Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/07/2025 has been entered.
Status of Claims
Claims 10 and 12-15 are pending and under examination. Claim 15 is new. Claims 1-9 and 11 are cancelled.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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.
Claims 10, 14 and 15 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Capon et al. (“Flexible antibodies with nonprotein hinges”, Proc. Jap. Acad., Ser. B 87, 2011, of record 892 dated 12/21/2022) in view of Barrio et al. (WO2009/015696A1, published 02/05/2009, of record 892 dated 12/21/2022), Peluso et al. (Analytical Biochemistry, vol. 312, pp. 113-124, published 2003, of record 892 dated 12/21/2022) and Kinney et al. (WO2007/050359A2, published 05/03/2007, of record 892 dated 06/21/2024).
With regard to claims 10 and 14, Capon teaches a significant need for antibodies that can bind targets with greater affinity and further teaches antibody-like molecules having nonprotein hinge regions that are more flexible and extendible and are capable of two-handed binding (abstract). Capon further teaches to join a ligand binding domain (Aβ peptide) to an IgG1 Fc dimer via discrete oxyethylene oligomers of various lengths and two-handed Aβ-Fc fusion proteins were obtained in quantitative yield and shown by surface plasmon resonance to bind an anti-Aβ antibody with a KD at least two orders of magnitude greater than the cognate Aβ peptide (see abstract). Capon teaches fused a 15 amino acid stretch representing the immunodominant epitope of Alzheimer’s Aβ(1-42) fibrils and successfully incorporated nonprotein chains between the Aβ and Fc moieties and our two-handed molecules bind targets with exceptional affinity, opening a promising avenue for the future development of improved antibody-based therapies (see p. 604, right col., para. 1). Capon teaches discrete oxyethylene oligomers of PEG12, PEG24 and PEG36 (see p. 608, right col., para. 2), which would read on a spacer wherein the spacer is 1 to 20 nm. Noted that the instant application specifically discloses spacer is PEG24 (see Fig. 1 and Table 1). Thus, the PEG24 would read on a spacer that is within 1 to 20 nm.
Capon teaches surface plasmon resonance studies where the major reaction product obtained for all four Aβ symmetroadhesins was the two-handed homodimer and such preparations had the ability to bind dimeric targets as two-handed molecules and the analysis was carried out using a monoclonal antibody capable of interacting with both of the Aβ sequences that were incorporated into the two-handed symmetroadhesin homodimers (see p. 611, right col., last para. – p. 612, left col., para. 1). Capon teaches the principal epitope (EFRHD) recognized by a number of monoclonal antibodies that are reactive with human Aβ(1-42) fibrils including 6E10 see p. 612, right col., para. 1). Capon teaches the molecules form two-handed native dimers display high affinity for an anti-Aβ monoclonal antibody and Aβ-PEGx-Fc dimers with a nonprotein hinge have an affinity that is two to five orders of magnitude greater than the cognate peptide and appear to bind better than the Aβ-Fc dimer (p. 615, left col., bottom of para. 2). Capon further teaches antibodies 6E10 using surface plasmon resonance SPR and Fig. 8 shows the results obtained when 6E10 was immobilized on the surface of the SRP chip (see p. 613, left col., para. 1 and Figs. 1 and 7). Furthermore, Capon teaches SPR studies were carried out using a Biacore with biotin and the sensor chip was loaded with the streptavidin capture reagent (see p. 606, right col., para. 2). Capon teaches kinetic results for Mab-6E10 binding measured by surface plasmon resonance with PEG12, PEG24 and PEG36 (see Table 4). Capon teaches the two-handed molecules bind targets with exceptional affinity, opening a promising avenue for the future development of improve antibody (p. 604, right col., para. 1).
Capon teaches therapeutic antibodies are directed against targets that are multimeric proteins, suggesting they could be improved if both arms could grasp a particular target molecule (see p. 604, left col., para. 3).
Even though Capon teaches peptides of amyloid β42 bind to IgGI Fc through discrete PEG24 spacer and 6E10 antibodies were immobilized on the surface of a SPR chip, the reference does not explicitly teach trapping amyloid β42 comprising contacting a sample containing amyloid β42 with spacers directly covalently bound to a glass solid support wherein the amyloid β42 are present in the sample as multimers or aggregates of a plurality of molecules wherein each said multimer or aggregate has a plurality of affinity sites.
