CTFR 18/048,673 CTFR 98126 DETAILED ACTION Claims 1-20 are pending. 12-151 AIA 26-51 12-51 Status of Claims Claims 1-20 are pending. Claims 1, 5, and 10-20 have been amended. Claims 1-20 are under examination. Withdrawn Claim Objections and/or Rejections The objection of the specification as set forth on p. 3 of the previous office action (mailed on 10/02/2025) has been withdrawn in view of the amendments (filed on 02/02/2026). The rejection of claims 1-20 under 35 USC 112(a) for failing to comply with written description as set forth on pp. 4-6 of the previous office action (mailed on 10/02/2025) has been withdrawn in view of the amended claims (filed on 02/02/2026). The rejection of claims 1-20 under 35 USC 112(a) for enablement as set forth on pp. 6-7 of the previous office action (mailed on 10/02/2025) has been withdrawn in view of the amended claims (filed on 02/02/2026). The rejection of claims 1-20 under 35 USC 112(b) for being indefinite as set forth on pp. 7-8 of the previous office action (mailed on 10/02/2025) has been withdrawn in view of the amended claims (filed on 02/02/2026). Claim Objections 1. Claims 1 is objected to because of the following informalities: Claim 1 is missing a word between “TTRs comprising a valine to methionine substitution at position 30 (TTRV30M) relative to SEQ ID NO: 3” and “at least on biotin molecule…”. Examiner suggests adding a word (“and”/”or”) between “3” and “at least”. Appropriate correction is required. Claim Rejections - 35 USC § 103 07-06 AIA 15-10-15 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. 07-20-aia AIA The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made. 07-23-aia AIA The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows: 1. Determining the scope and contents of the prior art. 2. Ascertaining the differences between the prior art and the claims at issue. 3. Resolving the level of ordinary skill in the pertinent art. 4. Considering objective evidence present in the application indicating obviousness or nonobviousness. 2. Claims 1-3, 5-12, 14-15, and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Chakrabartty et al., (US 9534048 B2), in view of Graef et al., (US 20130203777 A1), in view of Walker et al., (US 20220324924 A1) (effectively filed on 07/06/2020). Instant claims 1 and 11 recite a method for detecting transthyretin (TTR) monomers in a biological sample from a subject and a composition comprising (a) contacting the sample with a TTR binding reagent for a sufficient time for the TTR binding reagent to bind to TTR monomers in the sample and form a complex comprising the TTR binding reagent and TTR monomers, the TTR binding reagent comprising multimers of TTRs comprising a valine to methionine substitution at position 30 (TTRV30M) relative to SEQ ID NO: 3, and at least one biotin molecule linked to the N-terminus of each variant TTR, and streptavidin molecules linked to the at least one biotin molecule on the TTRs; and (b) detecting the presence of the complex. Chakrabartty teaches a method for detecting transthyretin (TTR) monomers in a biological sample from a subject ( see column 1 lines 10-12 “The disclosure relates to antibodies for detecting misfolded proteins and specifically to antibodies for detecting misfolded transthyretin (TTR) intermediates.”, see column 2 lines 9-12 “In another embodiment, the antibody or binding fragment thereof specifically binds a non-native forms such as misfolded and/or monomeric forms of TTR. In yet another embodiment, the antibody or bind”) comprising: A) contacting the sample with a TTR binding reagent ( see column 8 lines 34-37 “When used to describe “selectively binds misfolded TTR for example, an antibody selectively binds misfolded TTR if it binds misfolded TTR,” see column 10 lines 21-32 “The term “natively folded as used herein with respect to the structure of a polypeptide or polypeptide multimer Such as TTR tetramer, refers to the normal folded structure of the polypeptide or multimer. As TTR natively folded is a tetramer, non-natively folded forms on TTR include mis folded TTR tetramer, misfolded TTR monomer and folded TTR monomer including molecules comprising wildtype amino acid sequence and mutations. The term “misfolded TTR as used herein refers to the secondary and tertiary structure of a TTR polypeptide monomer or multimer…”, the instant application teaches that a TTR binding reagent is a multimer of a monomer ( [0040] )) for a sufficient time for the TTR binding reagent to bind to TTR monomers in the sample and form a complex comprising the TTR binding reagent and TTR monomers, ( see column 3 lines 66-67 and column 1-7 “Another aspect includes a method of detecting a nonnative forms of TTR such as misfolded TTR conformation and/or monomeric TTR in a test sample), the method comprising contacting the test sample with an antibody or binding fragment thereof described herein under conditions suitable to form a specific antibody antigen complex between the antibody and TTR; determining if