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 .
Applicant’s arguments and amendments have been thoroughly reviewed and considered. Claims 1-2 and 11-23 remain withdrawn. Claims 24-27 are pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/23/2025 and 1/27/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Response to Applicant’s Amendments
Nucleotide and/or Amino Acid Sequence Disclosures
The specification was objected to because the Sequence Incorporation by Reference paragraph was defective. In light of Applicant’s amendments to the specification submitted on 1/27/2026, this objection has been withdrawn.
Claim Objections
Claims 25 and 27 were objected to due to minor informalities. In light of Applicant’s amendments to the claims submitted 1/27/2026, these objections have been withdrawn. However, see new grounds of objection below.
35 USC 112(d) Rejection
Claim 25 was rejected as several of the options presented allegedly failed to further limit the claim upon which they depended. Regarding the 35 USC 112(d) Rejections, Applicant argues that the options pointed out by the Examiner do further limit the invention of claim 24 (Remarks, pages 18-19). The Examiner agrees with the Applicant, and so these rejections have been withdrawn.
35 USC 103 Rejections
Claims 24-27 were rejected under 35 U.S.C. 103 as being unpatentable over Makarov et al. (WO 2020/010124 A2), in view of Oliphant et al. (US 2003/0108900 A1), and in view of Zhang et al. (US 2010/0151448 A1).
Applicant’s arguments and amendments have been thoroughly reviewed and considered. These rejections have been withdrawn, but see new grounds of rejection and “Response to Applicant’s Arguments” below.
Response to Applicant’s Arguments
Regarding the 35 USC 103 Rejections, Applicant argues that the combination of references fails to teach or suggest every claimed limitation, the secondary reference Oliphant teaches away from the claimed invention, and the presently claimed method unexpectedly solves a problem that has long plagued those skilled in the art (Remarks, page 19, para. 5).
Pages 20-23 of Applicant’s Remarks explain how the method of the instant invention is intended to work, and particularly how an exemplary primer set of the claimed method can suppress non-specific amplification. It is noted that the elected claims are product claims – i.e. a primer set and a kit – and not method claims. Being product claims, there is no specific use required for the primers in the primer set. The final clause of instant claim 24 requires particular functions of the primer set when “under a condition that allows nucleic acid hybridization or annealing,” but the use of such conditions is still not required by the claim.
On pages 29-31 of their Remarks, Applicant discusses the unexpected benefits of using the claimed primer set and the technical solution it presents. Applicant specifically points to data presented in Examples 1 and 5. In Example 1, the conclusion was that “the system of the present invention could be used to obtain asymmetric amplification of target nucleic acid,” and does not discuss any unexpected benefits (instant specification, page 36, para. 4). In Example 5, conventional multiplex asymmetric PCR and primers of the present invention were compared, and it was concluded that the present system had more sensitivity to effectively detect targets at low concentrations (instant specification, page 46). MPEP 716.02 discusses allegations of unexpected results. Though increased sensitivity could potentially be considered a superior property of the claimed invention (see MPEP 716.02(a)), Applicant does not explain why said results would be unexpected. In discussing the results of this example, Applicant states that their sensitivity results were “mainly because the system of the present invention used low-concentration target-specific primers and high-concentration universal primers…,” and so it appears these results are at least partially attributed to the concentration of components used. The instant claims require no specific concentrations of any component in the primer set.
Furthermore, MPEP 716.02(b) I states that the burden is on Applicant to establish that results are unexpected and significant. MPEP 716.02(d) states that unexpected results should also be commensurate in scope with the claimed invention. This means that any potentially unexpected results must apply over the entirety of a claimed range. Example 5 uses specific primer and probe sequences, with a specific universal tag primer also being used for the inventive PCR. In the instant claims, no specific sequences are required, and so the claimed primers are much more broad than those of Example 5. Additionally, in the instant claims, the first and second universal sequences can differ based on one or more nucleotides located at the 3’ end of the first universal sequence that are each independently deleted or substituted, but in Example 5, only one nucleotide appears to be substituted between first and second universal sequences (where the second universal sequences are taken to be the 5’ ends of the forward primers that are mostly in common with the Tag primer). Thus, the claimed structure of the universal sequences, which appear to be of paramount importance to Applicant’s instant invention, are much more broad in scope than what is presented in Example 5. For at least these reasons, this example is not considered commensurate in scope with the claimed invention.
Thus, the Examiner does not find these arguments persuasive.
On pages 31-32 of their Remarks, Applicant argues that their invention fulfills a long-felt and unmet need in that it solves problems related to primer dimers, and specifically it fulfills a need evidenced by Oliphant. MPEP 716.04 addresses this secondary consideration. Section I states, “Establishing long-felt need requires objective evidence that an art recognized problem existed in the art for a long period of time without solution. The relevance of long-felt need and the failure of others to the issue of obviousness depends on several factors. First, the need must have been a persistent one that was recognized by those of ordinary skill in the art. In re Gershon, 372 F.2d 535, 539, 152 USPQ 602, 605 (CCPA 1967).” In Oliphant, primer-dimers are not recognized as a problem the reference is unable to solve – in fact, they are only mentioned in para. 332, where said dimers can be removed in a washing step, showing they are not a problem in the invention of Oliphant.
Additionally, the disclosure of a single reference (i.e. Oliphant) does not show evidence of a persistent problem plaguing the art, nor does it show the failure of others at solving said problem. In Applicant’s provided non-patent literature of their own work, which highlights that primer-dimers can decrease sensitivity, it also teaches the use of HANDS, which by the work’s own admission, does inhibit primer-dimer accumulation (see page G, column 1, para. 2, which states, “HANDS inhibits PD accumulation by adding a homo-oligonucleotide to all primers to generate the panhandle structure”). Thus, before Applicant’s own work, previous techniques had been developed to deal with the issue of primer-dimers.
