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 .
Status of the Claims
Claims 1-7 are pending and examined herein.
Priority
The present application, filed 02/05/2024, is a 371 of PCT/JP2022/029921, filed 08/04/2022, which claims foreign priority of JP2021-130019, filed 08/06/2021. Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The Information Disclosure Statement(s) filed 06/05/2024 and 07/23/2025 are acknowledged and have been considered.
Claim Objections
Claim 1 is objected to because of the following informalities: Claim 1 recites “a method of measuring thyroglobulin by immunoassay in a sample,” which is grammatically awkward. Appropriate correction would be to amend the phrase to “a method of measuring thyroglobulin in a sample isolated from the body by an immunoassay, comprising…” or “a method of measuring thyroglobulin in a sample isolated from the body using an immunoassay, comprising…” Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1-7 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1 and 6 recite a broad genus of a monoclonal antibody or an antigen-binding fragment thereof whose corresponding antigen is thyroglobulin treated with the reducing agent. However, the specification does not describe the claimed genus with sufficient structural or representative support. The specification describes that the present inventors have conducted extensive research and consequently found that the thyroglobulin/anti-thyroglobulin antibody immune complex can be dissociated by reduction treatment and that they succeeded in producing a monoclonal antibody whose corresponding antigen is thyroglobulin dissociated by treatment with a reducing agent ([0007], page 3).
The specification further explains that the antibody used in the method of the present invention is a monoclonal antibody whose corresponding antigen is Tg treated with a reducing agent (Tg-SH), and that a monoclonal antibody whose corresponding antigen is Tg-SH may be obtained by the conventional hybridoma technique using Tg-SH as the immunogen ([0019], page 8). However, the specification identifies only a limited number of obtained antibodies: 9E12, A1010, A1024, A2029, and A2068 ([0043], page 21).
The specification states that the epitopes of the monoclonal antibodies are contained in the sequences of SEQ ID NOs: 1 to 5, respectively and explains that the fact that five different monoclonal antibodies were obtained by the hybridoma technique using Tg-SH as the immunogen has indicated that a monoclonal antibody whose corresponding antigen is Tg-SH can be reproducibly obtained ([0020], page 9). The specification further discloses that in a particular embodiment, another antibody against Tg-SH which recognizes an epitope different from that recognized by the antibody against Tg-SH may be used, and that epitopes recognized by an antibody against Tg-SH and another antibody against Tg-SH are not limited to a specific combination ([0024], page 11). Additionally, the specification reports that 9E12 recognized TGN, and A1010 recognized TGC, and A1024, A2029 and A2068 recognized TG5F ([0046], page 22). These disclosures reasonably conveys possession of the specifically obtained monoclonal antibodies and the antigenic epitopes recognized by those antibodies, but they do not reasonably convey possession of the full genus of monoclonal antibodies or antigen-binding fragments whose corresponding antigen is thyroglobulin treated with a reducing agent.
The specification also does not disclose VH sequences, VL sequences, CDR sequences, complete antibody amino acid sequences, nucleic acid sequences encoding the antibodies, deposited hybridomas, or common structural features that define the claimed antibody genus. The claims, however, are not limited to 9E12, A1010, A1024, A2029, A2068, or to antibodies having any disclosed structural features. Therefore, the specification does not reasonably convey possession of the full scope of the antibodies and antigen-binding fragments recited in claims 1 and 6.
Claim 2 further recites a monoclonal antibody whose corresponding epitope is contained in any one of SEQ ID NOs: 1 to 5. The specification provides epitope mapping for the five disclosed antibodies, stating that the epitope of the 9E12 antibody was contained within CELQRETAFLKQADYVP (SEQ ID NO: 1), the epitope of the A1024 antibody was contained within VIFDANAPVAVRSK (SEQ ID NO: 2), the epitope of the A2029 antibody was contained within VPDSEFPVMQCLTDCT (SEQ ID NO: 3), the epitope of the A2068 antibody was contained within LGDQEFIKSLTPLEGTQ (SEQ ID NO: 4), and the epitope of the A1010 antibody was contained within TPWPDFVPRAGGENYK (SEQ ID NO: 5) ([0049], page 24). However, this disclosure identifies only epitope locations for five obtained antibodies. It does not provide sufficient representative species or structural characteristics to show possession of every monoclonal antibody or antigen-binding fragment that recognizes an epitope contained in any one of SEQ ID NOs: 1 to 5.
