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 .
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.
Withdrawn Rejections
The rejection of claim 56 under 112b is withdrawn in response to the amendments.
Priority
Acknowledgment is made of the present application as a proper National Stage (371) entry of PCT Application No. PCT/US2019/061687, filed 11/15/2019, which claims benefit under 35 U.S.C. 119(e) to provisional application No. 62/768,479, filed 11/16/2018.
Status of the Claims
Claims 31-37, 41 and 49-63 are pending; claims 1-30, 38-40 and 42-48 are canceled; claims 61-63 are newly recited. Claims 31-37, 41 and 49-63 are examined below.
Maintained Rejections
Claim Rejections - 35 USC § 103
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.
Claims 31-36, 49-52 and 57 are rejected under 35 U.S.C. 103 as being unpatentable over Romestand et al. Biomacromolecules 2010, 11, 5, 1169–1173 https://doi.org/10.1021/bm9012056 Cite No. 3 of IDS filed 7/19/2022 (hereinafter Romestand) in view of Chang et al. Journal of Controlled Release 156 (2011) 195–202 doi:10.1016/j.jconrel.2011.07.021 ("Chang") as evidenced by Laskowski and Burk J. Chem. Phys. 7, 465–469 (1939) (hereinafter Burk) (Cited in PTO 892 filed 2/21/2025).
Regarding claims 31-36, 49 and 51, Romestand teaches a method for detecting presence of an analyte in a sample (“[a]n easily synthesized DendriGraft poly-lysine DGL-G3 (third generation) was shown to act as an efficient carrier for raising antibodies directed against small molecules. The immunological properties of three different forms of DGL-G3 were investigated:… a surface-modified form bearing histamine (DGL-G3-Histamine)” Abstract, “Antibody Production and Characterization. Two tests were used: an indirect ELISA test to analyze antibody production and a competitive ELISA test to check the affinity of antibodies against the histamine hapten…The well-plates were filled at 4°C with 50 µL per well of immunoconjugate (DGL-G3, fluorescein-DGL-G3, DGL-G3-histamine, or BSA-histamine)” page 1171 column 1 paragraphs 1-2), the method comprising:(i) contacting a sample suspected of comprising an analyte with a compound (“Next, wells were rinsed twice with PBS and filled at 2 h at 37 °C with 50 µL of serum” page 1171 column 1 paragraph 2) comprising:(a) a substrate binding domain; (b) a branching domain comprising a small molecule the small molecule linked to a branch of a branch point, wherein the small molecules independently have a molecular weight of less than 1,000 Da; and (c) a linker linking the substrate binding domain and the branching domain (“surface-modified form bearing histamine (DGL-G3-Histamine)” Abstract). See Figure 1 of Romestand showing DGL-G3-Histamine. Note that the molecular weight of histamine is less than 1000 Da according to the instant disclosure (“histamine (111.14 g/mol)” paragraph 3 “g/mol (Da)” paragraph 8). Below is a screenshot of DGL-G3-histamine from Figure 1 of Romestand for reference:
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. Therefore, the histamines attached to the branch of the DGL-G3 address a branching domain comprising a small molecule, wherein the small molecules independently have a molecular weight of less than 1,000 Da. The NH functional group attaching the DGL-G3 to the histamine is interpreted as the substrate binding domain. The 5 hydrocarbon atom chain in between the first NH (next to the DGL-G3) and the second NH is interpreted as the linker. The structure between the histamine and the linker is interpreted as a branching domain comprising the histamine linked to a branch of a branch point. Romestand further teaches (ii) detecting binding of an analyte binding molecule to the compound, wherein the analyte binding molecule is an antibody comprising a detectable label, producing a chromogenic, fluorescence or electrochemical signal and comprising contacting the sample from (i) with a molecule capable of binding with the analyte binding molecule and comprises a detectable label (“The colorimetric reaction was stopped after incubation for 15 min in the dark by the addition of 25 µL of a4 N H 2 SO 4 solution per well. The optical density (OD) was measured at 492 nm on an ELISA plate reader… filled with 200 μL of 1/10 000 sheep antirabbit IgG peroxidase diluted in PBS” page 1171 column 1 paragraphs 2-3). Romestand further teaches wherein the compound and the analyte bind competitively with the analyte binding molecule, wherein the analyte is histamine (“competitive ELISA test to check the affinity of antibodies against the histamine hapten… histamine…was covalently linked to wells…Sera … were preincubated…with diluted immunoconjugates…Then, 200 µL of each competitive sample was applied to wells previously coated with histamine derivatives” page 1171 column 1 paragraphs 1 and 3).
Romestand fails to teach the branching domain comprising a plurality of small molecules each small molecule linked to a branch of a branch-point, wherein the small molecule is histidine or a histidine-phenylalanine dimer wherein the branchpoint comprises at least one lysine.
