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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 November 25, 2025 has been entered.
Status of Claims / Response to Amendment
This office action is in response to an amendment filed on November 25, 2025.
Claims 1-10, and 13-14 were previously pending. Applicant amended claim 1.
Claims 1-10, and 13-14 are currently pending, with claims 8-10 and 13-14 withdrawn from consideration.
Claims 1-7 are under consideration
All of the amendment and arguments have been thoroughly reviewed and considered. All of the previously presented rejections have been withdrawn as being obviated by the amendment of the claims, which added new limitations to the claims, that were not considered in the previous rejections.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
The priority date of the instant claims 1-7 is April 23, 2019, filling date of the NETHERLANDS Patent Application Number 2022993, to which the present application claims priority.
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.
Claim 1 recites "suitable buffer," which is defined in the specification as follows:
"The term "suitable buffer", as is used herein, refers to an aqueous buffered
solution of which the pH is at a nearly constant value." (Page 8, lines 7-10)
For the purpose of applying prior art, claim 1 recites "suitable amount of time," which is not defined by the application's disclosure. The application's disclosure describes the term "suitable amount of time" as follows:
"A method of the invention is performed for a suitable amount of time to
amplify the DNA template. Said amount of time preferably is 0.5-48 hours, more
preferably 1-24 hours, more preferred 2-20 hours, such as at least 5 hours, at least
8 hours, at least 12 hours, or at least 16 hours." (page 12, lines 26-29)
In view of the application's disclosure, while several time ranges are described as preferable for a suitable amount of time to amplify the DNA template, they do not limit the term "suitable amount of time" to only consist of these time ranges. Thus, under BRI, the term "suitable amount of time" is interpreted as any amount of time.
For the purpose of applying prior art, claim 1 recites " incubating said materials in a suitable buffer and for a suitable amount of time to allow replication and amplification of said template DNA molecule."
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, the claim recitation "to allow replication and amplification of said template DNA molecule" describes an intended result. It does not incorporate any additional step into the method claim nor does it modify any existing method step in the claim. In other words, it merely states the intended outcome of the incubating step and makes no manipulative difference.
Therefore, this descriptive claim language "to allow replication and amplification of said template DNA molecule" does not distinguish the claimed method from prior art methods that disclose all the claimed steps.
Claim Rejections - 35 USC § 103 -- New
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 1-7 are rejected under 35 U.S.C. 103 as being unpatentable over McEwan (US20110294167A1 - Nucleic acid amplification ; Published on 2011-12-01; cited as US Patent Application Publication # 1 on IDS filed 01/22/2024) , in view of
Frick (Frick DN, Richardson CC. DNA primases. Annu Rev Biochem. 2001;70:39-80. doi: 10.1146/annurev.biochem.70.1.39. PMID: 11395402);
Zaher (Zaher et al. T7 RNA polymerase mediates fast promoter-independent extension of unstable nucleic acid complexes. Biochemistry. 2004 Jun 22;43(24):7873-80. doi: 10.1021/bi0497300. PMID: 15196031);
Smeekens (Smeekens et al.; Promoter and nonspecific DNA binding by the T7 RNA polymerase. Nucleic Acids Res. 1986 Mar 25;14(6):2811-27. doi: 10.1093/nar/14.6.2811. PMID: 3960735; PMCID: PMC339700); and
Krupp (Krupp G. RNA synthesis: strategies for the use of bacteriophage RNA polymerases. Gene. 1988 Dec 10;72(1-2):75-89. doi: 10.1016/0378-1119(88)90129-1. PMID: 2468576).
A) McEwan teaches methods for amplifying nucleic acids without exogenously-added primers (entire document; Abstract for example).
