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 Claims / Response to Amendment
This office action is in response to an amendment filed on December 18, 2025.
Claims 1-9, 11, 13-15, 18-24 were previously pending. Applicant amended claims 1, 5 and 24; cancelled claims 13 and 15; claims 25-26 are newly added.
Claims 1-9, 11, 14, 18-26 are currently pending, with claims 3, 9, 11, 14 and 20 withdrawn.
Claims 1-2, 4-8, 18-19, 21-26 are under consideration.
All of the amendment and arguments have been thoroughly reviewed and considered. All of the previously presented objection and rejections have been withdrawn as being obviated by the amendment of the claims, which added new limitations to the claims, that were not considered in the previous rejections.
Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
This office action contains new grounds for rejection necessitated by amendment.
Priority
For the instant claims 1-2, 4-8, 18-19, 21-26 in this application, the applicant claims priority of the US provisional application 63/016,194, which has a filling date on April 27, 2020.
Claim Interpretation
In evaluating the patentability of the claims presented in this application, claim terms have been given their broadest reasonable interpretation (BRI) consistent with the specification, as understood by one of ordinary skill in the art, as outlined in MPEP§ 2111.
For the purpose of applying prior art, claims 1 and 5 are drawn to a primer set comprising elements including "primer sequence a," "primer sequence b," "primer sequence e," "primer sequence f," and other positionally related components. These elements are interpreted in accordance with arrangement as shown in FIGs 1-3 of the current application's disclosure, reproduced below.
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For the purpose of applying prior art, claim 1 recites "cycling probe," which is defined by the application's disclosure in para [0170]:
"[0170] The term "cycling probe" that can be cleaved by an enzyme after annealing to a target nucleic acid sequence, wherein such cleavage releases an intact target nucleic acid."
Therefore, in light of the specification and under BRI, the term "cycling probe" is interpreted to encompass any probe cleavable by an enzyme.
For the purpose of applying prior art, claim 1 recites "modified base," which is defined by the application's disclosure in para [0167]:
"[0167] The term "modified base" is used herein to refer to a base that is not a canonical, naturally occurring base (e.g., adenine, cytosine, guanine, thymine, or uracil)."
For the purpose of applying prior art, claim 19 recites "RNase H2 cycling probe," which is not defined in the application's disclosure. Thus, under BRI the term "RNase H2 cycling probe" is interpreted to encompass any probe cleavable by RNase H2 enzyme.
New Grounds of Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claim 24 is rejected under 35 U.S.C. 112(b), 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 24 recites primer sequence a comprising the first modified base and further comprises a fifth modified base, and primer sequence a' of the second strand comprising the second modified base further comprises a sixth modified base, and wherein:
"the first modified base is a first number of bases, in primer sequence a, from the fifth modified base;
the second modified base is a second number of bases, in primer sequence a', from the sixth modified base; and
the first number and the second number are the same."
This claim language is indefinite because it is unclear how the recited modified bases are spatially related ꟷ specifically, whether the fifth modified base and sixth modified base are required to pair with each other on the opposite strands when the primers form a duplex via hybridization. For instance, the fifth modified base could be located either upstream (toward the 5’ end) or downstream(toward the 3’ end) of the first modified base within primer sequence a. Accordingly, if the first and second numbers of bases are the same, the spatial distance between the fifth and sixth modified bases, located on different strands of a duplex (a hybridized with c'-a') could represent multiple possible configurations, such as being directly paired (distance = 0) or separated by twice the number of bases (distance = 2N), therefore not paired. It is unclear whether the claimed primers encompass the first configuration (i.e., fifth and sixth modified bases pair with each other) , the second configuration (i.e., fifth and sixth modified bases do not pair with each other), or both. Therefore, the scope of the claim is indefinite.
For the purpose of compact prosecution and applying prior art under 35 USC§ 102 and 103, the fifth modified base and sixth modified base are interpreted to encompass both configurations (i.e., distance = 0 or 2N).
New Grounds of 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 following are new grounds of rejections necessitated by Applicant's amendments. Although the claims were previously rejected as being unpatentable over some of the same reference(s), Applicant's amendments have necessitated the inclusion of new grounds of rejections in this Office action. It is noted that, to the extent that they apply to the present rejection; Applicant's arguments are addressed following the rejection.