Claims 3 and 7 depend from claims 1 or 2 and further recite use of the monoclonal antibody or antigen-binding fragment in a sandwich assay. The specification describes sandwich assay formats and states that a sandwich assay is a method in which an anti-target antigen antibody is immobilized on a solid phase and reacted with a test sample, followed by reaction with a labeled secondary antibody ([0029], page 14). However, the sandwich assay disclosure does not cure the lack of written description for the broad antibody genus incorporated from claims 1 and 2.
Claim 4 recites first and second antibodies whose corresponding epitopes are contained in specified SEQ ID NOs. The specification states that, for sandwich assays, it is preferable to use different antibodies in combination and that one of the antibodies may be a monoclonal antibody ([0019], page 9). The specification also states that, in sandwich assays, the first antibody is at least one selected from the group consisting of an antibody whose epitope is contained in the amino acid sequence of SEQ ID NO: 1 and an antibody whose epitope is contained in the amino acid sequence of SEQ ID NO: 5, and the second antibody is selected from antibodies whose epitopes are contained in SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4 ([0030], page 15). However, the specification still only identifies a limited set of antibodies and epitope regions, without structural features sufficient to demonstrate possession of the full scope of first and second antibodies encompassed by claim 4.
Claim 5 depends from claim 4 and further recites that the first antibody is a capture antibody and the second antibody is a labeled antibody. The specification states that the first antibody is used as a capture antibody and the second antibody is used as a labeled antibody ([0031], page 15). However, claim 5 still incorporates the unsupported antibody genus of claim 4 and is not limited to the disclosed antibody clones or any disclosed antibody structures.
Accordingly, the specification reasonably describes the specific antibodies and epitope mapping experiments disclosed in the application, but does not reasonably convey possession of the full scope of the broadly recited monoclonal antibodies and antigen-binding fragments in claims 1–7.
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 1-7 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 1 is directed to “a method of measuring thyroglobulin by immunoassay.” However, the body of claim 1 only affirmatively recites “a pretreatment step of treating the sample isolated from the body with a reducing agent.” Claim 1 does not positively recite performing the immunoassay, contacting the reduced sample with the recited monoclonal antibody or antigen-binding fragment, detecting antibody-antigen binding, generating a signal, or determining/measuring an amount of thyroglobulin. Accordingly, it is unclear what active steps are required to complete the claimed method of measuring thyroglobulin by immunoassay, and whether merely treating the sample with the reducing agent satisfies the claimed method. Additionally, claim 1 recites “a monoclonal antibody or an antigen-binding fragment thereof whose corresponding antigen is thyroglobulin treated with the reducing agent.” This limitation is unclear because the claim appears to define the monoclonal antibody or antigen-binding fragment by its binding target, but does not clearly indicate whether the antibody or antigen-binding fragment is limited to one that specifically binds thyroglobulin only after reducing-agent treatment, or whether the claim broadly encompasses any anti-thyroglobulin antibody capable of binding thyroglobulin that has been treated with the reducing agent. Therefore, the metes and bounds of claim 1 are unclear. Appropriate correction is required.
Claims 2–7 are rejected under 35 U.S.C. 112(b) as being indefinite because they depend, directly or indirectly, from claim 1 and therefore incorporate the indefiniteness of claim 1. Appropriate correction is required.