a specific antibody TTR complex is formed thereby detecting misfolded TTR and/or monomeric TTR in the test sample). Chakrabartty teaches (b) detecting the presence of the complex ( see column 3 lines 66-67 and column 1-7 ) ( instant claims 1 and 11 ). Chakrabartty teaches the use of a solid support and that solid support being a microplate (see column 5 lines 29-35 “The misTTR antibody preferentially binds GdnHCl-unfolded TTR on the ELISA plate whereas the commercially available antibody readily binds folded tetrameric TTR. (b) Competition ELISA with the misTTR antibody, which selectively binds monomeric TTR in the presence”) ( instant claims 6-7 and 14-15 ). Chakrabartty teaches wherein detecting comprises contacting the complexes with a detection reagent and the detection reagent, being an antibody, is linked to a detectable marker comprising a fluorescent molecule, a luminescent molecule, a radioisotope, and an enzyme capable of catalyzing a detectable chemical reaction ( see column 14 lines 48-55 “the label is preferably capable of producing, either directly or indirectly, a detectable signal. For example, the label may be radio-opaque or a radioisotope, such as 3H, 14C, 32P, 35S, 123I, 125I, 131I; a fluorescent (fluorophore) or chemiluminescent (chromophore) compound, such as fluorescein isothiocyanate, rhodamine or luciferin; an enzyme, such as alkaline phosphatase, beta-galactosidase or horseradish peroxidase; an imaging agent; or a metal ion.”, see column 14 lines 56-59 “In another embodiment, the detectable signal is detectable indirectly. For example, a secondary antibody that is specific for an antibody described herein and contains a detectable label can be used to detect the antibody.”) ( instant claims 8-10 and 18-19 ). Chakrabartty does not teach the TTR binding reagent comprising multimers of: TTRs comprising a valine to methionine substitution at position 30 (TTRV30M) relative to SEQ ID NO: 3, and at least one biotin molecule linked to the N-terminus of each TTR, and streptavidin molecules linked to the at least one biotin molecule on the TTRs. Chakrabartty does not teach the use of biotin and streptavidin and the biotin being linked to the N-terminus of the TTR binding reagent. Graef teaches the TTR binding reagent comprising multimers of: TTRs comprising a valine to methionine substitution at position 30 (TTRV30M) ( see [0188] “The transthyretin used in the screening methods can be …mutant transthyretin … V30M”) relative to SEQ ID NO: 3 ( see [0188] teaching TTR with V30M mutation, see [0256] ), and at least one biotin molecule linked to the N-terminus of each TTR, and streptavidin molecules linked to the at least one biotin molecule on the TTRs ( see [0233] – [0236] teaching the use of biotin and streptavidin, see [0020] ) ( instant claims 1, 5, and 11 ). Graef teaches wherein the affinity moiety is biotin ( see [0323]- [0233] “Biotinylation of TTR.”) and wherein the affinity moiety is linked to the N-terminus of the TTR binding reagent ( see [0232] – [0234] “Biotinylation of TTR” using “EZ-Link Sulfo-NHS-LC-Biotin”. This reagent is known in the art to bind biotin to primary amine groups including the N-terminus) ( instant claims 2-3 and 12 ). Graef teaches wherein the method further comprises binding the complex to streptavidin ( see [0236] “After pretreatment of the streptavidin-coated chip (Sensor Chop SA, Biacore), ˜4000 RU biotinylated TTR was immobilized on one channel leaving the second flow channel as a blank (streptavidin alone) control.”) ( instant claim 5 ). Graef teaches the use of human TTR, but does not explicitly teach that the sequence of SEQ ID NO: 3 is human TTR. Walker teaches that instant SEQ ID NO: 3 is the sequence of human TTR ( see SEQ ID NO: 1 of Walker, see [0142] ) ( instant claims 1 and 11 ). It would have been obvious to one of ordinary skill in the art at the time of the instant application to modify the methods of detecting TTR monomers in a biological sample as taught by Chakrabartty with the TTR variant TTRV30M and the affinity moiety molecule linked to that variant as taught by Graef and with the teaching of the sequence for human TTR taught by Walker . Graef provides motivation by demonstrating the usefulness of adding a biotin tag to the TTRV30M in order to conjugate it to the SPR streptavidin sensors, in order to determine binding kinetics ( see [0019] - [0020] ). It is known in the art that streptavidin and biotin are affinity molecules that work together. Graef demonstrates the successful use of streptavidin with immobilized TTR binders ( see [0253] ). The artisan would have reasonable expectation of success based on the cumulative disclosure of these prior art references at the time the instant application was filed. 