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 .
Status of the Claims
Claims 1-7 are pending; claims 1 and 7 are amended; claim 6 is withdrawn; and claims 1-5 and 7 are examined below.
Priority
The present application was filed 09/16/2019, is a continuation of PCT/KR2019/009573, filed 07/31/2019. Acknowledgement is made of applicant’s claim for foreign priority under 35 U.S.C 119(a)-(d) to application No KR10-2019-0080618, filed 07/04/2019 in The Republic of Korea.
Claim Objections
Claims 1 and 7 are objected to because of the following informalities:
Newly amended claims 1 and 7 recite “line are separated each other”. There appears to be a grammatical error. It is suggested to replace “are separated each other” with --- are separated from each other---. Appropriate correction is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The rejection of the claims under 35 U.S.C. 103 is maintained for reasons of record reiterated below.
Claims 1-3, 5 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Chang et al., US7332350B2, 02/19/2008 (see PTO-892, 11/09/2023), in view of Nazareth et al., USPGPUB20130164858A1, 07/27/2013 (see PTO-892, 02/10/2022), Ma et al., CN106248975, 12/21/2016 (see PTO-892, 02/10/2025), Yang et al., CN108931654A, 12/04/2018 (see PTO-892, 06/06/2024), and Polito et al., US6136610, 10/24/2000 (see PTO-892, 11/09/2023).
Regarding claim 1, Chang teaches a one-step diagnostic device for detecting normal pregnancy and distinguishing it from ectopic pregnancy (an immune device that detects whether a woman is pregnant or not; Chang, ‘Abstract’, lines 1-3). Chang further teaches an inner strip, comprising a specimen receiving pad (sample region for receiving a test sample; Chang, see Figure 3, number 28 and Column 4, lines 65-67), a colored particulate pad downstream of the specimen receiving pad (conjugate region; Chang, see Figure 3, number 27 and column 4, lines 64-65), the conjugate pad comprising monoclonal anti-I-hCG antibody, bound to colored particulates and further comprising antibody against modified hCGs, see the antibodies bound to colored particulates and incorporated into a colored particulate pad (Chang, column 6, lines 12-21, Chang teaching I-hCG, which is overexpressed in atopic pregnancy, is provided bound to colored particulates, incorporated into the particulate pad; simultaneously, antibody against modified hCG is also bound and incorporated). Chang further teaches that the monoclonal antibody bound to colored particulates is used as the mobile phase (i.e., the antibodies are not immobilized at the conjugate region; Chang, ibid and column 5, lines 21-25).
Chang further teaches that “modified” hCGs include free β-core-fragment (i.e., bcf hCG) Chang, column 2, lines 37-39).
Chang further teaches an antibody immobilized nitrocellulose domain (signal detection region) downstream of the conjugate region (Chang, see Figure 3, number 26 and column 4, lines 45-58). Chang further teaches a normal pregnancy line where an anti-β-hCG antibody has been immobilized (Chang, see figure 2b, number 23 and column 4, lines 45-58), an ectopic pregnancy line where an anti-α-hCG monoclonal antibody has been immobilized (Chang, see figure 2b, number 22 and column 4, lines 45-58), and a completion line where a rabbit anti-mouse immunoglobulin polyclonal antibody has been immobilized (analogous to the claimed ligand; Chang, Figure 2b, Number 21 and column 4, lines 45-58).
Chang further teaches that the test completion line where a rabbit anti-mouse Ig antibody has been immobilized is visually observable in a non-pregnant female, a female with a normal pregnancy, and a female with an ectopic pregnancy (constant signal, regardless of hCG and modified hCG concentration, because the ligand does not bind I-hCG or modified hCG; Chang, column 16, see Claim 6). As such, Chang teaches three separate lines.
Chang further teaches that the anti-α-hCG and anti-I-hCG antibodies are interchangeable with respect to their location at the device (Chang, column 7, lines 29-37; column 15, claim 4) and further that the anti-β-hCG and anti-modified hCG antibodies are interchangeable (Chang, column 16, claim 5), namely that rather anti-I-hCG be that which is bound the particulate for the mobile phase, that anti-I-hCG can be immobilized at the detection region. That is, in addition to the format above, Chang also teaches immobilized antibody against I-hCG and immobilized antibody against modified hCGs, used with particle-bound anti-β-hCG antibody conjugate and particle-bound anti-a-hCG antibody conjugate. Chang further teaches using an anti-I-hCG monoclonal antibody in combination with an anti-α-hCG monoclonal antibody detects I-hCG. As such, it is clear that the anti-α-hCG monoclonal antibody also binds I-hCG (Chang, column 3, line 64-column 4, line 3).
