DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Preliminary Amendment
2. The preliminary amendment filed on October 16, 2023 has been entered.
Claims 1 and 32-47 are pending and the subject of this Office action on the merits.
Priority
3. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. 16/956,552, filed on June 19, 2020.
Information Disclosure Statement
4. Applicant’s submission of an Information Disclosure Statement (IDS) on June 27, 2025 is acknowledged. The cited references have been considered, except for Non-Patent Literature Citations C18, C40, and C48. These three references have not been considered because the copy required by 37 CFR 1.98(a)(2) has not been provided, either in the instant application or in the parent application cited in the transmittal letter accompanying the IDS (i.e., Application Serial No. 16/956,552).
It is also noted that citation B1 in the “Foreign Patent Documents” section has been corrected to indicate the document number of the provided document.
As well, the following citations are duplicate citations: (i) C4 and C61, (ii) C38 and C49, and (iii) C47 and C60. The duplicate citations have been lined through.
Applicant is advised that the date of any re-submission of any item of information contained in this IDS or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e) as well as assertions under 37 CFR 1.98(a)(4). See MPEP § 609.05(a).
Drawings
5. The drawings filed on April 20, 2023 are objected to because the data in Figure 2 is not aligned with the values on the two axes.
Substitute Specification
6. The substitute specification filed on October 16, 2023 has been entered.
The substitute specification is objected to because the continuity information in the first paragraph should be updated to indicate that prior-filed Application Serial No. 16/956,552 has issued as US 11,655,496.
The substitute specification is also objected to because its title is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. The new title could indicate, for example, that the amplification method is non-isothermal and is conducted with a polymerase and a nicking enzyme.
Abstract
7. The abstract is objected to because it is longer than the maximum permitted length of 150 words and also uses the legal phraseology “said.” See MPEP 608.01(b). Appropriate correction is required.
Claim Objections
8. Claim 1 is objected to because of the following minor informalities:
(i) the semicolon at the end of step (a) should be replaced with a colon;
(ii) each instance of “single stranded” should be hyphenated;
(iii) the word “the” should be inserted after “recreates” in line 2 of step (c) to improve internal claim consistency;
(iv) replacing “which extension” in line 2 of step (c) with “wherein extension” is suggested;
(v) the word “and” should be inserted after the semicolon at the end of step (c)
(vi) the claim contains an extra space after the hyphen in “non-isothermal” and “steps (b)-(d)” in lines 15 and 17, respectively; and
(vii) the word “an” should be inserted after the second instance of “upper” in the third-from-last line of the claim.
Claims 40 and 41 are objected to because the word “of” is missing after the word “range” in line 1 of each claim.
Claims 43-45 are objected to because the word “of” is missing after the word “range” in line 2 of each claim.
Claim 46 is objected to because the word “of” is missing after the word “range” in line 1.
Claim Rejections - 35 USC § 112
9. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 34 and 35 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 34 and 35 are new claims filed in a preliminary amendment submitted after the filing date of the instant application.
Claim 34 depends from claim 32 and recites, “wherein the upper temperature dwell time is less than the lower temperature dwell time.”
Claim 35 depends from claim 32 and recites, “wherein the upper temperature dwell time is greater than the lower temperature dwell time.”
Claim 32, though, recites “wherein the upper temperature dwell time and the lower temperature dwell time are the same.”
It is not possible to satisfy the requirements of claims 32 and 34 or claims 32 and 35. In other words, it is not possible for the dwell times to be the same as recited in claim 32 and different as recited in each of claims 34 and 35. Therefore, claims 34 and 35 contain new matter. The original disclosure, including the portion of the originally filed specification pointed to by Applicant also does not provide support for claims 34 and 35.1 Accordingly, these claims are rejected under 35 U.S.C. 112(a) for containing new matter.
It appears that claims 34 and 35 were intended to depend from claim 33 or claim 1, particularly in view of the discussion in the first paragraph of page 8 of the originally filed specification. Amending each of claims 34 and 35 to depend from claim 33 would address the new matter issue.
Claim Rejections - 35 USC § 112
10. 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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 34, 35, and 37 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 34 and 35
Claim 34 depends from claim 32 and recites, “wherein the upper temperature dwell time is less than the lower temperature dwell time.”
