DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election of Group I (claims 1-13), drawn to methods of detecting analyte concentration in multiple liquid samples, in the reply filed on 07/14/2026 is acknowledged. Since Applicant did not expressly state that the election was made with traverse, the election is treated as an election without traverse. Claims 14-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Status of the Claims
Claims 1-18 are pending. Claims 14-18 are withdrawn. Claims 1-13 are examined herein in view of the restriction.
Priority
The present application, filed 02/08/2024, is a continuation of PCT/US2022/074665, filed 08/08/2022, which claims benefit of U.S. Provisional Patent Application 63/231,676, filed 08/10/2021. The provisional application provides written-description support for the full scope of claims 1–6 and 8–12, including the claimed assay methods, the recited streptavidin polymer molecular weights, and the use of the term “about,” which is expressly defined in the provisional specification. Accordingly, claims 1–6 and 8–12 are entitled to the August 10, 2021 provisional filing date.
However, claims 7 and 13 recite a solution comprising 20–85% DMSO by weight. The provisional application discloses regeneration using 100% DMSO, but does not disclose or otherwise provide written-description support for the claimed 20–85% DMSO range. That subject matter is first supported in PCT/US2022/074665. Accordingly, claims 7 and 13 are entitled to the August 8, 2022 PCT filing date, but not the August 10, 2021 provisional filing date.
Information Disclosure Statement
The Information Disclosure Statement(s) filed 07/21/2025 are acknowledged and have been considered.
Drawings
The drawings are objected to because inconsistent terminology is used to identify the streptavidin reagent. The drawings variously use “SA-Poly” AND “SA-CR” for apparently corresponding loading reagents or operations. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities: The disclosure is inconsistent with the drawings and uses inconsistent terminology for the streptavidin reagent loaded onto the solid support. The specification generally identifies the reagent as the “streptavidin capture reagent” or “SA-CR,” whereas FIGS. 4-6 and 8 identify the corresponding operation as “SA Poly Loading,” while other figures (e.g., FIGS. 10, 11, 13, 14) inconsistently alternate among “SA-CR,” and “SA-Poly” (pp. 2-3). It is unclear whether these expressions identify the same reagent or whether “SA-CR” encompasses compositions other than the claimed streptavidin polymer. Although the specification indicates that the streptavidin capture reagent may comprise a streptavidin polymer, “SA-CR” and “SA-Poly” are not used consistently as expressly interchangeable terms. Accordingly, it is unclear from the disclosure whether “SA-CR” and “SA-Poly” are intended to identify the same streptavidin reagent or different reagents. The specification and drawings must be amended to use consistent terminology or expressly clarify the relationship between “SA-CR” and “SA-Poly.” Appropriate correction is required.
The disclosure is objected to because of the following informalities: Paragraph [0053] further refers to an adhesion layer 310, interference layer 304, analyte-binding molecules 306, and analyte molecules 308. These reference numerals do not appear in FIG. 2 or any other submitted drawing. FIG. 2 identifies the interference layer, analyte-binding molecules, and analyte molecules by reference numerals 204, 206, and 208, respectively, and does not separately identify the recited adhesion layer. The specification and drawings must be corrected or clarified so that the referenced components and their corresponding reference numerals are consistent. Appropriate correction is required.
Claim Objections
Claim 3 is objected to because of the following informalities: The word “Claim” should be changed to “claim” to conform to standard claim drafting practice. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-13 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites in the preamble “a method of detecting an analyte in multiple liquid samples comprising an analyte.” However, the body of claim 1 recites only the step of “contacting the surface with a liquid sample having an analyte.” The body of claim 1 does not require contacting the surface with more than one liquid sample, repeating the detection procedure with additional liquid samples, or otherwise determining analyte concentrations for multiple samples. Those additional operations are first recited in dependent claim 2. It is therefore unclear whether claim 1 requires the method to be performed using multiple liquid samples, as stated in the preamble, or whether the claim is satisfied by performing the recited steps using only one liquid sample, as set forth in the body of the claim. For purposes of compact prosecution, the phrase “multiple liquid samples” in the preamble of claim 1 will be treated as an intended-use or purpose statement that does not independently require performance of the method on more than one liquid sample. Claim 1 will therefore be interpreted as encompassing performance of the recited method using at least one liquid sample. Claim 2 will be interpreted as affirmatively requiring repeated assay cycles using a new liquid sample during each cycle, as expressly recited therein. Appropriate correction is required.
Claim 1 further recites the limitation "the immunocomplex formed" in lines 12-13. There is insufficient antecedent basis for this limitation in the claim. Claim 1 does not previously introduce an immunocomplex and therefore fails to provide express antecedent basis for “the immunocomplex.” Although the claim recites a biotinylated first binding partner of a binding pair and an analyte that is a second binding partner of the binding pair, the claim does not expressly state that the first and second binding partners bind to form the subsequently recited immunocomplex. It is therefore unclear whether “the immunocomplex” refers to a complex formed between the first and second binding partners, a complex involving the streptavidin polymer and one or both binding partners, or some other complex formed at the surface. For purposes of compact prosecution, the phrase “the immunocomplex formed at the surface” in claim 1 will be interpreted as the surface-bound complex formed by binding between the recited biotinylated first binding partner and the recited analyte that constitutes the second binding partner of the binding pair. Appropriate correction is required.
