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 .
Please note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 1/15/2026 has been entered.
Claim Status
Claims 1-4 and 6-13 are pending.
Claim 9 remains withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-4, 6-8, and 10-13 are being examined on the merits.
Claim Objections
Claims 1 and 10 are objected to because of the following informalities:
Claim 1 defines “a surface quantitative sub-detection region” in line 6. In lines 7 and 21, claim 1 refers to “the surface quantitation sub-detection region” (emphasis added). Please choose either “quantitative” or “quantitation” and maintain consistent claim terminology throughout.
Claim 1, line 7, reads “each of the surface quantitation sub-detection region is independently” and should read “each of the surface quantitation sub-detection [[region]]regions is independently”.
Claim 1, line 23, reads “the first detectable marker of the capturing nucleic acid” and should read “the first detectable marker of the quenching product capturing nucleic acid” to maintain consistent terminology throughout the claim.
Claim 10 defines “a surface quantitative sub-detection region” in line 4. In lines 5 and 19, claim 1 refers to “the surface quantitation sub-detection region” (emphasis added). Please choose either “quantitative” or “quantitation” and maintain consistent claim terminology throughout.
Claim 10, line 21, reads “the first detectable marker of the capturing nucleic acid” and should read “the first detectable marker of the quenching product capturing nucleic acid” to maintain consistent terminology throughout the claim.
Appropriate correction is required.
Claim Rejections - 35 USC § 112b - Indefiniteness
Withdrawn Rejections
The rejection of claims 1-8 and 10 under 35 U.S.C. 112(b) is withdrawn in light of Applicant’s amendments.
New Rejections, Necessitated by Amendments
Claims 1-4, 6-8, and 10-13 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation "the signal" in line 23. There is insufficient antecedent basis for this limitation in the claim. While it is clear that this is referring to a signal generated from the first detectable marker, use of the language “the signal” implies that a signal of the first detectable marker has already been defined previously in the claim. To clarify any confusion, line 23 should read “[[the]]a signal of the first detectable marker”.
Claim 1 recites the limitation "the 5’ end universal amplification primer" in line 27 and "the 3’ end universal amplification primer" in line 34. There is insufficient antecedent basis for these limitations in the claim. A first and second primer of a primer pair are defined in part (e) of the claim, but these are not specifically denoted as universal amplification primers. It is unclear what universal amplification primers are being referenced here as no universal amplification primers have been defined.
Claim 1 recites the limitation "the specific sequence at the 5’ end of a target gene" and “the specific sequence at the 3’ end of the target gene” in lines 28 and 31, respectively. There is insufficient antecedent basis for these limitations in the claim. No specific sequence of a target gene has been defined in the claim.
Claims 2-4, 6-8, and 11-13 depend from claim 1, inherit these deficiencies, and are rejected on the same basis.
Claim 2 is directed to the detection system of claim 1 “wherein the ratio (Q1/Q0) of the number of the quenching amplification product within 25 nt or less to the surface probe (Q1) to the number of the corresponding surface probe (Q0) is 0.5 to 100.” This limitation is unclear. Even though the claim was amended to read that the quenching amplification product is within 25 nt or less to the surface probe, the specification still does not clarify what this distance is referring to or provide a way of measuring it. The specification provides no explanation in regards to how this would be measured or if the working example indeed meets the requirement of this limitation.
Claim 8 recites the limitation "the 5’ end universal amplification primer" in line 4 and "the 3’ end universal amplification primer" in line 8. There is insufficient antecedent basis for these limitations in the claim. A first and second primer of a primer pair are defined in part (e) of claim 1 (from which claim 8 depends), but these are not specifically denoted as universal amplification primers. It is unclear what universal amplification primers are being referenced here as no universal amplification primers have been defined.
Claim 8 recites the limitation "the specific sequence at the 5’ end of a target gene" and “the specific sequence at the 3’ end of the target gene” in lines 5 and 6, respectively. There is insufficient antecedent basis for these limitations in the claim. No specific sequence of a target gene has been defined in the claim.
Claim 10 recites the limitation "the signal" in line 21. There is insufficient antecedent basis for this limitation in the claim. While it is clear that this is referring to a signal generated from the first detectable marker, use of the language “the signal” implies that a signal of the first detectable marker has already been defined previously in the claim. To clarify any confusion, line 21 should read “[[the]]a signal of the first detectable marker”.