Claim 35 depends from claim 32 and recites, “wherein the upper temperature dwell time is greater than the lower temperature dwell time.”
Claim 32, though, recites “wherein the upper temperature dwell time and the lower temperature dwell time are the same.”
Since it is not possible to satisfy the requirements of claims 32 and 34 or claims 32 and 35, it is not clear whether claims 34 and 35 were intended to depend from a different claim (e.g., claim 1 or claim 33) or if some other meaning was intended for these claims. In any case, at the very least, the intended dependency of claims 34 and 35 is not clear, and they are indefinite.
Claim 37
Claim 37 depends from claim 1 and recites “wherein the transition times between the upper temperature and the lower temperature and between the lower temperature and the upper temperature are substantially the same for the plurality of temperature shuttles.”
Claim 37 is indefinite because its requirements are not entirely clear. Although it is clear that the claim requires the transition times between the lower and upper temperature and between the upper and lower temperature to not vary between different temperature shuffles (e.g., if 50 temperature shuttles are performed, the transition time between the lower and upper temperature and between the upper and lower temperature does not vary between shuttles). It is not clear, though, whether the two transition times must also be identical to one another (e.g., 10 seconds to transition from the upper temperature to the lower temperature and 10 seconds to transition from the lower temperature to the upper temperature). In view of the foregoing, claim 37 is indefinite.
Claim Rejections - 35 USC § 112
11. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS. —Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 34 and 35 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 34 depends from claim 32 and recites, “wherein the upper temperature dwell time is less than the lower temperature dwell time.”
Claim 35 depends from claim 32 and recites, “wherein the upper temperature dwell time is greater than the lower temperature dwell time.”
Claim 32, though, recites “wherein the upper temperature dwell time and the lower temperature dwell time are the same.”
It is not possible to satisfy the requirements of claims 32 and 34 or claims 32 and 35. Consequently, claims 34 and 35 no longer require all of the elements of the claim from which they depend, and they are rejected under 35 U.S.C. 112(d) for this reason. It appears that these claims may have been intended to depend from claim 1 or claim 33.
Applicant may cancel the claims, amend the claims to place them in proper dependent form, or present a sufficient showing that the dependent claims comply with the statutory requirements.
Double Patenting
12. 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.
13. Claims 1 and 32-47 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 11,655,496 B2.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘496 patent overlap in scope with the instant claims and recite or suggest all of their limitations.
The instant claims are drawn to a non-isothermal nucleic acid amplification method that comprises the use of a nicking enzyme, at least one oligonucleotide primer, and a polymerase. The method also requires “shuttling, a plurality of times, between an upper temperature and a lower temperature during the amplification process” (claim 1), wherein one of the polymerase and the nicking enzyme is more active at the upper temperature, and the other of the nicking enzyme and the polymerase is more active at the lower temperature.
The claims of the ‘496 patent are also drawn to a non-isothermal nucleic acid amplification method that comprises the use of a nicking enzyme, at least one oligonucleotide primer, and a polymerase. Like the instant claim 1, the method recited in the claims of the ‘496 patent require “shuttling, a plurality of times, between an upper temperature and a lower temperature during the amplification process” (‘496 patent, claim 1), wherein one of the polymerase and the nicking enzyme is more active at the upper temperature, and the other of the nicking enzyme and the polymerase is more active at the lower temperature.
Regarding the instant claim 1, claim 1 of the ‘496 patent recites all of its limitations except for the requirement in the three lines of the claim, which require the temperature of the reaction mixture to be held constant at the upper temperature for an upper temperature dwell time and/or for the reaction mixture to be held constant at a lower temperature for a lower temperature dwell time. This requirement is met by claims 16 and 17 of the ‘496 patent, though, which recite, respectively, particular time ranges for an upper temperature dwell time and a lower temperature dwell time. The requirement for an upper or lower temperature dwell time clearly indicates, or at the very least suggests, that the temperature is, or can be, held constant at the upper or lower temperature. Thus, the instant claim 1 is not patentably distinct from the claims of the ‘496 patent.
