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.
Priority
The present application was filed 05/29/2015; acknowledgement is made of Applicant’s claim of benefit under 35 U.S.C. 119(e) to provisional application No. 62/067,702, filed 10/23/2014.
Status of the Claims
Claims 1-3, 5, 9, 11-18, 20-24, 26, 37-38, 40, 42-43, 45-51, 53-55 and 57-64 are pending; clams 1, 5, 9, 11-12, 15-17, 20, 26, 51, 53 and 58 are amended; claims 37-38, 40, 42, 43 and 45-50 are withdrawn; claims 63 and 64 are newly recited; and claims 4, 6-8, 10, 19, 25, 27-36, 39, 41, 44, 52 and 56 are canceled. As such, claims 1-3, 5, 9, 11-18, 20-24, 26, 51, 53-55 and 57-64 are examined below.
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 1-3, 5, 9, 11-18, 20-24, 26, 51, 53-55 and 57-62 are rejected under 35 U.S.C. 103 as being unpatentable over Rutter et al. US PG Pub No. 2011/0070658A1 in view of Walker et al., US PG Pub No. 2011/0117670A1, Eisinger et al., US Patent No. 4,943,522A1, Davis et al., US PG Pub No. 2009/0203059A1 and Harlow & Lane (Harlow, E. and Lane, D., Antibodies: A Laboratory Manual (1988) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, Pages 72-76.
Rutter et al. teach an immunoassay system comprising capture antibodies having an affinity to HbA, HbS and HbC (see para [0041], Rutter teaching embodiments comprising a mixture of antibodies specific for variants of hemoglobin HbA, HbA2, HbF, HbC, HbD, HbE and HbS), the mixture thereby addressing each of a first, second and third immobilized on a substrate in a configuration wherein simultaneous detection and visualization of presence of each is provided (see the capture antibodies located on the same device in a capture zone(s), see paras [0017], [0018], [0023], [0055]-[0057], thereby allowing binding and visualization to occur simultaneously, in particular at para [0055], from the description of Rutter’s capture zone it is understood this is a discrete (spatially discrete) zone, see teaching the strip may include more than one capture zone for hemoglobin), the system of Rutter’s invention also comprises a conjugated detector antibody that binds hemoglobin generally (e.g., paras [0013], [0016] and [0057], i.e. a single detector antibody), and further the system comprising a capture reagent that serves as a control (para [0023]).
Although Rutter does teach capture and detection of hemoglobin, including hemoglobin variants other than glycated hemoglobin, Rutter fails to teach the system is capable of detection of hemoglobinopathies, fails to teach the first, second and third capture antibodies having binding affinity to the N-terminus of each of HbA, HbS and hbC, and fails to teach and conjugated detector antibody has affinity for the C-terminus of hemoglobin α or β chain, and fails to teach the control reagent as an antibody.
Walker et al. also teach an invention that determines variants and the glycated forms of hemoglobin (abstract). Walker teach hemoglobin variants affect immunologically determined levels of glycated hemoglobin, Walker teach it is important to know the presence of variants and their proportions relative to HbA as well as the presence of thalassemias to achieve a proper determination of glycemic control for those suffering from diabetes (see para [0006]). The invention of Walker discloses systems/antibodies having selective binding for multiple hemoglobin variants, their invention teaching monoclonal antibodies that bind the HbA, HbS, and HbC antigens (see for example paras [0027], [0040], [0047], [0107], [0108], [0113], [0114], Table 1, Example 2, referencing antibodies that bind each of the variants as claimed). See e.g. Example 2, para [0113], Walker teach an immunoassay comprising antibodies of the invention (as indicated above, said capture antibodies coupled to beads) and further a detection antibody (para [0114]) conjugated to a detectable moiety (phycoerythrin-labeled antibody for hemoglobin).
Regarding the detection antibody, Walker does teach a detector antibody that is a labeled universal detection antibody (an antibody that binds all hemoglobin species) (para [0044]). Walker teaches the detection antibody as a pan reactive antibody (see starting at paras [0072] to para [0078], antibodies that bind the multiple forms of Hb, antibodies that bind at the N-terminal region, but in a region absent the known position of the variant residue that distinguishes the species of variants).Walker indicate such antibodies were well known, that any number of immunogens can be used in order to obtain them, for example antibodies that bind the β and α epitopes (e.g., paras [0074], [0075]). See also paras [0073]-[0078]). At para [0078], Walker does teach detection antibody that binds the β globin chain (binding a sequence common to all variants, the sequence from the beta globin chain).
Additionally, regarding the variant residues, Walker does teach the variation which distinguishes between the different hemoglobin species (HbA, HbS and HbC) as being a varied amino acid residue in the N-terminal region of the beta chain (para [0041]); see previously cited above, Walker does address the different capture antibodies as claimed. See at para [0026] Walker teach detection of multiple hemoglobin variants (two or more) in multiplex manner.