Chang teaches the “Development of lysine–histidine dendron modified chitosan for improving transfection efficiency in HEK293 cells” (Title). Chang further teaches that “lysine–histidine (KH) dendrons were designed for effective modification of histidines” (page 195 col. 2 para. 2, See “Fig. 1. Structure of KH Dendron” page 196 col. 1). Note that the KH dendrons taught by Chang (see Fig. 1) are a compound comprising a substrate binding domain (SH), a branching domain comprising a plurality of small molecules each small molecule linked to a branch of a branch-point, wherein the branchpoint comprises at least one lysine; wherein the small molecule is histidine (the lysines are interpreted as the branching domains and branch-points comprising the histidines, see Figure 1). Figure 1 of Chang is copied here for convenience:
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. Note that part of the Cystein and the β-Alanine are interpreted as the linker linking the substrate binding domain and the branching domain. Chang further teaches that the KH dendron has “practicability for experimental procedures and clinical applications… the structure of the KH dendron is composed of endogenous amino acids and the biocompatibility of the KH dendron is predictable” (page 196 col. 1 para. 1). Chang further teaches that “[t]he structure of dendron provided buffering capacity, not only from the imidazole group but also from the primary amino groups of histidines” (page 200 col. 2 para. 3).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Romestand to rely on the branching domain comprising a plurality of small molecules each small molecule linked to a branch of a branch-point, wherein the branchpoint comprises at least one lysine, wherein the small molecule is histidine taught by Chang because Chang suggests that the compound comprising a plurality of lysines and histidines provides biocompatibility, buffering capacity and is applicable for both experimental and clinical applications. A person having ordinary skill in the art would have had a reasonable expectation of success because both Romestand and Chang teach a compound comprising a substrate binding domain, a branching domain comprising at least one small molecule, and a linker linking the substrate binding domain and the branching domain.
Regarding claim 50, Romestand in view of Chang teach the method of claim 31 as discussed above.
Romestand in view of Chang further teach wherein the linker has a length between 5 and 200 angstroms (Figure 1 of Romestand). The 5 hydrocarbon atom chain in between the first NH (next to the DGL-G3) and the second NH, is interpreted as the linker in Figure 1 of Romestand. And as evidenced by Burk “[t]he average distance between the center of the first and last carbon atoms of a freely rotating hydrocarbon has been evaluated as 1.50 1 where 1 is the carbon-carbon distance of 1.54A” (Abstract). Therefore, Romestand teaches a linker with a length of approximately 5 x 1.54 = 7.7 angstroms.
Regarding claim 52, Romestand in view of Chang teach the method of claim 51 as discussed above.
Romestand further teaches that “[t]he use of synthetic peptide antigens for the production of vaccines1,2 as well as the use of haptens for the production of antibodies for diagnostic immunoassays3-14 suffers the problem of finding carriers devoid of side effects” (page 1169 col. 1 para. 1). Romestand further teaches that the DGL-G3 is a possible predictable solution to the need of carriers devoid of side effects (“In this present work, our objective was to find a truly
nonimmunogenic carrier with a minimum MW around 20 kDa and a large number of peripheral reactive groups for hapten conjugation.2,14,15 We chose to study the third generation of dendrigraft poly-L-lysine (DGL-G3), a synthetic polymer with an idealized structure constituted by nine equivalent dendrons (Scheme 1B-D) linked to the core” page 1169 col. 2 para. 4, “DGL-G3 has an ideal MW of 22 kDa, is nontoxic, and its production can be scale up” page 1172 col. 2 para. 2). Romestand further teaches that “DGL-G3 appears consequently to be a good carrier able to improve the specificity of antibodies for diagnostic immunoassays” (” page 1172 col. 2 para. 2).
Romestand in view of Chang further suggest wherein the branch-point comprises a first lysine linked to a second lysine, and wherein the carboxyl group of the first lysine is linked to the epsilon-amino group of the second lysine. See Figure 1 of Chang showing wherein the branch-point comprises a first lysine and second lysine. However, Chang fails to teach wherein the carboxyl group of the first lysine is linked to the epsilon-amino group of the second lysine. However, below is Scheme 1B of Romestand showing wherein the carboxyl group of the first lysine is linked to the epsilon-amino group of the second lysine:
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.
Although the dendrimer of Romestand is no longer interpreted as the branching domain, it would have been obvious to have relied on the structure of Romestand wherein the carboxyl group of the first lysine is linked to the epsilon-amino group of the second lysine in the branching domain of Chang because Romestand teaches that this configuration is nontoxic and effective as a carrier, i.e. a possible predictable solution to the current need of biocompatible carriers according to Romestand. A person having ordinary skill in the art would have had a reasonable expectation of success because both Romestand and Chang teach a poly-lysine dendrimer with small molecules attached.
Regarding claim 57, Romestand in view of Chang teach wherein the branching domain has the formula C(x)aMb, wherein: C is a sub unit of the branching domain having a maximum of possible x branches, and the branch-point comprises one or more sub unit C and at least one subunit C is attached to the linker through a branch; M is a small molecule attached to the subunit C through a branch; a is an integer ≥ 1; and b is an integer ≥ 2, provided that b ≤(a)(x-2) +1 (
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page 196 of Chang). From the structure taught by Chang, a branching domain is interpreted as being the section (shown below) of the structure taught by Chang:
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. This structure shows x = 4 maximum possible branches (two branches on the terminal lysine and a single branch per intermediate lysine) and a=18 subunits C (each lysine contains 6 carbon atoms, each carbon is interpreted as a subunit C). The histidines, b = 2 are attached to the subunit C through a branch. Finally, a sub unit C is attached to the linker through a branch. Therefore, a = 18 ≥ 1, b = 2 ≥ 2 and b ≤(a)(x-2) +1; i.e., 2 ≤ (18)(4-2) + 1 or (2 ≤ 37). Therefore, Romestand in view of Chang address the instant claim.