Claims 1-2, 4-8, 18-19, 21-26 are rejected under 35 U.S.C. 103 as being unpatentable over Higuchi (WO2016100388A1 - Exponential base-greater-than-2 nucleic acid amplification; Published on 2016-06-23; cited as Foreign Patent Document #010 in IDS filed 10/31/2023), in view of
Hoshika (Hoshika et al. Artificial genetic systems: self-avoiding DNA in PCR and multiplexed PCR. Angew Chem Int Ed Engl. 2010 Jul 26;49(32):5554-7. doi: 10.1002/anie.201001977. PMID: 20586087; PMCID: PMC6027612.), and
Han (US5763181 A - Continuous fluorometric assay for detecting nucleic acid cleavage; Published on: 1998-06-09; cited as U.S. Patent Document #004 in IDS filed 10/31/2023), as evidenced by Walder (US8911948 B2 - RNase H-based assays utilizing modified RNA monomers; Published on 2014-12-16).
A) Higuchi 1 teaches methods and compositions for highly efficient nucleic acid amplification with increased sensitivity and speed (entire document, Abstract for example).
Regarding claim 1, Higuchi teaches a nucleic acid primer set comprising oligonucleotides as shown in Fig 2 below.
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While Higuchi teaches that its primer sequences can include modified bases to manipulate nucleic acid duplex stability and achieve the desired nucleic acid complex configuration ([0091] c-a/c'-a' is more stable than a-b/a'-b'; [0060-0061]; [0102-0103]; page 27, lines 9-11, Tm can be adjusted by including stabilizing or destabilizing bases), it does not explicitly teach that the a’ in c’-a’ (Figure 2) comprise a 2nd modified base, or that sequence a of the first outer primer comprise a 1st modified base. Furthermore, Higuchi does not explicitly teach that the first modified base does not form a stable hydrogen-bonded base pair with the second modified base.
However, it would have been obvious to make such modifications in view of Higuchi and Hoshika. Higuchi already teaches the use of modified bases (stabilizing or destabilizing) to adjust the melting temperature (Tm) or stability of specific nucleic acid hybridization structures. This allows the primer regions to exhibit different hybridization preference within a complex.
Higuchi also present a specific primer configuration shown in Fig. 2, which supports a greater than two-fold increase in amplification efficiency (see para. [0090- 0091] and Fig 2) .
In this configuration, sequences a and a' are complementary, leading to the following possible hybridization schemes:
A.1. (c-a-b) with (c’-a’) or
A.2. (c-a-b) with (d’-a’-b’);
B.1. (a) with (c’-a’); or
B.2. (a) with (d’-a’-b’)
Fig. 2 illustrates the preferred configuration, A1 and B2, which support the increased amplification efficiency. In this configuration, it is essential that both the inner primer b in (c-a-b) and the outer primer (a) bind to the target sequence (d’-a’-b’), forming a nested primer configuration. For this to occur, the hybridization of c-a with c'-a' must be more stable than a-b with a'-b' (i.e., A.1. is preferred over A.2.) (see [0091] line 1). This ensures that the outer primer binding site is not blocked by undesirable hybridization, allowing sequence a' in the target sequence to bind to the outer primer (a) (i.e., B.2. is preferred over B.1.).
Similarly, the hybridization of B2 [(a) with (d’-a’-b’)] need to be more stable than B1 [(a) with (c’-a’)]. Higuchi suggests potential approaches to achieve this preferred configuration, such as using of stabilizing or destabilizing bases. The general principle is to increase the relative stability of the preferred hybridization compared to the undesirable hybridization. This can be achieved by incorporating more stabilizing bases in the preferred hybridization, or more destabilizing bases in the undesirable hybridization.
Hoshika teaches an improvement to PCR amplification assays, known as “self-avoiding molecular recognition system” (SAMRS),” which eliminates PCR artifacts due to non-specific or undesirable binding when multiple probes and primers are used simultaneously (entire document). SAMRS bases are modified nucleotide bases with "pseudo-complementarity" pairing properties. They bind stably to their natural DNA complements but do not form stable duplexes with other SAMRS bases, even if fully complementary. (Hoshika, page 2, para 1-2)
Accordingly, SAMRS bases incorporated into primers can prevent the formation of undesired duplexes between primers.
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the primer complexes disclosed in Higuchi (Fig. 2) by incorporating the SAMRS destabilizing bases taught in Hoshika. Specifically, sequence (a) would include at least one SAMRS base , and the corresponding complementary region in (c'-a') would also include at least one SAMRS base at a nucleotide position that pairs with the SAMRS base in (a). The skilled artisan in view of the teachings of Higuchi and Hoshika would appreciate that this modification would prevent the undesired hybridization of (a) with (c’-a’) (hybridization scheme B.1.) while allowing the preferred hybridization of (a) with (d’-a’-b’) (hybridization scheme B.2.), as shown in Fig. 2 of Higuchi.