Response to Remarks
While the amendments to claim 2 regarding the removal of “effective hybridization distance” renders previous rejection regarding this specific term moot, as acknowledged by Applicant in the Remarks of 1/15/2026 on pg 8, this still does not provide clarity as to what is being measured here to determine a ratio. The specification provides no means of measuring this and the claim itself remains unclear as to what exactly is being determined.
Claim Rejections - 35 USC § 112d – Failure to Further Limit
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 11 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. In the instant case, claim 11 depends from claim 1, wherein the probes which are targeted by the first and second primer are comprised of regions described as being the reverse complement of either the 5’ end universal amplification primer (X2’) or the 3’ end universal amplification primer (X1’). This implies that one of the primers used to amplify the third probe is a universal primer, and therefore the limitation that one of the first and the second primer is a universal primer does not further limit claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Interpretation
Regarding claim 2: It was detailed above in the 112b indefinite rejection of claim 2 that the limitation of the Q1/Q0 ratio was unclear. The addition of the limitation “the number of the quenching amplification product within 25 nt or less to the surface probe” does not clarify what the ratio is or how the ratio is being measured in this claim.
Regarding claim 5: In the interest of compact prosecution, the examiner is interpreting the subsequent limitations in the following way. “None” (“B3 is none”) is being interpreted to mean that the segment is not necessary to the structure of the quenching product capturing nucleic acid, and therefore the structure of Formula I could be: B0-B1-B2-B3 or B0-B1-B2.
Claim Rejections - 35 USC § 103
Withdrawn Claim Rejections
The rejection of claims 1, 3-8, and 10 under 35 U.S.C. 103 as being unpatentable over Wenz et al. (US 2004/0110134 A1, published June 10, 2004) in view of Hassibi et al. (US 2017/0362648 A1, published December 21, 2017) is withdrawn in light of Applicant’s amendments to the claims and cancellation of claim 5.
New Claim Rejections, Necessitated by Amendments
It is noted on the record that claim 2 is not included in the rejection below in view of the prior art, not because the claim is free and clear of the prior art, but rather due to the lack of clarity of the claim making it impossible to discern how it would be interpreted in light of the prior art. It was detailed in the 112b rejection of claim 2 that the limitation of the Q1/Q0 ratio is unclear, especially in regards to the quenching amplification product being within 25 nt or less to the surface probe.
Claims 1, 3-4, 6-8, and 11-13 are rejected under 35 U.S.C. 103 as being unpatentable over Wenz et al. (US 2004/0110134 A1, published June 10, 2004; cited on PTO-892 of 2/26/2025) in view of Hassibi et al. (US 2017/0362648 A1, published December 21, 2017; cited on PTO-892 of 2/26/2025) and Guo et al. (Nucleic Acids Research, 1994).
Wenz et al. teaches a system for quantitating target nucleic acids using ligation-dependent amplification and subsequent hybridization of amplicons to probes attached to a solid support (Abstract).
Regarding to claim 1: Wenz et al. teach a quantitative PCR which employs ligation-dependent amplification of target nucleic acids which are then detected through binding to a probe attached to a solid support at an addressable location. Specifically, Wenz et al. teach generation of a microarray (solid phase carrier) provided with n sub-detection regions, wherein n is a positive integer >= 2, and at least one sub-detection region is a surface quantitative sub-detection region…[which] is independently immobilized with a capture oligonucleotide (paragraph [0085], Figure 14). Wenz et al. teach a first probe, a second probe (“the probe set comprises (a) at least one first probe, comprising a first target-specific portion, and (b) at least one second probe, comprising a second target-specific portion and a 3' primer-specific portion”; paragraph [0006]), a ligase for connecting the first probe and the second probe to form the third probe (paragraph [0007] and [0056]), and a primer pair for amplifying the third probe (at least one primer set…to generate a first amplification product; paragraph [0007]).
Wenz et al. teaches that the structure of the first probe is X2’-T2’ (II) wherein, X2’ is a reverse complement of the 5’ end universal amplification primer and T2’ is a reverse complement of the specific sequence at the 5’ end of a targeting gene (Figure 3B and paragraph [0129]; “The first probe 22 further comprises a 5' primer-specific portion (5') and a target-specific portion 15a”). Wenz et al. specifically teach the 5’ end of the first probe is a “universal priming sequence” (paragraph [0233]).