Eisinger et al. teach an example of an immunochromatographic apparatus/system comprising a porous membrane for promoting lateral flow as an assay substrate (see abstract), the substrate comprising an affixed specific binding member for capture of an analyte described as an indicator zone, see col. 5, lines 12-18). See at col. 5, lines 12-18 Eisinger teach a membrane may contain multiple indicator zones to detect different analytes (see also col. 11, lines 45-48, col. 16, lines 60-65 and Figure 9, i.e., discrete zones capable of differentiation). See also col. 18, starting at line 10, Eisinger teach detection performed relying on detectable particles (see lines 19-39), and further using non particulate labels (such as enzymes) col. 18 starting at line 61 to col. 19.
Davis is another example of a lateral flow immunoassay device (see abstract and Figure 1) structurally similar to that as taught by the combination of the cited prior art above (a chromatographic assay device which operates on the principle of lateral flow of fluid as in Rutter and Eisinger); see at para [0008] Davis teach providing a control band (immobilized anti-IgG) at the substrate device, specifically providing excess labeled antibody, such that even if the targeted analyte is present in the sample, there is sufficient labeled species present to ensure some passes beyond the capture band. Davis teach as such, whether or not the analyte is present, some labeled antibody reaches the control band. As such, Davis is teaching a control that demonstrates proper operation of the device regardless of presence/absence of analyte.
Harlow & Lane also provide extensive guidance for producing highly specific antibodies that recognize antigens by using peptides as immunogens; noting that this approach has the advantage in that particular regions of a protein can be targeted specifically for antibody production (page 73). Harlow & Lane teach that carboxy and amino terminal sequences are often exposed and can be targeted for producing antibodies; surprisingly high percentage of the resulting antibodies will recognize the native protein (see pages 75-76). As to the size of the peptide, Harlow & Lane suggest using peptides of about 10-15 amino acids in length (page 76).
Although Rutter’s invention does encompass providing more than one capture zone (see referring to para [0055], Rutter describing having more than one capture zone, capture zone described their own bands/spots), it also would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the lateral flow immunochromatographic device of Rutter, the device having capture antibodies for each of the hemoglobin variants as indicated, so that each of the different capture antibodies specific to the variants is located in its own indicator zone (discrete capture zones which are differentiable) in the capture region, as also taught by Eisinger, thereby allowing the simultaneous detection and visualization of each of the hemoglobin variant forms (differentiated from one another), one being motivated to adopt this configuration/format in order to determine the presence of the variants and their proportions relative to HbA in order to properly achieve/assist in achieving glycemic control for diabetic patients (for example, see Walker, teaching it is desirable for this reason, to know/detect each of the variants and their amounts, modifying to have each separately presented would accommodate the ability to determine the presence of each relative to HbA).
The ordinarily skilled artisan would have a reasonable expectation of success considering Rutter already disclose the ability to detect hemoglobin with immunochromatographic systems at discrete capture zones (multiple distinct bands/spots, e.g., para [0055]), Rutter further teaching that providing capture antibody to each variant on such devices was known in the art. As such, one would expect the modification, to provide each capture antibody as its own indicator zone, to be an improvement since the modification would allow each variant to be distinguished from each of the others, while detection and visualization occurs simultaneously on the same singular substrate.
It would have been further prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to have provided the control reagent of Rutter as an antibody that binds residual detector antibody, as in Davis, in order to demonstrate proper operation of the device regardless of whether or not analyte is present in the sample (the motivation is in order to demonstrate proper operation of the device during its use). The modification (to have provided control reagent of Rutter as an antibody that binds residual detector antibody as in Davis) would be considered an obvious matter of applying a known technique to a known immunochromatographic product, specifically the prior art contained the base product, namely immunochromatographic lateral flow devices (for example, as in Rutter and/or Eisinger). Further the prior art contained the known technique of providing on such devices a control band capable of binding residual detector (labeled) antibody for the purpose of demonstrating proper operation of the device (see referring to Davis), independent of the presence of targeted analyte(s). One having ordinary skill in the art would have recognized that applying the technique of providing a control band to bind residual detector antibody would have yielded predictable results, namely the ability to confirm proper operation of the device during its use. One having ordinary skill would have a reasonable expectation of success in modifying the device to provide a control as in Davis because the device of Davis, similarly to that as taught by the combination of the cited art, operates by lateral flow of sample through conjugate (the conjugate is already present at the device, and would be available to bind at a control for showing proper operation, this modification feasible considering it was already an art recognized technique, as shown by Davis).
Further, it would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the capture antibodies and the detector antibody, specifically to have relied on a universal detection antibody (detection antibody) with affinity to the C-terminal region of the β chain and capture antibodies having N-terminal affinity, by applying the known technique of Harlow & Lane when employing capture antibody (as in Rutter) and a universal detection antibody (as in Walker). One would be motivated to modify the capture and detector antibodies to target the N-terminal, and C-terminal regions respectively as claimed because it was known in the art that the variant residues (the residues distinguishing the variants) is located in the N-terminal region; thereby a detector antibody that binds the C-terminal region would not interfere with or be affected by binding at the variant. One of ordinary skill would have a reasonable expectation of success because the motivation would result in an antibody that binds all of the variants.