A skilled artisan, understanding the specific configuration shown in Fig.2 of Higuchi, which needed to achieve the predictable result of increased amplification efficiency, and in view of Higuchi's teaching that modified bases can be used to achieve the desired configuration, would find it obvious to apply the SAMRS bases from Hoshika to the primers. This would ensure that the primer (a) binds more stably to the target sequence (d’-a’-b’) rather than to sequence (c’-a’), resulting in the desired configuration being the most stable form.
This combination would have been obvious as it represents the KSR principle of predictable use of prior art elements (i.e., modified bases in Hoshika) according to a known method (i.e., methods for nucleic acid amplification using a primer set comprising modified bases, disclosed in Higuchi) to yield predictable results (i.e., hybridized primer configuration in Fig. 2 of Higuchi). (See MPEP §2143).
The combined teachings of Higuchi and Hoshika teaches all the claim limitations, except for a cycling probe.
Han teaches methods and compositions for performing a fluorometric assay to detect nucleic acid cleavage, which can be used to enhance the efficiency and detection of well-known nucleic acid amplification techniques such as PCR (entire document; col 10, lines 21-25 for example).
Regarding claim 1, Han teaches the use of cycling probes with FRET in detecting specific DNA sequences (entire document; col 21-22: Example 3 for example), wherein the cycling probe comprises an enzyme cleavage site and a label (col 6, lines 31-34; entire document; col 21-22: Example 3 for example), enzyme mediated cleavage of the cycling probe within the probe target duplex results in release of the intact target sequence, which can repeatedly recycle through the reaction pathway (col 21, lines 32-35).
Han further suggests that cycling probes with FRET offer several advantages, such as preserving intact target for probe binding, which serves as a catalytic cofactor of continuous reaction. Additionally, the use of FRET-based cycling probes can further amplify the detection signal, resulting in an improved signal-to-noise ratio, thus enhancing detection efficiency:
"Catalytic hybridization amplification" (CHA), alternatively known as "cycling probe technology," is described in published PCT application WO 89/09284, and U.S. Pat. Nos. 5,011,769 and 4,876,187. Briefly, CHA is an improved hybridization assay method whereby the target sequence to be detected is able to capture many molecules of the probe in a repeating series of reactions (i.e., "cycling probe"). Essentially, enzyme mediated cleavage of the probe within the probe target duplex results in release of the intact target sequence, which can repeatedly recycle through the reaction pathway. The target sequence serves as a catalytic cofactor for the cleavage of a complementary, labeled nucleic acid probe that is hybridized to the target. The detectable signal in this reaction results from cleavage of the probe, e.g., after repeated CHA cycles, one measures the labeled probe cleavage product. The CHA method is useful in detecting specific DNA or RNA sequences.
The present inventors have reasoned that the last step of CHA (i.e., measuring the labeled probe cleavage product), could be more expeditiously and efficiently carried out by employing the presently disclosed fluorometric assay, based on FRET, for detecting DNA cleavage.
It is expected that the high efficiency of FRET will provide a means to amplify the detection signal. For example, if the donor fluorescence is quenched to 10% of its initial intensity, then complete cleavage of the oligonucleotide substrate (probe) by the RNase H enzyme used in CHA, will result in a 10 fold amplification of the signal. Moreover, only 10% cleavage of the probe will still result in a two fold increase in the detection signal. This intrinsic signal amplification will provide an excellent tool to improve signal-to-noise ratio and thereby increase the confidence in data interpretation." (col 21-22)
Therefore, instead of detecting each DNA amplicon only once, with the cycling probes the same DNA amplicon can be detected multiple times, therefore greatly increases the signal.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teaching of a primer set comprising modified bases for PCR taught by Higuchi and Hoshika with the cycling probes using FRET taught by Han, because all references are in the same or overlapping field of nucleic acid amplification and detection, with the shared objective of improving the sensitivity and efficiency of detecting specific nucleic acid target sequences. More specifically, Higuchi teaches a method for highly efficient nucleic acid amplification using a primer set, while Han teaches the use of cycling probes with FRET to enhance nucleic acid detection approaches such as PCR by further amplifying the signal.