Claim 2 recites the limitation "the corresponding epitope" in line 1. There is insufficient antecedent basis for this limitation in the claim. Specifically, there is insufficient antecedent basis for “the corresponding epitope” in claim 2. Claim 1 recites a monoclonal antibody or antigen-binding fragment thereof “whose corresponding antigen is thyroglobulin treated with the reducing agent,” but claim 1 does not previously introduce a “corresponding epitope.” Therefore, it is unclear what epitope or feature is being referenced by “the corresponding epitope.” Additionally, the phrase “the corresponding epitope of the monoclonal antibody” is unclear because an epitope is generally understood to be the portion of an antigen recognized by an antibody, whereas the claim language may be read as referring to an epitope possessed by the monoclonal antibody itself. Thus, it is unclear whether claim 2 requires an epitope recognized by the monoclonal antibody, an antigen-binding region/paratope of the monoclonal antibody, or an epitope comprising or consisting of the amino acid sequence of any one of SEQ ID NOs: 1 to 5. Therefore, it is unclear what epitope or feature is being referenced by “the corresponding epitope.” For purposes of compact prosecution, “the corresponding epitope” will be interpreted as an epitope on thyroglobulin recognized by the monoclonal antibody, wherein the epitope is contained in an amino acid sequence of any one of SEQ ID NOs: 1 to 5. Appropriate correction is required.
Claim 7 depends from claim 2, and therefore incorporates the indefinite limitation. Appropriate correction is required.
Likewise, claim 4 recites the first antibody comprises at least one selected from the group consisting of an antibody whose corresponding epitope is contained in the amino acid sequence of SEQ ID NO: 1 and an antibody whose corresponding epitope is contained in the amino acid sequence of SEQ ID NO: 5, and the second antibody comprises at least one selected from the group consisting of an antibody whose corresponding epitope is contained in the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4. The phrase “corresponding epitope” is indefinite because it is unclear what the epitope corresponds to. Specifically, an epitope is generally understood to be the portion of an antigen recognized by an antibody, whereas the claim language may be read as referring to an epitope possessed by the antibody itself. Thus, it is unclear whether claim 4 requires (i) an epitope recognized by the first and second antibodies, (ii) an antigen-binding region (paratope) of the first and second antibodies, or (iii) an epitope comprising or consisting of the amino acid sequences of SEQ ID NOs: 1–5. Consequently, the metes and bounds of the claimed first and second antibodies cannot be determined with reasonable certainty.
For purposes of compact prosecution, the “corresponding epitope” will be interpreted as an epitope on thyroglobulin recognized by the recited first or second antibody, wherein the epitope is contained in the respective amino acid sequence(s) recited in claim 4. Appropriate correction is required.
Claim 5 is rejected under 35 U.S.C. 112(b) as being indefinite because claim 5 depends from claim 4 and therefore incorporates the indefinite limitation “corresponding epitope” recited in claim 4. Appropriate correction is required.
Claim 6 recites “a monoclonal antibody or an antigen-binding fragment thereof whose corresponding antigen is thyroglobulin treated with the reducing agent.” The phrase “whose corresponding antigen is thyroglobulin treated with the reducing agent” is unclear because the claim appears to define the monoclonal antibody or antigen-binding fragment by its binding target, but does not clearly indicate whether the antibody is limited to an antibody that specifically binds thyroglobulin only after reducing-agent treatment, or whether the claim broadly encompasses any anti-thyroglobulin antibody capable of binding thyroglobulin that has been treated with the reducing agent. Accordingly, the metes and bounds of the claimed monoclonal antibody or antigen-binding fragment are unclear. Appropriate correction is required.
Claim Rejections - 35 USC § 102
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 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 –
(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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 and 3 are rejected under 35 U.S.C. 102(a)(1) and102(a)(2) as being anticipated by Yamamoto et al. (WO 2018/047792 A1 – IDS dated 06/05/2024; refer to Espacenet English translation provided).
Regarding claim 1, Yamamoto teaches a method for measuring thyroglobulin in a sample isolated from a living organism by immunoassay ([0007], page 8). Yamamoto teaches pretreating a biological sample with a pretreatment solution comprising a reducing agent. ([0012], page 13). The reducing agents comprising 2-(diethylamino)ethanethiol hydrochloride (DEAET), tris(2-carboxyethyl)phosphine hydrochloride (TCEP), dithiothreitol (DTT), and 2-mercaptoethanol ([0019], pages 21-22).