Chang also teaches a third line as a control line (see at Figure 2b, and the description thereof, line designated by reference number 21 designates a completion line, namely a line comprising rabbit anti-mouse immunoglobulin polyclonal antibody, this line captures colored particulate conjugates).
Chang further teaches a specimen absorbing pad downstream of the antibody immobilized membrane (wicking region connected to and located downstream of the signal detection region; Chang, Figure 3, number 25 and column 4, line 62). Chang further teaches that the pads are combined sequentially in a partially overlapping manner (Chang, column 4, lines 66-67). Chang further teaches that the specimen is absorbed and transported by capillary action (mobile phase moves by capillary phenomenon; Chang, column 6, lines 66-71).
Although Chang is teaching a device that detects both I-hCG and a modified hCG in a sample, and as such does teach a labeled anti-I-hCG conjugate probe, and does teach a test line for detecting I-hCG comprising antibody that binds/captures I-hCG (namely an anti-alpha-hCG which binds the complex between the conjugated anti-I-hCG and the I-hCG in the sample) and a test line for detecting modified hCGs, of which free βcf hCG is taught as an example of a modified hCG form, Chang fails to specifically exemplify a device having a first test line with an anti-I-hCG antibody immobilized (device comprising both the labeled anti-I-hCG and an anti-I-hCG immobilized at a test line) and a second test line having an immobilized anti-modified hCG antibody that is an anti-bcf hCG antibody (device comprising both labeled anti-bcf hCG antibody, and an anti-bcf hCG antibody immobilized at the test line).
Although Chang does teach a third line that is a control line, Chang further fails to teach a third conjugate with a probe in the conjugate region that is not immobilized at the conjugate region (i.e., a third mobile conjugate) and fails to teach a control line that binds the third mobile conjugate.
Nazareth teaches that βcf hCG is the predominant form of hCG in urine from about seven weeks of pregnancy and that high levels of βcf hCG can cause false negative results in urine-based pregnancy tests (Nazareth, page 1, paragraph [0005], lines 4-10]). Nazareth further teaches that accurate and rapid detection of low levels of various hCG isoforms and minimization of false negative results is desirable (Nazareth, page 1, see paragraph [0006]). Nazareth further teaches a device capable of detecting βcf hCG in addition to one more isoforms of hCG and teaches that this device can enhance clinical sensitivity by lowering the likelihood of false negative pregnancy test results (Nazareth, page 1, paragraph [0007], lines 7-9 and 12-16). Nazareth further teaches a device for detecting hCG isoforms in a liquid sample, wherein the device comprises a substrate comprising a first antibody that recognizes all clinically relevant hCG isoforms and a second antibody that is specific for an epitope unique to βcf hCG and a third antibody that binds multiple hCG isoforms, but not βcf hCG and that the first antibody can be conjugated with a detectable label (Nazareth, page 1, see paragraph [0008]) and that the second and third antibody are immobilized at one or more capture sites (test lines; Nazareth, page 1, paragraph [0009], lines 1-3). Nazareth further teaches that the liquid sample flows from the proximal portion to the distal portion and across a substrate so as to contact one or more antibodies. Nazareth further teaches that antibodies can be designed to recognize specific hCG isoforms (Nazareth, page 3, see paragraph [0024]). Nazareth further teaches that hCG isoforms include intact hCG and βcf hCG (Nazareth, page 3, paragraph [0025], lines 7-9). Nazareth further teaches that the capture antibody can be a monoclonal antibody that specifically binds βcf hCG or intact hCG (Nazareth, page 4, paragraph [0034], lines 6-9). Nazareth further teaches that one or more antibodies are bound to detectable label components (Nazareth, page 4, paragraph [0035], lines 1-3). Nazareth is silent on pairing an antibody specific for βcf hCG conjugated with a probe with an immobilized antibody specific for βcf hCG.