Wenz et al. teaches that the structure of the second probe is T1’-P1’-X1’ (III) wherein, T1’ is a reverse complement of the specific sequence at the 3’ end of the targeting gene; P1’ is a barcode index sequence of a marker gene amplification combination; and X1’ is a reverse complement of the 3’ end universal amplification primer (Figure 3B and paragraph [0129]; “the second probe 23 comprises a target-specific portion 15b, an addressable support-specific portion 4, and a 3' primer-specific portion”). Wenz et al. specifically teach the 3’ end of the second probe is a “universal priming sequence” (paragraph [0233]). The “addressable support-specific portion” reads on P1’, as a barcode that is specific to the target gene and allows identification of the target gene amplification product when hybridized with the surface probe (paragraph [0068] and Figure 3).
Wenz et al. teach a capture oligonucleotide (quenching product capturing nucleic acid) with the formula B0-B2. Wenz et al. teaches that the 5’ end of the capture oligonucleotide consists of “a 5’ amino linker” (paragraph [0265]). In addition, the capture oligonucleotides were “24mers”, indicating that they contained a 24nt sequence complementary to the sequence of the target nucleic acid amplification product generated through ligation-dependent amplification (paragraph [0265] and Figures 2 and 3). Wenz et al. teach that the quenching product capturing nucleic acid specifically binds with the quenching target nucleic acid amplification product through complementary pairing between the capture region (P1) and the “addressable support-specific portion” reads on P1’, which is used as a barcode that is specific to the target gene and allows identification of the target gene amplification product when hybridized with the surface capture probe (paragraph [0068] and Figure 3).
Wenz et al. does not teach wherein the detection system is an integrated single unitary system and comprises the following components…altogether, wherein at least one of the first primer and the second primer is a quenching primer, or that one end or one side of the quenching primer is connected with a quencher (claim 1). Wenz et al. does not teach the capture oligonucleotide immobilized to the solid phase carrier surface as having a first detectable marker selected from the group consisting of a fluorophore, a chemiluminescent label, a quantum dot, and a combination thereof or that the quenching amplification product generated by the quenching primer through amplification and at least one of the quenching product capturing nucleic acid of the surface quantitation sub-detection region can be combined to form a double-stranded structure and in the double-stranded structure, the quencher of the quenching amplification product causes the signal of the first detectable marker of the capturing nucleic acid to be quenched; the quencher is labeled at the 5’ end of the quenching amplification product (claim 1). However, amplification of nucleic acids using quenching primers and use of surface-immobilized probes containing a fluorophore which is quenched upon binding of the quenching amplification product within a single unitary detection system was known in the art, as taught by Hassibi et al.
Hassibi et al. teach an array comprising a solid support having a surface and a plurality of different probes, the different probes immobilized to the surface at different addressable locations, each addressable location comprising a fluorescent moiety; a PCR primer for each nucleic acid sequence that comprises a quencher; whereby amplified molecules hybridize with probes, thereby quenching signal from the fluorescent moiety (paragraph [0023]). Hassibit et al. teach that the detection system is a single unitary system in which all components are held in contact with one another (paragraphs [0193 and 0223]). Hassibi et al. teach that the detectable marker attached to one end of the quenching product capturing nucleic acids includes “small molecules, fluorescent proteins, and quantum dots” (paragraph [0167]). Hassibi et al. teach this quencher “is…at the 5’ end of the primer.” Amplification of the target nucleic acids produces “amplicons which contain quenchers” at the “5’ end of the amplicon” which hybridize with the fluorescent moiety-containing probe immobilized to the surface of the solid phase carrier (paragraphs [0086 and 0125]), form a double-stranded DNA structure and “results in a change in signal” due to quenching of the fluorophore (paragraph [0129] and Figure 1). Hassibi et al. also teach that the quenching product capturing nucleic acids contains a sequence that is complementary to a nucleic acid target sequence in an analyte, which enables hybridization between the capture probe and the target analyte (this reads on P1’ and P1).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Wenz et al. with Hassibi et al. One would be motivated to combine with Hassibi et al. because Hassibi et al. teach that their system of quenching amplification product and quenching product capturing nucleic acid with a fluorophore allows detection of real-time characteristics of affinity-based assays (Abstract). Hassibi et al. teach that integration of all components into a single system is advantageous given that one does not have to wash out fluid when in contact with the solid substrate while being able to obtain measurements of fluorescent signals at multiple time points (paragraph [0037]). Additionally, Hassibi et al. teach that this allows for real time measuring of fluorescent changes (paragraph [0077]). One would have a reasonable expectation of success given that Hassibi et al. successfully perform a qPCR detection reaction based on hybridization analysis between a fluorophore-labelled surface-immobilized probe and a quencher labelled amplified analyte.