Claim 1 additionally recites the limitation "the interferometry phase shift" between the second interferometry pattern and the baseline interferometry pattern in lines 14-15. There is insufficient antecedent basis for this limitation in the claim. Specifically, no interferometry phase shift is previously introduced in the claim. While the phrase may have been intended to refer to a phase shift calculated or measured from the two recited interferometry patterns, the claim does not expressly introduce an interferometry phase shift before referring to “the interferometry phase shift.” Consequently, the claim language does not clearly establish whether the phase shift is a previously determined property, a newly measured difference between the patterns, or another interferometric measurement. For purposes of compact prosecution, the phrase “the interferometry phase shift” in claim 1 will be interpreted as the difference in interferometric phase between the recited second interferometry pattern and the recited baseline interferometry pattern. The later phrase “the phase shift” will be interpreted as referring to that same difference. Appropriate correction is required.
Claims 2–7 depend directly or indirectly from claim 1 and therefore incorporate all limitations of claim 1. Accordingly, claims 2–7 inherit the indefiniteness of claim 1. Appropriate correction is required.
Claim 2 further refers to eluting “the immunocomplex” from the surface. Because the identity and composition of “the immunocomplex” are not clearly established in claim 1, claim 2’s further use of that term does not cure the defect. Claims 6 and 7 likewise inherit the same uncertainty through their dependency from claim 2. Appropriate correction is required.
Claim 3 is additionally indefinite because it recites the limitation "the first member of the binding pair is an antigen, and the second member of the binding pair is an antibody" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. Claim 1 previously introduces a “biotinylated first binding partner of a binding pair” and an analyte that is “a second binding partner of the binding pair.” Claim 3 does not refer to the previously recited first and second binding partners, but instead introduces the different terminology “the first member” and “the second member.” Neither “a first member” nor “a second member” was previously recited. It is therefore unclear whether “the first member” and “the second member” are intended to be the same components as the first and second binding partners recited in claim 1 or whether the terms “member” and “binding partner” identify different components of the assay. Accordingly, claim 3 fails to provide clear antecedent basis for “the first member” and “the second member.” For purposes of compact prosecution, “the first member” and “the second member” will be interpreted as referring, respectively, to the first binding partner and the second binding partner recited in claim 1. Thus, claim 3 will be interpreted as requiring the first binding partner to be an antigen and the second binding partner to be an antibody. Appropriate correction is required.
Claim 8 recites in the preamble “a method of detecting a biotinylated analyte in multiple samples comprising an analyte.” However, the body of claim 8 recites only “contacting the surface with a liquid sample having a biotinylated analyte.” The body does not require contacting the surface with more than one liquid sample, repeating the method with additional samples, or otherwise determining analyte concentrations for multiple samples. Repetition using new liquid samples is first introduced in dependent claim 9. It is therefore unclear whether claim 8 requires detection in multiple samples, as stated in the preamble, or whether the claim is satisfied by performing the method using a single liquid sample. For purposes of compact prosecution, the phrase “multiple samples” in the preamble of claim 8 will be treated as an intended-use or purpose statement that does not independently require performance of the method on more than one sample. Claim 8 will therefore be interpreted as encompassing performance of the recited method using at least one liquid sample. Claim 9 will be interpreted as affirmatively requiring repeated assay cycles using new liquid samples, as expressly recited therein. Appropriate correction is required.
Claim 8 also recites the limitation "the immunocomplex formed at the surface" in lines 11-12. There is insufficient antecedent basis for this limitation in the claim. Claim 8 does not previously introduce an immunocomplex and therefore lacks antecedent basis for “the immunocomplex.” Moreover, claim 8 does not recite first and second immune-binding partners, an antibody, an antigen, or another expressly identified pair of immunological components that would form an immunocomplex. Rather, claim 8 recites immobilized biotin, a streptavidin polymer, and a biotinylated analyte. It is therefore unclear whether “the immunocomplex” refers to a complex between the biotinylated analyte and the streptavidin polymer, a complex involving an unrecited antibody or analyte-binding reagent, or another surface-bound complex. Thus, both the antecedent basis and the constituent components of “the immunocomplex” are unclear. For purposes of compact prosecution, the phrase “the immunocomplex formed at the surface” in claim 8 will be interpreted broadly as the surface-bound complex formed when the biotinylated analyte associates with the streptavidin-polymer-containing surface. No unrecited antibody, antigen, or additional immune-binding reagent will be imported into claim 8 for purposes of examination. Appropriate correction is required.
Claim 8 additionally recites the limitation "the interferometry phase shift" between the second interferometry pattern and the baseline interferometry pattern in lines 13-14. There is insufficient antecedent basis for this limitation in the claim. As in claim 1, no interferometry phase shift is previously introduced before the definite article “the” is used. It is therefore unclear whether the phrase refers to a previously determined phase shift or to a phase shift first generated or calculated during the determining step. Accordingly, the scope of claim 8 cannot be determined with reasonable certainty. For purposes of compact prosecution, the phrase “the interferometry phase shift” in claim 8 will be interpreted as the difference in interferometric phase between the recited second interferometry pattern and the recited baseline interferometry pattern. The later phrase “the phase shift” will be interpreted as referring to that same difference. Appropriate correction is required.
Claims 9–13 depend directly or indirectly from claim 8 and therefore incorporate all limitations of claim 8. Accordingly, claims 9–13 inherit the indefiniteness of claim 8. Appropriate correction is required.
Claim 9 further refers to eluting “the immunocomplex” from the surface. Because the identity and composition of “the immunocomplex” are not clearly established in claim 8, claim 9’s further use of that term does not cure the defect. Claims 12 and 13 likewise inherit the same uncertainty through their dependency from claim 9. Appropriate correction is required.
Ultimately, these interpretations are adopted solely to permit a complete examination of the claims under all applicable statutory provisions and do not resolve or withdraw the indefiniteness identified above.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Tan et al. (US 7394547 B2) in view of Desai et al. (US 6638728 B1), Luff et al. (Integrated Optical Mach-Zehnder Biosensor. Journal of Lightwave Technology. Vol. 16, No. 4, April 1998), and Choo et al. (US 20110236911 A1).