The person of ordinary skill would have had a reasonable expectation of success in combining these teachings because all three references teach sequence-specific nucleic acid detection via amplification, specifically with Higuchi teaching a PCR primer set and Han offering an additional cycling probe that further improves PCR and increases detection efficiency, thus demonstrating technical compatibility. Doing so would have yielded the predictable result of a primer set for enhanced nucleic acid detection by incorporating Han's cycling probes to further amplify detection signals in amplicon products in a PCR reaction.
The skilled artisan would have been motivated to combine the cycling probe technology of Han with the primer set taught by the combined teachings of Higuchi and Hoshika, to leverage the known advantages of FRET-based cycling probes, as highlighted by Han, resulting in reagent composition for a more sensitive and efficient assay.
B) Regarding claim 2, Higuchi teaches primer set additionally comprises at least one second primer (FIG. 3).
Regarding claim 4, Higuchi teaches the Tm of combined sequence c-a, in double-stranded form, is greater than that of combined sequence a-b, in double-stranded form ([0010]).
Regarding claim 5, The combined teachings of Higuchi and Yang teaches its limitations. Higuchi teaches nucleic acid primer set comprising oligonucleotides as shown in Fig 3 below. The primer set in Fig. 3 is the “reverse” primer set to the “forward” primer set of Fig 2. (page 26, lines 14-20) It would have been obvious to modify primer sequence (e) and its complementary sequence in (g’-e’) for the same reasons discussed for claim 1 above.
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Regarding claim 6, Higuchi teaches the Tm of combined sequence g-e, in double-stranded form is greater than that of combined sequence e-f, in double- stranded form ([0015]).
Regarding claim 7, Higuchi teaches clamp sequence c is not capable of being copied during amplification ([0037]).
Regarding claim 8, Higuchi teaches clamp sequence c comprises) 2'-O-methyl RNA([0038]).
Regarding claim 18, Han teaches probe comprising a modified base (col 8, lines 4-8; col 10, lines 46-49) wherein the modified base is a modified form of a unmodified base selected from the group consisting of adenine, thymine, uracil, guanine, and cytosine (Col 10, lines 46-52, 5’ Cytosine of SEQ ID NO: 1 is modified with primary amine; col 16, lines 59-60, 5-Amino (12)-2'-deoxyuridine).
Regarding claim 19, Han teaches a cycling probe which is a RNase H2 cycling probe by teaching cycling probes consist of DNA-RNA-DNA strands (col 22, lines 15-16), as evidenced by Walder. Walder teaches RNase H2, specifically it teaches RNase H2 cleaves RNA ribonucleotide embedded within a DNA sequence (col 5, lines 19-22). Therefore, the probe taught by Han comprising RNA ribonucleotide embedded within a DNA strand is a RNase H2 cycling probe cleavable by RNase H2.
Regarding claim 21, Han teaches an RNase cycling probe (col 3, lines 58-60; col 6, lines 60-67; col 22, line 7, RNase H; claim 14).
Regarding claim 22, it recites:
"wherein the first modified base of primer sequence a is a first number of bases from the 5' end of primer sequence a; and the second modified base of primer sequence a' is the first number of bases from the 3' end of primer sequence a'. "
Thus, this limitation is interpreted to mean that the modified bases are complementary pairs located on the two strands of the sequences forming a hybridization duplex [(a) with (c’-a’)]. This limitation is obvious in view of the combined teachings of Higuchi, Hoshika, and Han, as discussed above.
Claim 23 recites:
"wherein the Tm of primer sequence a of the first double-stranded primer sequence / primer sequence a' of the first double-stranded primer sequence, in double-stranded form, is greater than the Tm of primer sequence a of the first outer primer / primer sequence a' of the first double-stranded primer sequence, in double-stranded form."
This limitation is interpreted to mean that the hybridization of (c-a) with (c’-a’) in the region where sequence a hybridizes sequence a’, has higher Tm than (a) with (c’-a’) in the same region.
This is obvious as evidenced by Table 1 of Hoshika. As discussed above, Higuchi in view of Hoshika and Han teaches and suggest a primer set, wherein (a) comprises at least one SAMRS bases, and the corresponding complementary sequence region in (c’-a’) also comprises at least one SAMRS bases at a nucleotide location that base-pairs with the SAMRS bases in (a), thereby preventing the undesired binding of (a) with (c’-a’).
Therefore, hybridization of (c-a) with (c’-a’) in the region where sequence a hybridizes sequence a’ comprises SAMRS base on only one strand, whereas hybridization of (a) with (c’-a’) in the complementary region where sequence a hybridizes sequence a’, comprises SAMRS base on both strands. According to Table 1 in Hoshika, dsDNA having SAMRS bases on one strand in a base pair location, has higher Tm than dsDNA having SAMRS bases on both strands in a base pair location (e.g., A-T* has Tm of 56.8, A*-T* has Tm of 52).