Claims 53-56 and 58-59 are rejected under 35 U.S.C. 103 as being unpatentable over Romestand in view of Chang as applied to claim 31 above, and further in view of Schnepf and Rau (WO 2004/077054 A1) (hereinafter Rau) (Cited in PTO 892 filed 2/21/2025).
Regarding claims 53-54, Romestand in view of Chang teach the method of claim 31 as discussed above.
Romestand in view of Chang fail to teach wherein the branching domain is selected from the group consisting of:
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Romestand also fails to teach wherein the branching domain is selected from the group consisting of:
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wherein M is a small molecule.
Rau teaches “quality control of binding measurements on microarrays” (Title). Rau further teaches a method for detecting presence of an analyte in a sample, the method comprising:(i) contacting a sample suspected of comprising an analyte with a compound (“a multiplicity of different compounds are brought into contact almost simultaneously with a target molecule, for example a protein which is associated with a disease or a therapeutic field of application, and the interaction between immobilized compound and target molecule, for example as a binding assay, is detected” page 1 paragraph 6), comprising: (a) a substrate binding domain (“the binding matrix comprises a self-assembling monolayer (SAM) as an organic layer. The self-organization of a SAM to form a dense film is normally carried out by hydrophobic interaction of long-chain hydrocarbons at one end of which a functional group is present, which enables the attachment to the carrier and at the other end of which a functional group enables the immobilization of the ligand. Compounds which comprise these functional building blocks (head group, foot group, hydrophobic part) are also called anchors or anchor molecules” page 5 paragraph 8); (b) a branching domain comprising a plurality of small molecules each small molecule linked to a branch of a branch-point (“the preferred structural motif is the guanidinium group… The guanidinium phenylalanine residue can be coupled to a framework structure via the carboxyl function of the phenylalanine. This framework carries the further structural motifs and together with them forms the control ligand” page 4 paragraph 2). Rau teaches that “[i]n particular, small organic molecules (small molecules or small molecular weight molecules or small organic molecules) are preferred for the ligands and the control ligands or their structural motifs which occur singly or multiply in control ligands” (page 6 paragraph 9). Rau further teaches “[i]n particular, compounds of the following structure are used as control ligands in the context of the present invention
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where X =…NH2” page 4 paragraph 4). Note that although Rau fails to use the language branching domain or branch point, the teachings of a “structural motif” and “framework” addresses the limitations of branching domain and branch-point, respectively, because the compound structure taught by Rau (above) effectively shows a branching domain and branch-points with small molecules linked to a branch of a branch-point. Rau further teaches (c) a linker linking the substrate binding domain and the branching domain (“the anchor can have a spacer portion which preferably contains ethylene glycol units” page 5 paragraph 8); and (ii) detecting binding of an analyte binding molecule to the compound (“[t]he binding measurement can be performed sequentially from sensor field to sensor field or sensor array row to sensor field series, or preferably in parallel, in that all fields are measured simultaneously. The measuring method is advantageously based on a radioactive, optical or electrical method. Thus, for example, radioactive fluorescence or luminescence-based detection (e.g. RIA, ELISA, etc.) is possible” page 6 paragraph 15). Rau further suggests that the method enables the detection of a wide variety of chemical or biological materials (“[m]icroarrays have more and more important importance in the last time. They enable the presentation of an enormous variety of chemical or biological materials for the most diverse fields of application” page 1 paragraph 3). Rau further teaches that “[t]he advantages of such microarrays lie in their ease of handling and their potential for miniaturization and possible automation in the production and use in instruments, such as measuring instruments” (page 5 paragraph 5). Note that the control ligand taught by Rau “where X =…NH2” (page 4 paragraph 4) addresses the branch-point of claim 53 and the branching domain of claim 54, i.e. Rau teaches the first structure of claim 53 and claim 54.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Romestand in view of Chang to rely on the branching domain structure taught by Rau because Rau suggests that this facilitates the use of the compound in microarrays for the detection of a wide variety of chemical or biological materials and Romestand is concerned with diagnostic immunoassays. A person having ordinary skill in the art would have had a reasonable expectation of success because both Rau and Romestand teach a method for detecting presence of an analyte in a sample comprising contacting a sample suspected of comprising an analyte with a compound and detecting binding of an analyte binding molecule to the compound.
Regarding claim 55, Romestand in view of Chang teach the method of claim 31 as discussed above.
Romestand in view of Chang fail to teach wherein the branching domain is selected from the group consisting of:
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Rau teaches the branching domain of claim 54 as discussed above.
Romestand in view of Chang and Rau teach wherein the branching domain is selected from the group consisting of:
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. Note that the first structure of claim 55 is the branching domain of claim 54 wherein the small molecule is histidine. Therefore, Romestand in view of Chang and Rau further address the method of claim 55.