Regarding claim 1, Tan teaches a method and apparatus for detecting the presence or amount of an analyte in a sample solution using fiber optic interferometry (Abstract, p. 1). Regarding step (a), Tan teaches that the fiber tip was coated with a polymer monolayer derivatized with biotin, that the polymer monolayer was prepared using a biotinylated lipid, and that the biotin polymer was adsorbed onto the fiber tip (Example 1, col. 11,p. 14). The fiber tip constitutes the claimed solid support having biotin immobilized on its surface. Regarding the contact and binding portions of step (b), Tan teaches that the biosensor tip was immersed in 50 µg/ml streptavidin in PBS for 9 minutes and that Figure 6 clearly shows the binding of streptavidin to the biotin already immobilized on the tip (Example 1, col. 12, patent p. 14; Fig. 6). Regarding step (c), Tan teaches that the streptavidin-contacted biosensor tip was rinsed briefly with PBS. Tan also teaches subsequent steps in which the tip was washed with PBS briefly and subjected to a final 10 minute rinse in PBS solution (Example 1, col. 12, p. 14; Fig. 6).
Regarding step (e), Tan teaches contacting an interferometric sensor with an aqueous PBS solution to establish a pre-binding baseline. In Example 5, controls using PBS were performed to determine baseline noise, and Figure 10 shows that analyte binding produced an increase in optical thickness relative to baseline (PBS) (Example 5, col. 14, p. 15; Fig. 10). Regarding the sample-contacting and surface-binding portions of step (f), Tan teaches that the lower surface of the assembly is then exposed to a sample of analyte, under conditions that favor binding of sample analyte to the analyte-binding molecules, and that as analyte molecules bind to this layer, the thickness of the layer increases, producing a shift in the extrema of the interference wave (col. 9, p. 13). Tan also teaches that the first reflecting surface is formed of a layer of analyte binding molecules, which are effective to bind analyte molecules specifically and with high affinity, wherein the analyte and anti-analyte molecules are opposite members of a binding pair (col. 7, p. 12; Fig. 2). Tan further teaches that, during antibody testing, the same tip was immersed in antibody for an association test and the real-time binding data were recorded, thereby obtaining the binding-dependent interferometric response of the surface-bound antibody-antigen complex (Example 3, col. 13, p. 15; Fig. 8). Regarding step (g), Tan teaches that, as analyte molecules attach to the surface, the thickness of the analyte-binding layer changes, the average thickness of the first reflecting layer changes accordingly, and the interference wave formed by the light waves reflected from the two surfaces is phase shifted in accordance with this thickness change (col. 8, p. 12). Tan further teaches measuring the amount of analyte by carrying out detection over a period sufficient to measure the thickness of the first reflecting layer at a plurality of different time points (col. 4, p. 10). Tan further teaches using an antibody carried on the tip, for constructing a calibration curve for the analyte using a set of analyte standards and that, using this calibration curve, one can then determine the concentration of the analyte in unknown solutions (cell culture supernatants, biological samples, process mixtures, etc.) (col. 10, p. 13). Thus, Tan teaches determining analyte concentration from the binding-induced interferometric phase response relative to a baseline and calibration curve.
Lastly, Tan expressly seeks to preserve the speed and simplicity of prior interferometric assays while significantly enhancing sensitivity and accuracy (col. 2, p. 9). Tan further teaches that the analyte-binding layer is preferably formed so that the sensor surface is densely coated, so that binding of analyte molecules to the layer forces a change in the thickness of the layer, rather than filling in the layer (col. 8, p. 12). Tan also teaches that the apparatus detects analyte concentration from the binding-induced change in optical thickness and corresponding interferometric phase response (cols. 2 and 8, pp. 9 and 12). These teachings would have directed one of ordinary skill in the art to known streptavidin surface configurations capable of increasing functional binding-site density, analyte-capture capacity, and the resulting interferometric signal.
However, Tan does not expressly teach that the streptavidin applied to the immobilized biotin is a streptavidin polymer having a molecular weight of at least about 145,000 Daltons, nor does Tan expressly teach contacting that streptavidin-polymer-containing surface with a biotinylated first binding partner, followed by an analyte that constitutes the complementary second binding partner.
Desai teaches the missing polymerized-streptavidin limitation. Desai explains that, when surfaces are coated with native streptavidin, only a limited number of protein molecules are bound or otherwise available to capture target molecules, resulting in low capacity for capturing the intended target molecule and diminished sensitivity of the assay. Desai addresses that deficiency using a coating comprising streptavidin in polymeric form, wherein the polymer is predominantly dimers, trimers and tetramers of the native molecule, thereby providing a high capacity for capturing target molecules, yielding assays with enhanced sensitivity, and an extended linear working range (cols. 1–2, p. 3). Desai further teaches that streptavidin monomers are tetrameric molecules having about a 67,000 Dalton molecular weight and that polymerization occurs through cross linking of the streptavidin molecules (col. 2, p. 3; Fig. 1). Since the present specification defines about as ±10%, the claimed threshold of at least about 145,000 Daltons encompasses molecular weights beginning at approximately 130,500 Daltons. Desai’s approximately 134,000-Dalton dimer therefore falls within the claimed range, and Desai’s trimers and tetramers exceed it. Desai further reports that a polymerized-streptavidin assay produced 70% higher capacity and a greater signal than the native-streptavidin surface (Example III, p. 5). Desai therefore supplies the streptavidin-polymer and molecular-weight limitation of step (b).