Ma teaches an immune diagnosis chromatography test paper (Ma, page 1, ‘Abstract’, line 1) comprising a test line T1 that is coated with anti-α-hCG, anti-β-hCG, or anti-complete-hCG (intact hCG) antibody and a test line T2 which is coated with an anti-hyperglycosylated-hCG antibody (Ma, page 4, see entire 4th paragraph). Ma further teaches preparing the device with a gold-labeled monoclonal or polyclonal antibody specific for α-hCG, β-hCG, or complete-hCG (intact hCG; Ma, page 5, see entire 7th paragraph). As such Ma is an example in the art that teaches an immunochromatographic device comprising an anti-intact-hCG (anti-I-hCG) antibody conjugated with a probe and an anti-I-hCG antibody immobilized at the first test line (two anti-I-hCG antibodies for capture and detection of I-hCG).
Yang teaches a device for early pregnancy detection with high sensitivity and specificity (Yang, page 2 of the attached translation, ‘Summary of the Invention’, see 1st paragraph). Yang further teaches coating an anti-βcf hCG antibody onto a first detecting line of a nitrocellulose membrane. Yang further teaches a second antibody (anti-α-hCG antibody) adhered to a second test line and a control line (Yang, abstract; pages 2-3 of the attached translation, steps 1-3). Yang further teaches labelling anti-βcf hCG antibody with colloidal gold (Yang, page 3, step 7; claim 1). Yang further teaches a nitrocellulose film, a conjugate pad and a sample pad and absorbent paper to obtain a urine pregnancy test kit (Yang, page 3, Step 9).
This design allows detection of hCG βcf by formation of a sandwich immune complex, whereby the core fragment is sandwiched between a first anti-βcf hCG antibody which is coated on a detection line of the nitrocellulose membrane, and a second labeled anti-βcf hCG antibody (see also page 7 of the attached translation).
Polito teaches another example of a lateral flow assay device (Polito, ‘Abstract’, lines 1-2). Polito further teaches a detection agent that comprises an analyte non-specific agent (conjugate with a probe), which is selected for its ability to bind to substances other than the analyte of interest (Polito, column 5, lines 41-43). Polito further teaches that these non-specific agents can bind to control zones (Polito, column 6, lines 3-4). Polito further teaches that control agents, present in the control zones, bind to the control binding agent to form a control binding pair and an advantage of the control binding pairs is that they are internal controls, i.e. the control against which the analyte measurement results may be compared. Therefore, the controls according to the invention may be used to correct for strip-to-strip variability (Polito, column 6, lines 32-41).
It would have been prima facie obvious to one having ordinary skill at the time of the claimed invention to have modified the device of Chang in order to provide an anti-intact-hCG (anti-I-hCG) antibody for the antibody immobilized on the control line as taught by Ma et al., in place of an anti-α-hCG antibody of Chang (Chang providing the anti-α-hCG at the capture line to capture/bind the intact-hCG bound to anti-I-hCG antibody labeled with a probe when the device is used) as an obvious matter of a simple substitution of one art recognized antibody used for detecting intact-hCG bound to an anti-intact-hCG antibody labeled with a probe for another, both recognized in the prior art as suitable for the same purpose (for capturing the complex of I-hCG bound the labeled anti-I-hCG as it migrates through the device), both binding intact-hCG (I-hCG) bound to an anti-intact-hCG antibody labeled with a probe. The ordinarily skilled artisan would have been motivated to do so, because the anti-I-hCG of Ma is being provided in Ma for the same intended purpose as the anti-α-hCG antibody of Chang, for capturing the I-hCG-anti-I-hCG labeled complex, both are recognized in the prior art as being provided to result in binding intact-hCG bound to an anti-intact-hCG antibody labeled with a probe. Substituting one monoclonal antibody capable and known in the art for binding/capturing intact-hCG bound to an anti-intact-hCG antibody labeled with a probe with another monoclonal antibody known to be usable for binding the same target (the complex), both of which are used in an immunochromatographic lateral flow assay, would be expected to yield a predictable result.
The ordinarily skilled artisan would have had a reasonable expectation of success in making the substitution, because both Chang and Ma teach a lateral flow assay with a gold labeled detection antibody and multiple test lines for the detection of different forms of hCG; as a result, one would have a reasonable expectation of success substituting Chang’s antibody known to bind intact-hCG bound to an anti-intact-hCG antibody labeled with a probe with the other antibody capable of binding the same complex.