Wenz et al. teach a capture oligonucleotide (quenching product capturing nucleic acid) with the formula B0-B2. Wenz et al. teaches that the 5’ end of the capture oligonucleotide consists of “a 5’ amino linker” (paragraph [0265]). In addition, the capture oligonucleotides were “24mers”, indicating that they contained a 24nt sequence complementary to the sequence of the target nucleic acid amplification product generated through ligation-dependent amplification (paragraph [0265] and Figures 2 and 3). Wenz et al. in view of Hasibi et al. do not teach that the quenching product capturing nucleic acid (or capture oligonucleotide) contains B1 within the structure, a flexible transition region consisting of a flexible transition nucleic acid fragment with a length of 1-100 nt. However, use of flexible transition regions made of nucleic acids in surface immobilized capture oligonucleotides is known in the art, as taught by Guo et al.
Guo et al. teach a method of allele-specific hybridization between PCR amplified product and a surface-bound oligonucleotide array (Abstract). Guo et al. teaches that the surface-bound oligonucleotide contains a 5’-amino modified linker region that links the oligonucleotide to the array surface, a flexible transition spacer region consisting of 15 dT nucleotides (Figure 1; 15 nt reads on 1-00 nt).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the system of Wenz et al. in view of Hasibi et al. with the teachings of Guo et al. One would be motivated to include the spacer region (flexible transition region) as taught by Guo et al. given the assertion by Guo et al. that inclusion of a spacer increased hybridization efficiency between amplification products and the surface-bound oligonucleotides through removal of steric interference with the support surface (pg 5460, col 1, paragraph 3). One would have a reasonable expectation of success given that Guo et al. successfully constructs a surface-immobilized oligonucleotide with a linking group, flexible transition region, and a capture region that readily binds to complementary amplification products in solution (Figure 3).
Regarding claim 3: Wenz et al. teach that the 5’ end universal primer sequence of the first probe (X2’) is 21nt (within the range of 15-50nt; paragraph [0233] and Table 2(I) on page 24).
Regarding claims 4 and 6-7: Wenz et al. teach “the length of…[the] target-specific portion” as 12-35nt (reads on T2’ is 15-60nt and T1’ is 15-60nt). Wenz et al. teach a specific example in which the T2’ and T1’ portions of the first and second probes is 15nt for each probe (RPS4x probes, T-SP are the capital letters not in a box; Table 2(I)). Wenz et al. teach an addressable-support specific sequence (reads on P1’) which is 12-35nt long (reads on 10-500nt). In a specific example that Wenz et al. provides, they teach a P1’ region that is 24nt long (paragraph [0233] and Table 2(I)).
In addition, regarding the lengths claimed in claims 4 and 6-7, it is noted that the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists (see In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985) (see MPEP 2144.05.01).
It is noted that the courts have found that “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05 II. Thus, the claimed ratio merely represents routine optimization of the hybridization distance.
Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
Applicant is advised that MPEP 716.01(c) makes clear that “[t]he arguments of counsel cannot take the place of evidence in the record” (In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965)). Thus, Applicant should not merely rely upon counsel’s arguments in place of evidence in the record.
Regarding claim 8: As noted in the rejection of claim 1 above, Wenz et al. teaches the structure of the first probe is X2’-T2’ (II) wherein, X2’ is a reverse complement of the 5’ end universal amplification primer and T2’ is a reverse complement of the specific sequence at the 5’ end of a targeting gene (Figure 3B and paragraph [0129]; “The first probe 22 further comprises a 5' primer-specific portion (5') and a target-specific portion 15a”), and the structure of the second probe is T1’-P1’-X1’ (III) wherein, T1’ is a reverse complement of the specific sequence at the 3’ end of the targeting gene; P1’ is a barcode index sequence of a marker gene amplification combination; and X1’ is a reverse complement of the 3’ end universal amplification primer (Figure 3B and paragraph [0129]; “the second probe 23 comprises a target-specific portion 15b, an addressable support-specific portion 4, and a 3' primer-specific portion”). Wenz et al. teaches that the first and second probe are ligated together to generate a ligation product (third probe) which now has the structure of X2’-T2’- T1’-P1’-X1’ (Figure 3C).
