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 amendment filed on June 11, 2026 is acknowledged and has been entered. Claims 1-14 and 22-26 have been canceled. Claims 15-21 and 27-38 are pending.
Claims 15-21 and 27-38 are discussed in this Office action.
All of the amendments and arguments have been thoroughly reviewed and considered but are not found persuasive for the reasons discussed below. Any rejection not reiterated in this action has been withdrawn as being obviated by the amendment of the claims. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is made FINAL.
Previous Grounds of Rejection maintained
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 15-18, 27-29 and 32-35 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Nadeau et al. (US PgPub 20090131647; May 2009).
With regard to claim 15, Nadeau teaches a reaction mixture for analyzing, quantitating or detecting one or more alleles or polymorphisms in a target nucleic acid,
wherein the reaction mixture comprises a first allele-specific primer, which is specific for a first allele, comprising a first 5'-universal tail which comprises a binding site for a first universal FRET-based reporter primer (UFP), wherein the first UFP comprises a first fluorophore and at least a first quencher moiety (see for example, p 13, Example 5 and Table 1 where primers specific for specific SNPs are included);
and a second allele-specific primer which is specific for a second allele, comprising a second 5'-universal tail which comprises a binding site for a second UFP, wherein the second UFP comprises a second fluorophore and at least a second quencher moiety (see for example, p 13, Example 5 and Table 1 where primers specific for specific SNPs are included);
wherein the first fluorophore and the second fluorophore are different and the first quencher moiety and the second quencher moiety are the same or different (paragraph 39-40 and Fig 1A where a reporter probe includes a donor and quencher).
With regard to claim 16, Nadeau teaches a reaction mixture of claim 15, wherein the first fluorophore and the second fluorophore are located at the 5'-end of the first UFP and the second UFP respectively, and the at least first quencher moiety and the at least second quencher moiety are located at an internal nucleotide of the first UFP and the second UFP respectively (paragraph 39-40 and Fig 1A where a reporter probe includes a donor and quencher).
With regard to claim 17, Nadeau teaches a reaction mixture of claim 15, further comprising a locus specific primer (see for example, p 13, Example 5 and Table 1 where primers specific for specific SNPs are included).
With regard to claim 18, Nadeau teaches a reaction mixture of claim 15, further comprising one or more nucleic acid polymerases (Abstract, legend to Fig 2A and paragraph 4).
With regard to claim 27, Nadeau teaches an oligonucleotide comprising an allele-specific portion and a 5'-universal tail, wherein the 5'-universal tail comprises a binding site for a universal FRET-based reporter primer and the universal tail is not complementary to the target nucleic acid sequence (paragraph 39-40 and Fig 1A where a reporter probe includes a donor and quencher).
With regard to claim 28, Nadeau teaches an oligonucleotide of claim 27, wherein the 5'-universal tail comprises a nucleotide sequence that is identical to the sequence of a universal FRET-based reporter primer (paragraph 39-40 and Fig 1A where a reporter probe includes a donor and quencher).
With regard to claim 29, Nadeau teaches an oligonucleotide of claim 27, wherein the 5'-universal tail comprises a nucleotide sequence that is complementary to the sequence of a universal FRET-based reporter primer (paragraph 39-40 and Fig 1A where a reporter probe includes a donor and quencher).
With regard to claim 32, Nadeau teaches a kit for analyzing, quantitating or detecting one or more alleles or polymorphisms in a target nucleic acid (see for example, p 13, Example 5 and Table 1 where primers specific for specific SNPs are included).
wherein the kit comprises a first allele-specific primer, which is specific for a first allele, comprising a first 5'-universal tail which comprises a binding site for a first universal FRET-based reporter primer (UFP), wherein the first UFP comprises a first fluorophore and at least a first quencher moiety (paragraph 39-40 and Fig 1A where a reporter probe includes a donor and quencher);
and a second allele-specific primer which is specific for a second allele, comprising a second 5'-universal tail which comprises a binding site for a second UFP, wherein the second UFP comprises a second fluorophore and at least a second quencher moiety (paragraph 39-40 and Fig 1A where a reporter probe includes a donor and quencher);
wherein the first and second fluorophore are different and the at least first quencher moiety and the at least second quencher moiety are the same or different (paragraph 39-40 and Fig 1A where a reporter probe includes a donor and quencher).