The instant claims 32 and 33 each depend from the instant claim 1. The instant claim 32 requires the upper temperature dwell time to be the same as the lower temperature dwell time, and the instant claim 33 requires the upper temperature dwell time to differ from the lower temperature dwell time. These requirements are suggested by claims 16 and 17 of the ‘496 patent since those claims recite ranges for the upper and lower temperature dwell time that overlap. More specifically, claim 16 of the ‘496 patent states that the upper temperature dwell time may be 1-10 seconds, and claim 17 of the ‘496 patent states that the lower temperature dwell time may be 2-40 seconds. Since these two ranges contain many points in common as well as points not in common, it would have been obvious to select a dwell time at the upper temperature that is the same as the dwell time at the lower temperature or an upper temperature dwell time that differs from the lower temperature dwell time. Thus, the instant claims 32 and 33 are not patentably distinct from the claims of the ‘496 patent.
The instant claims 34 and 35 each depend from the instant claim 32.2 The instant claim 34 requires the upper temperature dwell time to be less the lower temperature dwell time, and the instant claim 35 requires the upper temperature dwell time to be greater than the lower temperature dwell time. These requirements are suggested by claims 16 and 17 of the ‘496 patent. More specifically, claim 16 of the ‘496 patent states that the upper temperature dwell time may be 1-10 seconds, and claim 17 of the ‘496 patent states that the lower temperature dwell time may be 2-40 seconds. In view of the values in the ranges recited in claims 16 and 17 of the ‘496 patent, the ordinary artisan would have recognized that the upper temperature dwell time could be longer than or shorter than the lower temperature dwell time. Thus, the instant claims 34 and 35 are not patentably distinct from the claims of the ‘496 patent.
The limitations of the instant claims 36, 38, and 39, which each depend from the instant claim 1, are also suggested by the claims of the ‘496 patent. In particular, since claim 14 of the ‘496 patent states that “each of the plurality of shuttles is substantially identical,” the ordinary artisan would have recognized that the transition times between the upper and lower temperature and also the dwell time at the upper and lower temperature could either be the same or varied for each of the plurality of temperature shuttles, and accordingly, would have selected either option in the absence of unexpected results. Thus, the instant claims 36, 38, and 39 are not patentably distinct from the claims of the ‘496 patent.
Regarding the instant claim 37, which depends from the instant claim 1, as discussed above, the requirements of this claim are not entirely clear. More specifically, it is clear that the instant claim 37 requires the transition times between the lower and upper temperature and between the upper and lower temperature to not vary between different temperature shuffles (i.e., if 50 temperature shuttles are performed the transition time between the lower and upper temperature and between the upper and lower temperature does not vary between shuttles). It is not clear, though, whether the two transition times must also be identical to one another (e.g., 10
seconds to transition from the upper temperature to the lower temperature and 10 seconds to transition from the lower temperature to the upper temperature). Both options are suggested, though, by the claims of the ‘496 patent. In particular, since claim 14 of the ‘496 patent states that “each of the plurality of shuttles is substantially identical,” the ordinary artisan would have recognized that the transition times between the upper and lower temperature should be the same for the plurality of temperature shuttles. The ordinary artisan also would have recognized that the transition times could be the same or different, depending on the particular reaction conditions and apparatus used, and accordingly, would have recognized either option as obvious in the absence of unexpected results. Thus, the instant claim 37 is not patentably distinct from the claims of the ‘496 patent.
The additional limitations recited in the instant claim 40, which depends from the instant claim 1, are suggested by claim 11 of the ‘496 patent. The instant claim 40 requires an upper temperature range between 50-68 ⁰C. Claim 11 of the ‘496 patent recites an upper temperature range of 50-64 ⁰C, which lies within the claimed range. And, no evidence of unexpected results has been presented with respect to the claimed range. This is sufficient to establish a prima facie case of obviousness per MPEP 2144.05 I.
The additional limitations recited in the instant claims 41-46, which each depend from the instant claim 1, are recited in claims 12, 13, and 15-18, respectively, of the ‘496 patent.
The limitations of the instant claim 47, which requires performing the method of the instant claim 1 and then quantifying the direct or indirect product(s) of the amplification reaction to determine the amount and/or concentration of a target nucleic acid in a sample are recited in claims 1, 16, 17, and 26 of the ‘496 patent.