Regarding claim 1, McEwan teaches a method for amplifying a template DNA molecule, comprising a) providing a template DNA molecule ([0128] human genomic DNA); b) providing an RNA polymerase ([0128] T7 primase is an RNA polymerase that synthesizes RNA primers; [0061]; [0065]) , a T7 RNA polymerase ([0004], lines 8-9), a DNA polymerase ([0128] phi29) and a combination of ribonucleotides and deoxyribonucleotides ([0128] lines 8-9); c) incubating the materials from step b in a suitable buffer ([0128] lines 7-8) and for a suitable amount of time ([0128] lines 14-16) to allow replication and amplification of said template DNA molecule.
McEwan teaches T7 RNA polymerase ([0004], lines 8-9). While McEwan teaches T7 RNA polymerase in the context of WGA, and does not specifically teach using T7 RNA polymerase in generating primers. The prior art (e.g., Frick, Zaher, Smeekens, Krupp) suggests that RNA polymerase (such as T7 RNA polymerase) is a known substitute for primase, and capable of the same function of providing primers.
Frick (cited by McEwan in [0065]) further suggests that RNA polymerases can function as alternatives to primases in providing primers for DNA polymerase:
“It should also be noted that DNA primases are not the sole means of providing primers for DNA polymerases. Other mechanisms for strand initiation include the use of DNA ends generated by recombination or repair, transcripts made by conventional RNA polymerases, or priming proteins attached to the ends of linear DNAs (12).” (page 42, para 1)
Zaher specifically teaches T7 RNA polymerase can produce anomalous transcripts in the absence of a promoter:
"T7 RNA polymerase is a processive, DNA-dependent RNA polymerase that has a high specificity for its 17 base pair (bp) promoter. In addition to normal transcription, the enzyme can produce anomalous transcripts in the absence of a promoter. "(Abstract)
Smeekens discloses that T7 RNA polymerase is capable of both promoter-specific binding and promoter-independent binding, and these activities are regulated by different factors:
"Promoter-specific binding was shown to be relatively insensitive to variations in the ionic strength of the incubation solution but dependent on the helical structure of the DNA. On the other hand, nonpromoter interior-site binding was independent of the superhelicity of the DNA but extremely sensitive to changes in the ionic strength. These results suggest that nonspecific binding results from ionic interactions between positively charged residues of the polymerase and the polyanionic backbone of the DNA, whereas promoter-specific binding is dependent upon base-specific contacts within the promoter sequence. A comparison between the transcriptional activity and binding strengths of the RNA polymerase to specific promoters indicates little correlation between these two properties. This suggests that differential promoter binding does not represent a major mechanism for regulating transcription in bacteriophage T7. Instead, factors which influence the efficiency or rate of formation of the polymerase-promoter open complex are found to have the major role in determining transcriptional levels in this system." (Abstract)
Krupp teaches that even oligos without any promoter sequence can be used as template DNA for T7 RNA polymerases (also SP6, see page 85-87; "(b) Oligos without promoter as template DNA "; Fig. 9).
Accordingly, a skilled artisan, informed by prior art teachings, would understand that T7 RNA polymerase can perform a priming function similar to that of a primase, both in a promoter-dependent and promoter-independent manner, thereby "initiating DNA amplification" as recited by the claim.
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 use T7 RNA polymerase in place of primase, in the exogenous-primer-free DNA amplification method taught by McEwan, representing the KSR principle of a simple substitution of one known element for another to obtain predictable results, see MPEP 2141. Given that each element performs a known function as per its prior art teaching, the combination to achieve a predictable result would have been obvious, as per MPEP 2143.
McEwan teaches a DNA amplification method that uses primase to generate RNA primers, thus eliminating the need for added primers. Frick, cited by McEwan suggests that RNA polymerases (e.g., T7 RNA polymerase) can also function to generate primers that serve as substrates for primer extension by DNA polymerase. Zaher, Smeekens, and Krupp support the general knowledge in the art that T7 RNA polymerase is capable of promoter-independent activity.
A skilled artisan, motivated by the need to improve nucleic acid amplification methods, as suggested by McEwan ([0007]), would have found it obvious to substitute T7 RNA polymerase for primase based on the recognition that both enzymes generate RNA products useable as primers for DNA polymerase, as suggested by Frick, Zaher, Smeekens, and Krupp.