Regarding the capture antibodies, additionally, it would have been prima facie obvious to rely on capture antibodies that have affinity to the N-terminus of each variant because like the carboxy terminal region, it was known that the “amino-terminal regions are exposed” and as such make good targets for binding, this coupled with the knowledge that the residues distinguishing variants are located in this region, it would have been obvious (motivation being this region as suitable for distinguishing targets, and because this region also would be expected to make a good target for binding based on Harlow).
One of ordinary skill would have a reasonable expectation of success because the motivation would result in an antibody that binds all of the variants (consistent with that of Blomberg et al.), and because generally it was recognized that terminal regions of the protein are exposed and make for good binding targets.
Independent claim 1, as amended, recites “wherein the immunoassay system is configured to assist in diagnosing sickle cell trait (HbAS), sickle cell disease, hemoglobin C disease, hemoglobin C train (HbAC) or sickle-hemoglobin C disease based on hemoglobin status”, however the amended language fails to recite or suggest further structure specific to the system, beyond the structures as discussed in detail above. Because the combination of the cited art is teaching a device that is structurally indistinguishable, that captures and detects (separately in separate zones), each of HbA, HbS and HbC, it addresses the claim. In particular, because the device as taught by the combination of the prior art is structurally indistinguishable from that which is claimed, comprising the same capture antibodies, the same conjugated detector antibody, the same fourth control antibody and the same substrate (and arrangement/configuration) as claimed, it is expected similarly capable of being configured to assist in diagnosing sickle cell disease, hemoglobin C disease, or sickle-hemoglobin C diseased based on hemoglobin status. This is further supported by Applicant’s own originally filed specification at page 14, the originally filed specification page 14, lines 16-28, indicates the ability to of the device/system to assist in diagnosis as claimed is a result of the system capture and detection each of HbS, HbC and HbA (see “The instant disclosure overcomes the above-noted deficiencies in existing testing methods, at least in part, by the use of an immunoassay platform that incorporates multiple pAbs and/or mAbs to HbS, HbC and HbA”). As noted above the combination of the cited art similarly results in a system that achieves the same capture in the same way, and as such, the system is necessarily also “configured” consistent with the configuration claimed. The prior art and the claimed invention systems are structurally indistinct systems. As such, the combination of the cited art addresses the amendments to claim 1, as well as newly recited claim 59.
Regarding claims 2 and 54, see as cited above, the system taught by the cited prior art comprises colorimetric immunoassay (e.g., the combination of the cited art addresses a detector antibody that is either a particulate label (colorimetric) or enzyme label (ELISA), the assay comprising a non-competitive assay).
Regarding claim 3, see as cited above, the combination of the cited art addresses a substrate comprising a chromatography matrix.
Regarding claim 51, see as cited above, the cited art addresses a substrate comprising a test strip that is a chromatography matrix, the immunoassay intended for the purpose of being used at point of care.
Regarding claim 53, it would have been obvious, and one of ordinary skill would have a reasonable expectation of success, to have arranged the capture zones in any order including in the order of HbC, HbS and HbA (such that sample first interacts with HbC, then HbS, then HbA) because regardless of their order/position, the sample will proceed through the device. Since each capture antibody is specific for a particular variant, it would have been further obvious that the order is insignificant because each variant (if present in a sample) will bind only at its corresponding capture antibody). It is not expected that arrangement of the capture antibodies (the arrangement of their order) would have modified the operation of the device. MPEP 2144.04.
Regarding claim 55, Walker does teach pre-treating samples in order to expose hemoglobin epitopes (see para [0115]). More particularly Rutter et al. teach systems comprising a lysis buffer for lysing blood samples prior to addition of sample to the immunochromatographic device in order to release hemoglobin from the cells (Triton® X-100, see e.g., paras [0029], [0034] and Figure 2, Figure 2 showing the system including the buffer). Specifically, Rutter teach a system comprising an immunochromatographic substrate (discussed in detail above), the system also comprising the lysis solution which includes a detergent. The lysis solution including the detergent reads on “extraction buffer including detergent” as presently claimed, since the purpose is to extract hemoglobin from the cells.
Regarding claim 61, see the Rutter teach a single (general) detector antibody (Rutter’s invention also comprises a conjugated detector antibody that binds hemoglobin generally (e.g., paras [0013], [0016] and [0057], i.e. a single detector antibody)).
Regarding claim 5, Rutter et al. is as cited previously in detail above (see above detailed citations).
Although Rutter does teach capture and detection of hemoglobin variants, including hemoglobin variants other than glycated hemoglobin, Rutter fails to teach the system capable of detection of hemoglobinopathies (does not distinguish the variants), and fails to teach the control reagent as an antibody. Further as noted, Rutter et al. fails to teach each capture antibody with affinity to the N-terminus, while detector antibody with affinity to the C-terminus.