Thus, the instant claims 1 and 32-47 are not patentably distinct from the claims of the ‘496 patent.
Prior Art
14. The pending claims are free of the prior art.
They are drawn to a non-isothermal nucleic acid amplification method that comprises the use of a nicking enzyme, at least one oligonucleotide primer, and a polymerase. The method also requires “shuttling, a plurality of times, between an upper temperature and a lower temperature during the amplification process” (claim 1), wherein one of the nicking enzyme and the polymerase is more active at the upper temperature, and the other of the nicking enzyme and the polymerase is more active at the lower temperature.
The following references constitute the closest prior art: (1) Lee et al. (US 2012/0208192 A1); (2) Kong et al. (US 2003/0211506 A1); (3) Yao et al. (US 2009/0092967 A1); (4) Gao et al. (Diagnostic Microbiology and Infectious Disease 2008; 60: 133-141); (5) Nagamine et al. (Biochemical and Biophysical Research Communications 2002; 290: 1195-1198); and (6) Maples et al. (US 2009/0017453 A1).3 Wang et al. (Analyst 2018; 143: 1444-1453; IDS reference), which is post-filing art, is also relevant because of its teachings concerning optimization of amplification reactions that use a DNA polymerase and a nicking enzyme.
Lee
This reference discloses a nucleic acid amplification method (see, e.g., the abstract and paras. 1 and 13-22). More specifically, the method of Lee includes the following steps (see, e.g., paras. 13-15 and 27; see also Examples 1 & 2 on page 6): (i) mixing a target nucleic acid with one or more complementary single-stranded primers under conditions that permit hybridization of the primers to the target nucleic acid; and (ii) using a polymerase to extend the primers to form newly synthesized nucleic acid. The method of Lee also includes shuttling, a plurality of times, between an upper temperature and a lower temperature during the course of the amplification reaction (see, e.g., paras. 13-15, 17, and 20; see also Examples 1 & 2 on page 6).
Lee teaches that the method may be used to improve various isothermal amplification reactions, including strand displacement amplification (SDA) reactions (para. 27), which as discussed in the specification of the instant application at pages 2-3, include a nicking step followed by polymerase-mediated extension of the nicked strands.
The reference does not teach that a nicking enzyme is present in the SDA reaction, and this is not an inherent feature of such reactions. Instead, as discussed on pages 2-3 of the specification of the instant application, SDA reactions can use modified nucleotides and a restriction endonuclease or a nicking enzyme and unmodified nucleotides.
Lee is also limited relative to the instant claims for at least two reasons. First, the reference fails to reduce the SDA embodiment to practice and only reduces a different isothermal amplification method (transcription mediated amplification (TMA)) to practice (see the Examples on page 6). TMA differs significantly from SDA because it uses reverse transcriptase, RNase H, and RNA polymerase for amplification, whereas SDA uses a DNA polymerase and either a nicking enzyme or modified nucleotides and a restriction endonuclease. Second, Lee does not discuss designing the disclosed temperature shuttles (i.e., oscillations) such that the upper temperature favors the activity of one enzyme and the lower temperature favors the activity of the other enzyme.
Kong & Yao
Each of these references discloses SDA reactions in which a nicking enzyme is substituted for the conventional modified nucleotides and restriction endonuclease (see Kong at Examples 4-5 on pp. 11-13; see Yao at Examples 1-2 on pp. 13-14). Kong and Yao each disclose several nicking enzymes suitable for use in these reactions (Kong at Examples 4-5; Yao at paras. 36-38), and Yao additionally discloses several examples of suitable DNA polymerases (paras. 39-40).
Neither reference contains any teachings that motivate shuttling between an upper and lower temperature as required by the claims, let alone shuttling between an upper temperature that favors one enzyme (e.g., the DNA polymerase) and a lower temperature that favors the other enzyme (e.g., the nicking enzyme).
Gao & Nagamine
Each of these references provide evidence that general properties of at least some of the enzymes disclosed in Kong and Yao were known prior to the effective filing date of the claimed invention. More specifically, Gao teaches that the N.BstNBI nicking enzyme used by Kong and Yao is active between 37°C and 65°C and has an optimum temperature of 55°C (pages 134 and 140). As well, Nagamine teaches that the Bst DNA polymerase used by Kong and Yao has a temperature optimum of 65°C (page 1197, column 2 – page 1198, column 1 and page 1196 column 1).