Regarding claim 56, Romestand in view of Chang teach the method of claim 31 as discussed above.
Romestand in view of Rau and Chang teach wherein the branching domain comprises:
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wherein, 2 ≤ d + f ≥ 100 , d > c, and e >f, wherein c, d, e and f are integers and each M is a small molecule (Figure 1 of Chang, Scheme 1B of Romestand, page 4 paragraph 4 of Rau, “[s]uch structural motifs are preferably linked by a framework, for example a natural amino acid, such as lysine or a peptide consisting of natural amino acids such as lysine. Thus, for example, it is possible to associate one or both amino functions of the lysine with a Guapphe residue with the aid of a peptide bond” page 4 paragraph 3 of Rau). Note that Rau addresses the limitations of wherein, 2 ≤ d + f ≥ 100 , d > c, and e >f, wherein c, d, e and f are integers and each M is a small molecule, when teaching that “structural motifs are preferably linked by a framework… a peptide consisting of natural amino acids such as lysine …it is possible to associate one or both amino functions of the lysine with a Guapphe residue” because it suggests the incorporation of multiple repetitive lysines wherein each lysisne carries two small molecules. Therefore, Romestand in view of Rau and Chang teach the instant claim .
Regarding claim 58, Romestand in view of Chang teach the method of claim 31 as discussed above.
Romestand in view of Chang fail to teach wherein the compound is linked to a substrate via the substrate binding domain.
Rau further teaches wherein the compound is linked to a substrate via the substrate binding domain (“[a]n anchor molecule of the general formula Z-R-Y is preferred. In this case, Z is an atom or an atom grouping which ensures the attachment to a solid support ” page 5 paragraphs 14-15).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Romestand in view of Chang to rely on wherein the compound is linked to a substrate via the substrate binding domain taught by Rau because Rau suggests that this enables ease of handling and their potential for miniaturization and possible automation in the production and use in instruments, such as measuring instruments. A person having ordinary skill in the art would have had a reasonable expectation of success because both Rau and Romestand teach a method for detecting presence of an analyte in a sample comprising contacting a sample suspected of comprising an analyte with a compound and detecting binding of an analyte binding molecule to the compound.
Regarding claim 59, Romestand in view of Chang and Rau teach the method of claim 58 as discussed above.
Romestand further teaches wherein a surface of the substrate is coated with a proteinaceous material (“The titer of antibodies directed against BSA, BSA-histamine, and DGL-G3-histamine was evaluated by direct ELISA analysis” page 1171 column 2 last paragraph, “Wells were then rinsed twice with PBS and saturated for 2 h at 37 °C with 50 µL of 5% silk milk in PBS” page 1171 column 1 paragraph 2).
Claim 37 is rejected under 35 U.S.C. 103 as being unpatentable over Romestand in view of Chang as applied to claim 31 above, and further in view of Kayyem and O’Connor (US 7160678 B1)-Cite No. 1 of IDS filed 5/13/2021 (hereinafter Kayyem).
Regarding claim 37, Romestand in view of Chang teach the method of claim 31 as discussed above.
Romestand in view of Chang fail to teach an electrode surface and the analyte binding molecule includes an electroactive component, and wherein the analyte binding molecule is detected by the electrode when the electroactive component is proximate to the electrode.
Kayyem teaches “compositions for the electronic detection of analytes utilizing monolayers” (Title). Kayyem further teaches that the “compositions compris[es] electrodes comprising a monolayer comprising conductive oligomers, and a capture binding ligand” (column 1 lines 63-66). Kayyem further teaches that “when the target analyte is a nucleic acid, the electrons from the ETMs [electron transfer moiety] need not travel through the stacked π orbitals in order to generate a signal. Instead, the presence of ETMs on the surface of a SAM, that comprises conductive oligomers, can be directly detected. Thus, upon binding of a target analyte to a binding species on the surface, a recruitment linker comprising an ETM is brought to the surface, and detection of the ETM can proceed. Thus, the role of the target analyte and binding species is to provide specificity for a recruitment of ETMs to the surface, where they can be detected using the electrode” (column 6 lines 58-67 and column 7 lines 1-2). Kayyem further teaches that “preferred electrodes are known in the art and include, but are not limited to, certain metals and their oxides, including gold” (column 9 lines 45-47). Kayyem further suggests that the fast rates of electron transfer enhances signal-to-noise ratio (“It should be understood that one benefit of the fast rates of electron transfer observed in the compositions of the invention is that time resolution can greatly enhance the signal-to-noise results of monitors based on absorbance, fluorescence and electronic current” (column 66 lines 6-10).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Romestand in view of Chang to rely on the electrode surface and the analyte binding molecule including an electroactive component, and wherein the analyte binding molecule is detected by the electrode when the electroactive component is proximate to the electrode taught by Kayyem because Kayyem suggests that this method enables an enhancement of signal-to-noise ratio in the analyte detection. A person having ordinary skill in the art would have had a reasonable expectation of success because Kayyem teaches that preferred electrodes are known in the art and include, but are not limited to, certain metals and their oxides, including gold.
