Patent Application 14725894 - LATERAL FLOW IMMUNOASSAY METHOD OF - Rejection

Patent Application 14725894 - LATERAL FLOW IMMUNOASSAY METHOD OF

Title: LATERAL FLOW IMMUNOASSAY METHOD OF SIMULTANEOUSLY DETECTING HEMOGLOBIN S, HEMOGLOBIN C, AND HEMOGLOBIN A IN NEWBORNS, INFANTS, CHILDREN, AND ADULTS

Application Information

• Invention Title: LATERAL FLOW IMMUNOASSAY METHOD OF SIMULTANEOUSLY DETECTING HEMOGLOBIN S, HEMOGLOBIN C, AND HEMOGLOBIN A IN NEWBORNS, INFANTS, CHILDREN, AND ADULTS
• Application Number: 14725894
• Submission Date: 2025-04-09T00:00:00.000Z
• Effective Filing Date: 2015-05-29T00:00:00.000Z
• Filing Date: 2015-05-29T00:00:00.000Z
• National Class: 435
• National Sub-Class: 007100
• Examiner Employee Number: 90066
• Art Unit: 1677
• Tech Center: 1600

Rejection Summary

• 102 Rejections: 0
• 103 Rejections: 2

Cited Patents

No patents were cited in this rejection.

Office Action Text

    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.  

Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection.  Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.  Applicant's submission filed on 05/13/2024 has been entered.
 
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
In the interest of compact prosecution, Applicant’s submission 05/13/2024 is accepted. However, Applicant is reminded of the proper format for amendments to the claims. See MPEP 714.
	In the present case, although claim 1 is presented (05/13/2024) consistent with previous amendments to the claims (02/06/2023), other claims are not accurately represented.
	Claim 17 has the status identifier “Currently Amended”, however no claim amendment is shown. It appears this claim should be presented as “Original”. 
	For example, claims 34, 35, 39 and 44 are shown presently as withdrawn (05/13/2024); however, referring to the previous claims (02/06/2023), these claims stand canceled. In the interest of compact prosecution these withdrawn claims are considered to remain canceled. 
	Claims 1-3, 5, 8, 9, 11-18, 20-24, 26, 37, 38, 40, 42, 43, 45-51, 53-55 and 57-60 are pending; claim 16 is amended; claims 37-38, 40, 42, 43 and 45-50 are withdrawn; and claims 4, 6-7, 10, 19, 25, 27-36, 39, 41, 44, 52 and 56 are cancelled (this includes claims 34, 35, 39 and 44 discussed above). Claims 1-3, 5, 8, 9, 11-18, 20-24, 26, 51, 53-55 and 57-60 are examined presently.

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, 51, 53-55 and 59 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), the system of Rutter’s invention also comprises a conjugated detector antibody that binds hemoglobin generally (e.g., paras [0013], [0016] and [0057]), 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 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). 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 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).
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 specific to the variants is located in its own indicator zone in the capture region, as in Eisinger, thereby allowing the simultaneous detection and visualization of each of the hemoglobin variant forms, one being motivated to do so 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 (Walker, teaching it is desirable for this reason, to know/detect each of the variants and their amounts).
The ordinarily skilled artisan would have a reasonable expectation of success considering Rutter already disclose the ability to detect hemoglobin with immunochromatographic systems, 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) 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 (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 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). One would be motivated to modify the detector antibody to target the C-terminal region 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.
Independent claim 1, as amended, recites “wherein the immunoassay system is configured to assist in diagnosing sickle cell disease, hemoglobin C disease, 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. 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. 

Claims 5, 8, 9, 11-18, 20-24, 26, 57, 58 and 60 are rejected under 35 U.S.C. 103 as being unpatentable over Rutter et al. in view of Walker et al., Eisinger et al. and Davis et al.
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.
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). 
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, 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 amended, recites “wherein the immunoassay system is configured to assist in diagnosing sickle cell disease, hemoglobin C disease, 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. As such, the combination of the cited art addresses the amendments to claim 5, as well as newly recited claim 60. 
Regarding claims 8 and 12, see as indicated previously above, the combination of the cited are results in a lateral flow device as claimed wherein the first, second and third capture antibodies are immobilized in an analyte capture zone.
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.