It would have further been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the device of Chang, detecting intact hCG and modified hCG, to detect as the modified form, βcf hCG as taught by both Chang and Nazareth, one motivated to specifically detect bcf hCG as the modified form because Chang specifically indicate bcf hCG as one of the possible modified species to detect when detecting modified forms, and because Nazareth further teach that high levels of βcf hCG can cause false negative results, Nazareth teaching that a device capable of detecting βcf hCG in addition to one or more isoforms of hCG can enhance clinical sensitivity by lowering the likelihood of false negative pregnancy test results.
One having ordinary skill in the art would have a reasonable expectation of success detecting bcf hCG as the modified form of bcf hCG because Chang specifically recognize this species as a modified form of the marker, and further because modifying to enhance sensitivity would not be expected to disrupt use of the device as it’s intended to be used, but rather be considered an improvement.
When detecting βcf hCG as the modified form, it would have further been prima facie obvious to one having ordinary skill before the effective filing date of the claimed invention, to have provided the combination of an antibody labeled with a probe specific for βcf hCG and an immobilized antibody specific for βcf hCG as an obvious matter of applying the known technique of Yang, who indicate that the core fragment can be successfully detected in this manner (by providing two anti-bcf hCG specific antibodies in sandwich binding format). One having ordinary skill in the art would have a reasonable expectation of success making this selection of an antibody pair specific for βcf hCG core fragment, as taught by Yang, because sandwich binding format is consistent with Chang’s teachings, which also similarly uses a pair of antibodies to detect modified hCG forms of interest.
Additionally, one having ordinary skill in the art would have been motivated to combine the teachings of Yang with that of Chang in order to rely on anti-bcf hCG as both the conjugate and immobilized antibodies because this modification would amount to a simple substitution of one known combination of antibodies for binding βcf hCG over another. The prior art contained the base method (see as taught by Chang, a device comprising binding reagents for detecting intact hCG (I-hCG) and modified hCG). Further, at the time, the prior art recognized detection of βcf hCG as the modified type of hCG to be detected (Chang, Nazareth) in a liquid sample. In the instant case, Yang specifically teaches it was known in the art at the time to detect βcf hCG using an antibody pair comprising a first antibody recognizing a βcf hCG and a second antibody that also specifically detects βcf hCG. It would have been an obvious matter of a simple substitution of one technique over the other to have used two antibodies specific for βcf hCG to detect βcf hCG as taught by Yang, in place of the antibody pair comprising one antibody specific for βcf hCG and one recognizing all clinically relevant hCG isoforms, as taught by Chang in view of Nazareth because both antibody pairings were recognized as suitable the same purpose, both detecting βcf hCG in a device comprising immobilized antibody on a test line and labeled antibody that is not immobilized (mobile). One of ordinary skill in the art would have recognized that applying the art recognized, known anti-βcf hCG specific antibodies (probe labeled or immobilized) would have predictably resulted in a device capable of detecting βcf hCG, because Yang specifically disclose this pair of antibodies for this intended purpose.
It would have further been prima facie obvious to one having ordinary skill before the effective filing date of the claimed invention, to have modified the device of Chang with respect to Chang’s control/reference line, namely to modify the device such that the reference control is a third conjugate (detection agent) that is analyte non-specific at the conjugate pad and a ligand on the test line that binds the third conjugate as taught by Polito, as an obvious matter of a simple substitution of one art recognized control/reference line over another, both recognized as suitable for the same purpose, both producing a signal whether a form of hCG is present in the sample or not, both indicating that the liquid sample is properly passing through the immune device. The ordinarily skilled artisan would have been motivated to do so, because of the teaching of Polito that those non-specific agents that bind to the control zone immobilized control reagents act as internal controls, against which an analyte measurement can be compared and can therefore be used to correct strip-to-strip variability. The control/reference line of Chang performs the same function specified in the claim in substantially the same way and produces substantially the same results of producing a signal whether a form of hCG is present in the sample or not. Substituting one control zone producing a signal whether a form of hCG is present in the sample or not, such as the control zone taught by Chang with another control zone such as that taught by Polito, both of which have been successfully used in lateral flow devices, would yield a predictable result.