Claim 41 is rejected under 35 U.S.C. 103 as being unpatentable over Schnepf and Rau (WO 2004/077054 A1) (hereinafter Rau) and Salahudeen and Nishtala Saudi Pharm J. 2016 Jul 9;25(2):165–175. doi: 10.1016/j.jsps.2016.07.002 (hereinafter Nishtala) (Cited in PTO 892 filed 2/21/2025) and Chang.
Regarding claim 41, Rau teaches a method for selecting a ligand capable of binding a small molecule (“a method for finding control ligands” page 6 last paragraph), the method comprising:(i) contacting a test ligand with a compound (“(a) providing potential control ligands on sensor fields; (b) measuring the binding between the potential control ligands and a plurality of mobile binding partners” page 6 last paragraph) comprising:(a) a substrate binding domain;(b) a branching domain comprising a plurality of small molecules each small molecule linked to a branch of a branch-point; and (c) a linker linking the substrate binding domain and the branching domain (compound of page 4 paragraph 4); and (ii) detecting binding of the test ligand with the compound (“(c) selection of control ligands on the basis of their binding values (measured values)” page 7 paragraph 1).
Rau fails to teach, wherein the small molecule is histidine or a histidine-phenylalanine dimer; step (ii) in the presence and in the absence of the small molecule, wherein the compound and the small molecule bind competitively with the test ligand, and selecting the test ligand having reduced binding in the presence of the small molecule.
Nishtala teaches “[a]n overview of pharmacodynamic modelling, ligand-binding approach and its application in clinical practice” (Title). Nishtala further teaches that “[t]he interaction between two and three ligands (drugs) at the same receptor binding site can usually be described by a competitive ligand binding model” (page 172 paragraph 2). Nishtala further teaches that “[t]he competitive binding models use a labelled concentration of ligand in the presence of various unlabelled ligand concentrations (known as the competitor or inhibitor) and measure binding at equilibrium” (page 172 paragraph 2). Further teaches that the “model can predict a zero-dose baseline effect (E0) in the absence of no drug and also follows the ‘law of diminishing returns’ at higher doses” (page 173 paragraph 7). Nishtala further suggests selecting the test ligand having reduced binding in the presence of the small molecule (“Competition binding models are useful for determining whether the unlabelled ligand has affected the ligand’s affinity for the receptor and compare the affinities of several ligands for the same receptor to find total versus free concentration or dose for the labelled ligand and unlabelled competitor or inhibitor” page 172 paragraph 2). Note that Nishtala suggests selecting the test ligand having reduced binding in the presence of the small molecule when teaching that this model is “useful for determining whether the unlabelled ligand has affected the ligand’s affinity for the receptor” because it implies that the usefulness of the model lies in the identification of a competition effect, therefore selecting the ligand that produces such results would be expected. Nishtala further teaches that the “model possess a widespread application in the field of functional receptor pharmacology” (page 173 paragraph 1). Nishtala further teaches that the model is “[a] useful model and a common descriptor for characterizing dose-response relationship” (page 173 paragraph 3). Nishtala further suggests that the competitive binding model can be used in small molecule ligands (“[a] recent study employed an Emax model to examine patient characteristics that predict adverse anticholinergic-type events in older people”) (page 173 paragraph 9).
Chang teaches the “Development of lysine–histidine dendron modified chitosan for improving transfection efficiency in HEK293 cells” (Title). Chang further teaches that “lysine–histidine (KH) dendrons were designed for effective modification of histidines” (page 195 col. 2 para. 2, See “Fig. 1. Structure of KH Dendron” page 196 col. 1). Note that the KH dendrons taught by Chang (see Fig. 1) are a compound comprising a substrate binding domain (SH), a branching domain comprising a plurality of small molecules each small molecule linked to a branch of a branch-point, wherein the branchpoint comprises at least one lysine; wherein the small molecule is histidine (the lysines are interpreted as the branching domains and branch-points comprising the histidines, see Figure 1). Figure 1 of Chang is copied here for convenience:
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. Note that part of the Cystein and the β-Alanine are interpreted as the linker linking the substrate binding domain and the branching domain. Chang further teaches that the KH dendron has “practicability for experimental procedures and clinical applications… the structure of the KH dendron is composed of endogenous amino acids and the biocompatibility of the KH dendron is predictable” (page 196 col. 1 para. 1). Chang further teaches that “[t]he structure of dendron provided buffering capacity, not only from the imidazole group but also from the primary amino groups of histidines” (page 200 col. 2 para. 3).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Rau to rely on the competitive binding model taught by Nishtala, i.e., including the presence and the absence of the small molecule, wherein the compound and the small molecule bind competitively with the test ligand, and selecting the test ligand having reduced binding in the presence of the small molecule because Nishtala teaches that this method/model has a widespread application in the field of functional receptor pharmacology, is useful and a common descriptor for characterizing dose-response relationship and Rau is concerned with binding measurements. A person having ordinary skill in the art would have had a reasonable expectation of success because Nishtala and Rau both teach methods associated with the binding of ligands to targets.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Rau in view of Nishtala to rely on the small molecule being histidine taught by Chang because Chang suggests that the compound comprising a plurality of histidines provides biocompatibility, buffering capacity and is applicable for both experimental and clinical applications. A person having ordinary skill in the art would have had a reasonable expectation of success because both Rau and Chang teach a compound comprising a substrate binding domain, a branching domain comprising at least one small molecule, and a linker linking the substrate binding domain and the branching domain.