Response to Arguments
Applicant's arguments filed 05/13/2024 have been fully considered but they are not persuasive for the following reasons.
Regarding the rejection of claims under 35 U.S.C. 103, remarks pages 12-13, Applicant asserts the rejection is applying inappropriate hindsight reasoning. Specifically, Applicant argues that although the prior art might appear combinable or modifiable in a manner that with yield the claimed invention, this in itself will not make the resultant modification obvious. Applicant refers to Cardiac Pacemakers, Inc. v. St. Jude Medical Inc., 381 F.3d 1371 (Fed. Cir. 2004), indicating the district court found that the claimed implantable heart stimulator would have been obvious because each of the claimed elements was previously known, the court deciding there was a known need to treat mixtures of arrhythmias, that it would have been obvious to combine known methods of separate treatment. Applicant refers next to the Federal Circuit’s disagreement (Federal Circuit determining the claims were not obvious), indicating that the Federal Circuit found that there is an important distinction between the general motivation to cure and uncured disease, that recognition of an unsolved problem does not render the solution obvious.
At remarks page 13, Applicant argues in the present case, the proposed motivations are recognition of unsolved problems.
In response to Applicant's argument that the Examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning.  But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the Applicant's disclosure, such a reconstruction is proper.  See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). It is maintained presently that only that which was within the level of ordinary skill was taken into account. The motivation to combine and reasonable expectation of success are all derived from the cited prior art, and do not rely on knowledge gleaned from the originally filed disclosure of the original application.
In response to Applicant’s argument, although the Federal Circuit, in Cardiac Pacemakers, Inc. v. St. Jude Medical, Inc., found the prior art acknowledged the problem, but had not previously recognized a solution to the problem, this is not consistent with the prior art applied to the present claims. In the present grounds of rejection, the motivations to combine the cited prior art are not solutions to unsolved problems.
For example, addressing the applied motivations in the order as they are set forth in the pending rejection above, (1) the first modification set forth, namely that it would have been prima facie obvious to have modified the lateral flow immunochromatographic device of Rutter so that each of the different capture antibodies specific to the variants is located in its own indicator zone in the capture region, as in Eisinger, the motivation there is that this modification would allow the simultaneous detection and visualization of each of the hemoglobin variant forms, one being motivated to do so 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. This motivation is specifically supported by Walker, Walker et al. teach that hemoglobin variants affect immunologically determined levels of glycated hemoglobin. The Examiner acknowledges that this could be considered a recognized problem in the prior art. Notably, Walker teach a solution to this problem, Walker specifically 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). 
As such the prior art is specifically presenting a problem/concern and a solution to address it, therefore Applicant’s argument is not persuasive that this particular motivation is a solution to an unsolved problem. 
As noted in the maintained rejection, the ordinarily skilled artisan would have a reasonable expectation of success modifying Rutter as indicated above, considering that Rutter already disclose the ability to detect hemoglobin with immunochromatographic systems, 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.
Regarding the next motivation, (2), the Examiner maintains that it would have been further prima facie obvious to have provided the control reagent of Rutter as an antibody that binds residual detector antibody, as in Davis, specifically because this allows the user 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 (i.e., 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 (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). 
The immediately discussed motivation above is not a recognition of an unsolved problem, but rather an art recognized technique for ensuring proper operation of an immunochromatographic device.
Finally (3), it is maintained that it would have been prima facie obvious 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). One would be motivated to modify the detector antibody to target the C-terminal region as claimed because it was known in the art that the variant residues (the residues distinguishing the variants) are 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. 
Similarly as above, it is maintained that this motivation is not merely recognition of an unsolved problem. 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). Specifically, to have relied on a universal detection antibody with affinity to the C-terminal region of the β chain, is merely applying a known technique (a way of achieving said universal antibody).
At remarks page 13, Applicant argues the Supreme Court in KSR urged that rejections cannot be sustained on merely conclusory statements, that there must be some articulated reasoning with some rationale underpinning to support legal conclusion of obviousness. Applicant specifically argues the references cited in the rejection do not meet the required standard to support obviousness rejection, arguing they do not teach or suggest each and every element in the claims. At remarks page 14, Applicant asserts that the cited prior art does not teach or suggest an immunoassay system for detection of hemoglobinopathies or lateral flow immunoassay device for the detection of hemoglobinopathies wherein the device is configured to assist in diagnosing sickle cell disease, hemoglobin C disease, or sickle hemoglobin C disease, based on hemoglobin status. Applicant argues that the cited prior art references pertain to diabetes and not hemoglobinopathies in the context of assisting diagnosis status as claimed. 
It is maintained for the reasons as indicated above, that the rejection articulates reasons to combine with rationale underpinning to support the conclusion of obviousness, as a result Applicant’s arguments at remarks pages 14-15 are not persuasive. Regarding the argued limitations, that the prior art fails to teach or suggest an immunoassay system for detection of hemoglobinopathies or lateral flow immunoassay device for the detection of hemoglobinopathies wherein the device is configured to assist in diagnosing sickle cell disease, hemoglobin C disease, or sickle hemoglobin C disease, based on hemoglobin status, the argued limitations are directed to the intended use of the claimed device (the examined claims are directed to a product/products). 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  the same argued/recited intended use, namely capable of detection of hemoglobinopathies, of being configured to assist in diagnosing sickle cell disease, hemoglobin C disease, or sickle-hemoglobin C diseased based on hemoglobin status. 
At remarks page 15, regarding claim 16, Applicant specifically argues that Rutter does not expressly disclose that the conjugated detection antibody is impregnated into the conjugate pad. However, this argument is not persuasive, see for example, paras [0058] and [0059] (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”). Rutter et al. communicates conjugate is provided in the conjugate pad (impregnated therein).
For all of these reasons, Applicant’s arguments are not persuasive.

Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114.  See MPEP § 706.07(b). 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.

Correspondence
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/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677