Walker et al. is also as cited previously in detail above (see above detailed citations).
Eisinger et al. is also as cited previously in detail above (see above detailed citations).
Davis is also as cited previously in detail above (see above detailed citations).
Harlow & Lane is as cited previously in detail above (see above detailed citations).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the lateral flow immunochromatographic device of Rutter, the device having capture antibodies for each of the hemoglobin variants as indicated, so that each of the different capture antibodies is located in its own indicator zone (see as suggested by Rutter, but also as in Eisinger) for the reasons as indicated previously above (see detailed analyses previously above, as the same reasoning also applies presently).
Additionally, it would have been further prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to have provided the control reagent of Rutter as an antibody that binds residual detector antibody, as in Davis, for the reasons as indicated previously above (see above analyses as the same reasoning also applies presently).
Independent claim 5, as previously amended, recites “wherein the immunoassay system is configured to…” see as discussed in detail previously above, the combination of the cited art addresses the claimed system. As such, the combination of the cited art addresses the amendments to claim 5, as well as newly recited claim 60.
Regarding claim 12, see as indicated previously above, the combination of the cited art results in a lateral flow device as claimed wherein the first, second and third capture antibodies are immobilized in an analyte capture zone at discrete (i.e., spatially distinct) capture zones.
Regarding claim 9, see the analyses above citing Davis, the control band as established by the combination of the cited art addresses the presently claimed “fourth capture antibody immobilized on the test strip in a fourth analyte capture zone” (immobilized fourth antibody as claimed).
Regarding claims 11 and 15, the limitations specific to the shape of the capture zones (see claim 11, rectangular shaped or circular shaped capture zones; claim 15 capture zones arranged in a linear array parallel and equidistant on chromatography matrix), see as in Rutter, capture zones are shown as equidistant parallel lines spanning the width of the membrane (rectangular, see Figure 7) and in Eisinger see Figure 9 described at col. 13, lines 53 to col. 14, showing indicator zones provided at equidistantly spaced circular spots. See Eisinger teaching (col. 13, end of column) geometry is arbitrary. The courts have held that changes in shape would have been obvious absent persuasive evidence that the particular configuration of the claimed structure was significant (MPEP 2144.04, IV, B). It would have been obvious to have provided the capture antibodies in the distinct positions, equidistant from one another in order to distinguish one from another, in either of rectangular or circular shape because Eisinger teach regarding devices comprising multiple binding reagent, that the geometry is arbitrary. One of ordinary skill in the art would have a reasonable expectation of success providing either shape capture zones (either rectangular or circular) considering the shape was an art recognized feature considered insignificant (Eisinger).
Regarding claim 13, see Rutter teaches a lateral flow devices comprising sample addition areas (Rutter, Figure 7, sample addition port and pad para [0058]). The device as taught by the combination of the cited art capable of receiving sample such as whole blood.
Regarding claim 14, the limitation “wherein the sample receiving area is configured to receive whole blood samples, dried blood samples, packed red cell samples, isolated or purified human hemoglobin protein samples, or freshly collected filter paper samples” fails to further limit the sample receiving area to any specific or particular structure. It would be expected that the device as taught by the combination of the cited prior art be considered configured to receive at least whole blood samples or isolated or purified human hemoglobin samples since such samples encompass fluid samples and the device as taught by the cited prior art is a lateral flow device capable of receiving fluid samples including blood (see e.g., Rutter teaching blood samples mixed with lysis solution added to the sample addition region, and Eisinger teaching whole blood samples added to a sample application zone, citations previously above).
Regarding claims 16 and 17, see as cited previously above, Rutter teach lateral flow devices comprising conjugate pad with conjugate impregnated thereon (Rutter, Figure 2 and paras [0058] and [0059], provided under or after sample pad, after addressing between sample and capture zones as at claim 17; e.g., para [0059] “provides sufficient time for the hemoglobin and glycated hemoglobin present in the sample to bind to the first and second detectably labeled agents, respectively that are present in the conjugate pad”).
Regarding claim 18, see Walker as cited above, the combination of the cited art addressing the detector antibody binding α or β chain as claimed (the antibody is necessarily one of a monoclonal or a polyclonal antibody, see further para [0072]). It would have been obvious to have provided the detector antibody of Walker as the detector antibody that binds each variant as an obvious matter of a known reagent for its known purpose (Walker specifically teaching the antibody detects all variant forms, as such, one would have a reasonable expectation of success).
Regarding claim 20, see as discussed above, the combination of the cited art addresses detectable moiety that is an enzyme or a particulate label.
Regarding claim 21, the combination of the cited art addresses the matrix material as claimed, see for example Rutter teach suitable known materials such as nitrocellulose, nylon and the like (col. 6, lines 52-55, thereby addressing nitrocellulose membrane as claimed).
Regarding claim 22, the combination of the cited art addresses a strip comprising the components of a sandwich assay (see capture and detector antibody sandwich the target analyte).