Luff provides direct evidence that polystreptavidin and biotinylated proteins are compatible with interferometric optical sensing. Luff teaches an integrated optical sensor based on the Mach–Zehnder interferometer that monitors biomolecular surface layers formed using a biotin-avidin-based biochemical system (Abstract, p. 583). Luff employs biotinylated thermally denatured bovine serum albumin (BSA-Bi) and polystreptavidin (pSA) and teaches alternate incubations of pSA and BSA-Bi, followed by a two min washing stage where the unbound material is flushed out with buffer (Luff, p. 589; Fig. 11). Luff further teaches that the interferometric response to the BSA-Bi/pSA layers is measured in terms of phase shift and attributes the binding to the high affinity constant between biotin and polystreptavidin (Luff, p. 589; Figs. 11–12). Luff therefore confirms that polystreptavidin remains functional on an interferometric sensor, binds biotinylated protein, withstands buffer washing, and produces a measurable interferometric phase response.
Choo directly teaches the claimed biotinylated first binding partner and complementary analyte arrangement. Choo teaches a bio-layer interferometry bridging assay in which streptavidin is immobilized on the surface of the optical assembly, the drug is biotinylated and binds to the optical assembly through a biotin-streptavidin interaction (first binding pair), and the anti-drug antibody (ADA) analyte is captured by the drug (second binding pair)([0067]; Fig. 3). Thus, the biotinylated drug is the claimed biotinylated first binding partner, and the anti-drug antibody analyte is the complementary second binding partner that binds the surface-bound biotinylated drug to form the claimed immunocomplex. Figure 3 visually depicts the streptavidin biosensor, biotinylated drug, and captured anti-drug antibody in that arrangement. Choo therefore supplies the limitations of step (d) and the binding-pair portion of step (f): contacting the streptavidin-containing surface with a biotinylated first binding partner, followed by contacting the surface with a sample containing a complementary analyte that binds the biotinylated first binding partner.
Therefore, 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 Tan’s biotin-functionalized phase-shift interferometric sensor by replacing Tan’s streptavidin with Desai’s polymerized streptavidin having a molecular weight of at least about 145,000 Daltons, and by using Choo’s expressly disclosed assay arrangement in which a biotinylated first binding partner is bound to the streptavidin-containing optical surface and thereafter captures its complementary analyte from the sample. Tan expressly seeks to significantly enhance sensitivity and accuracy and teaches use of a densely coated analyte-binding layer; Desai expressly identifies the limited capture capacity and diminished sensitivity associated with native streptavidin and teaches polymerized streptavidin to increase target-capture capacity, sensitivity, and linear working range; and Choo expressly teaches the same streptavidin–biotin capture chemistry on an interferometric optical assembly, with a biotinylated drug serving as the capture member and an anti-drug antibody serving as the analyte. These teachings provide a direct teaching, suggestion, and motivation to use Desai’s higher-capacity polymerized streptavidin and Choo’s biotinylated capture-partner arrangement in Tan’s sensor to increase the density of functional capture molecules and strengthen the analyte-dependent phase response while retaining Tan’s existing interferometric measurement and calibration method. One of ordinary skill would have had a reasonable expectation of success because Desai demonstrates that polymerized streptavidin retains functional biotin-binding capacity, Luff directly demonstrates that polystreptavidin binds biotinylated protein and generates measurable phase shifts on an interferometric sensor after buffer washing, and Choo demonstrates that a biotinylated first binding partner bound through streptavidin captures its complementary analyte on a BLI sensor. The modification would therefore have predictably produced Tan’s interferometric assay with a polymerized-streptavidin layer of the claimed molecular weight, a biotinylated first binding partner, formation of the claimed surface-bound immunocomplex, and calibration-based analyte quantitation.
Regarding claim 3, Tan expressly teaches that the analyte-binding molecules in the assembly may be antigen molecules, for use in detecting the presence of antibodies specific against that antigen (col. 3, p. 10), and identifies antigen-antibody pairs as opposite members of the binding pair used in the interferometric assay (col. 1, p. 9).
Regarding claim 8, refer to the discussion above. Luff teaches an interferometric optical sensor employing biotinylated thermally denatured bovine serum albumin (BSA-Bi) and polystreptavidin (pSA) in PBS (p. 587). Luff further teaches an initial incubation of the sensor surface with BSA-Bi, followed by alternate 8 min incubations of pSA and BSA-Bi, with a two min washing stage where the unbound material is flushed out with buffer.
Therefore, 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 Tan’s biotin-functionalized phase-shift interferometric sensor by replacing Tan’s streptavidin with Desai’s polymerized streptavidin having a molecular weight of at least about 145,000 Daltons and thereafter contacting the polymerized-streptavidin-containing surface with a liquid sample containing a biotinylated analyte, as taught by Luff. Tan expressly seeks to significantly enhance sensitivity and accuracy and teaches use of a densely coated binding surface; Desai expressly identifies the limited capture capacity and diminished sensitivity of native streptavidin and teaches polymerized streptavidin to increase target-capture capacity, sensitivity, signal, and linear working range; and Luff expressly teaches, on an interferometric optical sensor, binding biotinylated BSA to polystreptavidin, washing away unbound material, and measuring the resulting phase shift.
These teachings provide a direct teaching, suggestion, and motivation to employ Desai’s higher-capacity polymerized streptavidin and Luff’s biotinylated-analyte binding arrangement in Tan’s sensor to increase capture of the biotinylated analyte and strengthen the analyte-dependent interferometric response. One of ordinary skill would have had a reasonable expectation of success because Desai demonstrates that polymerized streptavidin retains functional biotin-binding capacity and provides increased signal, while Luff directly demonstrates that a biotinylated molecule binds polystreptavidin on an interferometric sensor after buffer washing and produces a measurable phase shift. The modification therefore would predictably have produced Tan’s interferometric assay with a polymerized-streptavidin layer of the claimed molecular weight, binding of a biotinylated analyte, and determination of analyte concentration from the binding-dependent interferometric phase response.