With regard to claim 33, Nadeau teaches a kit of claim 32, wherein the first fluorophore and the second fluorophore are located at the 5'-end of the first UFP and the second UFP respectively, and the at least first quencher moiety and the at least second quencher moiety are located at an internal nucleotide of the first UFP and the second UFP respectively (?).
With regard to claim 34, Nadeau teaches a kit of claim 32, further comprising a locus specific primer (see for example, p 13, Example 5 and Table 1 where primers specific for specific SNPs are included).
With regard to claim 35, Nadeau teaches a kit of claim 32, further comprising one or more nucleic acid polymerases (Abstract, legend to Fig 2A and paragraph 4).
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.
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.
Claim(s) 19-21 and 30-31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nadeau et al. (US PgPub 20090131647; May 2009) as applied over 15-18, 27-29 and 32-35 above and further in view of Xi et al. (US Patent 9,476,093; October 2016).
With regard to claim 19, Xi teaches a reaction mixture of claim 15, further comprising a pyrophosphorolysis enzyme (Abstract; col 1 and col. 4 and col. 7 where pyrophosphatase is included).
With regard to claim 20, Xi teaches a reaction mixture of claim 15, further comprising a polyphosphorolysis enzyme (Abstract, col. 1 where “activation by polyphosphorolysis (APP) reactions” is described).
With regard to claim 21, Xi teaches a reaction mixture of claim 20, further comprising one or more polyphosphorolyzing agents (Abstract, col. 1 where “activation by polyphosphorolysis (APP) reactions” is described).
With regard to claim 30, Xi teaches an oligonucleotide of claim 27, wherein the 3' end of the oligonucleotide comprises a blocking agent such that the blocked end is configured to be activated by a pyrophosphorolysis enzyme (Abstract; col 1 and col. 4 and col. 7 where pyrophosphatase is included).
With regard to claim 31, Xi teaches an oligonucleotide of claim 30 wherein the blocking agent is a dideoxynucleotide (ddN) (col. 7, where dideoxynucleotide is described).
With regard to claim 36, Xi teaches a kit of claim 32, further comprising a pyrophosphorolysis enzyme (Abstract; col 1 and col. 4 and col. 7 where pyrophosphatase is included).
With regard to claim 37, Xi teaches a kit of claim 32, further comprising a pyrophosphorolysis enzyme (Abstract; col 1 and col. 4 and col. 7 where pyrophosphatase is included).
With regard to claim 38, Xi teaches a kit of claim 37, further comprising one or more polyphosphorolyzing agents (Abstract, col. 1 where “activation by polyphosphorolysis (APP) reactions” is described).
It would have been prima facie obvious to one of ordinary skill in the art at the time the
invention was made to have adjusted the teachings of Nadeau to include the polyphorolysis and pyrophosphorolysis enzymes and activation as described by Xi to arrive at the claimed invention with a reasonable expectation for success. Both Nadeau and Xi are focused on detection of specific nucleic acid targets. Xi teaches “methods for polymerizing, amplifying, and/or sequencing a target nucleic acid from a test sample using activation by polyphosphorolysis (APP) reaction. Polyphosphorolysis refers to the removal of a non-extendable nucleotide from a nucleic acid (e.g., an oligonucleotide) in the presence of one or more polyphosphorolyzing agents and an enzyme that exhibits polyphosphorolyzing activity. APP may be used to polymerize and/or amplify and/or sequence nucleic acid molecules, including but not limited to ribonucleic acid (e.g., RNA) and/or deoxyribonucleic acid (e.g., DNA), or hybrids thereof. Other uses for the methods described herein will be readily understood by one of skill in the art. " (col. 5, lines 5-16). Xi also teaches “The methods are useful to, for example, detect minimal residual disease-causing agent(s) (e.g., rare remaining cancer cells during remission, especially mutations in the p53 gene or other tumor suppressor genes previously identified within the tumors), and/or measure mutation load (e.g., the frequency of specific Somatic mutations present in normal tissues, such as blood or urine)” (col. 1, line 37-43). Therefore, one of ordinary skill in the art at the time the invention was made would have been motivated to have adjusted the teachings of Nadeau to include the polyphorolysis and pyrophosphorolysis enzymes and activation as described by Xi to arrive at the claimed invention with a reasonable expectation for success.
Response to Arguments
Applicant's arguments filed June 11, 2026 have been fully considered but they are not persuasive.
