-29 are rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
Claim Rejections - 35 USC § 101
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.
Claims 16-26 and 28-29 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claim(s) recite(s): “determining …using an antibody” and “comparing” (claim 16); “determining the ratio of hydrolyzable tryptophan product to free tryptophan in the feces” (claim 18); “comprising a determination of the etiology when the subject suffers from a disorder” (claim 20); and, “comprising a determination of the effective amount of one of the following” (claim 21). This judicial exception is not integrated into a practical application because the elements recited in addition to the judicial exception fail to provide any of the considerations set forth in MPEP 2106.05(a-c), (e) and (h) that constitute integration of the judicial exception into a practical application. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements were well-understood, routine and conventional activities in the art prior to the effective filing date of the application.
The claims are directed to methods and processes are one of the statutory categories of invention (STEP 1:YES).
This claim recites comprising determining, making a determination, and comparing, all of which are abstract mental concepts that belong to enumerated group (c) of the Abstract Idea Groupings described in MPEP § 2106.04(a)(2): Mental processes — concepts performed in the human mind (including an observation, evaluation, judgment, opinion). The claims additionally recite determining a ratio of tryptophan in the subject's fecal sample that has undergone a condensation reaction with an aldose or ketose in the gastrointestinal tract and is present in the feces as a hydrolyzable L-tryptophan product (claim 16) and “determining the ratio of hydrolyzable tryptophan product to free tryptophan in the feces” (claim 18), which is a mathematical calculation deemed patent ineligible subject matter (See MPEP 2106.04(a)(2)(I)(c)). But more importantly, the claims recite a natural correlation/phenomenon/law of nature whereby, as claimed, the fecal sample that has undergone a condensation reaction with an aldose or ketose in the gastrointestinal tract and the presence of the resulting hydrolyzable L-tryptophan product is assessed. In this way, these claims are directly analogous to the claims in Mayo Collaborative Servs. v. Prometheus Labs, that were drawn to a correlation that is the consequence of how a certain compound is metabolized by the body, 566 U.S. 66, 75-77, 101 USPQ2d 1961, 1967-68 (2012). See also MPEP 2106.04(b). In Mayo, the claims at issue recited naturally occurring correlations (the relationships between the concentration in the blood of certain thiopurine metabolites and the likelihood that a drug dosage will be ineffective) along with additional elements including telling a doctor to measure thiopurine metabolite levels in the blood using any known process. 566 U.S. at 77-79, 101 USPQ2d at 1967-68. This is analogous to determining the presence of L-tryptophan in fecal samples that were produced as a result of a condensation reaction with an aldose or ketose in the gastrointestinal tract. Therefore, the claims recite at least one judicial exception (STEP 2A, Prong One: YES). MPEP 2106.04(II)(B) states: care should be taken not to parse the claim into multiple exception; if possible examiners should treat the claim for Prong Two and Step 2B purposes as containing a single judicial exception. For this analysis, the Examiner will focus on the natural phenomenon.
According to Step 2A, Prong Two, set forth in set forth in MPEP 2106.04 II A (2), the claims are next evaluated with respect to whether the judicial exception is integrated into a practical application. These considerations are set forth in MPEP 2106.05 (a) through (c), (e), and (h). This analysis turns to the additional steps/elements recited within the claim. In independent claim 16, the additional steps/elements are: “(a) collecting a defined fecal sample of said subject;(b) extracting the fecal sample in a buffer to produce an extract of fecal amino acids and soluble fecal compounds;(c) separating said extract from insoluble components and preparing aliquots of said extract, one for direct determination of L-tryptophan in said aliquot and one for determination of L-tryptophan in said aliquot after hydrolysis of any glycated tryptophan and any sugar-tryptophan adducts;(d) treating an aliquot of said extract with a strong acid or base to hydrolyze any condensation products of an aldose or ketose with an amino acid or L-tryptophan;(e) adding to said aliquots a derivatization reagent which reacts with the a-amino groups of amino acids or L-tryptophan to prepare a L-tryptophan derivative”. This encompasses basic steps that are necessary to observe the natural phenomenon and in Sequenom the Court stated: “It is important to note that the ' 540 patent does not merely claim uses or applications of cffDNA, it claims methods for detecting the natural phenomenon. Because generally one must be able to find a natural phenomenon to use it and apply it, claims covering the only commercially viable way of detecting that phenomenon do carry a substantial risk of preempting all practical uses of it” Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1379, 115 USPQ2d 1152, 1158 (Fed. Cir. 2015). Such is the case here, where the claims recite determining the amounts of L-tryptophan derivative in said aliquots using an antibody specific for L-tryptophan derivative with a high level of generality such that it encompasses any immunoassay. There are no additional elements that reflect an improvement within the technical field; there are no additional elements that apply the natural correlation/phenomena judicial exception to a particular treatment, or which utilize a particular machine. There are no additional elements that effect a transformation of matter; and, there are no additional elements that apply the judicial exception in some other meaningful way beyond generally linking it to a field selected from those listed in claim 20. In this way the claims, as a whole, amount to nothing more than a drafting effort designed to monopolize the natural phenomenon itself. ((STEP 2A, Prong Two: NO).