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Regarding claim 24, it recites:
“wherein primer sequence a of the first outer primer comprises a fifth modified base that is complimentary to a fifth unmodified base of the first template strand sequence a' wherein the fifth unmodified base is selected from the group consisting of adenine, thymine, uracil, guanine, and cytosine; primer sequence a' of the second strand comprises a sixth modified base that is complimentary to a sixth unmodified base of the primer sequence a of the first strand of the first double-stranded primer sequence,
wherein the sixth unmodified base is selected from the group consisting of adenine, thymine, uracil, guanine, and cytosine; the first modified base is a first number of bases, in primer sequence a, from the fifth modified base; the second modified base is a second number of bases, in primer sequence a', from the sixth modified base; and the first number and the second number are the same. “
Therefore, the claim requires the primer set in claim 1 further comprising additional modified bases in primer sequence (a) and its corresponding complementary sequence region in (c’-a’); wherein the additional modified bases have corresponding locations in their respective sequence regions a or a’.
New claim 25 depends from claim 24 and further recites:
"The primer set of claim 24, wherein the first number is at least two; and the first modified base is 5' of the fifth modified base and the second modified base is 3' of the sixth modified base or the first modified base is 3' of the fifth modified base and the second modified base is 5' of the sixth modified base."
These claims are obvious in view of Hoshika’s teaching: “when both primers had four or eight Samrs components, PCR amplification efficiently gave only the desired amplicon.” (page 4) Therefore, a skilled artisan in view of the combined teachings of Higuchi, Hoshika and Han, and specifically considering Hoshika’s teaching that having both primers comprising four or eight SAMRS modified bases could efficiently give desired amplicon, free of artifacts, would have found it obvious to include four or eight consecutive SAMRS modified bases in each primer ; wherein each the modifications are positioned in the primers so they pair with each other on separate strands to maximize the destabilizing effects of the modifications. In other words, the distance between the modified bases on one strand would be the same as the other strand because they mirror each other.
Consequently, the first modified base position within the four consecutive modified bases on a primer would be at least two bases away from the last modified base position on the primer (e.g., in 5’ NNNNNNA*T*C*G* 3’: A* and G* are 2 bases apart). The bases would occupy the claimed positions because they pair with each other on opposite strands.
Regarding claim 26, it recites:
“wherein primer sequence a of the outer primer in a double strand form with the first template strand sequence a' is more stable than primer sequence a of the outer primer in a double strand form with primer sequence a' of the second strand.”
This limitation is obvious in view of the combined teachings of Higuchi, Hoshika and Han because it does not further limit the claimed primer set.
MPEP§ 2111.04 states: "Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure.
In this instant case, this wherein clause does not further recite any structural features applicable to the claimed primer set, but instead describes an intended outcome in terms of the stability of primers in their double-stranded form. However, the claim does not actually require the primers to be in double-stranded form. Therefore, the descriptive language in claim 26 does not further distinguish the claim from the prior art.
Additionally, in view of the combined teachings of Higuchi, Hoshika and Han, the described stability in claim 26 would have been an obvious and predictable characteristics of the primers having structures (e.g., Higuchi’s primers having first and second modified bases) taught and suggested by the prior art, as discussed above for claim 1.
Response to Applicant Arguments
The previously set forth 103 rejections of claims 1-2, 4-8, 18-19 and 21-24 have been withdrawn in view of the recent claim amendment filed on December 18, 2025, which added new limitations to the claims, that are not addressed in the previous rejections.
Applicant's arguments filed on December 18, 2025 have been fully considered but are not found persuasive.
First, Applicant argues that "the addition of a cycling probe to the Higuchi reference would frustrate its "highly efficient nucleic acid amplification" and therefore such a modification is not obvious." (Remarks, page 17), asserting that Higuchi teaches exponential amplification, while Han teaches linear amplification (Remarks, page 18-19).
This argument is not persuasive. While they both share "amplification" in the terms, the references teach amplification in different yet technically complementary context ꟷ Higuchi teaches exponential amplification of nucleic acids, while Han teaches linear amplification of detection signal using cycling probes. In other words, the two components serve different functions within an assay: one amplifies the target nucleic acid thereby generating amplicons, while the other amplifies the detection signal (e.g. fluorescent signal) generated from cycling probes binding to the amplicons and then released by cleavage.