One having ordinary skill in the art would have a reasonable expectation of success making this modification because it would not be expected to disrupt the intended use of the device, Polito (like Chang) is similarly teaching a lateral flow device and so one having ordinary skill would expect success applying the control of Polito to the device of Chang and the cited art, the advantage being the ability to correct strip-to-strip variability (the control working regardless of binding/conjugates binding to analytes present or absent in the sample).
With regard to the claimed “first” and “second” test lines, wherein the first test line is located downstream of the conjugate region and the second test line is located downstream of the first test line, the ordinarily skilled artisan would readily appreciate that the placing of the two test lines as an obvious matter of design choice (See MPEP 2144.04, the rearrangement of parts has typically been held by the courts as an obvious matter of design choice). In this case, the anti-I-hCG antibody does not bind to modified hCG and the anti-modified hCG antibody does not bind to I-hCG and therefore switching the placement of the two test lines would not modify the operation of the device.
Regarding claim 2, Chang teaches that various types of colored particulates can be bound to the antibody, including for example colloidal gold particles (Chang, column 6, lines 15 and 20-24, nanometer sized particles, see at line 24-25, 20-60 nm).
Regarding claim 3, Chang teaches an antibody-immobilized nitrocellulose membrane region as the signal detection region (Chang, column 4, lines 63-64 and Figure 3).
Regarding claim 5, Chang and the cited art above as applied to claim 1 teach an immune device substantially as claimed. Both Chang and Nazareth teach that hCG and its various forms are produced during pregnancy (Chang, col. 2; Nazareth, [0003]-[0005]). Yang also indicates that full segment (intact) hCG and hCG beta core fragment are indicative of pregnancy. Furthermore, the limitation of claim 5 “wherein the immune device determines that a pregnancy is present when the control line and the first test line[…]” it is also noted that the claimed limitation is directed to the intended use of the claimed device. As discussed previously in detail above (see claim 1), Chang and the prior art teaches a pregnancy device with two test lines and a control line, the test lines comprising antibodies with the claimed specificities, namely anti-I-hCG and modified hCG (anti-βcf-hCG), and the control line an antibody not specific for either of the test targets. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art is capable of performing the intended use, then it meets the claim. In the instant case, the device as taught by Chang and the cited art operates when used in order to emit color when the substrate binds to the antibodies on test line 1, test line 2, and the control line. The device of Chang and the cited art, which is structurally indistinguishable from that presently claimed, would therefore be expected capable of determining if a pregnancy is present when the control line and the first test line, the control line and the second test line or the control line and the first and second test lines emit a color. Because the prior art device would be capable of performing the recited intended use, the reference meets the claim.
Regarding claim 7, Chang and the cited art above teaches an immune device substantially as claimed.
Claim 7 is substantially similar to the limitations of claim 1 in the limitations of the immune device as claimed, claim 7 differing only in the last three wherein clauses where the first “wherein” clause recites how the test sample moves through the device and contacts the antibody conjugates and binds the anti-I-hCG antibody if I-hCG is present in the sample and the anti-βcf-hCG-antibody if βcf-hCG is present in the sample. The second “wherein” clause recites formation of the conjugate complex comprising the antibody conjugate and the two hCG isoforms respectively. Finally, the third “wherein” clause recites binding of the conjugate complex comprising either I-hCG or βcf-hCG and the respective antibody conjugates to the immobilized antibodies at the test line.
As discussed previously in detail above, Chang teaches a device substantially as claimed (see above cited summary of Chang). Chang also teaches, that the pads (regions) are combined in a partially overlapping manner (connected; Chang, column 4, lines 65-66) and that the specimen is absorbed and transported by capillary action (mobile phase moves by capillary phenomenon; Chang, column 6, lines 66-71).
Chang further teaches that a specimen is applied to the specimen receiving pad (sample region), absorbed and transported to react with the monoclonal antibody-bound colored particulates incorporated in the colored particulate pad (moves to the conjugate region; Chang, column 6, lines 56-61), specifically, when a body fluid from a pregnant female is applied to the specimen receiving pad, I-hCG and modified hCGs bind to the specific antibodies bound to colored particles (test sample binds the specific antibody conjugate; Chang, column 7, lines 40-44). Chang further teaches that that the specimen will bind the monoclonal antibodies bound on the colored particulates, where I-hCG and modified hCGs present in the specimen will respectively bind to monoclonal antibodies (i-hCG binds the anti-I-hCG antibody conjugate; form a complex; Chang, column 6, lines 59-64). Chang further teaches that the I-hCG and modified hCGs bind to monoclonal antibodies bound to colored particles then move along the nitrocellulose membrane phase (moves to the signal detection region) and where two kinds of monoclonal antibodies are immobilized, the antigen-antibody complexes will respectively bind in a sandwich form resulting in two result lines (at the first test line and/or at the second test line; Chang, column 6, line 61- column 7, line 2).