07-21-aia 3. Claims 4, 13, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Chakrabartty , Graef , and Walker as applied to claims 1-3, 5-12, 14-15, and 18-20 above, and in view of Kay et al., (“Chapter 13: High-Throughput Biotinylation of Proteins”. High Throughput Protein Expression and Purification. Methods in Molecular Biology, vol 498. Humana Press, p185-198) (2009). The teachings of Chakrabartty , Graef , and Walker as it pertains to claims 1-3, 5-12, 14-15, and 18-20 are discussed in the 35 USC 103 rejection above. Chakrabartty does not teach the TTR binding reagent wherein the TTR binding reagent has the sequence of, or is at least 90% similar to that of SEQ ID NO: 1 and the TTR binding reagent comprising at least one polypeptide consisting of SEQ ID NO: 1. Graef teaches human TTR and Walker teaches the sequence of human TTR ( instant claims 4, 13, and 20 ). Graef and Walker do not teach the use of an AviTag. Kay teaches the use of an AviTag, with the sequence of “GLNDIFEAQKIEWHE” ( see pg. 188 ) ( instant claims 4, 13, and 20 ). The addition of the AviTag to the TTR V30M sequence would result in being 100% similar to SEQ ID NO: 1, as shown below. PNG media_image1.png 401 843 media_image1.png Greyscale TTR is known in the art to be a polypeptide, thus it would have been obvious to one of ordinary skill in the art to include it in the TTR binding reagent with the AviTag taught by Kay , because as Kay teaches, the addition of AviTag allows for effective biotinylation ( see pg. 186 ). It would have been obvious to one of ordinary skill in the art before the instant application to modify the AviTag taught by Kay , with the TTR and TTR V30M sequence taught by Graef and Walker , with the methods of detecting TTR monomers in a biological sample as taught by Chakrabartty . Kay teaches these claimed limitations are beneficial because the AviTag allows for effective biotinylation ( see pg. 186 ). Regarding Graef’s chemical biotinylation, Kay indicates that “two drawbacks of in vitro chemically biotinylated target protein is that the number of biotin added is not uniform and the modification of certain lysine residues may lead to inactivation of the binding site(s).” whereas “when recombinant proteins are fused to the AviTag and incubated in vitro with purified BirA, they can be biotinylated efficiently on the central lysine residue in the AviTag … and there is a single biotin attached per protein molecule” ( see pg. 186 ). The artisan would have had reasonable expectation of success by using standard materials and methods as taught by Kay , as it has been a standard microbiological technique for several decades. The artisan would have reasonable expectation of success based on the cumulative disclosure of these prior art references at the time the instant application was filed. 4. Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Chakrabartty , Graef , and Walker as applied to claims 1-3, 5-12, 14-15, and 18-20 above, and in view of Rai et al., (WO 2022093274 A1) (2020). The teachings of Chakrabartty, Graef, and Walker as they pertain to claims 1-3, 5-12, 14-15, and 18-20 are discussed in the 35 USC 103 rejection above. Chakrabartty does not teach the use of a lateral flow device. Rai teaches wherein the solid support is a lateral flow device ( see claim 54 “The kit of claim 50 wherein the kit is selected from the group consisting of an enzyme- linked immunosorbent assay (ELISA) type, and a lateral flow immunochromatographic assay (LFA) type.”) ( instant claim 16 ). It would have been obvious to one of ordinary skill in the art before the instant application to combine the use of a lateral flow immunoassay with TTR as taught by Rai , with the TTR and TTR V30M sequences taught by Graef and Walker , with the methods of detecting TTR monomers in a biological sample as taught by Chakrabartty . Rai teaches these claimed limitations are beneficial because TTR can effectively be detected using a lateral flow assay device ( see page 5 lines 29-32, see page 19 lines 12-15 ). Rai further teaches motivation by teaching that the lateral flow assay may be implemented in any location including at a hospital, a clinic, a laboratory, as well as in the “field” at a needed location apart from any medical or laboratory facility ( see page 8 lines 30-31 and page 9 lines 1-5 ) and provide a low-cost, point-of-care, screening kit…for use by anyone with minimal training” ( see page 29 lines 20-24 ). The artisan would have reasonable expectation of success based on the cumulative disclosure of these prior art references at the time the instant application was filed. 5. Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Chakrabartty , Graef , and Walker as applied to claims 1-3, 5-12, 14-15, and 18-20 above, and in view ThermoFisher Scientific ("Avidin-Biotin Interaction"; retrieved online from (Avidin-Biotin Interaction | Thermo Fisher Scientific - US); available online date 09/15/2015 as evidenced by the WayBack Machine). The teachings of Chakrabartty, Graef, and Walker as they pertain to claims 1-3, 5-12, 14-15, and 18-20 are discussed in the 35 USC 103 rejection above. Chakrabartty does not teach the TTR binding reagent comprising four TTRs linked to each streptavidin molecule. Graef teaches the use of biotinylated TTRs ( see [0232] – [0234] ) and the use of streptavidin ( see [0233] – [0236] teaching the use of biotin and streptavidin, see [0020] ). ThermoFisher teaches that streptavidin contains up to four biotin conjugates ( see “Introduction: The Avidin-biotin interaction” ). It would have been obvious to one of ordinary skill in the art at the time of the instant application to combine the teachings of streptavidin-biotin interactions taught by ThermoFisher , with the TTR and TTR V30M sequences taught by Graef and Walker , with the methods of detecting TTR monomers in a biological sample as taught by Chakrabartty . One of ordinary skill in the art would know that streptavidin binds four biotinylated molecules (biotinylated TTRs), thus there would be four TTRs linked to each streptavidin molecule. ThermoFisher provides motivation by teaching that streptavidin is the ideal reagent as has a lower degree of nonspeicifc binding ( see under “Streptavidin” ). ThermoFisher further provides motivation by teaching that Streptavidin and Biotin probe use is beneficial for protein detection because of the probes ability to amplify the original protein signal to improve detection of proteins expressed at low levels by forming large Streptavidin-biotin complexes ( see under “Protein Detection” ). The artisan would have reasonable expectation of success based on the cumulative disclosure of these prior art references at the time the instant application was filed. Response to Arguments The arguments filed on 02/02/2026 have been considered by the examiner. On pp. 9-10 applicant argues that there is no prima facia obviousness because the combination of cited references does not teach each element of the claims. Applicant argues that Graef and Chakrabartty does not teach the newly amended limitation of “TTR binding reagents comprising multimers of: of TTRs comprising a valine to methionine substitution at position 30 (TTRV30M) relative to SEQ ID NO: 3, and at least one biotin molecule linked to the N-terminus of each variant TTR, and streptavidin molecules linked to the at least one biotin molecule on the TTRs. However, Graef teaches streptavidin-biotin interactions (see [0020]). Graef teaches the biotinylation of TTR ( see [0232] – [0234] ). Graef teaches the use of human TTR ( see abstract, see [0214] ). Graef does not explicitly state the sequence of SEQ ID NO: 3 is human TTR. However, Walker teaches that instant SEQ ID NO: 3 is human TTR ( see SEQ ID NO: 1 of Walker, see [0142] ). On pp. 10-11 applicant argues that there is no teaching or suggestion in either of Chakrabartty or Graef that the TTR-specific antibodies of Chakrabartty could be substituted with the claimed TTR binding reagent to detect TTR monomers and one of ordinary skill in the art would not have made the proposed modification and there is no prima facie case of obviousness. However, Chakrabartty teaches the use of TTRs ( see column 1 lines 10-12 , see column 2 lines 9-12 ). Chakrabartty teaches TTR mutations and specifically teaches V30M ( see column 1 lines 33-45 , see column 6 lines 52-57 ). Further, Chakrabartty teaches that changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art ( see column 5 lines 1-7 ). Graef explicitly teaches using the streptavidin-biotin interaction with TTRV30M relative to SEQ ID NO: 3 ( see [0188], see [0256] ). Graef teaches that the TTR can be a mutant such as V30M ( see [0188] ). Thus, one of ordinary skill in the art would have proposed the modification because both references teach the mutation of V30M and as Chakrabartty teaches changes and modification within the scope (such as mutations) will be apparent to those skilled in the art. Conclusion No claim is allowed. 07-40 AIA Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL . See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a). A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MCKENZIE A DUNN whose telephone number is (571)270-0490. The examiner can normally be reached Monday-Tuesday 730 am -530pm, Wednesday-Friday 730 am-430 pm. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached at (571)272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /MCKENZIE A DUNN/ Examiner, Art Unit 1678 /GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678 Application/Control Number: 18/048,673 Page 2 Art Unit: 1678 Application/Control Number: 18/048,673 Page 3 Art Unit: 1678 Application/Control Number: 18/048,673 Page 4 Art Unit: 1678 Application/Control Number: 18/048,673 Page 5 Art Unit: 1678 Application/Control Number: 18/048,673 Page 6 Art Unit: 1678 Application/Control Number: 18/048,673 Page 7 Art Unit: 1678 Application/Control Number: 18/048,673 Page 8 Art Unit: 1678 Application/Control Number: 18/048,673 Page 9 Art Unit: 1678 Application/Control Number: 18/048,673 Page 10 Art Unit: 1678 Application/Control Number: 18/048,673 Page 11 Art Unit: 1678 Application/Control Number: 18/048,673 Page 12 Art Unit: 1678
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