Regarding the method claimed, the specification itself states: “The evaluation comprises as well known in the art a generation of a response curve of absorbance unit (optical density) versus concentration, using the values obtained from a standard so that the L-tryptophan in the sample or aliquot can be determined directly from this curve” (emphasis added, [0041]). Regarding the additional elements the specification states: “[0061] Extraction of the stool matrix: Using a stool sample preparation system filled with amino acid extraction buffer (IDKTM Amino Extract - Immundiagnostik AG, Bensheim, DE - Art.No. K7999), 15 mg of crude stool samples were collected in each case. The stool was suspended in 750 pl extraction buffer (IDKTM Amino Extract) and its matrix extracted for 10 minutes (dilution 1:50). The extracts were transferred to 1.5 mL Eppendorf tubes, solids pelleted by centrifugation, and 200 pL of the supernatant was transferred to a sealable Eppendorf reaction tube for alkaline treatment. The alkaline treatment was performed in 0.6 M NaOH in extraction buffer: 200 pL of supernatant (stool extract) was mixed with 60 pL of 0.6 M NaOH (pH > 12) and heated at 98°C for 20 minutes. The treated extract was neutralized with 60 pL of 0.6 M HCI (final dilution 1:80). 25 pL of treated and untreated extract were each derivatized for immunological determination of free or treated (free and unblocked) tryptophan content. Quantitative determination of L-tryptophan was performed as described in Example1using the IDK® Tryptophan highly sensitive ELISA (Immundiagnostik AG, Bensheim, DE - Art.No. KR3730)”. Therefore, in in accordance with MPEP 2106.07(a)(III)(A), the examiner has cited express statements in the specification indicating that the additional claimed elements were sufficiently well-known and commercially available prior to filing.
Lastly, in accordance with MPEP 2106.07(a)(III)(C), the examiner cites publications within the field of technical expertise, that demonstrate the well-understood, routine, conventional nature of the additional element(s). The following prior art teaches it was well established in the field of technical expertise tryptophan levels differed in fecal samples from patients with IBD, ulcerative colitis (UC) and/or Crohn’s disease (CD) (Bosch et al., JPGN, Volume 66, Number 5, May 2018). The Bosch et al. prior art teaches increased levels of tryptophan, were strongly predictive for the discrimination of patients with IBD versus healthy controls (HCs; see pg. 775, paragraph bridging columns). Therefore, the evidence demonstrates the steps/elements, recited in addition to the judicial exception, were all well understood, routine, conventional activities in the field of fecal sample analysis prior to filing the application at hand (STEP 2B: NO). The claimed steps/elements recited in addition to the judicial exception(s), alone or in combination, do not make an inventive contribution over the methods that were known in the art prior to filing, and they amount to mere observation of the natural phenomenon itself, with the words “apply it” in order to append it to the field of use.
For all of these reasons, Claims 16-26 and 28-29 are directed to the judicial exception without significantly more, and the claims are rejected.
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.
Claim 16-18, 20, 23, 25-26, and 28-29 are rejected under 35 U.S.C. 103 as being unpatentable over Bosch et al., JPGN, Volume 66, Number 5, May 2018 taken with the IDK® Tryptophan ELISA manual, published 10 October 2019; Retrieved from: https://www.listarfish.it/product_files/4358/Tryptophan_K7730.pdf; Retrieved on 03/17/2026.