Claims 2, 6, 9 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Tan et al., Desai et al., Luff et al., and Choo et al., as applied to claims 1 and 8 above, and further in view of Biacore (Biacore Sensor Surface Handbook. GE Healthcare. Feb. 2005), Andersson et al. (Identification and Optimization of Regeneration Conditions for Affinity-Based Biosensor Assays. A Multivariate Cocktail Approach. Analytical Chemistry. Vol. 71, No. 13, July 1999), and Tedeschi et al. (Antibody Immobilisation on Fibre Optic TIRF Sensors. Biosensors & Bioelectronics. Vol. 19, No. 2, November 2003).
With respect to the teachings of Tan et al., Desai et al., Luff et al., and Choo et al., see the discussion above, which applies equally here. These references differ from the instant claims in failing to expressly teach or specify further contacting the surface first with an acidic solution having a pH of about 1.0–4.0, then contacting the biotin-immobilized surface with dimethyl sulfoxide (DMSO) to elute the immunocomplex while leaving biotin immobilized on the surface; contacting the biotin-immobilized surface with an aqueous wash solution having a pH of 6.0–8.5; and repeating the assay cycle 3–15 times with a new liquid sample in each cycle (claims 2 and 9); nor the acidic solution has a pH of 1.5-2.5 (claim 6 and 12).
Tan teaches that its interferometric apparatus may be used to determine both the rate of association and dissociation of analyte from a surface-bound binding layer. Tan further teaches that, for where the method is used for measuring the rate of dissociation of analyte to the second layer, the reacting steps can include immersing the second layer in a dissociation buffer for a period of time until a decrease in thickness of the first reflecting layer is observed. Tan’s Figure 7 likewise presents on and off curves generated from the association and dissociation of antibodies (col. 4, p. 10; Fig. 7). These teachings would have directed one of ordinary skill in the art to known biosensor-regeneration techniques to identify suitable dissociation conditions capable of removing the surface-bound immunocomplex while preserving the immobilized sensing layer for subsequent measurements.
Biacore teaches that analysis is performed by injecting sample over the surface in a carefully controlled fashion and that regeneration is the process of removing bound analyte from the surface after an analysis cycle without damaging the ligand, in preparation for a new cycle (pp. 7–8). Biacore further teaches that regeneration scouting is performed by testing a few (suggested 5) repeated cycles of analyte binding and regeneration with each condition, and examining trends in the response levels within each condition (p. 65). Biacore instructs that regeneration conditions be tested using analyte that reflects the experimental samples if possible. This is particularly important if the samples are complex mixtures such as cell culture medium or body fluids, where binding of non-analyte components to the surface can complicate the regeneration behavior (p. 66). Biacore further teaches that for streptavidin-biotin capture specifically, the streptavidin-biotin interaction has an equilibrium dissociation constant of about 10-15 M, that dissociation of biotinylated ligands from the streptavidin surface is generally negligible, and that regeneration is normally directed toward removing bound analyte while leaving the biotinylated ligand on the surface (pp. 23-24). This directly supports regeneration of the surface without removing the immobilized biotin-containing sensing architecture. Biacore also teaches antibody-based surfaces that are easily regenerated at low pH using glycine-HCl (p. 25). Thus, acidic regeneration of an antibody-antigen immunocomplex was an expressly recognized regeneration technique.
Andersson teaches that Biacore systems are used for repeated affinity-based biosensor measurements and that the sensor surface must be regenerated before a measurement is repeated. Andersson explains that the purpose of regeneration is to break the noncovalent bonds between the antibody paratope and the antigen epitope without permanently affecting the antibody-antigen binding characteristics (p. 2475). Andersson expressly teaches that 10–100 mM HCl or 10 mM glycine pH 1.7–2.2 are used for antibody-antigen surface regeneration (p. 2475). These disclosed pH values fall within the claimed range of about pH 1.0–4.0 or a pH of 1.5-2.5. Andersson further teaches that combinations of agents affecting different antibody-antigen binding forces are useful and that DMSO with an increase or decrease in pH is suggested for breaking antibody-antigen bonds (p. 2475). Andersson’s organic stock solution expressly contains DMSO, formamide, ethanol, acetonitrile, and 1-butanol, while its acidic stock contains oxalic acid, phosphoric acid, formic acid, and malonic acid (p. 2476). Andersson also explains that a drastic pH decrease combined with nonpolar solvents is a good regeneration treatment in many cases because the two components disrupt different forces involved in antigen-antibody binding (p. 2480). Regarding repeated assay use, Andersson teaches that the surface should be completely regenerated so that measurements remain comparable from one cycle to another and reports repeated regeneration testing 20 times, with the sensor response differing by less than 1% between cycle 1 and cycle 20 and surface activity remaining greater than 99% (pp. 2476 and 2479; Fig. 4).
Tedeschi independently teaches regeneration of antibody-coated optical biosensor surfaces with both acid and DMSO. Tedeschi states that polar organic solvents such as dimethylsulfoxide were evaluated for dissociating the antigen-antibody complex and hence to regenerate the immunosensor surface (Abstract, p. 85). Tedeschi specifically compares DMSO with a standard HCl-glycine solution, identified as 0.1 M glycine HCl in 50% ethylene glycol, pH 1.75, for regenerating surface-bound antibodies (p. 88). The pH of 1.75 falls squarely within the claimed range of about 1.0–4.0 or 1.5-2.5. Tedeschi further teaches that DMSO can substitute for water near the antibody, alter protein folding at the binding region, and possibly reduce the affinity between antibody and antigen. The disclosed DMSO treatment uses 1% of DMSO in glycerol/H2O 1:4 as a wash for regenerating the surface (p. 88). Tedeschi demonstrates that the DMSO-treated surfaces retained approximately 90% of the original binding capacity, that the relative binding capacity remained approximately constant over successive washing procedures, suggesting that DMSO should be an efficient regenerating agent for repeated cycles (p. 91; Fig. 5). Tedeschi also teaches successive assay operations in which PBS washing is used between analyte additions and identifies the PBS buffer as having neutral pH, the optical fiber is exposed to DMSO to dissociate the surface complex, and a subsequent addition of labeled antigen produces a new signal increase, showing that the immobilized antibody remains capable of forming another immunocomplex after regeneration (pp. 91–92; Figs. 6–7).