Additionally, Yamamoto teaches the use of a monoclonal antibody, polyclonal or antigen-binding fragment thereof in an assay for measuring thyroglobulin (Tg) ([0022], page 25 and [0025], page 29). The antibody against Tg may be either a polyclonal antibody or a monoclonal antibody ([0025], page 29). Yamamoto further discloses that the antibody against Tg may also be an antibody fragment derived from such a full-length antibody, and identifies F(ab')2, Fab', Fab, Fv ([0025, page. 29).
Lastly, Yamamoto teaches that the corresponding antigen is thyroglobulin treated with the reducing agent by disclosing that the reducing agent may also be used in the pretreatment solution ([0019], pages 21-22), and the biological sample mixture obtained in the pretreatment step is then subjected to the reaction step of the immunoassay, wherein the antigen in the mixture is reacted with the antibody against Tg ([0022], page 25). Accordingly, the corresponding antigen recognized by the anti-Tg antibody is thyroglobulin that has undergone the reducing-agent pretreatment.
Regarding claim 3, Yamamoto teaches immunoassays include direct competition, indirect competition, and sandwich methods, and sandwich ELISA ([0032], page 38). Yamamoto further teaches use of the antibody as a first antibody or second antibody, disclosing that the sandwich method involves immobilizing an anti-target antigen antibody on a solid phase, reacting it with a test sample containing the target antigen after blocking, reacting it with a labeled secondary antibody against the target antigen ([0035], page 43Accordingly, Yamamoto discloses, expressly or inherently, each and every limitation of claims 1 and 3.
Accordingly, claims 1 and 3 are anticipated under 35 U.S.C. 102.
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 2 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Yamamoto et al. in view of Saboori et al. (Peptides of Human Thyroglobulin Reactive with Sera of Patients with Autoimmune Thyroid Disease. The Journal of Immunology (1950). Vol. 163, No. 11, December 1999).
Regarding claim 2, with respect to the teachings of Yamamoto, see the discussion above, which applies equally here. Furthermore, Yamamoto teaches that the antibody against Tg used in the method of the present invention is an antibody that recognizes at least a portion of the amino acid sequence of Tg as an epitope ([0024], page 28), that any antibody that recognizes a known epitope can be used, and that the antibody is preferably one that recognizes a Tg-specific epitope (particularly a human Tg-specific epitope) ([0024], page 28). Also, Yamamoto teaches that the antibody against Tg may be either a polyclonal antibody or a monoclonal antibody ([0025], page 29), and that antibodies against Tg can be prepared using previously known methods ([0026, page 30).
However, Yamamoto differs from the instant claim in failing to teach or specify that the corresponding epitope of the monoclonal antibody is contained in an amino acid sequence of any one of SEQ ID NOs: 1 to 5.
Saboori teaches peptides of human thyroglobulin reactive with antibodies and specifically teaches that mAbs raised against Tg provide powerful tools to map the various epitopes of the Tg molecule, that mAb 137C1 recognized a conformational epitope, and that this mAb reacted with two peptides of Tg with molecular masses of 15 kDa and 23 kDa (page 6244). Saboori further teaches that one of the peptides (15 kDa) reactive with this mAb was located at the carboxyl-terminal end of the Tg molecule (page 6244). Additionally, Saboori teaches the amino acid sequence and location of the 15-kDa peptide reactive with mAb 137C1, including KVPTFATPWPDFVPRAGGENYK (Figure 3, page 6246), which contains the claimed SEQ ID NO: 5 sequence TPWPDFVPRAGGENYK. Saboori further teaches that the 15-kDa peptide reacted strongly with mAb 137C1 (Results, page 6246), and that these results show that each peptide not only inhibited binding of mAb 137C1 to the same peptide, but it also inhibited the binding of this mAb to the other peptide and intact Tg (Results, page 6247).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Yamamoto’s method by selecting, as the monoclonal antibody used in Yamamoto’s Tg immunoassay, an anti-Tg monoclonal antibody having an epitope corresponding to the 15-kDa Tg peptide region taught by Saboori, because Yamamoto expressly directs the skilled artisan to use Tg antibodies that recognize known Tg epitopes, preferably human Tg-specific epitopes, and Saboori identifies a human Tg peptide region containing SEQ ID NO: 5 that is reactive with anti-Tg mAb 137C1. One of ordinary skill in the art would have had a reasonable expectation of success because Yamamoto teaches that any antibody recognizing a known Tg epitope may be used in Tg immunoassay and that monoclonal antibodies are suitable anti-Tg antibodies, while Saboori experimentally confirms antibody recognition of the relevant Tg peptide region through mAb 137C1 reactivity and competitive inhibition of mAb 137C1 binding to Tg and the peptide. Thus, the combination merely applies Saboori’s known Tg epitope-recognizing monoclonal antibody teaching in Yamamoto’s known Tg immunoassay for the predictable purpose of measuring Tg using an antibody that recognizes a known human Tg epitope.