Claim 60 is rejected under 35 U.S.C. 103 as being unpatentable over Romestand et al. Biomacromolecules 2010, 11, 5, 1169–1173 https://doi.org/10.1021/bm9012056 Cite No. 3 of IDS filed 7/19/2022 (hereinafter Romestand) in view of Delcayre et al. (US 20060222654 A1) Cite No. 1 of IDS filed 5/13/2021 (hereinafter Delcayre) and Chang.
Regarding claim 60, Romestand teaches a method for raising antibodies specific to a small molecule (“[a]n easily synthesized DendriGraft poly-lysine DGL-G3 (third generation) was shown to act as an efficient carrier for raising antibodies directed against small molecules” Abstract), the method comprising using a compound comprising:(a) a substrate binding domain; (b) a branching domain comprising a plurality of small molecules each small molecule linked to a branch of a branch-point; and (c) a linker linking the substrate binding domain and the branching domain (Abstract). See Figure 1 of Romestand showing DGL-G3-Histamine.
Romestand fails to teach contacting T cells with the compound and wherein the small molecule is histidine or a histidine-phenylalanine dimer.
Delcayre teaches “[t]he present invention further discloses methods of isolating cells producing a single antibody specific of a variant antigen comprising: 1) preparing immunogenic vesicles, preferably exosomes, displaying a variant antigen; 2) raising an antibody response by immunizing a non-human animal with the said immunogenic vesicles; 3) collecting lymphocytes from immunized animal; 4) preparing vesicles, preferably exosomes, displaying said variant antigen of step 1 and a marker; 5) preparing vesicles, preferably exosomes, displaying the native antigen and not displaying said marker; 6) suspending the lymphocytes of step 3 with the vesicles displaying said variant antigen and marker of step 4 and with an excess of the vesicles displaying said native antigen of step 5; and, 7) identifying and isolating cells producing a single antibody specific of an antigen variant reacting with the vesicles of step 4 (paragraph 19). Delcayre further teaches that “[i]n a preferred embodiment of the above-disclosed methods of isolating cells producing a single antibody specific of a variant antigen according to the present invention, said variant antigen is a mutated antigen and said native antigen is a wild-type antigen. Optionally, said variant antigen is the antigen contacting molecules selected in the group consisting of… small molecule” (paragraph 29). Delcayre further teaches that “[t]he invention presents many advantages over traditional approaches of antibody preparation. It is most advantageous when dealing with poorly immunogenic antigens, membrane proteins or multi-component polypeptide complexes… [a] further advantage of this invention is that the polypeptides can be expressed by exosome producing cells and thus subjected to natural pathways of processing and post-translational modifications (glycosylations, etc.)” (paragraph 79). Delcayre further teaches that “[p]referred exosome-producing cells of this invention are mammalian tumor cells, mammalian B and T lymphocytes and mammalian dendritic cells, typically of murine or human origin” (paragraph 115).
Chang teaches the “Development of lysine–histidine dendron modified chitosan for improving transfection efficiency in HEK293 cells” (Title). Chang further teaches that “lysine–histidine (KH) dendrons were designed for effective modification of histidines” (page 195 col. 2 para. 2, See “Fig. 1. Structure of KH Dendron” page 196 col. 1). Note that the KH dendrons taught by Chang (see Fig. 1) are a compound comprising a substrate binding domain (SH), a branching domain comprising a plurality of small molecules each small molecule linked to a branch of a branch-point, wherein the branchpoint comprises at least one lysine; wherein the small molecule is histidine (the lysines are interpreted as the branching domains and branch-points comprising the histidines, see Figure 1). Figure 1 of Chang is copied here for convenience:
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. Note that part of the Cystein and the β-Alanine are interpreted as the linker linking the substrate binding domain and the branching domain. Chang further teaches that the KH dendron has “practicability for experimental procedures and clinical applications… the structure of the KH dendron is composed of endogenous amino acids and the biocompatibility of the KH dendron is predictable” (page 196 col. 1 para. 1). Chang further teaches that “[t]he structure of dendron provided buffering capacity, not only from the imidazole group but also from the primary amino groups of histidines” (page 200 col. 2 para. 3).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Romestand to rely on the contacting step with T cells taught by Delcayre because it would be a simple matter of applying a known technique to a known method. In this case, both Romestand and Delcayre teach a method for raising antibodies specific to a small molecule. Delcayre simply uses the art-recognized technique of using T cells in the contacting step of the method for raising antibodies specific to a small molecule. Therefore, a person having ordinary skill in the art would have found it obvious to apply the technique of Delcayre to the base method taught by both references. One would be motivated to make such a modification because Delcayre teaches that this method is most advantageous when dealing with poorly immunogenic antigens, membrane proteins or multi-component polypeptide complexes. A person having ordinary skill in the art would have had a reasonable expectation of success because both Romestand and Delcayre teach methods of raising antibodies specific to a small molecule.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Romestand in view of Delcayre to rely on the small molecule being histidine taught by Chang because Chang suggests that the compound comprising a plurality of histidines provides biocompatibility, buffering capacity and is applicable for both experimental and clinical applications. A person having ordinary skill in the art would have had a reasonable expectation of success because both Romestand and Chang teach a compound comprising a substrate binding domain, a branching domain comprising at least one small molecule, and a linker linking the substrate binding domain and the branching domain.