Therefore, 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 further modify the interferometric assays of Tan, as modified by Desai, Luff, and Choo, by regenerating the analyte-bound surface after measurement through sequential contact with an acidic solution having a pH of about 1.0–4.0 or a pH of 1.5-2.5, followed by DMSO to further elute the surface-bound immunocomplex while retaining the immobilized biotin-containing sensing architecture, thereafter washing the surface with an aqueous PBS solution having a substantially neutral pH within about 6.0–8.5, and repeating the binding, measurement, regeneration, and washing cycle five times using a newly introduced liquid-sample aliquot during each cycle. Tan expressly teaches measuring analyte dissociation and immersing the sensing layer in a dissociation buffer until a decrease in reflecting-layer thickness is observed, thereby directing the skilled artisan to known biosensor-regeneration procedures for removing bound analyte and reusing the interferometric sensor. Biacore teaches that regeneration removes bound analyte without damaging the immobilized ligand and prepares the surface for a new analysis cycle; that regeneration of a streptavidin–biotin capture surface is directed toward removing bound analyte while retaining the immobilized biotinylated ligand; that antibody-based surfaces may be regenerated at low pH using glycine-HCl; and that regeneration conditions should be evaluated through a few, suggested five, repeated cycles of analyte binding and regeneration. Andersson expressly teaches acidic antibody–antigen regeneration conditions, including glycine at pH 1.7–2.2, and further teaches that a decrease in pH together with DMSO-containing nonpolar-solvent treatment is useful because the treatments disrupt different intermolecular forces maintaining the antibody–antigen complex. Tedeschi independently teaches glycine-HCl at pH 1.75 and DMSO as regeneration agents for an antibody-coated optical biosensor and teaches PBS washing between successive analyte additions, wherein the neutral PBS falls within the claimed aqueous-wash pH range of about 6.0–8.5. These teachings provide an express teaching, suggestion, and motivation to apply the acidic solution first to weaken ionic and electrostatic interactions within the surface-bound complex, then apply DMSO to disrupt remaining polar and hydrophobic interactions, and thereafter wash with neutral aqueous PBS to remove dissociated analyte and residual regeneration reagents and restore conditions suitable for the next assay cycle.
One of ordinary skill would also have understood Biacore’s repeated analyte-binding and regeneration protocol to require introducing another liquid-sample aliquot after each regeneration because regeneration expressly prepares the surface for a new analysis cycle, and each new binding cycle requires renewed contact between the regenerated surface and analyte-containing liquid. Although Biacore does not expressly require successive samples to differ in composition, introducing a newly supplied sample or fresh aliquot for each cycle would have been the ordinary and necessary implementation of the disclosed repeated sample-injection process. A skilled artisan therefore would have introduced a new liquid sample during each of Biacore’s five suggested cycles to obtain another binding-dependent interferometric response and determine the analyte concentration for that cycle. One of ordinary skill would have had a reasonable expectation of success because Biacore teaches preservation of the immobilized ligand during analyte regeneration and repeated operation for five cycles, Andersson demonstrates that complementary acidic and solvent-based regeneration treatments can preserve greater than 99% surface activity through repeated regeneration, and Tedeschi demonstrates renewed analyte binding after DMSO treatment and neutral PBS washing of an optical immunosensor. The modification therefore would predictably have provided the sequential regeneration, neutral washing, repeated cycling, and new-sample analysis required by the claims.
Claims 4, 5, 10 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Tan et al., Desai et al., Luff et al., and Choo et al., as applied to claims 1 and 8 above, and further in view of BioTez (BioTez. Polystreptavidin R. Catalogue Number: 10 120 030 / 10 120 050/ 10 120 100. Version December 2019.) as evidenced by Frontiers in TBI Traumatic Brain Injury (Neurology, Nerve, Neuro cell culture. Polystreptavidin R, 5mg. July 7, 2021. Polystreptavidin R, 5mg – Frontiers in TBI Traumatic Brain Injury) and Grant et al. (SARS-CoV‑2 Coronavirus Nucleocapsid Antigen-Detecting Half-Strip Lateral Flow Assay Toward the Development of Point of Care Tests Using Commercially Available Reagents. Analytical Chemistry. Vol. 92, N0. 16, August 2020).
With respect to the teachings of Tan et al., Desai et al., Luff et al., and Choo et al., see the discussion above, which applies equally here. These references differ from the instant claims in failing to expressly teach or specify that the streptavidin polymer have a molecular weight of at least about 465,000 Daltons (claims 4 and 10), nor that the streptavidin polymer have a molecular weight of at least about 970,000 Daltons (claims 5 and 11).