Neither of these references discusses relative enzyme activity at different temperatures. For example, although Gao teaches that the N.BstNBI enzyme is active between 37°C and 65°C, the level of activity at, for example, 50°C, 40°C, or 62°C is not discussed.
Maples
Like Kong and Yao, this reference discloses an isothermal amplification method, termed “nicking and extension amplification reaction” (NEAR), that uses a nicking enzyme and a DNA polymerase (see, e.g., the abstract, Fig. 1, paras. 14-17, and paras. 107-120). Maples teaches that advantages of the disclosed method include its simplicity, isothermal nature, and ability to be conducted rapidly (e.g., in 1-20 minutes, with shorter reaction times described as preferred) (see, e.g., paras. 14, 20, and 110-111).
Conclusion
The above references, considered together and in light of the general knowledge in the art, fail to teach or suggest the claimed amplification method for the following reasons.
First, as to Maples, the ordinary artisan would not have been motivated to modify that method to incorporate the temperature shuttling disclosed in Lee at least because doing so would eliminate the simplicity and isothermal nature of the method of Maples.
Second, regarding Maples and also regarding Kong and Yao, it is not clear that incorporating the temperature oscillations (shuttling) of Lee would improve these methods. Lee teaches in paras. 14-15 and 27 that the disclosed temperature shuttling can improve the signal-to-noise ratio and reduce the overall assay time of isothermal amplification methods, including SDA, which is similar to the NEAR method of Maples as well as the methods disclosed in Kong and Lee (see, e.g., paras. of Lee). The problem, though, is that Lee only demonstrated these improvements in a very different isothermal amplification method—TMA, which uses completely different enzymes (RNA polymerase, reverse transcriptase, and RNase H) (see Examples 1-2 on p. 6). Given the differences in TMA and the methods disclosed in Maples, Yao, and Kong, and since the teachings of Wang indicate that shifts away from an optimal reaction temperature when practicing NEAR lead to reduced yield and/or an increase in non-specific amplification products (abstract and pp. 1445-1448), it is not clear that the advantages observed by Lee for TMA would extend to the methods disclosed in Maples, Yao, or Kong.
Still further, the prior art fails to teach or suggest designing an amplification reaction to include temperature shuttles (i.e., oscillations) such that the upper temperature favors either a nicking enzyme or a polymerase and the lower temperature favors the activity of the other enzyme. This is also required by claim 1. The prior art, e.g., Gao and Nagamine, discloses temperature optimums and/or activity ranges for different enzymes commonly used in isothermal amplification methods that make use of a nicking enzyme and a polymerase, but there is nothing in the art that teaches or suggests converting the method disclosed in Maples, Kong or Yao to a non-isothermal method designed to shuttle between an upper temperature that favors one enzyme and a lower temperature that favors the other enzyme. Instead, Kong, Maples, and Yao each describe using a single temperature at which both enzymes work, and the post-filing art of Wang teaches that shifts away from an optimal reaction temperature when practicing NEAR lead to reduced yield and/or an increase in non-specific products (abstract and pp. 1445-1448). Therefore, the ordinary artisan would have lacked a proper rationale as well as a reasonable expectation of success in using the prior art disclosures to arrive at the claimed methods.
In view of the foregoing, the instant claims are free of the prior art.
Conclusion
15. No claims are currently allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Angela Bertagna whose telephone number is (571)272-8291. The examiner can normally be reached 8-5, M-F.
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/ANGELA M. BERTAGNA/Primary Examiner, Art Unit 1681
1 Applicant points to page 8, lines 1-7 of the originally filed specification as providing support for the subject matter of claims 34 and 35. See page 8 of the Remarks filed on October 16, 2023.
2 As discussed above in the rejections under 35 U.S.C. 112(b) and 35 U.S.C. 112(d), it appears that the instant claims 34 and 35 were intended to depend from the instant claim 1 or the instant claim 33. Here, they are treated as depending from the instant claim 1 or the instant claim 33.
3 Each of these references is cited on the IDS filed on June 27, 2025.