Allowable Subject Matter
Claims 61-63 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
There were no prior art references found that teach the compound comprising the histidine-phenylalanine dimer claimed. Therefore, this subject matter appears to be free of the prior art.
Response to Arguments
Applicant's arguments filed 6/3/2026 have been fully considered but they are not persuasive.
Regarding the 103 rejections,
Applicant argues that “Here, Chang is not from the same field of endeavor as the claimed invention, which is directed toward methods and compositions for improved immunodetection of small molecules, such as histamine. Chang is directed to gene delivery, specifically developing lysine-histidine (KH) dendron modified chitosan for improving gene transfection efficiency by promoting endosomal escape” (page 12 para. 2).
However, although Chang may not be from the same field of endeavor as the claimed invention, Chang is considered reasonably pertinent to the problem with which Applicants were
concerned. Therefore, Applicant’s argument regarding the field of endeavor of Chang is not persuasive.
Applicant further argues that “Chang also is not reasonably pertinent to the problem with which Applicants were concerned. The problem to be solved by Chang is improving the gene transfection efficiency of chitosan by promoting its endosomal escape property through increased buffering capacity…In other words, the purpose of Chang is to provide a modified chitosan-based gene carrier with enhanced buffering capacity via lysine-histidine dendrons to achieve more efficient intracellular gene delivery, which is a solution to a problem very different than that addressed by the Applicants” (bridge paragraph pages 12-13).
However, contrary to Applicant’s argument, Chang is considered reasonably pertinent to the problem with which Applicants were concerned. Applicants are concerned with methods and compositions for improved immunodetection of small molecules. Applicant’s inventive concept appears to be the compound comprising a substrate binding domain, a branching domain comprising at least one small molecule, and a linker linking the substrate binding domain and the branching domain, wherein the small molecule is histidine, from the claims. Given that Chang is interested in carrier compounds for gene delivery and the instant case is interested in carrier compounds for analyte detection, both are interested in carriers, and more specifically both are interested in a compound comprising a substrate binding domain, a branching domain comprising at least one small molecule, and a linker linking the substrate binding domain and the branching domain, wherein the small molecule is histidine. Therefore, Chang is considered reasonably pertinent to the problem with which Applicants were concerned.
Applicant further argues that “Second, the problems faced when designing chitosan-based gene carrier with enhanced buffering capacity is not reasonably pertinent to the problems faced when designing methods and compositions for improved immunodetection of small molecules. The gene carriers and immunodetection have different functionalities and purposes. As such, Chang would not have logically commended itself to the Applicants' attention” (page 13 para. 2).
However, contrary to Applicant’s argument, problems faced when designing chitosan-based gene carrier with enhanced buffering capacity are reasonably pertinent to the problems faced when designing methods and compositions for improved immunodetection of small molecules. Both problems originate in the field of chemistry/biology. Furthermore, both the gene carriers of Chang or the compound claimed have the function of carrying at least histidine in a sample. Therefore, Applicant’s arguments are not persuasive.
Applicant further argues that “Chang and Romestand also operate in two entirely different technological fields and address entirely different problems. Romestand is directed to raising and characterizing antibodies against small molecules (specifically histamine) using DGL-G3 polylysine dendrimers as immunogenic carriers in diagnostic immunoassays…Chang, by contrast, is directed to "improving transfection efficiency in HEK293 cells." See e.g., Title and Abstract. Chang's lysine-histidine dendrons are designed for gene delivery…Thus, the histidines in Chang are not serving as haptens or analyte surrogates for antibody recognition. Instead, they are providing pH-responsive buffering to disrupt endosomes during intracellular trafficking of nucleic acids” (page 13 last paragraph and page 14 para. 1).
However, contrary to Applicant’s argument, Chang and Romestand both operate in the biochemistry field concerning carrier compounds comprising a substrate binding domain, a branching domain comprising at least one small molecule, and a linker linking the substrate binding domain and the branching domain to be used in an in vitro sample. Therefore, Chang and Romestand share similar problems and requirements involving the use of the claimed compound in a sample.
Applicant further argues that “The Office's stated motivation, that Chang's compound provides "biocompatibility, buffering capacity and is applicable for both experimental and clinical applications" (See, for example, Office Action, p. 18, 2nd paragraph), does not supply a rational basis for combining these references. Buffering capacity and biocompatibility are relevant to Chang's transfection context but are irrelevant to the problem Romestand seeks to solve, which is producing specific antibodies against small-molecule haptens for diagnostic immunoassays. A PHOSITA working in the field of immunoassay development, i.e., Romestand's field would have no reason to consult the gene therapy/transfection literature, i.e., Chang's field to find a replacement hapten for an antibody based detection system” (page 14 para. 2).