The person of ordinary skill would have had a reasonable expectation of success in making this substitution, because Frick teaches that RNA polymerase and primase are functional analogs in that they both can synthesize RNA primers for primer extension by DNA polymerase. And McEwan already teaches T7 RNA polymerase in a related context of synthesizing RNA transcripts. The fact that T7 RNA polymerase is capable of both promoter-specific binding and promoter-independent activities, as discussed above, is supported by prior art.
Therefore, substituting one RNA-primer generating enzyme for another in a method for exogenous-primer-free DNA amplification represents a straightforward and technically compatible modification. Doing so would have yielded the predictable result of an exogenous-primer-free DNA amplification method in which T7 RNA polymerase generates RNA primers for DNA polymerase, enabling amplification without exogenously added primers.
Therefore, claim 1 is obvious over McEwan, in view of Frick, Zaher, Smeekens, and Krupp. This rationale aligns with the principle of KSR for a simple substitution of one known element (T7 RNA polymerase) for another(primase) to obtain predictable results, see MPEP 2141.
B) Regarding claim 2, McEwan teaches RNA polymerase is a single subunit RNA polymerase by teaching T7 RNA polymerase([0004], lines 8-9), which is a single subunit RNA polymerase per application's own disclosure (specification, page 4, lines 4-6).
Regarding claim 3, McEwan teaches DNA polymerase is a DNA- dependent DNA polymerase with strand-displacement activity ([0128] phi29).
Regarding claim 4, McEwan teaches ribonucleotides comprise at least one ribonucleotide with a purine nucleobase ([0128] rATP).
Regarding claim 5, McEwan teaches replication and amplification comprises providing at least one oligonucleotide complementary to the template DNA molecule ([0062]lines 2-4), a mix of random oligonucleotides ([0112] random hexamers).
Regarding claim 6, McEwan teaches at least one species of the nucleotides or ribonucleotides is modified or labeled ([0104] lines 5-8).
Regarding claim 7, McEwan teaches amplified product is detected by fluorescence ([0104] lines 1-5) or by chemical means ([0104] luminol).
Response to Arguments: Claim Rejections - 35 USC § 103
The previously set forth 103 rejections of claims 1-7 have been withdrawn in view of the recent claim amendment filed on November 25, 2025, which added new limitations to the claims, that are not addressed in the previous rejections.
Applicant's arguments filed on November 25, 2025 have been fully considered but are not found persuasive.
First, Applicant argues the following:
"McEwan provides improved systems and methods for amplifying nucleic acids through use of a primase and a DNA polymerase with strand displacement ability without, for example, exogenously-added primers.
Applicant respectfully submits that McEwan's invention is thus fundamentally different from the claimed method, as it does not rely on true RNA polymerases, but on primase activity of unrelated enzymes for primer generation." (Remarks, page 4).
"Frick and Richardson cannot remedy the deficiencies of McEwan." (Id.). Because T7 RNA polymerase and T7 primase have different sequence structure.
This argument has been fully considered but is not persuasive.
As discussed in the rejection above. McEwan teaches T7 RNA polymerase ([0004], lines 8-9). While McEwan teaches T7 RNA polymerase in the context of WGA, and does not specifically teach using T7 RNA polymerase in generating primers. The prior art (e.g., Frick, Zaher, Smeekens, Krupp) suggests that RNA polymerase (such as T7 RNA polymerase) is a known substitute for primase, and capable of the same function of providing primers.
Additionally, Applicant's argument regarding sequence differences is not persuasive. While proteins with similar sequences may often have similar functions, the reverse is not necessarily true. The fact that two proteins have different sequences does not preclude them from performing the same or similar function. It is well-known in the field of molecular biology that proteins with different sequences can fold into similar structures, and serve as functional analogs through mechanisms such as convergent evolution 1.