Therefore, this argument is not persuasive, and Applicant has not yet provided evidence that their invention fulfills a long-felt and unmet need.
Due to Applicant’s amendments to the claims, further search and consideration of the claims was required. This searching revealed additional prior art, and as a result, new grounds of rejection are provided below. Thus, Applicant’s arguments against the references provided in the Non-Final Rejection are considered moot.
Claim Objections
Claim 25 is objected to because of the following informalities: in option (4), all recitations of “a forward nucleotide sequence” should read “the forward nucleotide sequence,” as this sequence is already initially recited in claim 24, from which this claim depends. Similarly, in option (7), all recitations of “a reverse nucleotide sequence” should read “the reverse nucleotide sequence.” Finally, in options (8) and (9), there should be a space between the option recitation and the limitation presented by the option (i.e. “(8) at least”). Appropriate correction is required.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 24-25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Liu et al (BioTechniques, 2007; cited in Applicant’s IDS).
It is noted that, as stated above in the “Response to Applicant’s Arguments” section, the claims are directed to a primer set, with no particular method for using the primers being required. Thus, the primers need not be used together in the same reaction in the prior art, so long as the primer set structures described by the claim are met by the prior art.
Liu teaches a TAIL-PCR method that blocks the amplification of nontarget products and suppresses small targets, while allowing amplification of large targets (Abstract). This method is especially useful for isolating unknown DNA sequences surrounded by known sequences, and incorporates designed degenerate and known-sequence-specific primers (Abstract and page 649, column 3, para. 1). Genomic DNA was transformed with vector constructs pCAMBIA1305.1 and pCAMBIA1300 (page 64, column 3, para. 3).
In the pre-amplification step, LAD primers were used, along with RB-0a or RB-0b (depending on whether pCAMBIA-1305.1 or pCAMBIA-1300 was used as a vector, respectively. This applies to the a and b notation of all the other primers used as well, see Figure 1 caption). As these RB primers are specific to the vectors integrated into the DNA, and so represent known sequences (see Figure 1 caption). Then in the TAIL-PCR reactions, AC1 and RB-1a or RB-1b were used with the pre-amplified product in primary reactions, and AC1 and RB-2a or RB-2b were used in the secondary reactions (pages 649-650, “PCR”).
The LAD primers are long arbitrary degenerate primers (see page 649, column 2, para. 2 and page 650, column 1, para. 2). These LAD sequences all share a common 5’ sequence that is equivalent to the AC1 sequence, followed by degenerate sequences, and then fixed 3’ ends. These 3’ ends are capable of anchoring the LAD sequences to the target sequences (page 650, column 1, para. 2), and so are considered to be specific to the target nucleic acids. As the 5’ LAD ends and the AC1 sequence are degenerate sequences, this sequence is considered a first universal sequence. Thus, the LAD primers are considered analogous to the claimed reverse primer and the AC1 sequence is considered analogous to the universal primer.
The RB-1a sequence, used in the primary TAIL-PCR, is specific to the vector target, as described above, but also contains a 5’ sequence tag. This tag is almost the same as the AC1 sequence, but differs in two substituted nucleotides (the underlined TC in Figure 1). Thus, the RB-1a sequence contains a universal sequence that is not the same as the first universal sequence at its 5’ end, making this universal sequence a second universal sequence, and a target specific portion at its 3’ end. Furthermore, the first universal sequence would be capable of hybridizing to the complement of the second universal sequence, as the universal sequences are very similar to one another. Liu also states that the RB-1a and the AC1 primers contain complementary ends, which are useful in suppressing PCR amplification of short products (page 652, column 1, para. 2). This would make the RB-1a sequence analogous to the claimed forward primer.
Thus, Liu meets all of the limitations of instant claim 24.
Regarding claim 25, as the AC1 sequence is analogous to the universal primer and only contains the sequence analogous to the first universal sequence, Liu is considered to meet option (1) of the claim.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claims 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al (BioTechniques, 2007; cited in Applicant’s IDS).
Liu teaches claims 24-25, as described above.
Regarding claim 26, this recites the primer set of claim 24 as a kit with an additional component. Claim 27 also requires at least one additional technical feature for the kit.
Liu clearly teaches all of the primers, and their use, in a single TAIL-PCR protocol. Thus, it would be prima facie obvious to the ordinary artisan that these primers could be packaged together in a kit, for both easy use and access to all of the needed primers in a single location, but also for potential commercial use and/or protocol sharing between users.
As for the additional components recited in claims 26 and 27, Liu recites the use of Ex Taq in each of the amplification reactions, as well as the use of a PCR buffer and dNTPs (pages 649-650, “PCR”). As the polymerase, buffer, and dNTPs are necessary for each of the amplification reactions, it would be prima facie obvious to also include at least these elements in the kit containing the primers, so that the kit would contain most of the elements needed to perform the amplification reaction. This would increase the utility of the kit, as users would need to procure less necessary reaction components separately, and would also increase the commercial value of the kit for potential consumers.
Thus, claims 26 and 27 are prima facie obvious over Liu.
Conclusion
No claims are currently allowable.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRANCESCA F GIAMMONA whose telephone number is (571)270-0595. The examiner can normally be reached M-Th, 7-5pm.
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/F.F.G./Examiner, Art Unit 1681
/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681
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