Regarding Claim 16, the Bosch prior art teaches collecting a fecal sample of said subject (pg. 774, second column). Bosch et al. extract the fecal sample in a buffer to produce an extract of fecal amino acids and soluble fecal compounds, wherein it teaches approximately 300 mg feces and 1000 mL distilled water were mixed by vortex for one minute to homogenize the samples (pg. 774, second column, second paragraph). The Bosch prior art teaches separating said extract from insoluble components and preparing aliquots of said extract wherein it teaches: “the supernatant was subsequently mixed with an internal standard solution with a one-to-one ratio. Finally, this mixture was centrifuged for 10 minutes and filtered (Whatman, Buckinghamshire, UK) into compatible containers for the final amino acid analyses (Biochrome 30) (pg. 774, second column, second paragraph). The Bosch et al. prior art teaches, “postcolumn derivatization with ninhydrin”, an acid, which reacts with the a-amino groups of amino acids (pg. 774, second column, second paragraph) which teaches treating an aliquot of said extract with an acid, as claimed. Ninhydrin of the prior art is s a derivatization reagent as recited by the instant claim. Table 2 of the Bosch et al. reference teaches determining the amounts of L-tryptophan derivative and comparing the amounts of L-tryptophan derivative in said aliquots to determine the amount of tryptophan present in the feces as a hydrolyzable L-tryptophan product. Specifically, the prior art discloses Tryptophan (median[LQR-UQR]) in healthy controls is 2.1 (1.4–3.4); 4.4 (3.1–5.7) in irritable bowel disease (IBD) patients; 4.8 (3.5–6.1) in ulcerative colitis (UC) patient samples; and 3.9 (2.8–5.6) in Crohn’s disease (CD) patient samples. The difference between IBD and Healthy Controls (HC) is statistically significant; also the difference between UC and HC is statistically significant.
Regard Claim 17, Bosch et al. teach the step of comparing the amount of hydrolyzable L-tryptophan product in the fecal sample of said subject with the amount of hydrolyzable L-tryptophan product in the feces of a healthy subject and demonstrate an increased amount of hydrolyzable L-tryptophan product (see Table 2).
Regarding Claim 18, while Bosch et al. provide the relative amounts of tryptophan in the samples, they do not determine the ratio per se. However, as stated in the rejection under 101 above, mathematical concepts are patent ineligible subject matter (see MPEP 2106.04(a)(2)(I)(c)) and, therefore, cannot be the subject matter that distinguishes the claimed method over the prior art.
Regarding claim 20, the Bosch et al. prior art teach the difference between IBD and Healthy Controls (HC) is statistically significant; and the difference between UC and HC is statistically significant (Table 2). Table 3 demonstrates the predictive value for the diagnosis of IBD, UC and CD. Therefore, the method teaches methods provide for a determination of the etiology when the subject suffers from ulcerative colitis and inflammatory bowel disease (IBD), as claimed, when compared to levels of from Healthy Controls, as recited by the claim.
The only element that the Bosch prior art is silent on is the antibody specific for L-tryptophan derivative, the IDK® Tryptophan ELISA manual, however, remedies this deficiency and teaches the same ELISA kit disclosed in the instant specification.
Regarding the antibody of instant claim 16, the IDK® Tryptophan ELISA manual discloses an L-tryptophan antibody (see pg. 22, Table at 3, line six) and a kit for the detection of L-tryptophan in samples.
Regarding claim 23, the method of the IDK® Tryptophan ELISA manual teaches an antibody is added which binds anti-L-tryptophan derivative antibodies, and the detector antibody is conjugated to a detection group, namely, “a peroxidase-conjugated antibody is added to each microtiter well to detect the L-tryptophan antibodies” (pg. 25, lines 11-12). This teaches the peroxidase of the instant claim.
Regarding claim 25, the method of the IDK® Tryptophan ELISA manual discloses antibodies which bind a tryptophan derivative (see pg. 22, Table at 3, line six).
Regarding claim 26, the IDK® Tryptophan ELISA manual teaches a kit comprising “a microtiter plate coated with L-tryptophan derivative (tracer)”, which teaches the microtiter plate wherein the tryptophan-derivative tracer is immobilized on a surface, as claimed. See also pg. 22 Materials supplied.
Regarding claim 28, the kit disclosed in the IDK® Tryptophan ELISA manual comprises the reaction buffer (REABUF) and a derivatization reagent that is used for all samples (see steps 2 and 3 bridging pages 25-26. Thus, the kit teaches the buffer for solubilization of an aromatic amino acid, as claimed.
Regarding claim 29, the ELISA kit requires: Calibrated precision pipets and 10-1000 µl single use tips and Multi-channel pipets or repeater pipets (see pg. 23, under bullet 4). The method further teaches, “Derivatisation of standards, controls and samples is carried out in single analysis in 1.5 ml polypropylene tubes”. This, teaches the “tool and tube system for transferring” samples into a vessel with buffer.
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the application, to use the IDK® Tryptophan ELISA in the method for fecal analysis as taught by Bosch. Motivation to do so is explicit wherein the manual teaches the IDK® Tryptophan ELISA confers the advantage of having high specificity of the antibody and the high correlation to studies comprising the high-performance liquid chromatography technique that was used in Bosch. Specifically the IDK® Tryptophan ELISA manual states: “The specificity of the antibody was tested by measuring the cross-reactivity against a range of compounds with structural similarity to L-tryptophan. The specificity is calculated in percent in relation to the tryptophan-binding activity:
5-HTP (5-hydroxytryptophan) < 0.5 %
L-phenylalanine < 0.1 %
L-tyrosine < 0.1 %
And the Correlation with HPLC-MS… was r = 0.98” (pg. 33, Specificity).