BioTez teaches the commercially supplied product Polystreptavidin R, identified as a chemically modified polymerized Streptavidin characterized by an extraordinary high Biotin binding capacity. BioTeZ expressly reports a molecular mass of >2,000–20,000 kDa, measured by Field-Flow-Fractionation technology (p. 1). This disclosed molecular-mass range is greater than both 465 kDa and 970 kDa and therefore satisfies the additional molecular-weight limitations of claims 4, 5, 10, and 11. BioTeZ further teaches that Polystreptavidin R coatings provide a universal immobilization principle for detecting and analyzing proteins, peptides, PCR-fragments, haptens etc., which must be present in a biotinylated form, and combine excellent binding capacity with high chemo and thermo stability and a long shelf life (p. 1). BioTeZ identifies the product as suitable for coatings of membranes, beads, biochips, plastics etc. and teaches that it is a reagent for surface coating with Maximum Biotin Binding Capacity that improves the signal-noise-relation (pp. 1–2). These teachings would have directed a skilled artisan seeking to improve Tan’s binding-dependent interferometric signal to employ BioTeZ’s higher-molecular-weight polymerized streptavidin as the polymerized streptavidin taught generally by Desai. Lastly, public accessibility and commercial availability of BioTez before August 10, 2021 are further corroborated by Grant et al., electronically published August 5, 2020, which expressly reports use of BioTeZ polystreptavidin catalog no. 10 120 050 in a lateral-flow assay, and by a publicly dated July 7, 2021 commercial listing, Frontiers in TBI Traumatic Brain Injury, identifying the same product and reporting a molecular weight exceeding 2,000 kDa. These corroborating materials confirm that the BioTeZ product and its identifying technical characteristics were available to interested members of the relevant public before the effective filing date.
Therefore, 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 further modify the polymerized-streptavidin interferometric assays of Tan, as modified by Desai, Luff, and Choo, by selecting BioTeZ Polystreptavidin R, having a molecular mass greater than 2,000 kDa, as the polymerized-streptavidin material, thereby providing a streptavidin polymer having a molecular weight of at least about 465,000 Daltons, as required by claims 4 and 10, and at least about 970,000 Daltons, as required by claims 5 and 11. Tan expressly seeks increased assay sensitivity and teaches use of a densely coated analyte-binding surface; Desai expressly teaches that polymerized streptavidin overcomes the limited capture capacity and diminished sensitivity of native streptavidin and provides increased target-capture capacity, enhanced sensitivity, greater signal, and an extended linear working range; and BioTeZ expressly characterizes Polystreptavidin R as a chemically modified polymerized streptavidin having extraordinary biotin-binding capacity, a molecular mass greater than 2,000–20,000 kDa, suitability for coating biochips and other solid-phase assay surfaces, maximum biotin-binding capacity, and an improved signal-to-noise ratio. These teachings provide an express teaching, suggestion, and motivation to select BioTeZ’s higher-molecular-weight polymerized streptavidin for the interferometric sensing surfaces of the combined references in order to increase the number and density of functional biotin-binding sites, increase capture of the biotinylated binding partner or analyte, and thereby strengthen the binding-dependent interferometric phase response.
One of ordinary skill would have had a reasonable expectation of success because BioTeZ expressly identifies Polystreptavidin R as polymerized streptavidin intended for coating solid phases and biochips, confirms its high biotin-binding capacity, and provides aqueous PBS-compatible coating conditions consistent with the biotin–streptavidin assay environments taught by Tan, Desai, Luff, and Choo. Desai further demonstrates that increasing the degree of streptavidin polymerization retains the same biotin-binding function while increasing capture capacity and assay signal. Substituting BioTeZ Polystreptavidin R for the polymerized streptavidin of the underlying combinations therefore would predictably have preserved the same surface-immobilization and biotin-capture functions while providing molecular weights exceeding both claimed thresholds and increasing the detectable binding-dependent signal, as required by claims 4, 5, 10, and 11
Claims 7 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Tan et al., Desai et al., Luff et al., Choo et al., Biacore, Andersson et al., and Tedeschi et al., as applied to claims 1, 2, 8 and 9 above, and further in view of Zuk et al. (WO 2021/071903 A1).
With respect to the teachings of Tan et al., Desai et al., Luff et al., Choo et al., Biacore, Andersson, and Tedeschi, see the discussion above, which applies equally here. These references differ from the instant claims in failing to expressly teach or specify that DMSO is in a solution comprising 20-85% DMSO by weight (claims 7 and 13).
Zuk supplies the missing concentration limitation in the same technical context of regenerating an interferometric biochemical-assay probe. Zuk teaches that, after acidic elution, a dimethyl sulfoxide (DMSO) solution is used as a second elution agent and that an aqueous solution (water or a buffer such as PBS) of DMSO is used with DMSO in an amount of 20–85%, 30–85%, or 40–80% by weight (pp. 14–15). Zuk further provides operative examples within the claimed range. Example 5 teaches regeneration using 10 mM glycine/HCl pH 2.0, followed by DMSO (typically 20–40% in PBS), while Table 3 expressly employs 30% DMSO in PBS following acidic regeneration (pp. 20–21, Table 3). Example 7 additionally teaches 10 mM glycine pH 2.0 and 75% DMSO in PBS, and Table 7 shows the sequential regeneration treatment of acidic glycine followed by 75% DMSO in PBS (p. 24, Table 7). Zuk also demonstrates that these DMSO concentrations are compatible with repeated interferometric assay operation. Table 4 reports 15 regeneration cycles using the same fluorescent-coated probe and anti-fluorescein-streptavidin conjugate, with consistent results across the cycles (pp. 21–22, Table 4).
Therefore, 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 further modify the DMSO-regeneration steps of the methods of claims 2 and 9 by employing an aqueous DMSO solution comprising 20–85% DMSO by weight, as expressly taught by Zuk. Tedeschi teaches that DMSO dissociates antigen–antibody complexes and regenerates an optical immunosensor, while Andersson teaches that DMSO-containing nonpolar-solvent treatments disrupt binding forces that may remain after acidic treatment. Zuk provides the express teaching, suggestion, and motivation to select the claimed concentration range because Zuk teaches sequential regeneration using low-pH glycine followed by DMSO and expressly identifies DMSO concentrations of 20–85%, 30–85%, or 40–80% by weight as operative concentrations. Zuk further provides working examples using 30% DMSO in PBS and 75% DMSO in PBS following acidic glycine regeneration, both of which fall within the claimed range. A skilled artisan therefore would have selected a concentration within Zuk’s disclosed range to provide sufficient solvent strength to remove immunocomplex remaining after acidic treatment while preserving the immobilized sensing layer for subsequent assay cycles.