Applicant argues "The Examiner equates Nadeau's reporter probes with Applicant's claimed universal FRET-based reporter primers. However, Nadeau does not disclose the claimed UFPs." (p 2 of remarks)
Applicant also argues "As described throughout the present specification, the UFP is not merely a reporter probe. Rather, the UFP is a specifically configured universal reporter primer that hybridizes to a universal tail sequence incorporated into an allele-specific primer and participates in signal generation during amplification" (p 2 of remarks).
Finally, regarding the 102 rejection over Nadeau, Applicant argues “Furthermore, the present specification describes a coordinated genotyping platform comprising: allele specific primers having universal tails; universal FRET-based reporter primers that bind the universal tails; locus-specific primers; and amplification-dependent signal generation. The specification as filed, specifically Examples 1-4, demonstrates successful SNP genotyping using this architecture and show allele discrimination comparable to commercial TaqMan® assays. Nadeau does not disclose this integrated UPP-based system” (p 2-3 of remarks).
These arguments have been considered, but they are not persuasive. First, it is noted the claims within the anticipation rejection include both a reaction mixture (of claim 1) and an oligonucleotide (claim 27). While Applicant’s comments regarding the overall system disclosed in the specification, and the “integrated UPP-based system” are noted, they are not relevant to the pending claims, as the pending claims are focused specifically on a more broadly claimed reaction mixture and an oligonucleotide. Those arguments are wholly unpersuasive.
Next, while Applicant’s remarks regarding the claimed invention and the argued distinctions between the UFP of the claims and the teachings of Nadeau, it is again noted, while Applicant did not address this claim directly, the invention of claim 27 is directed fundamentally to an allele specific primer with a 5’ “universal” tail. Nadeau teaches allele specific primers with universal tails throughout the disclosure, as noted in the rejection which is maintained. Next, while the mixture of claim 15 includes two allele specific primers with universal tails which bind to a “UFP” and while it is noted that the p in UFP refers to a primer, the claims are drawn to a composition, not to a method. Even if the “reporter probes” of Nadeau are not used as primers within Nadeau and are instead used for signalling or reporting, the claim does not in any way require that the claimed UFP function as a primer (or primers), only that UFP include particular quenchers and fluorophores. Those features of the individual components of the claim are entirely taught by Nadeau and the arguments are therefore also wholly unpersuasive. The rejection is maintained.
Finally, regarding the obviousness rejection, Applicant argues "Nadeau is directed to adapter-mediated allele detection using allele-specific signal primers and reporter probes. Allele discrimination in Nadeau is achieved through mismatch-dependent primer extension." (p 3 of remarks). Applicant argues "Xi, by contrast, is directed to activation by polyphosphorolysis (APP) reactions using blocked oligonucleotides that must first be activated by pyrophosphorolysis before extension can occur. Next, Applicant argues "present claims are directed to a specific integrated architecture that combines: allele-specific primers; universal tail sequences; universal FRET-based reporter primers; and pyrophosphorolysis-activatable oligonucleotides. The present specification repeatedly describes embodiments in which APP functionality is integrated directly into the genotyping platform." (p 3 of remarks) Applicant also argues the combined references are joined only based on impermissible hindsight.
Finally, Applicant argues “present claims 30 and 31 require an oligonucleotide comprising: an allele-specific portion; a universal tail comprising a binding site for a universal FRET-based reporter primer; and a pyrophosphorolysis-activatable blocking group, including a dideoxynucleotide in certain claims. Nadeau teaches universal-tail primers but not pyrophosphorolysis-activatable primers. Xi teaches APP-enabled blocked primers but not universal-tail reporter-primer architectures. Neither reference teaches nor suggests an oligonucleotide simultaneously possessing all of these features. (p 4 of remarks).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant’s remarks are noted but they are not persuasive. Applicant’s argument, for example, that Xi APP-enabled blocked primers but not universal-tail reporter-primer architectures. First, it is noted, Xi not only teaches blocked primers, Xi also teaches activation by polyphosphorolysis and pyrophosphatase as claimed. Since the rejection is an obviousness rejection, it is the combination of references and neither reference alone which renders the claimed invention obvious.
The references are properly combinable and render the claimed kits and reaction mixtures obvious and the rejection is maintained.
Conclusion
No claims are allowed. All claims stand rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHANIE KANE MUMMERT whose telephone number is (571)272-8503. The examiner can normally be reached M-F 9:00-5:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gary Benzion can be reached at 571-272-0782. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/STEPHANIE K MUMMERT/Primary Examiner, Art Unit 1681
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