Regarding claims 23 and 24, as indicated previously above, the device as taught by the combined prior art simultaneously detects HbS, HbC and HbA. Further the devices capable of quantitative determination of analyte (see e.g., abstract, and paras [0007], [0052] of Rutter, and Eisinger et al., col. 20, lines 28-30 and Example 6).
Regarding claim 26, see also as addressed previously, the combination of the cited prior addresses a device configured to be used at point of care.
Regarding claim 57, see as cited above Eisinger teach labels including colored particles (col. 5, line 30 for example); see at lines 31-32, Eisinger teach detection by means of, for example, direct visual observation, by developing a color (see also col. 13, lines 35-36 describing the ability to see color; and col. 18, lines 36-39, and also lines 62-63, referring to visible particle entrapment as convenient). It would have been further obvious to have detected the detector antibody by visualization of color for convenience. One having ordinary skill would have a reasonable expectation of success considering the modification would amount to using a known label for its art recognized purpose.
Regarding claim 58, it would have been obvious, and one of ordinary skill would have a reasonable expectation of success, to have arranged the capture zones in any order including in the order of HbC, HbS and HbA (such that sample first interacts with HbC, then HbS, then HbA) because regardless of their order/position, the sample will proceed through the device. Since each capture antibody is specific for a particular variant, it would have been further obvious that the order is insignificant because each variant (if present in a sample) will bind only at its corresponding capture antibody). It is not expected that arrangement of the capture antibodies (the arrangement of their order) would have modified the operation of the device. MPEP 2144.04.
Regarding claim 62, see the Rutter teach a single (general) detector antibody (Rutter’s invention also comprises a conjugated detector antibody that binds hemoglobin generally (e.g., paras [0013], [0016] and [0057], i.e. a single detector antibody)).
Claim(s) 63 and 64 are rejected under 35 U.S.C. 103 as being unpatentable over Rutter et al. in view of Walker et al., Eisinger et al., Davis et al., and Harlow & Lane, as applied to claims 54 and 57, and further in view of Boyanapalli, US PG Pub No. 2012/0225422A1 and Babu et al., US PG Pub No. 2013/0230846A1.
Rutter et al. and the cited prior art teach a system/device substantially as claimed (see as cited in detail previously above, referring to the point of care, immunochromatographic assay device described in detail above). Rutter et al. does teach (para [0045]), detection methods can be based on absorption, change of color, optical methods (light scattering, fluorescence reflectance, luminescence, etc.), may be relied upon in their invention. Rutter teach embodiments comprising signal from a first detectable and/or second detectable marker are measured using a light source at the point of immobilization, and other embodiments for example that detect fluorophore emission (paras [0046], [0047]).
Rutter et al. fails to teach detectable by a visual color that is blue.
Immunochromatographic test strip devices/systems are well known in the prior art, another example, see Boyanapalli, utilizes colorimetric detection as referenced in Rutter above. See paras [0009], [0017], [0018], [0019] teaching that when colored nanoparticles are used, the ligand-bound nanoparticles assemble at the capture zone leading to a visible result. See further paras [0029]-[0031], Boyanapalli describe the use of blue colored nanoparticles.
Babu et al. is also teaching a lateral flow device (abstract), the device also using detectable labeled conjugate (para [0173]), that labeled conjugate can be for example, colored latex beads, fluorescent nanoparticles, etc. Babu teach visual label may be any label visible to the naked eye, including but not limited to colored particles (para [0175]). See for example, paras [0282]-[0283] Babu describe using a blue dyed latex bead conjugate label.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified Rutter and the prior art in order to rely on colorimetric labels, as in Boyanapalli and Babu, namely blue colored nanoparticles (Boyanapalli), as an obvious matter of a known colorimetric label available and usable for detection of a targeted analyte by way of immunochromatographic test device (such labels were an art recognized, known label usable for detection on this type of assay device), one further motivated because these labels are recognized in the prior art as visible by the naked eye (simplified detection by visual inspection).
One having ordinary skill in the prior art would have a reasonable expectation of success using a label known and available, shown to be capable of detection by way of immunochromatographic test strip device/system.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Response to Arguments
Applicant's arguments filed 07/10/2026 have been fully considered but they are not persuasive.
Regarding the rejection of claims under 35 U.S.C. 103, Applicant argues (remarks page 12-13, that the Office has cited references from incompatible fields in support of the instant rejections, arguing references from diabetes management (Rutter, Walker), general laboratory manuals (Harlow and Lane) and protease detection (Davis). Applicant remarks that Davis, in particular, focuses on the detection of active protease enzymes in a sample, a mechanism entirely unrelated to the immunological detection of intact hemoglobin variants. Applicant asserts that there is no evidence that one of ordinary skill in the art seeking to detect hemoglobinopathies would look to the field of protease detection in samples for structural components of an immunoassay system or device.