As discussed previously in detail above, although Chang is teaching a device that detects both I-hCG and a modified hCG in a sample, and as such does teach a labeled anti-I-hCG conjugate probe, and does teach a test line for detecting I-hCG comprising antibody that binds/captures I-hCG (namely an anti-alpha-hCG which binds the complex between the conjugated anti-I-hCG and the I-hCG in the sample) and a test line for detecting modified hCGs, of which free βcf hCG is taught as an example of a modified hCG form, Chang fails to specifically exemplify a device having a first test line with an anti-I-hCG antibody immobilized (device comprising both the labeled anti-I-hCG and an anti-I-hCG immobilized at a test line) and a second test line having an immobilized anti-modified hCG antibody that is an anti-bcf hCG antibody (device comprising both labeled anti-bcf hCG antibody, and an anti-bcf hCG antibody immobilized at the test line).
Although Chang does teach a third line that is a control line, Chang further fails to teach a third conjugate with a probe in the conjugate region that is not immobilized at the conjugate region (i.e., a third mobile conjugate) and fails to teach a control line that binds the third mobile conjugate.
Nazareth is as cited in detail above teaching that it is desirable to detect βcf hCG, because high levels of βcf hCG present in a sample can lead to false negative results in urine-based pregnancy tests (see above for complete citation of Nazareth).
Ma is as cited in detail previously above, see above Ma teaches detection/capture of I-hCG bound to anti-I-hCG labeled conjugate by using immobilized anti-I-hCG (dual anti-I-hCG antibody binding and detection of I-hCG as a suitable art recognized way to detect I-hCG, see complete citation of Ma previously above).
As explained previously above, Yang teaches coating an anti-βcf hCG antibody onto a first detecting line of a nitrocellulose membrane. Yang further teaches a second antibody (anti-α-hCG antibody) adhered to a second test line and a control line (Yang, abstract; pages 2-3 of the attached translation, steps 1-3). Yang further teaches labelling anti-βcf hCG antibody with colloidal gold (Yang, page 3, step 7; claim 1).
Polito et al. is as cited in detail teaching that control agents, present in the control zones, bind to the control binding agent to form a control binding pair and an advantage of the control binding pairs is that they are internal controls, i.e. the control against which the analyte measurement results may be compared (see complete citation of Polito as set forth in detail above).
It would have been prima facie obvious to one having ordinary skill in the art before the claimed invention was effectively filed to have modified Chang with the teachings Nazareth, Ma, Yang, and Polito for the same reasons as discussed in detail previously above (see analyses of the rejection of claim 1, as the same reasoning applies presently).
As explained previously in detail above in the rejection of claim 1, the combined teachings establish a prima facie case of obviousness, namely result in a device comprising antibodies specific for I-hCG and βcf-hCG, capable of detecting both isoforms as presently claimed.
In summary, Chang and the cited art above teach a device substantially as claimed, where the test sample moved from the sample region to the conjugate region to contact one or more specific, labeled antibodies, the labeled antibodies form a complex with the specific substrate (if present in the sample), move to a signal detection region where they are immobilized by a second set of specific antibodies, wherein the antibodies of different specificities are immobilized in separate test lines and the labeled antibody-substrate complexes bind to the specific antibody respectively. As explained previously in detail above, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art is capable of performing the intended use, then it meets the claim. In the instant case, the device of Chang and the cited art is able to bind the specific substrate to form labeled antibody-substrate complexes that move along the device to bind specific immobilized antibodies at separate test sites. The device of Chang and the cited art above would therefore be capable of determining if one or both substrates are present. Because the prior art device is expected capable of performing the recited intended use, the reference meets the limitations of the claim.