Barrio teaches immunoassays which allow the detection of polypeptides in samples with a higher sensitivity than assays of the state of the art (see abstract). Barrio teaches Alzheimer’s disease (AD) is a progressive degenerative disease of the central nervous system characterized by progressive and increasing memory loss, followed by loss of control of limbs and bodily functions and eventual death (see pg. 1, lines 12-17). Barrio teaches that Aβ(1-42) associates with Alzheimer’s disease (AD) and suitable candidate as AD biomarker (see p. 3, lines 25-30). Barrio teaches β amyloid (1-42) test has a lower detection limit of 20 pg/ml, which allows the detection of Aβ42 in CSF (see p. 7, lines 8-12 and lines 18-20). Barrio teaches the capture antibody is immobilized onto a solid support and the plate was coated using the 6E10 mAb capture antibody which recognizes amino acids 1-17 in the amyloid Aβ42 peptide (see p. 21, lines 10-11 and p. 27, lines 1-5). Barrio teaches a solid support (see pg. 19, lines 30-31). Barrio further teaches that the solid support includes polyethylene (see p. 20, middle of paragraph).
Kinney teaches antibodies that -differentially -recognize multi- dimensional conformation of Aβ- derived diffusible ligands, also known as ADDLs (see abstract). Kinney further teaches that Aβ-derived diffusible ligands or ADDLs refer to soluble oligomers of amyloid β1-42 which are desirably composed of aggregates of less than eight or nine amyloid β1-42 peptides and are found associated with Alzheimer’s Disease (see p. 10, lines 2-8).
Peluso teaches specifically oriented capture and the intensity of specific signal produced on a feature of an array is related to the amount of analyte that is captured from the biological mixture by the immobilized antibody (abstract). Peluso teaches that surface plasmon resonance revealed a packed and dense monolayer of Fab’ fragments that are on average 90% active when specifically oriented (abstract and pg. 123, left col., para. 2). Peluso further teaches that specific orientation of capture agents consistently increases the analyte-binding capacity of the surfaces, with up to 10-fold improvements over surfaces with randomly oriented capture agents (abstract; and Fig. 1). Peluso teaches polyethylene glycol system (see p. 116, left col., Microarray assays – p. 117, right col., para. 1; and Fig. 1, SA is streptavidin). Peluso teaches immunoassays require one of the antibodies to be immobilized onto a surface proteins can be covalently coupled to chemically activated surfaces through the reaction of lysine side chains (see p. 113, right col., bottom of last para.). Peluso teaches surface plasmon resonance (SPR) assays were performed on a BIAcore 3000 using a biotinylated self-assembled monolayer formed on a gold-coated glass surface and the surface was biotinylated for binding of SA (streptavidin) (see pg. 116, right col., para. 3 and Fig. 1). Peluso further teaches that the SA was loaded onto the surface and typically 320 was loaded to achieve a saturated surface of SA whereby typically obtained a surface coverage (see pg. 116, right col., bottom of para. 3 and Fig. 1).
It would have been obvious at the time the invention was made for a person of ordinary skill in the art to have modified the two-handed molecules having nonprotein hinge region (symmetroadhesins) with 6E10 monoclonal antibodies of Capon because Capon teaches that the two-handed molecules bind targets with exceptional affinity due to the capability of two-handed binding with the flexibility and extendibility of the molecules (see Fig. 7). Furthermore, it would have been obvious to have modified the two-handed molecules of Capon with 6E10 monoclonal antibody of Barrio in detecting Alzheimer’s Disease because Barrio teaches amyloid Aβ42 is a suitable biomarker to detect Alzheimer and further teaches that the immobilized 6E10 monoclonal antibodies on solid support recognize amino acids 1-17 of the amyloid Aβ42 with sensitivity. Therefore the person would have replaced the Aβ peptides on Capon’s symmetroadhesins with 6E10 monoclonal antibodies and attached it on a solid support to produce symmetroadhesins for detecting Aβ42 polypeptides because Capon teaches amyloid β42 are reactive/sensitive with 6E10 antibodies and molecules with nonprotein hinges have an affinity that is two to five orders of magnitude greater than cognate and protein hinged molecules and display high affinity. Because of the flexibility and extendibility of the molecule, it would have been obvious that the modified the two-handed molecules thus would cooperatively or together bind to the amyloid β1-42 molecule because Capon teaches the symmetroadhesin is capable of two-handed binding.