There is no teaching in the cited references that expressly criticizes, discredits, or otherwise discourages using a cycling probe in combination with exponential amplification.
While Applicant asserts that exponential amplification of nucleic acids taught in Higuchi and linear amplification of detection signal using cycling probes in Han would be incompatible due to different temperature requirements (Remarks, page 18-19). This is not persuasive because it is not required that these amplification steps to occur simultaneously.
In fact, the combination of cycling probes with exponential nucleic acid amplification methods such as PCR is not only obvious but expressly taught in the prior art. Anticipation is the epitome of obviousness. Connell v. Sears, Roebuck & Co.,722 F.2d 1542, 1548, 220 USPQ 193, 198 (Fed. Cir. 1983) (citing In re Fracalossi, 681 F.2d 792, 215 USPQ 569 (CCPA 1982)).
Han explicitly teaches its method can be used to enhance the efficiency and detection of well-known nucleic acid amplification techniques such as PCR (Col 10, lines 21-25), which is exponential nucleic acid amplification.
Hendricks 2(page 23-24) further supports this teaching by providing additional examples for cycling probes applications (page 23-24), such as the use of CataCleave probes with PCR:
"In the CataCleave probes reported by Harvey et al., the emission donor and acceptor were fluorescein and rhodamine, respectively. CataCleave probes were employed for detection of accumulating amplification products from real-time PCR reactions. Such reactions employed a thermostable RNase H and a short, isothermal step for detection of amplicons by the CP reactions in each amplification cycle." (page 24)
Therefore, the combined use of cycling probe with exponential amplification reagents is obvious in view of prior art.
With respect to combining cycling probes with primers for amplification (e.g., PCR), Applicant further argues that "Cycling Probes Compete with Primers" when binding to target nucleic acid (Remarks, page 19-23), citing Figures 11 and 12 of the present application and asserting that the use of a cycling probe resulted in more amplification cycles being required to reach a threshold level of fluorescence.
This argument is not persuasive. A minor increase in the number of amplification cycles does not rise to the level of inoperability when using cycling probes with amplification primers. In addition, the data relied upon by Applicant is from the present application, which would not have been considered by a person of ordinary skill in the art before the effective filling date and therefore cannot be relied upon to demonstrate nonobviousness. As noted above, combining cycling probes with PCR primers was already known in the art. Accordingly, combining cycling probes with the primers taught in Higuchi would have been obvious.
Third, Applicant argues that Hoshika teaches away, asserting that in Hoshika the primers that "efficiently gave only the desired amplicon" have at least four consecutive SAMRS components (Remarks, page 23-25).
This argument is not persuasive. Evidence concerning whether the prior art teaches away from a given invention must relate to and be commensurate in scope with the ultimate claims at issue. See, e.g., MeadWestVaco Corp. v. Rexam Beauty and Closures, Inc., 731 F.3d 1258, 1264–65 (Fed. Cir. 2013); In re Kahn, 441 F.3d 977, 990 (Fed. Cir. 2006)
Here, the claims do not exclude primers having four or more consecutive modified bases, nor do they exclude primers comprising additional modified bases beyond those specifically recited. If a primer contains four consecutive modified bases, the first and fourth modified bases are separated by two base positions, which meets the limitation of claim 25, reciting "wherein the first number is at least two." As the claims are to be analyzed based on their own terms, arguments based on features not claimed are outside the scope of the examination for patentability.
Double Patenting- Obvious Type – New Grounds
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 4-8, 18 and 26 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1, 2, 4, 8-9, 13-14, 22, 25, 27 and 30-31 of U.S. Patent No. 11352622 B2 (‘622 Patent), in view of Han (US5763181A - Continuous fluorometric assay for detecting nucleic acid cleavage; Published on: 1998-06-09; cited as U.S. Patent Document #004 in IDS filed 10/31/2023).