With regard to the claimed “first” and “second” test lines, wherein the first test line is located downstream of the conjugate region and the second test line is located downstream of the first test line, the ordinarily skilled artisan would readily appreciate that the placing of the two test lines as an obvious matter of design choice (See MPEP 2144.04, the rearrangement of parts has typically been held by the courts as an obvious matter of design choice). In this case, the anti-I-hCG antibody does not bind to modified hCG and the anti-modified hCG antibody does not bind to I-hCG and therefore switching the placement of the two test lines would not modify the operation of the device.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Chang, in view of Nazareth, Ma, Yang and Polito as applied to claim 1 above, and further in view of Ahn et al, KR101250464B1, published 04/15/2013 (see PTO-892, 11/09/2023).
Regarding claim 4, Chang and the cited art above teaches a device substantially as claimed.
Although Chang teaches a wicking region comprising an absorbent pad, Chang is silent as to whether the wicking region of their device includes a porous support and absorbent dispersed in pores of the porous support or adsorbed or coated on the fiber of the porous support.
Ahn teaches an immunochromatographic test strip (Ahn, page 8, lines 5), with an absorbent pad (i.e., wicking region) downstream of the signal detection pads (Ahn, page 8, lines 20-21). Ahn further teaches that the absorbent pad is a porous support and is preferably adsorbed with an absorbent such as calcium chloride, magnesium chloride, diatomite, bentonite, dolomite, or gypsum (Ahn, page 8, see 11th paragraph).
Chang is silent as to a coating of the absorbent pad; however, it would have been prima facie obvious to one having ordinary skill before the effective filing date of the claimed to have modified Chang and the cited art in order to have used an absorbent pad, such as that taught by Ahn, as the porous pad of Chang as an obvious matter of applying a known technique. In particular, different types of absorbent pads (e.g., one with coating that is adsorbed to the substrate), were recognized in the art for the purpose of wicking sample/reagent to the end of the device. Ahn teach it is preferable to adsorb an absorbent at the wicking region (Ahn, teaching preferably adsorbed). As a result, one would be motivated to apply this technique as an art recognized way of improving absorption at the wicking region (apply the known technique to improve the known type of device).
One having ordinary skill would have a reasonable expectation of success given that Ahn teaches a lateral flow assay device, such as that which is recited by Chang, therefore the modification would be considered an improvement and not disrupt the intended operation of the device.
Response to Arguments
Applicant's arguments filed 06/102025 have been fully considered but they are not persuasive.
Applicant argues the rejection of claims under 35 U.S.C. 103, starting on page 5 that the cited combination of the prior art fails to disclose the claimed combination of features, including the combination of features of “a signal detection region connected to a conjugate region, the signal detection region comprising a first test line having anti-I-hCG antibody immobilized and a second test line having an anti-βcf-hCG immobilized wherein the first test line is located downstream of the conjugate region closer to the conjugate region than the second test line, located downstream of the first test line. Applicant argues that the prior rejection asserting that the terminology first and second test lines does not clearly require any particular order of placement of the lines is no longer applicable because the amended claim 1 requires any particular order of placement of the lines.
Applicant further argues in response to the assertion that the placing of the two test lines is an obvious matter of design choice, that there are technical advantages to the placement of the lines and therefore the feature could not be a design choice.
Applicant argues, starting on page 6, that by having the test line for detecting βcf hCG in addition to the test line for detecting I-hCG, the false negative caused by the hook phenomenon due to high concentration of I-hCG and/or the interference of βcf hCG is minimized and that by having a separated control line, when a target sample does not exist in the sample, a color may be rendered in the control line even though the color is not rendered in the test line. As such, a response in the control line means that the liquid sample is properly passing through the immune device. As such, applicant argues the features of the second test line being downstream of the first test line and the first test line, second test line and control line are separated from another are associated with the particular technical advantages and should not be considered a mere design choice. Applicant further argues that a device having no structure as recited in amended independent claim 1, the operation would be different from the operation in the embodiments according to the features of amended claim 1.
This argument is not persuasive.
Applicant points to paragraph [0088] in the specification, which recites an immunochromatographic strip which “includes the test line for detecting βcf hCG in addition to the test line for detecting I-hCG”, but does not teach a special technical feature that relies on the order that the two test lines are placed in, nor does it recite that having two different test lines minimizes the hook effect or the interference by βcf hCG.