Similarly, it would have been obvious to the person to have used the modified symmetroadhesins that have two-handed binding capabilities to bind to multimeric or aggregated amyloid β (1-42) in the sample as taught by Kinney because Capon teaches that it has been recognized in the art to use antibodies against targets that are multimeric proteins, suggesting that could be improved if both arms could grasp a particular target molecule and Kinney teaches that soluble oligomers of amyloid β1-42 which are desirably composed of aggregates of less than eight or nine amyloid β1-42 peptides and are found associated with Alzheimer’s Disease. The person would have used the modified symmetroadhesins having 6E10 monoclonal antibodies against aggregated amyloid β1-42 to detect Alzheimer’s Disease because symmetroadhesins improves binding by both arms grasping to a target molecule.
Additionally, it would have been obvious to have used Fab or Fab’ fragments and covalently coupled the Fc region of the molecules to the solid support at a specific orientation because Peluso teaches specific orientation of antibody fragments produces a 10-fold detection improvement over surfaces with randomly oriented antibodies without protein hinges while covalently coupled to chemically activated surface. Meanwhile, Peluso teaches proteins can be covalently coupled to chemically activated surfaces through the reaction of lysine side chains of protein to surfaces. Therefore, the Fc region of Capon would be able to directly couple to the solid support as taught by Barrio. Also, it would have been obvious to have packed the modified monoclonal fragments to a gold-coated glass surface as taught by Peluso because Capon already recognizes SPR (Biacore) is through loading the sensor chip and Peluso teaches gold-coated glass chip to achieve surface coverage for SPR (Biacore). Therefore, the person would recognize to pack the fragments in Peluso’s orientation on the gold-coated glass for SPR measurements.
The person of ordinary skill in the art would have a reasonable expectation of success in covalently attaching 6E10 antibodies or fragments thereof to the Fc regions having nonprotein hinges because it has been well understood in the art to employ PEG for covalent binding of antibodies or fragments which possess reactive amino acid groups similarly to Aβ peptides.
With respect to the interval between binding positions, the references do not explicitly teach 1 to 50 angstroms (Å) (claim 10) or 1.5 to 30 angstroms (Å) (claim 14). Peluso does teach that the surface has revealed a packed and dense monolayer of Fab’ fragments that are on average 90% active when specifically oriented (abstract and Fig. 1). Thus, the spacing between spacers on a solid support is clearly a result effective parameter that the person of ordinary skill in the art would routinely optimize. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation” Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). Optimization of parameters is a routine practice that would be obvious to a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal spacings for antibody binding to achieve the desired results of analyte-binding capacity, which as disclosed by Capon and Peluso depend on factors such as angles and orientations of the immobilized antibodies. “No invention is involved in discovering optimum ranges of a process by routine experimentation.” Id. at 458, 105 USPQ at 236-237. The “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” Since Applicant has not disclosed that the recited spacings in the claims are for any particular purpose (other than for binding to antibodies or fragment thereof) or solve any stated problem. Peluso teaches that the surface has revealed a dense monolayer of Fab’ fragments that are on average 90% active when specifically oriented. There is no evidence of record as to the criticality of the claimed spacings on the solid support and absence of unexpected results, it would have been obvious for the person to discover the optimum effective parameters in packing a dense monolayer for analyte-binding capacity.
With respect to claim 15, Capon teaches discrete oxyethylene oligomers of PEG12, PEG24 and PEG36 (see p. 608, right col., para. 2), which would read on the spacers are non-peptidic.
Claim 12 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Capon et al. in view of Barrio et al., Peluso et al., and Kinney et al., as applied to claim 10 above, and further in view of Mojtahedian et al. (US20070157325A1, published 07/05/2007, of record dated 12/21/2022).