Applicant’s argument is not persuasive, for example, although Rutter’s device is useful related to diabetes, Rutter as noted above (see also para [0007] in addition to para [0041]) teaches analysis of hemoglobin, glycated hemoglobin and other variants (including those claimed). See also Walker also addresses other hemoglobin variants, Walker does teach the variation which distinguishes between the different hemoglobin species (HbA, HbS and HbC) as being a varied amino acid residue in the N-terminal region of the beta chain (para [0041]); see previously cited above, Walker does address the different capture antibodies as claimed. See at para [0026] Walker teach detection of multiple hemoglobin variants (two or more) in multiplex manner.
Applicant’s remarks that Davis is directed to protease detection fails to also acknowledge that Davis is relevant in that it is another example in the prior art of a lateral flow immunoassay device/system, the argument doesn’t acknowledge that Davis is teaching a structurally similar system to that of the earlier cited reference (an chromatographic assay device which operates on the principle of lateral flow of fluid as in Rutter and Eisinger). Davis is cited as teach providing a control band (immobilized anti-IgG) at the substrate device, specifically providing excess labeled antibody, such that even if the targeted analyte is present in the sample, there is sufficient labeled species present to ensure some passes beyond the capture band. Davis teach, whether or not the analyte is present, some labeled antibody reaches the control band. As such, Davis is teaching a control that demonstrates proper operation of the device regardless of presence/absence of analyte.
Applicant argues one of ordinary skill in the art would have no rational motivation to modify a diabetes-centric assay or protease detection product to arrive at the system or device for detection of hemoglobinopathies, such as sickle cell disease. Applicant asserts that in the immunoassay system or device of the present invention, there are no cleavable components, i.e., no protease or peptides are cleaved by protease enzymes during the hemoglobinopathies.
However, Applicant’s argument (focused on that there is no motivation to modify Davis) is not persuasive as it overlooks the fact that Davis is not cited as primary reference, and also that the primary reference (Rutter) is focused on hemoglobin detection, and that one would be motivated to modify a lateral flow assay device (as that of Rutter’s, or Eisinger) to have provided control reagent of Rutter as an antibody that binds residual detector antibody as in Davis would be considered an obvious matter of applying a known technique to a known immunochromatographic product; one having ordinary skill in the art would have recognized that applying the technique of providing a control band to bind residual detector antibody would have yielded predictable results, namely the ability to confirm proper operation of the device during its use. One having ordinary skill would have had a reasonable expectation of success in modifying the device to provide a control as in Davis because the device of Davis, similarly to that as taught by the combination of the cited art, operates by lateral flow of sample through conjugate (the conjugate is already present at the device, and would be available to bind at a control for showing proper operation, this modification feasible considering it was already an art recognized technique, as shown by Davis).
At remarks pages 13-14, Applicant further references amendments to the claims to overcome rejection (see referring to amendments at claims 1 and 5), Applicant remarks that Rutter (page 15) at best teaches a chromatographic test strip for glycated hemoglobin (HbA1c) quantification in diabetes monitoring, that it uses a single capture zone with one anti-total Hb antibody capturing hemoglobin indiscriminately, plus a boronic acid derivative detection detecting only glycated Hb. Applicant assert that Rutter's method requires contacting hemoglobin released from cells with a first fluorophore- labeled agent (antibody) that binds hemoglobin and a second fluorophore-labeled agent that binds only glycated hemoglobin before (emphasis on before) immobilizing the detectably labeled hemoglobin and glycated hemoglobin on the same region of a test strip or solid support. Applicant remarks that subsequently, the solid support is exposed to light of two different wavelengths, and a detector simultaneously measures the emitted fluorescent signals to determine the percentage of glycated hemoglobin in the sample; measuring glycated hemoglobin (HbA1c) in blood samples determines long-term blood glucose levels by calculating the percentage of hemoglobin in red blood cells that is coated with sugar (glucose).
Applicant argues that Rutter does not teach: hemoglobinopathy detection without the use of powered emitters or optical detectors; three N-terminus binding capture antibodies with selective binding affinity for HbA, HbS, and HbC; spatially discrete capture zones per variant; or a C-terminal alpha-chain detector antibody.
However, the rejection relies on Rutter as a whole, it is not disputed that Rutter teach detection of glycated hemoglobin, however, Rutter also teach detection of other variants, (see as cited in full detail in the pending rejection above). It is understood from Rutter that Rutter does teach discrete zones (discrete being spatially distinct, see e.g., at para [0055], from the description of Rutter’s capture zone it is understood this is a discrete zone, see teaching the strip may include more than one capture zone for hemoglobin).
Regarding the limitations that Rutter requires powered emitters and optical detectors, notably there is nothing in the present claim language that excludes the use of any type of optical or reader system from visualizing the capture analytes.