Regarding claim 7, as discussed above and here, Yamamoto teaches that the reaction process may consist of only a primary reaction step, or it may include a secondary reaction step, such as in the sandwich reaction ([0028], page 33). Yamamoto further teaches that the sandwich method, involves immobilizing an anti-target antigen antibody on a solid phase, reacting it with a test sample containing the target antigen, then reacting it with a labeled secondary antibody against the target antigen, and then quantifying the label ([0035], page 43). Furthermore, Yamamoto teaches that, when a secondary reaction is included, the method may use another antibody against Tg that recognizes a different epitope from the antibody against Tg, and that the use of such alternative antibodies is preferable, for example, when a sandwich assay is employed ([0030], page 36).
Claims 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Yamamoto et al. in view of Saboori et al. and Clarke et al. (A Novel Mass Spectrometry–Based Assay for the Accurate Measurement of Thyroglobulin From Patient Samples Containing Antithyroglobulin Autoantibodies. Journal of Investigative Medicine. Vol. 60, No. 8, December 2012).
Regarding claim 4, with respect to the teachings of Yamamoto, see the discussion above, which applies equally here.
However, Yamamoto differs from the instant claim in failing to teach or specify that the first antibody has a corresponding epitope contained in SEQ ID NO: 1 or SEQ ID NO: 5, and that the second antibody has a corresponding epitope contained in SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.
As discussed above, Saboori teaches the first-antibody epitope limitation, disclosing that mAb 137C1 recognizes the Tg peptide region containing SEQ ID NO: 5 (Results, pages 6246 - 6247).
Clarke teaches the second-antibody epitope limitation, disclosing an antipeptide-antibody approach using Tg peptide T129. Specifically, Clarke teaches that the selected Tg peptide T129 (12 amino acid, VIFDANAPVAVR) was used to generate chicken anti-T129 peptide IgY antibodies (Materials and Methods, page 1159). Clarke further teaches that patient samples underwent a series of steps consisting of reduction, alkylation, and tryptic digestion after which a selected specific Tg peptide was captured from the mixture using proprietary antipeptide antibody (IgY) beads raised against the peptide of interest (Materials and Methods, page 1158). The Tg peptide VIFDANAPVAVR is contained within the amino acid sequence of the claimed SEQ ID NO: 2 (VIFDANAPVAVRSK), and therefore is an epitope contained within the amino acid sequence of SEQ ID NO: 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 modify Yamamoto’s sandwich Tg immunoassay by selecting, as the first anti-Tg antibody, Saboori’s mAb 137C1 or an antigen-binding fragment thereof recognizing the Tg peptide region containing SEQ ID NO: 5, and selecting, as the second anti-Tg antibody, Clarke’s anti-T129 peptide antibody or an antigen-binding fragment thereof recognizing the Tg peptide VIFDANAPVAVR which is contained within the amino acid sequence of SEQ ID NO:2 - because Yamamoto expressly directs the skilled artisan to use Tg antibodies that recognize known Tg epitopes, preferably human Tg-specific epitopes, and further teaches use of another anti-Tg antibody recognizing a different epitope in a sandwich assay. One of ordinary skill in the art would have had a reasonable expectation of success because Saboori experimentally confirms mAb 137C1 reactivity with the Tg peptide region containing SEQ ID NO: 5 and competitive inhibition of mAb 137C1 binding to intact Tg, while Clarke confirms that antipeptide antibodies can be raised against and used to capture the Tg-specific peptide VIFDANAPVAVR contained within SEQ ID NO: 2. Thus, the modification applies known Tg epitope-recognizing antibodies from Saboori and Clarke in Yamamoto’s known Tg sandwich immunoassay for the predictable purpose of measuring Tg using different known human Tg epitope regions.