However, contrary to Applicant’s argument, buffering capacity and biocompatibility are relevant to Romestand. For example, see page 1169 col. 1 para. 1 of Romestand teaching that there is a need for biocompatible small molecule carriers that resists denaturation (“The use of synthetic peptide antigens for the production of vaccines as well as the use of haptens for the production of immunoassays antibodies for diagnostic suffers the problem of finding carriers devoid of side effects…Consequently, the carrier should present many functional groups (e.g., amines, carboxylic acids) easy to derivatize and resist to the denaturation by the organic solvents potentially needed during the immunoconjugate synthesis process. Moreover, it must be nontoxic, inexpensive, and the final conjugate must be water-soluble”). Therefore, Applicant’s argument is not persuasive.
Applicant further argues that “The Office's rationale that both references teach "a compound comprising a substrate binding domain, a branching domain comprising at least one small molecule, and a linker linking the substrate binding domain and the branching domain" (Office Action, p. 18, 2nd paragraph) represents an impermissible level of abstraction. Structural similarity at such a high level of generality does not establish a motivation to combine references that use these structural elements for entirely different biological purposes, hapten presentation for antibody generation (Romestand) versus DNA condensation for gene transfection (Chang)” (page 14 para. 3).
However, the fact that both references teach the claimed compound provides a reasonable expectation of success in combining the histidines of Chang with Romestand because both references face similar challenges regarding constructing, maintaining and using the compound. Note that both references use the compound as a carrier in an in vitro sample in the field of biochemistry. Therefore, there is no impermissible level of abstraction.
Applicant further argues that “Even assuming arguendo that Chang qualifies as prior art against the Applicants' claimed invention and a PHOSITA would have been motivated to combine the teachings of Romestand and Chang, the claimed invention demonstrates unexpected results that rebut the prima facie case of obviousness…One would ordinarily expect that using the actual target molecule (histamine) as the competitive hapten would yield equal or better performance than using a structurally related but different molecule (histidine)…The specification provides a mechanistic explanation for this unexpected result: when histidine is conjugated through its carboxylate group to a linker, the remaining portion of the molecule effectively exposes the entire histamine structure, both the imidazole ring and the amine group, for antibody recognition…The Office's dismissal of the unexpected results evidence was conclusory, stating only that it "is not considered a persuasive argument against the new grounds of rejection set forth above in view of Chang" (Office Action, p. 28). However, the Office did not address the substance of the evidence or explain why the demonstrated superiority of histidine over histamine in competitive immunodetection would have been expected… Applicants submit that these results are commensurate in scope with the claims. Claim 31 is directed to a method using a compound wherein the small molecule is "histidine or a histidine phenylalanine dimer", and the data directly compare the claimed histidine-containing compounds against the closest prior art (histamine-containing conjugates of Romestand)” (page 14 last paragraph to page 17 para. 1).
However, the arguments directed to the unexpected result of the use of histidine over histamine are not persuasive. In this case, Chang provides sufficient motivation and reasonable expectation of success in using histidine, namely because of its biocompatibility and buffering capacity, and Romestand page 1169 col. 1 para. 1 teaches that there is a need for biocompatible small molecule carriers that resists denaturation. Note that all arguments and evidence of unexpected results must be considered; however, they do not necessarily control the obviousness conclusion (MPEP 2145). Evidence of non-obviousness must be weighed against the evidence of obviousness. In this case, there is not enough evidence that histidine would have been non-obvious over histamine.
Applicant further argues that “Here, Romestand, Chang, Rau, and Kayyem, taken in any combination, fail to teach or suggest each and every feature of independent claim 31 on which the rejected claims 37, 53-56, and 58-59 are dependent…While the Examiner cites Rau and Kayyem to allegedly show features of rejected dependent claims, Rau and Kayyem, taken alone or in any combination fail to cure the deficiencies in Romestand and Chang as applied to base claim 31” (page 18 para. 5).
However, there are no deficiencies in the rejection of base claim 31 (see rejection above), therefore, Applicant’s arguments are not persuasive.
Applicant further argues that “Specifically, neither Rau nor Nishtala teaches or suggest the feature of "wherein the small molecule is histidine or a histidine-phenylalanine dimer" and thus neither remedy the deficiencies of Chang, as discussed above, e.g., related to the skilled person's lack of motivation to use histidine as the small molecule” (page 19 para. 1).
However, there is motivation in using histidine (see rejection above) and there are no deficiencies in Chang. Therefore, Applicant’s arguments are not persuasive.
Applicant further argues that “Romestand and Chang neither teach nor suggest the claimed feature that "the small molecule is histidine or a histidine-phenylalanine dimer". Further, while the Examiner cites Delcayre to allegedly show additional features present in claim 60, Delcayre, however, does not cure the deficiencies of Romestand and Chang. As such, Romestand, Delcayre, and Chang, taken in any combination, fail to teach or suggest each and every feature of claim 60” (page 19 para. 5).
However, there are no deficiencies in Romestand and Chang. Therefore, Applicant’s arguments are not persuasive.
Conclusion
THIS ACTION IS MADE FINAL. 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.
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/Fernando Ivich/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
Prosecution Insights