Regarding claims 11 and 12: Wenz et al. teaches that both the first and second primers are a universal primer and specifically exemplify a universal primer that is 21nt long (paragraph [0082] and Table II).
Regarding claim 13: Hasibi et al. teaches primers that have a quenching agent. Given the motivation to combine provided above in regard to the combination of Wenz et al. and Hassibit et al., Wenz et al. would be motivated to provide a quenching agent on the universal primers used in their methodology.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Wenz et al. (US 2004/0110134 A1, published June 10, 2004; cited on PTO-892 of 2/26/2025) in view of Hassibi et al. (US 2017/0362648 A1, published December 21, 2017; cited on PTO-892 of 2/26/2025).
Wenz et al. teach quantitative PCR which employs ligation-dependent amplification of target nucleic acids which are then detected through binding to a probe attached to a solid support at an addressable location. Specifically, Wenz et al. teach generation of a microarray (solid phase carrier) provided with n sub-detection regions, wherein n is a positive integer >= 2, and at least one sub-detection region is a surface quantitative sub-detection region…[which] is independently immobilized with a capture oligonucleotide (paragraph [0085], Figure 14). Wenz et al. teach a first probe, a second probe (“the probe set comprises (a) at least one first probe, comprising a first target-specific portion, and (b) at least one second probe, comprising a second target-specific portion and a 3' primer-specific portion”; paragraph [0006]), a ligase for connecting the first probe and the second probe to form the third probe (paragraph [0007] and [0056]), and a primer pair for amplifying the third probe (at least one primer set…to generate a first amplification product; paragraph [0007]).
Wenz et al. teaches packaging necessary reagents for their quantitative PCR described above packaged into a kit “designed to expedite performing the subject methods” (paragraph [0224]). Wenz et al. teaches including “components in pre-measured unit amounts” (reads on containers). As detailed above, Wenz et al. teach a solid support provided with n sub-detection regions each independently immobilized with a capture oligonucleotide (quenching product capturing nucleic acid that is single-stranded), a first probe, a second probe, a ligase, a primer set, and an amplification product capable of creating a double-stranded structure with the capture oligonucleotide. All of these components would be advantageous to include in the kit for the reason asserted by Wenz et al. above. Wenz et al. also teach inclusion of a buffer or buffer component for PCR amplification, a polymerase for PCR amplification, and instructions (paragraph [0227]).
Wenz et al. does not teach wherein at least one of the first primer and the second primer is a quenching primer, or that one end or one side of the quenching primer is connected with a quencher. Wenz et al. does not teach that the capture oligonucleotide immobilized to the solid phase carrier surface as having a first detectable marker selected from the group consisting of a fluorophore, a chemiluminescent label (luminescent label), and a quantum dot or that the quenching amplification product generated by the quenching primer through amplification and at least one of the quenching product capturing nucleic acid of the surface quantitation sub-detection region can be combined to form a double-stranded structure and in the double-stranded structure, the quencher of the quenching amplification product causes the signal of the first detectable markers of the capturing nucleic acid to be quenched. However, amplification of nucleic acids using quenching primers and use of surface-immobilized probes containing a fluorophore which is quenched upon binding of the quenching amplification product within a single unitary detection system was known in the art, as taught by Hassibi et al.
Hassibi et al. teach an array comprising a solid support having a surface and a plurality of different probes, the different probes immobilized to the surface at different addressable locations, each addressable location comprising a fluorescent moiety; a PCR primer for each nucleic acid sequence that comprises a quencher; whereby amplified molecules hybridize with probes, thereby quenching signal from the fluorescent moiety (paragraph [0023]). Hassibit et al. teach that the detection system is a single unitary system in which all components are held in contact with one another (paragraphs [0193 and 0223]). Hassibi et al. teach that the detectable marker attached to one end of the quenching product capturing nucleic acids includes “small molecules, fluorescent proteins, and quantum dots” (paragraph [0167]). Hassibi et al. teach this quencher “is at the 3’ end of the primer [or] at the 5’ end of the primer.” Amplification of the target nucleic acids produces “amplicons which contain quenchers” at the “5’ end of the amplicon” which hybridize with the fluorescent moiety-containing probe immobilized to the surface of the solid phase carrier (paragraphs [0086 and 0125]), form a double-stranded DNA structure and “results in a change in signal” due to quenching of the fluorophore (paragraph [0129] and Figure 1). Hassibi et al. also teach that the quenching product capturing nucleic acids contains a sequence that is complementary to a nucleic acid target sequence in an analyte, which enables hybridization between the capture probe and the target analyte (this reads on P1’ and P1).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the kit of Wenz et al. with the teachings of Hassibi et al. One would be motivated to combine with Hassibi et al. because Hassibi et al. teach that their system of quenching amplification product and quenching product capturing nucleic acid with a fluorophore allows detection of real-time characteristics of affinity-based assays (Abstract). Additionally, Hassibi et al. teach that this allows for real time measuring of fluorescent changes (paragraph [0077]). One would have a reasonable expectation of success given that Hassibi et al. successfully perform a qPCR detection reaction based on hybridization analysis between a fluorophore labelled surface-immobilized probe and a quencher labelled amplified analyte.