Regarding claim 5, as discussed above, Yamamoto teaches a sandwich Tg immunoassay using a first/capture antibody immobilized on a solid phase and a second/labeled antibody against Tg ([0035], page 43).
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Yamamoto et al. in view of Maertens et al. (US 7,935,490 B2).
Yamamoto supports the kit limitation by disclosing a reagent for immunoassay of thyroglobulin ([0007], page 8). Specifically, Yamamoto teaches that the Tg measurement reagent of the present invention is a measurement reagent that can realize the Tg measurement method described above, and includes a pretreatment solution containing either or both a surfactant and an acidifying agent as a component, in addition to the components used in conventional immunoassays ([0039], page 51). Yamamoto further discloses that the reagent may comprise each component in a form isolated from each other or in the form of a composition, including components provided in a form contained in a different container (e. g., a tube, a plate), or some components may be provided in the form of a composition (e.g., in the same solution). ([0040], page 52). Also, Yamamoto teaches that, when the sandwich method is employed, the reagent may include i) a pretreatment solution, ii) an antibody against Tg, iii) a buffer, and as optional components, iv) another antibody against Tg, v) a labeling substance, vi) a diluent, and, if necessary, vii) a substrate that reacts with the labeling substance ([0041], page 54). Lastly, as discussed above, Yamamoto discloses that the antibody against Tg may be either a polyclonal antibody or a monoclonal antibody ([0025], page 29).
However, Yamamoto does not expressly teach that the Tg immunoassay kit/reagent includes a pretreatment solution comprising the reducing agent as a kit component.
Maertens teaches immunodiagnostic assays using reducing agents, and discloses a solid phase immunoassay comprising on said solid phase an antigen in the presence of a reducing agent (Abstract, page 1). Maertens further teaches a kit containing at least a solid phase such as a microtiterplate, a membrane strip or silicon chip which contains an antigen in the presence of a reducing agent (column 9, page 26). Maertens further discloses that the reducing agent may be DTT, DTE or TCEP (column 9, page 26).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Yamamoto’s thyroglobulin immunoassay reagent by providing the pretreatment solution comprising the reducing agent together with the anti-Tg monoclonal antibody or antigen-binding fragment in an immunoassay kit, as taught by Maertens, because Yamamoto teaches a Tg immunoassay reagent that can realize Yamamoto’s Tg measurement method, teaches that a reducing agent may be used in the pretreatment solution, teaches the use of anti-Tg monoclonal antibodies and antibody fragments, and expressly contemplates providing immunoassay reagent components separately or together, while Maertens expressly teaches immunodiagnostic assay kits using reducing agents and identifies the same known reducing agents, including DTT and TCEP. One of ordinary skill in the art would have had a reasonable expectation of success because both references concern immunoassay reagent systems in which reducing agents are used to improve antigen-antibody reactivity, and packaging Yamamoto’s known pretreatment/reducing-agent component with Yamamoto’s known anti-Tg antibody component in a kit would have predictably facilitated performance of the Tg immunoassay without changing the known function of the reducing agent or the anti-Tg antibody.
Ultimately, claims 2, 4, 5, 6, and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Yamamoto in view of Saboori, Clarke, and Maertens, as applied above. The cited combinations provide the claimed Tg immunoassay framework, epitope-defined anti-Tg antibody selections, sandwich/capture/labeled antibody configuration, and kit/reagent configuration comprising a reducing agent. Therefore, the claimed subject matter as a whole would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
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/E.O./Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 July 6, 2026
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