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 July 09, 2026.
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Claims 1-10, and 13-14 are currently pending, with claims 8-10 and 13-14 withdrawn from consideration.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.
No rejection has been overcome by amendment. 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.
Response to Arguments
Applicant's arguments filed on July 09, 2026 have been fully considered.
Claim Rejections - 35 USC § 103
In the prior Office Action (Final Office Action- 01/09/2026):
Claims 1-7 are rejected under 35 U.S.C. 103 as being unpatentable over McEwan, in view of Frick; Zaher; Smeekens ; and Krupp.
These rejections are maintained in this Office Action for reasons below.
Applicant argues that the rejections above should be withdrawn (Remarks, page 4-8).
Applicant's arguments have been fully considered but are not found persuasive.
First, Applicant argues that substituting T7 RNA polymerase for primase is not obvious because these enzymes differ in their primary functions recognized in the art (Remarks, page 5), and asserts that "Frick, the very reference the Examiner relies upon, discusses RNA polymerases and primases as alternative mechanisms for providing primers, not as interchangeable equivalents." (Remarks, page 5).
This is not persuasive. As discussed in the rejection, McEwan teaches a DNA amplification method that uses primase to generate RNA primers, thus eliminating the need for added primers. Although no single prior art reference explicitly teaches using T7 RNA polymerase to generate primers in a DNA amplification reaction, this would have been the next logical step based on the suggestions throughout the art.
Frick teaches 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, Smeekens, and Krupp support the general knowledge in the art that T7 RNA polymerase is capable of both promoter dependent and promoter-independent activity. The claim does not exclude DNA template containing promoter sequences and does not exclude promoter-dependent priming by RNA polymerase.
A person of ordinary skill is also a person of ordinary creativity, not an automaton, and in many cases will be able to fit teachings of multiple patents together like pieces of a puzzle (See MPEP § 2141.03). Given this creativity and the ability to fit teachings of multiple references together like the pieces of a puzzle, one of ordinary skill in the art 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.
Second, Applicant argues unexpected results, asserting:
"The unexpected result is that T7 RNA polymerase can efficiently prime DNA amplification independent of its cognate promoter; a finding that was contrary to the prevailing understanding in the art." (Remarks, page 6)
This argument is not persuasive.
As discussed above, the ability of RNA polymerase to generate primers was known in the art. Therefore, this property is not unexpected. McEwan teaches a DNA amplification method that uses primase to generate RNA 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 both promoter dependent and promoter-independent activity.
The assertion of efficient priming, independent of promoter is not commensurate in scope with the claims. The claimed method broadly encompasses any method using an RNA polymerase selected from T7, T3, or SP6 RNA polymerase, a DNA polymerase and a combination of ribonucleotides and deoxyribonucleotides for amplification of a DNA template. The claim does not exclude DNA template containing promoter sequences and does not exclude promoter-dependent priming by RNA polymerase. Thus, the claims are broader than the asserted result. Any method that performs the recited steps using the claimed "T7, T3, or SP6 RNA polymerase" would fall within the scope of the claim, including methods using RNA polymerase promoter-containing templates.
Accordingly, the alleged unexpected result is not commensurate in scope with the claimed, broader invention.
Third, Applicant argues that the prior art references teach away from using T7 RNA polymerase for promoter-independent DNA amplification, and a skilled artisan would not have had reasonable expectation of success because:
"A person of ordinary skill in the art, reading the prior art's emphasis on T7 RNA polymerase's promoter specificity, would have expected that attempts to use T7 RNA polymerase for promoter-independent DNA priming would fail." (Remarks, pages 7-8)
Applicant asserts:
"The statement in Frick that "RNA polymerases can provide primers" is a generalized, passing observation, not a specific teaching that T7 RNA polymerase could efficiently prime DNA amplification in a promoter-independent manner." (Remarks, pages 7)
This is not persuasive.
The prior art references do not explicitly discourage or criticize the use of T7 RNA polymerase in DNA amplification; thus, they do not teach away from the claimed invention.
Similar to the discussion above, the core issue here is the argument is not commensurate in scope with the claim. The claim as currently written, is not limited to the asserted "efficient priming" in promoter independent manner. Rather, the claim broadly encompasses a method using an RNA polymerase selected from T7, T3, or SP6 RNA polymerase, a DNA polymerase and a combination of ribonucleotides and deoxyribonucleotides for amplification of a DNA template.
As discussed in the rejection, 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. Accordingly, 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.
For the reasons above, Applicant's arguments are unpersuasive. Accordingly, the rejections are maintained.
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.
For the purpose of applying prior art, claim 1 recites:
A method for amplifying a template DNA molecule, comprising
a) providing a template DNA molecule;
b) providing an RNA polymerase selected from T7, T3, or SP6 RNA polymerase, a DNA polymerase and a combination of ribonucleotides and deoxyribonucleotides;
c) incubating the materials from step a and b in a suitable buffer and for a suitable amount of time to allow replication and amplification of said template DNA molecule,
wherein said RNA polymerase initiates DNA amplification independent of its cognate promotor.
Here, the wherein clause "wherein said RNA polymerase initiates DNA amplification independent of its cognate promotor" is interpreted as a descriptive statement identifying an inherent property of the recited RNA polymerase, and does not impose a manipulative difference on the claimed method. The wherein clause describes how DNA amplification occurs, but it does not incorporate any additional step into the method claim nor does it modify any existing method step in the claim.
Accordingly to the specification, promoter-independent amplification initiation is an inherent function of any T7, T3, or SP6 RNA polymerase, independent of where they are sourced (see Example 7). Accordingly, this wherein clause does not distinguish the claimed method from prior art methods that teach the claimed providing steps and incubating steps using T7, T3, or SP6 RNA polymerase.
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.
Maintained 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.
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 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 a and 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).
Prior Art
Below are relevant prior art not used in rejection but pertinent to the claims or disclosure.
The reference below also teach amplifying a template DNA molecule using a reaction comprising T7 RNA polymerase and a DNA polymerase:
Kievits (Kievits et al. NASBA isothermal enzymatic in vitro nucleic acid amplification optimized for the diagnosis of HIV-1 infection. J Virol Methods. 1991 Dec;35(3):273-86. doi: 10.1016/0166-0934(91)90069-c. PMID: 1726172.)
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/TIAN NMN YU/Examiner , Art Unit 1681 /AARON A PRIEST/Primary Examiner, Art Unit 1681
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