One of ordinary skill would have had a reasonable expectation of success because Zuk expressly demonstrates the claimed sequential regeneration arrangement using low-pH glycine followed by 30% or 75% DMSO in PBS and reports consistent assay performance through 15 regeneration cycles. These disclosures show that DMSO concentrations within the claimed 20–85% range are compatible with the same acid-then-DMSO regeneration sequence, aqueous assay environment, and repeated-use biosensor operation recited in the underlying claims. The modification therefore would predictably have provided the DMSO concentration required by claims 7 and 13 while maintaining regeneration efficiency and the repeated-use capability of the assay surface.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 6, 9–13, and 19 of U.S. Patent No. 12,399,173 B2 in view of Tan et al., Desai et al., BioTez, and Zuk et al.
The patented claims are directed to interferometric assay methods employing an immobilized hapten, formation of a surface-bound immunocomplex, determination of analyte concentration from an interferometry phase shift relative to a baseline and calibration curve, acidic elution, aqueous washing, and repeated assay cycles using new samples. Patented claims 9 and 10 additionally employ streptavidin and biotinylated analytes or binding-pair members, while patented claims 13 and 19 recite streptavidin linked to polymers having molecular weights of 1,000–500,000 Daltons.
The instant claims are directed to substantially the same interferometric assay subject matter, but recite a surface architecture in which biotin is immobilized on the support and a streptavidin polymer binds to the immobilized biotin. As discussed in the rejection under 35 U.S.C. § 103, Tan teaches an interferometric sensor surface having immobilized biotin to which streptavidin binds, and Desai teaches replacing native streptavidin with polymerized streptavidin having a molecular weight within the scope of at least about 145,000 Daltons. It would have been obvious to employ Tan’s immobilized-biotin surface and Desai’s polymerized streptavidin in the closely related interferometric assay methods of the patented claims to increase surface binding capacity and assay sensitivity while retaining the patented interferometric detection and regeneration functions. The modification would have predictably produced the surface architecture recited in the instant claims and therefore does not render those claims patentably distinct.
More specifically, instant claims 1 and 8 are not patentably distinct from patented claims 9 and 10 because the patented claims already recite a probe-based interferometric assay employing streptavidin, a biotinylated analyte or biotinylated first binding-pair member, formation of a surface-bound complex, measurement of an interferometry phase shift relative to a baseline, and calibration-based analyte quantitation. Tan and Desai merely provide the obvious surface arrangement of immobilized biotin and polymerized streptavidin.
With respect to instant claim 2, patented claims 9 and 10 recite acidic treatment at about pH 1.0–4.0, DMSO treatment, aqueous washing at pH 6.0–8.5, and repetition of the assay 3–15 times using a new sample during each cycle. Accordingly, claim 2 merely applies the regeneration sequence already claimed in the patent to the obvious immobilized-biotin/polymerized-streptavidin surface discussed above.
With respect to instant claim 3, patented claim 11 recites that the first member of the binding pair is an antigen and the second member is an antibody. Claim 3 therefore does not further distinguish the instant method from the patented method.
With respect to instant claims 4 and 10, patented claims 13 and 19 recite polymers having molecular weights of 1,000–500,000 Daltons. That range overlaps the claimed requirement of at least about 465,000 Daltons. Selection of a molecular weight within the overlapping portion of the ranges for the same polymer-binding function would have been an obvious variation.
With respect to instant claims 5 and 11, the patented claims do not expressly recite a streptavidin-polymer molecular weight of at least about 970,000 Daltons. BioTez teaches Polystreptavidin R having a molecular mass greater than 2,000 kDa and identifies that material as suitable for coating solid assay surfaces and binding biotinylated assay components. It would therefore have been obvious to employ BioTez’s known higher-molecular-weight polystreptavidin in the patented assay to increase biotin-binding capacity and assay signal, predictably providing a molecular weight satisfying claims 5 and 11.
With respect to instant claims 6 and 12, patented claim 6 expressly recites an acidic solution having a pH of 1.5–2.5. Application of that expressly claimed subrange to the closely related methods of patented claims 1, 9 and 10 would have been an obvious variation producing the same immunocomplex-elution function.
With respect to instant claims 7 and 13, patented claims 9 and 10 recite DMSO treatment following acidic elution but do not specify the DMSO concentration. Zuk teaches aqueous DMSO regeneration solutions comprising 20–85% DMSO by weight, including working embodiments employing 30% and 75% DMSO following acidic regeneration. It would therefore have been obvious to select a DMSO concentration within Zuk’s disclosed range for the patented acid-then-DMSO regeneration method to provide sufficient solvent strength to remove the surface-bound complex while preserving the immobilized sensing layer for subsequent cycles.
With respect to instant claim 9, patented claim 9 expressly recites acidic treatment at about pH 1.0–4.0 followed by DMSO, aqueous washing at pH 6.0–8.5, and repetition 3–15 times using a new sample in each cycle. Claim 9 therefore differs principally in the obvious immobilized-biotin/polymerized-streptavidin surface architecture supplied by Tan and Desai.
Accordingly, claims 1–13 are not patentably distinct from claims 1, 3, 6, 9–13, and 19 of U.S. Patent No. 12,399,173 B2 because the differences between the patented claims and the instant claims would have been obvious to one of ordinary skill in the art in view of Tan, Desai, BioTez, and Zuk.
Conclusion
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/E.O./Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 August 6, 2026
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