Applicant also argues the citation of Walker et al. (remarks pages 15-17), arguing Walker discloses monoclonal antibodies for common hemoglobin variants, HbA, HbS, HbC, HbD, and HbE, and their glycated forms in bead based assay (emphasis on bead based assay) for correcting and monitoring HbA1c measurements in diabetic patients not for hemoglobinopathy detection. Applicant argues Walker’s method requires the use of an expensive flow cytometry instrument or system with two distinct lasers and advanced optical detectors to measure fluorescent emissions from color-coded, antibody conjugated microspheres or beads to detect and quantify, with use of calibration curves, proportion of glycated hemoglobin variants (HbA1c) relative to total hemoglobin in a blood sample. Applicant asserts Walker is not teaching lateral flow device for POC testing.
In response, notably it is Rutter et al., cited as the primary reference, that is teaching an immunochromatographic test strip (nitrocellulose membrane, see para [0023] and Figure 7, and as cited in detail above), Rutter is teaching a point of care system (see also para [0007], [0024]). It is also noted that the instant system is recited using open claim language “comprising”, for example, the claimed system is not limited to consisting of only those three variants (does not exclude detection of glycated hemoglobin). It is maintained for the reasons discussed in detail previously and above, that it would have been obvious to have modified Rutter’s system. As noted above, although Rutter’s invention does encompass providing more than one capture zone (see referring to para [0055], Rutter describing having more than one capture zone, capture zone described their own bands/spots), it also would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the lateral flow immunochromatographic device of Rutter, the device having capture antibodies for each of the hemoglobin variants as indicated, so that each of the different capture antibodies specific to the variants is located in its own indicator zone (discrete capture zones which are differentiable) in the capture region, as also taught by Eisinger, thereby allowing the simultaneous detection and visualization of each of the hemoglobin variant forms (differentiated from one another), one being motivated to adopt this configuration/format in order to determine the presence of the variants and their proportions relative to HbA in order to properly achieve/assist in achieving glycemic control for diabetic patients (for example, see Walker, teaching it is desirable for this reason, to know/detect each of the variants and their amounts, modifying to have each separately presented would accommodate the ability to determine the presence of each relative to HbA).
Although Walker’s motivation is for determining each relative to HbA, it is still the result that the device as modified by the cited art (while motivated differently than Applicant’s own motivation) results in a system/structure that is not distinct from that which is claimed.
Additionally, regarding Walker, it would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the detector antibody, specifically to have relied on a universal detection antibody with affinity to the C-terminal region of the β chain, by applying the known technique of Harlow & Lane when employing a universal detection antibody (as in Walker, see as cited Walker is teaching a universal detector antibody).
Applicant argues (remarks page 16) that one of ordinary skill would not have looked to Walker and Rutter, asserting that Walker’s antibodies were developed for a different purpose (HbA1c correction for blood glucose measurement, not detection of hemoglobinopathies), (2) transfer from a bead based, flow cytometry platform to a lateral flow requires not trivial optimization, and further that Walker is not teaching discrete spatial separation of capture zones.
These arguments are not persuasive for reasons discussed previously and above. For example, at para [0055], from the description of Rutter’s capture zone it is understood this is a discrete (spatially discrete) zone, see teaching the strip may include more than one capture zone for hemoglobin), Walker is not relied upon as addressing this limitation. The reasons to modify are maintained for the reasons discussed in detail below.
Additionally (remarks pages 17-18) Applicant argues that the selection of C-terminus of hemoglobin alpha chain as the detector epitope is a non-obvious inventive choice, that this is a conserved region across the claimed variants, that it is accessible and immunogenic, and avoids the variant distinguishing N-terminal beta chain residues, enabling unbiased detection. This argument is not persuasive, particularly as Harlow & Lane teach similarly that this C-terminal region is accessible and immunogenic (generally), and considering the prior art also similarly notes what Applicant argues, that this region is conserved (making it ideal for detection). Applicant’s argument is consistent with motivation as derived from the cited prior art.
At page 18 Applicant argues that the disclosed systems and devices are configured to simultaneously detect HbS, HbC and HbA in a sample, that this is relevant to accurately differentiate various forms of SCD and sickle cell traits. Applicant therefore argues that the disclosed device and systems are “configured” to differentiate sickle cell conditions, that the cited art is not. However, see as indicated in the amended grounds of rejection, the claimed invention is not structurally distinct- despite the assertion that it is by applicant, the combination of the cited art is also simultaneously detecting and visualizing HbS, HbC and HbA, so absent a structural difference it is considered “configured” the same way.
At remarks page 19 Applicant presents further arguments specific to dependent claim limitations, Applicant arguing the cited prior art does not address “spatially discrete” zones as claimed. However,see as cited in detail above, the cited prior art is considered to address this limitation (from the language of Rutter it is understood that the device accommodates more than one capture zone, see referenced above).
Regarding claims 13 and 14 (page 19-20), Applicant also argues Rutter’s lysis is for HbA1c release in a diabetes context for fresh blood, that applying that technique to a multi-variant hemoglobinopathy detection system is not straightforwardly obvious. This argument is not persuasive, regarding claim 13, see Rutter teaches a lateral flow devices comprising sample addition areas (Rutter, Figure 7, sample addition port and pad para [0058]). The device as taught by the combination of the cited art capable of receiving sample such as whole blood.