Second, Applicant argues the previously set forth rejection "does not provide the specific motivation or teaching that would lead a person of ordinary skill in the art to substitute T7 RNA polymerase for primase in McEwan's system" (Remarks, page 5) and a person of ordinary skill would not have had a reasonable expectation of success (Remarks, page 6).
This argument has been fully considered but is not persuasive. As set forth in the rejection above, the new grounds of rejection expressly provides the motivation and rationale to modify and combine the teachings in cited references. The new grounds of rejection identifies why a person of ordinary skill in the art would have been motivated to make the substitution and would have had a reasonable expectation of success.
Accordingly, the rejection is properly made.
Third, Applicant argues unexpected results and provides the following rationale as support:
"The method as claimed is based on the unexpected observation that a RNA polymerase such as T7 RNA polymerase is able to efficiently mediate priming of both native, double stranded DNA and denatured, single-stranded DNA templates for subsequent amplification by a DNA polymerase, in the absence of a consensus T7 promoter sequence and exogenously added oligonucleotide primers.
It was subsequently found that also other RNA polymerases such as SP6 and T3 RNA polymerase are able to initiate DNA amplification in the absence of a consensus SP6 or T3 promoter sequence, respectively.
The unexpected nature of the findings lies in the fact that transcriptional activity of DNA dependent RNA polymerases like T7, T3, and SP6 RNA polymerases has been widely described and recognized as being highly specific for their respective promoter sequences, and that binding of said RNA polymerases only occurs on double-stranded DNA promoter sequences. The unexpected discovery cannot be rendered obvious by the general statement in Frick that RNA polymerases can provide primers, particularly when the prior art teaches that these RNA polymerases require specific and double-stranded promoter sequences for activity." (Remarks, page 5-6)
This argument is not persuasive.
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support. See MPEP§ 716.02 (d)
The question of unexpected result is whether the claimed invention possesses unexpected properties compare to the closest prior art. The evidence relied upon should establish “that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.” Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength “are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration.”)
Here, Applicant's argument is not commensurate in scope with the claim. The claims do not exclude templates containing promoter sequences or exogenously added primers.
Furthermore, Applicant's argument provides no objective evidence supporting the assumption that promoter-independent priming by RNA polymerase such as T7 RNA polymerase is unexpected. While some references, such as Golomb et al., 1977. J Virol 21: 743-752, cited in the specification (page 11), disclose that T7 polymerase requires a specific promoter for in vitro transcription; other prior art references ꟷ including those cited in the rejection above ꟷ teach promoter independent activity by T7 RNA polymerase. Thus, the prior art presents mixed teachings, and not all support the view that such activity is unexpected.
Applicant does not address this conflicting teachings in the art or provide evidence sufficient to rebut it.
According to MPEP § 2145, office personnel must consider the appropriate weight to be accorded to each piece of evidence. An obviousness rejection should be made or maintained if evidence of obviousness outweighs evidence of nonobviousness. See MPEP § 706, subsection I. ("The standard to be applied in all cases is the ‘preponderance of the evidence’ test. In other words, an examiner should reject a claim if, in view of the prior art and evidence of record, it is more likely than not that the claim is unpatentable.").
In this case, the prior art supports a reasonable expectation of success in template-independent priming and binding activity by T7 RNA polymerase. Per MPEP 2145, absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient.
In the absence of objective evidence of unexpected results, the preponderance of the evidence supports unpatentability.
In conclusion, while Applicant's arguments have been thoroughly considered, they are not persuasive. The applicant is encouraged to submit objective evidence of unexpected properties in the form a comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims (see MPEP 716.02(b) ), in response to this Office Action.
Conclusion
No claims are allowed.
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/TIAN NMN YU/Examiner , Art Unit 1681 /AARON A PRIEST/Primary Examiner, Art Unit 1681
1 see en.wikipedia.org/wiki/List_of_examples_of_convergent_evolution#In_proteins.2C_enzymes_and_biochemical_pathways