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Rather, the special technical feature is the presence of two test lines, one for I-hCG and one for βcf hCG. Applicant recites on page 4, paragraph [0010] of the specification that each of the “i-hCG antibody and βcf hCG antibody” are ‘free of mutual interference”, and that the device is “disposed such that even when the hook phenomenon occurs due to the high concentration of I-hCG, the kit may accurately diagnose pregnancy based on a color rendering of the βcf hCG test line”. Put another way, the test device measures both I-hCG and βcf hCG independently, because there is no cross-reactivity between the antibodies. Rather, if the hook effect renders the I-hCG test line a false negative, the βcf hCG test line is used to determine if pregnancy is present. As recited in the specification on page 14 at paragraph [0049], the presence of each of I-hCG and βcf hCG is detected based on a signal resulting from the presence of a sandwich complex in each of the first and second test lines. Pregnancy is confirmed when the control line and the first test line, the control line and the second test line, or the control line and the first and second test lines emit a color. Binding of I-hCG to I-hCG antibody does not affect binding of βcf hCG to βcf hCG antibody and vice versa and therefore does not minimize the hook effect caused by excess I-hCG nor is there interference of i-hCG binding by βcf hCG. As such, switching the order of the test lines detecting I-hCG and βcf hCG would not affect the function of the device.
As explained previously in detail above, Chang teaches three separate lines, see Fig. 2b (Chang, Sheet 4 of 5) below:
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Chang teaches a strip comprising a conjugate region (24), a normal pregnancy line (23; anti-β hCG monoclonal antibody), an ectopic pregnancy line (22; anti-αhCG monoclonal antibody) and a control line (21; anti-mouse antibody; Chang, column 4, lines 45-58). As such Chang teaches three separate lines, two test and one control line, the control line being downstream of the two test lines, and the combination of Chang and the prior art teach the three test lines comprising the specific antibodies as claimed. The combination of the prior art differs from the claimed device in the placement of the two test lines, i.e. the first test line having an anti-I-hCG antibody immobilized and the second test line downstream of the first test line having an anti-βcf hCG antibody immobilized. However, as explained previously in detail above, the anti-I-hCG antibody does not bind to modified hCG and the anti-modified hCG antibody does not bind to I-hCG and as such switching the placement of the two test lines would not modify the operation of the device and therefore it is maintained that the placing of the two test lines as an obvious matter of design choice (See MPEP 2144.04, the rearrangement of parts has typically been held by the courts as an obvious matter of design choice).
Therefore the rejection of claims 1-5 and 7 is maintained.
Applicant further argues that the reasoning to combine Chang and Nazareth is based on impermissible hindsight because Chang teaches the separation of signal detection regions intended to simultaneously confirm ectopic pregnancy and pregnancy and Chang neither discloses nor suggest the utilization of βcf hCG for pregnancy diagnosis nor the problem of false negatives or interference by high concentrations of βcf hCG. Applicant argues that neither Chang nor Nazareth discloses or suggest the necessity of solving the problem of false negatives caused by high concentrations of I-hCG.
This argument is not persuasive.
The necessity of solving the problem of false negatives is directed to the intended use of the device. Applicant is reminded that a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See MPEP 2111.04.
Applicant further argues that according to Nazareth the capture sites are not separated and that by contrast the claimed device has a configuration in which signal detection regions are separated. Still further, applicant argues that that the reasoning that the device of claim 1 would have been easily derived by selecting the configuration of Chang which is intended to distinguish between ectopic pregnancy and pregnancy and replacing the modified-hCG detection region of Chang with βcf-hCG detection region of Nazareth is considered to constitute impermissible hindsight reasoning. Applicant further argues that based on Ma a person of ordinary skill in the art would consider replacing the modified hCG with h-hCG rather than of βcf hCG because h-hCG is indicative of abnormal pregnancy.
These arguments are not persuasive.
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). As explained previously in detail above, rather than by hindsight reasoning one of ordinary skill in the art would have been motivated to specifically detect βcf hCG because of the teaching of Nazareth that high levels of βcf hCG can cause false negative results. This motivation would not be negated by the teaching of Ma that h-hCG is indicative of abnormal pregnancy, because the motivation to specifically detect βcf hCG would be to avoid false positive results.
For all the reasons above, the arguments are not persuasive.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Communication
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/STEFANIE J. KIRWIN/Examiner, Art Unit 1677
/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677