Further, claim 14 is addressed, specifically, the limitation “wherein the sample receiving area is configured to receive whole blood samples, dried blood samples, packed red cell samples, isolated or purified human hemoglobin protein samples, or freshly collected filter paper samples” fails to further limit the sample receiving area to any specific or particular structure. It would be expected that the device as taught by the combination of the cited prior art be considered configured to receive at least whole blood samples or isolated or purified human hemoglobin samples since such samples encompass fluid samples and the device as taught by the cited prior art is a lateral flow device capable of receiving fluid samples including blood (see e.g., Rutter teaching blood samples mixed with lysis solution added to the sample addition region, and Eisinger teaching whole blood samples added to a sample application zone, citations previously above). Applicant’s remarks have not persuasively argued reasons as to why/how the claimed sample receiving area is distinct.
Regarding claim 16 (remarks page 20), Applicant further argues the positioning of the conjugate pad and the sample receiving area is not addressed by the cited art. However, see as cited previously above, Rutter teach lateral flow devices comprising conjugate pad with conjugate impregnated thereon (Rutter, Figure 2 and paras [0058] and [0059], provided under or after sample pad, after addressing between sample and capture zones as at claim 17; e.g., para [0059] “provides sufficient time for the hemoglobin and glycated hemoglobin present in the sample to bind to the first and second detectably labeled agents, respectively that are present in the conjugate pad”).
Further regarding remarks at page 20-21, Applicant goes on to argue each of claims 20, 53, 55, 58, 61 and 62, however, the rejections are maintained for the reasons as indicated above, each of these limitations is as addressed above in the pending grounds of rejection.
At remarks pages 21-22 Applicant refers to the Declaration pursuant to 37 CFR 1.132 by co-inventor Dr. Frank Wang (hereinafter referred to as the Wang Declaration), as well as exhibits A to E.
At the Wang Declaration paragraph 5 it is indicated that Sickle Scan™ is a commercial embodiment of the claimed invention, that the structural elements as claimed correspond to the structure of this commercial device, and the commercial success and clinical acclaim described are attributed to these features.
The Wang Declaration asserts that prior to the subject application, methods and devices for POC detection of hemoglobinopathies like Sickle cell disease represented a long-felt need in the art and medical communities worldwide (paragraph 6), asserting this is evidenced by the true and accurate copy of the RFI: Challenges and Opportunities for the Development of a Point of Care Device for the Diagnosis of Sickle Cell Disease, issued by the National Heart, Lung and Blood Institute of the US NIH on April 6, 2012, attached presently as Exhibit A.
The Wang Declaration at paragraph 7 asserts Williams et al., (referred to at remarks as Exhibit B) is evidence the Applicant’s Sickle SCAN™ is s solution to the long felt need. However, this evidence is not evidence that if persons skilled in the art who were presumably working on the problem knew of the cited prior art of record, they would still be unable to solve the problem. It is not disputed that Applicant’s invention is a rapid, POC screening tool that allows rapid detection of the hemoglobin variants that distinguish hemoglobinopathies, however, Applicant’s remarks and evidence are not persuasive that the claimed invention is unobvious over the cited prior art of record. This is similarly the case regarding Applicant’s cited Exhibits C, D and E (Kanter et al., which is cited as stating the Sickle SCAN has “an unprecedented capacity to differentiate SCD…”, Nguyen-Khoa et al., cited as stating this commercial scan “fulfills analytical conditions for neonatal screening of sickle cell disease”, and Nwegbu et al., which references the scans high sensitivity of detection).
Applicant’s evidence suggests that prior to the invention, no one in this art took the step toward a point of care immunochromatographic test device capable of detecting the various hemoglobin variants. However, prior to Applicant’s filing date Rutter et al. took that step and taught such a system/device capturing and detecting hemoglobin, the reference specifically naming the ability/suggestion to detect the specific claimed variants, and teaching the ability to provide more than one/multiple capture zones (see Rutter discussed previously above). In doing so, Rutter et al. supplied the key element required to satisfy the long-felt need that Applicant’s contend was recognized in the art. Newell, 864 F.2d at 768 (“[O]nce another supplied the key element, there was no long-felt need or, indeed, a problem to be solved.”). As a result, the system set forth in claims of the instant application is nothing more than a system that would have resulted from following the combined teachings of the cited prior art (taking into account the knowledge and techniques recognized in the prior art prior to Applicant’s effective filing date, i.e., regarding the use of the terminal regions of targeted analytes for antibody binding, regarding general lateral flow technique, e.g., the control strategy as in Davis, etc.).
At remarks page 22 Applicant also refers to new claims 63 and 64, see the amended grounds of rejection as set forth in detail previously above.
Correspondence
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/ELLEN J MARCSISIN/ Primary Examiner, Art Unit 1677
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