Instant claim 1 recites:
A nucleic acid primer set for amplifying a target nucleic acid in a sample,
wherein the target nucleic acid comprises a first template strand and, optionally, a second template strand, wherein the second template strand is complementary to the first template strand,
the primer set comprising a cycling probe (‘622 Patent, claim 30) and oligonucleotides in the form of, or capable of forming, at least two first primers (‘622 Patent, claim 1) capable of hybridizing to the first template strand,
wherein the at least two first primers comprise a first outer primer and a first inner primer (‘622 Patent, claim 1),
the first outer primer comprising a primer sequence a (‘622 Patent, claim 1)that specifically hybridizes to first template strand sequence a', primer sequence a comprising a first modified base that is complimentary to a first unmodified base of the first template strand sequence a'
wherein the first unmodified base is selected from the group consisting of adenine, thymine, uracil, guanine, and cytosine; and
the first inner primer comprising a single-stranded primer sequence b that specifically hybridizes to first template strand sequence b' (‘622 Patent, claim 1), wherein b' is adjacent to, and 5' of, a', and
wherein single-stranded primer sequence b is linked at its 5' end to a first strand of a first double- stranded primer sequence (‘622 Patent, claim 1) comprising :
a primer sequence a (‘622 Patent, claim 1)adjacent to, and 5' of, single-stranded primer sequence b; and
a clamp sequence c (‘622 Patent, claim 1) adjacent to, and 5' of, primer sequence a, wherein the clamp sequence c is not complementary to a first template strand sequence d', which is adjacent to, and 3' of, the first template strand sequence a';
wherein a second strand of the first double-stranded primer sequence comprises primer sequence c' (‘622 Patent, claim 1) adjacent to, and 3' of, primer sequence a', wherein combined sequence c'-a' is complementary to combined sequence c-a, primer sequence a' comprising a second modified base (‘622 Patent, claim 1) that is complimentary to a second unmodified base of the primer sequence a of the first strand of the first double-stranded primer sequence, wherein the second unmodified base is selected from the group consisting of adenine, thymine, uracil, guanine, and cytosine (‘622 Patent, claim 25, 27);
wherein the first unmodified base of the first template strand sequence a' is complementary to the second unmodified base of the primer sequence a; and the first modified base does not form a stable hydrogen-bonded base pair with the second modified base (‘622 Patent, claim 22);
wherein the cycling probe is configured to be cleaved by an enzyme to initiate release of a label from the cycling probe and release of the first template strand, the second template strand, or an amplicon of the first or second template strand, in an intact form, from the cycling probe.
While '622 Patent claims a probe ('622 Patent, claim 30 for example), it does not specifically claim cycling probe comprises an enzyme cleavage site and a label.
Han fills this gap by teaching use of cycling probes with FRET in detecting specific DNA sequences (entire document; col 21-22: Example 3 for example), for performing a fluorometric assay to detect nucleic acid cleavage, which can be used to enhance the efficiency and detection of well-known nucleic acid amplification techniques such as PCR (entire document; col 10, lines 21-25 for example).
It would have been prima facie obvious to a person of ordinary skill in the art to combine the known element taught in Han with the claimed invention of ‘622 Patent, because both references pertain to nucleic acid amplification and detection.
As suggested by Han :
“The described fluorometric assay for detecting nucleic acid cleavage can also be utilized to improve the efficiency and detection signal of a number of well-known procedures for amplifying or detecting a specific DNA or RNA sequence, such as polymerase chain reaction (PCR).” (col 10, lines 21-25)
Thus, a skilled artisan would understand that integrating the prior art element from Han into ‘622 Patent's claimed primer set would have yielded the predictable result of a primer set, for enhanced nucleic acid detection by incorporating Han's cycling probes to further amplify detection signals in amplicon products in a PCR reaction. This is because, instead of detecting each DNA amplicon only once, with the cycling probes the same DNA amplicon products from PCR amplification reaction can be detected multiple times (see Example 3), therefore greatly increases the signal. Such combination represents a predictable use of prior art element according to a known method to yield predictable results (See MPEP §2143).
Therefore, the instant claim 1 lacks patentable distinction over the ‘622 Patent in view of Han. Therefore, instant claims 1 and 26 are obvious over claims 1, 22, 25, 27 and 30 of the ‘622 patent, in view of Han. Instant claims 2, 4-8 and 18 are obvious over claims 2, 4, 8-9, 13-14 and 31 of the ‘622 patent, in view of Han.
Claims 1, 2, 5, 7-8, 18 and 26 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1, 15-16, 26, 29, 31 and 34-35 of U.S. Patent No. 12098368 B2 (‘368 Patent), in view of Han (US5763181A - Continuous fluorometric assay for detecting nucleic acid cleavage; Published on: 1998-06-09; cited as U.S. Patent Document #004 in IDS filed 10/31/2023).