Response to Remarks
Applicant's arguments filed 1/15/2026 have been fully considered but they are not persuasive for the following reasons.
Applicant has traversed the rejection of claims 1, 3-8, and 10 as obvious over Wenz et al. in view of Hasibi et al. As noted above, the rejection of claims 1, 3-8, and 10 over Wenz et al. in view of Hasibi et al. have been withdrawn in light of Applicant’s amendments to the claims and cancellation of claim 5. New claim rejections have been made to address the amendments.
Applicant argues that Hassibi et al. does not teach all of the limitations of the present claims (pgs 10-15 of Remarks), specifically that Hassibi et al. does not include a barcode sequence in the amplification products (pg 11-13 of Remarks). In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As detailed above, Wenz et al. teaches the use of a barcode system for specific hybridization between amplification products and barcoded probes on the microarray surface. Hassibi et al. is relied upon for the teaching of the use of fluorescently labeled surface-bound probes and primers with quenchers to generate quenching amplification products, for the enablement of real-time assessment of amplification products. Furthermore, the problems that applicant points out with the methodology of Hassibi et al. are inconsequential given that Hassibi et al. is modifying the teachings of Wenz et al. Wenz et al. overcomes issues such as target-specific amplification (use of first and second probes which are ligated to form a third probe with a barcode region and universal amplification regions) and false negative hybridization (use of barcodes; pg 13-14 of Remarks).
Applicant argues that the presently claimed system provides advantages that are not realized by Hassibi (pg 15 of Remarks). In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., first probe carries its own Quencher; starting concentration normalization, annihilation normalization, background normalization, proximity between the Q groups and F groups) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant argues that the method of Wenz et al. does not read on the current method given that the fluorescent groups are located on the primers on Wenz’s design (pg 15-16). In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The use of fluorophores on the immobilized capture probe and quenchers on the primers, as taught by Hassibi, provides the benefit of allowing real-time signal detection on the microarray surface, as detailed above.
Applicant argues that in Hassibi’s method, PCR amplification and hybridization are performed sequentially (pg 16 of Remarks). Hassibi teaches that readout occurs during PCR amplification, and teaches that amplification and detection can occur simultaneously (Abstract and paragraph [0016]).
The advantage that Hassibi’s method of quenching primers generating amplicons that bind to capture oligonucleotides with fluorophores which generates a decrease in signal that can be measured in real time is the scientifically supported reasoning as to why a skilled artisan would have been directed to combine Wenz and Hassibi in the asserted fashion. The attachment of fluorophores and quenchers to oligonucleotides and primers is successfully employed in Hassibi for amplification and detection of amplicons, while the use of a ligation-dependent amplification reaction with barcoded hybridization domains is successfully employed by Wenz. There is no indication that the combination of the two methodologies would yield unpredictable or unattainable results.
Applicant argues on page 17 of Remarks that “The Office appears to be picking and choosing among elements of Wenz and Hassibi to create a certain combination of elements”. Applicant asserts that the 103 combination rejection “relies upon impermissible hindsight, absent some reasonable rationale to do so”. 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). Reasonable rationale to combine was supplied by the teachings of Hassibi as recited in the 103 rejection above. Hassibi additionally teaches that one would want to use “quenchers rather than fluorescently labeled amplicons in solution [because it] has the advantage that it minimizes the fluorescent background of the solution, thus increasing the quality of the measurement of the fluorescence at the surface” (paragraph [0084]).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAILEY E CASH whose telephone number is (571)272-0971. The examiner can normally be reached Monday-Friday 8:30am-6pm ET.
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/KAILEY ELIZABETH CASH/Examiner, Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683