Capon, Barrio, and Peluso and Kinney have been discussed in the above rejection. Barrio further teaches detecting the total amount of Aβ peptides, the 6E10 mAb is used to capture the Aβ peptides and then detected using 4G8 (see p. 5, lines 30-33).
However the references do not teach two kinds of the immunoglobin, immunoglobulin F(ab’) fragment, or F(ab) fragment are bound to the support in a mixed state.
Mojtahedian teaches identification of novel biomarkers for Alzheimer’s disease (see abstract). Mojtahedian teaches ELISA assays are performed using 6E10 and 4G8 antibodies (see paras. [0019] and [0101].
It would have been obvious to have used the method of detecting amyloid β as taught by Capon and Barrio with 6E10 and 4G8 antibodies of Mojtahedian because the combination of 6E10 and 4G8 antibodies will detect different forms of amyloid β biomarkers in a sample. The person would have a reasonable expectation of success in using 6E10 and 4G8 because it has been well understood in the art that 6E10 and 4G8 antibodies bind to different forms of amyloid β.
Claim 13 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Capon et al. in view of Barrio et al., Peluso et al., and Kinney et al., as applied to claim 10 above, and further in view of Hansen et al. (US2009/0252731A1, published 10/08/2009, of record dated 12/21/2022).
Capon, Barrio, and Peluso and Kinney have been discussed in the above rejection. Capon teaches using surface plasmon resonance for detection (see p. 613, left col., para. 1). Barrio further teaches the complexes can be washed to remove any excess of protein/peptide found in the original sample which did not bind to the capture antibody (see p. 24, lines 13-15).
However, the references do not explicitly teach eluting the amyloid β bound to the immunoglobulin F(ab’) or F(ab) fragments from the affinity support and collecting the amyloid β so eluted.
Hansen teaches targetable constructs that are multivalent carriers of bi-specific antibodies (see abstract). Hansen teaches targeting metabolic disease such as amyloid in amyloidosis (see para. [0079]). Hansen teaches surface plasmon resonance (see para. [0306]). Hansen teaches washing the impurities present in the fluid volume of the column, as well as those bound nonspecifically to the antibody, solid support or column wall, are removed and in the elution step, the target molecule is removed from the column (see para. [0169]).
It would have been obvious to have used the method of detecting Aβ42 as taught by Capon and Barrio with a washing and eluting step of Hansen because the process of washing and eluting will provide the removal of the target to be efficiently detected. The person would have a reasonable expectation of success in eluting the target because it was been well understood to detect the target by surface plasmon resonance.
Response to Arguments
Applicant's arguments filed 11/07/2025 have been fully considered but they are not persuasive.
Applicant argues on page 5 that a plurality of spacers recited in the claims are directly covalently bound to a solid support and claim has been amended to recite the solid support is from specific materials for the solid supports. Applicant further argues on page 6 that even if a person were motivated to swap the AB peptide of Capon with a 6E10 antibody, an affinity support of a symmetroadhesin on a solid support would not read on a plurality of spacers as claimed because the affinity support would not comprise a plurality of PEG24 spacers directly covalently bound to a support made of one of the recited materials.
The arguments are not found persuasive for the following reasons. The claim recites “an affinity support which comprises” which is an open-ended recitation of what is part of the affinity support and the added materials are still generic in term of structures to the recitation of the spacer is “directly covalently bound”. The person of ordinary skill in the art would recognize that functional structures are required on these materials to “directly covalently bound” the spacer to the claimed solid support. As stated in the Final dated 05/08/2025, because the claims recite generic structures to produce the outcome of “directly covalently bound”, the solid support would include any functional structures known in the art for covalent attachments. In other word, glass would require more than just the structure of glass to “directly covalently bound to the spacer” and binding positions on the support precisely between 1 to 50 angstrom. As stated above, the claims recite an open-ended recitation of the affinity support. For example, the sequence in the hing region of an antibody (DKTHT) as disclosed by Capon would be part of the solid support for the covalent attachment as required by the claimed invention because as shown in Capon such structure would produce a directly covalently bound structure to the spacer of Capon.
Conclusion
No claim is allowed.
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/N.P.N/Examiner, Art Unit 1678
/SHAFIQUL HAQ/Primary Examiner, Art Unit 1678