In KSR International Co. v. Teleflex, Inc., the Supreme Court has stated that combining prior art elements according to known methods to yield predictable results is prima facie obvious if the following rationale can be applied:
(1) the prior art includes each element claimed though not necessarily in the same reference.
(2) it was within the technical grasp of one of ordinary skill in the art to combine the elements as claimed by known methods, and that in combination, each element merely would have performed the same function as it did separately.
(3) one of ordinary skill in the art would have recognized that the results of such combination were predictable.
(KSR International Co. v. Teleflex, Inc. 127 S. Ct. 1727, 82 USPQ2d 1385, Supreme Court, April 30, 2007).
One of ordinary skill in the art would recognize the use of the IDK® Tryptophan ELISA, as taught by the product manual, in combination with the fecal analysis methods, as taught by the Bosch reference. A skilled artisan would be motivated to combine the prior art elements because combination would predictably result in a method for determining L-tryptophan in the feces of a subject. Based on the guidance and direction within the prior art, such combination would have been well within the technical grasp of a skilled artisan. Since each of the elements in combination are merely performing the same function as they did separately, then one of ordinary skill in the art would have been able to predictably combine the elements with a reasonable expectation of success. Therefore, the invention as a whole is prima facie obvious.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Bosch et al., 2018 taken with the IDK® Tryptophan ELISA manual, published 10 October 2019, as applied to Claims 16-18, 20, 23, 25-26, and 28-29 above, and further in view of Yang et al., Analytical Chemistry, Vol. 78, No. 13, 2006.
The teachings of Bosch et al. and the IDK® Tryptophan ELISA manual as they pertain to claims 16-18, 20, 23, 25-26, and 28-29 is outlined in the rejection above.
Neither Bosch or the Manual disclose the instantly-elected derivatization reagent of tryptophan-beta-alanine-hydroxysuccinimidyl ester.
The Yang et al. publication teaches a reagent comprising N-hydroxysuccinimide ester contacting an amino acid that, binding to tryptophan, teaches the derivatization agent of the claims (see Yang et al. Scheme 2, pg. 4704).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the application that this derivatization reagent could be substituted for the derivatization reagent(s) disclosed in either the Bosch et al. methods or the IDK® Tryptophan ELISA manual. Motivation to make this substitution is explicit in the Yang et al. publication wherein it teaches: “Detection sensitivity increased as the N-alkyl chain length of the …derivatizing agent was increased … N-Acylation of amino acids with the Cn-NA-NHS reagents in water produced a stable product in roughly 1 min” (Abstract). The Yang et al. reference further states: “It is further concluded that during the course of in vitro derivatization of amino acids to increase their ionization efficiency the opportunity arises to introduce stable isotope coding of amino acids according to sample origin. This is in effect a type of molecular bar coding that allows a unique mass code to be placed on samples from different sources. It also greatly facilitates comparative quantification studies. After mixing differentially coded samples, it is possible to determine the relative concentration of individual amino acids between these samples in a single analysis” (pg. 4708, last paragraph of Conclusions). Thus, the motivation is that the use of the N-hydroxysuccinimide ester derivatization reagent confers distinct advantages for the quantification of amino acids. As stated above, combining prior art elements according to known methods is prima facie obvious if the following rationale can be applied:
(1) the prior art includes each element claimed though not necessarily in the same reference.
(2) it was within the technical grasp of one of ordinary skill in the art to combine the elements as claimed by known methods, and that in combination, each element merely would have performed the same function as it did separately.
(3) one of ordinary skill in the art would have recognized that the results of such combination were predictable.
(KSR International Co. v. Teleflex, Inc. 127 S. Ct. 1727, 82 USPQ2d 1385, Supreme Court, April 30, 2007). The prior art includes each element though not in the same reference. It would have been well-within the technical grasp of a skilled artisan to substitute one derivatization reagent for another, and one would have recognized that this would predictably result in the production of derivatized amino acids, such as tryptophan. Each of the elements in combination are merely performing the same function as they did separately, and each reagent is taught by the art to yield successful derivatization. Therefore, the invention as a whole is prima facie obvious, if not actually anticipated by the references.
Thus, the method of claim 22 is obvious in view of the combined teachings of the prior art, and the claim is rejected.
Conclusion
No claim is allowed.
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/STACEY N MACFARLANE/ Examiner, Art Unit 1675