Instant claim 1 recites:
A nucleic acid primer set for amplifying a target nucleic acid in a sample,
wherein the target nucleic acid comprises a first template strand and, optionally, a second template strand, wherein the second template strand is complementary to the first template strand,
the primer set comprising a cycling probe (‘368 Patent, claim 34) and oligonucleotides in the form of, or capable of forming, at least two first primers (‘368 Patent, claim 1) capable of hybridizing to the first template strand,
wherein the at least two first primers comprise a first outer primer and a first inner primer (‘368 Patent, claim 1),
the first outer primer comprising a primer sequence a that specifically hybridizes to first template strand sequence a'(‘368 Patent, claim 1), primer sequence a comprising a first modified base that is complimentary to a first unmodified base of the first template strand sequence a'
wherein the first unmodified base is selected from the group consisting of adenine, thymine, uracil, guanine, and cytosine; and
the first inner primer comprising a single-stranded primer sequence b that specifically hybridizes to first template strand sequence b', wherein b' is adjacent to, and 5' of, a' (‘368 Patent, claim 1), and
wherein single-stranded primer sequence b is linked at its 5' end (‘368 Patent, claim 1)to a first strand of a first double- stranded primer sequence comprising :
a primer sequence a adjacent to, and 5' of, single-stranded primer sequence b (‘368 Patent, claim 1); and
a clamp sequence c adjacent to, and 5' of (‘368 Patent, claim 1), primer sequence a, wherein the clamp sequence c is not complementary to a first template strand sequence d', which is adjacent to, and 3' of, the first template strand sequence a';
wherein a second strand of the first double-stranded primer sequence comprises primer sequence c' adjacent to, and 3' of, primer sequence a', wherein combined sequence c'-a' is complementary to combined sequence c-a, primer sequence a' comprising a second modified base that is complimentary to a second unmodified base of the primer sequence a of the first strand of the first double-stranded primer sequence(‘368 Patent, claim 1), wherein the second unmodified base is selected from the group consisting of adenine, thymine, uracil, guanine, and cytosine(‘368 Patent, claims 29, 31);
wherein the first unmodified base of the first template strand sequence a' is complementary to the second unmodified base of the primer sequence a; and the first modified base does not form a stable hydrogen-bonded base pair with the second modified base (‘368 Patent, claim 26);
wherein the cycling probe is configured to be cleaved by an enzyme to initiate release of a label from the cycling probe and release of the first template strand, the second template strand, or an amplicon of the first or second template strand, in an intact form, from the cycling probe.
The '368 Patent claims most of the limitations in instant claim 1.
While the '368 Patent claims a probe (‘368 Patent, claim 34 for example), it does not specifically claim cycling probe comprises an enzyme cleavage site and a label.
Han fills this gap by teaching use of cycling probes with FRET in detecting specific DNA sequences (entire document; col 21-22: Example 3 for example), for performing a fluorometric assay to detect nucleic acid cleavage, which can be used to enhance the efficiency and detection of well-known nucleic acid amplification techniques such as PCR (entire document; col 10, lines 21-25 for example).
It would have been prima facie obvious to a person of ordinary skill in the art to combine the known element taught in Han with the claimed invention of ‘368 Patent, because both references pertain to nucleic acid amplification and detection.
As suggested by Han :
“The described fluorometric assay for detecting nucleic acid cleavage can also be utilized to improve the efficiency and detection signal of a number of well-known procedures for amplifying or detecting a specific DNA or RNA sequence, such as polymerase chain reaction (PCR).” (col 10, lines 21-25)
Thus, a skilled artisan would understand that integrating the prior art element from Han into ‘368 Patent's claimed primer set would have yielded the predictable result of a primer set, for enhanced nucleic acid detection by incorporating Han's cycling probes to further amplify detection signals in amplicon products in a PCR reaction. This is because, instead of detecting each DNA amplicon only once, with the cycling probes the same DNA amplicon products from PCR amplification reaction can be detected multiple times (see Example 3), therefore greatly increases the signal.
Such combination represents a predictable use of prior art element according to a known method to yield predictable results (See MPEP §2143).
Therefore, instant claims 1 and 26 are obvious over claims 1, 26, 29, 31 and 34 of the ‘368 patent, in view of Han. Instant claims 2, 5, 7-8 and 18 are obvious over claims 1, 15-16 and 35 of the ‘368 patent, in view of Han.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/TIAN NMN YU/Examiner , Art Unit 1681 /AARON A PRIEST/Primary Examiner, Art Unit 1681
1 Higuchi shares a co-inventor and the same applicant as the present application, and has a publication date of 2016-06-23, which is over 3 years prior to the effective filling date of the present application.
2 Hendricks et al. "Signal amplification-based techniques." Nucleic Acid Testing for Human Disease. CRC Press, 2016. 19-64.