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 election with traverse of Group I, and influenza A virus and influenza B virus in the reply filed on 10/29/2025 is acknowledged. The traversal is on the ground(s) that the prior art reference does not teach that the primers are RPA primers. Applicant argues that RPA primers are distinguishable from conventional PCR primers. This is not found persuasive because the broadest reasonable interpretation of “RPA primers” includes “shorter primers” as taught by Li et al., of record in IDS. Li et al. teaches “Shorter PCR primers (typically between 18 and 25 nucleotides) can also be used in the RPA reaction but may decrease the reaction speed and sensitivity. Furthermore, the prior art rejections of record evidence that the claimed products are not free of the art, and therefore no special technical feature in view of the prior art is currently present. Rejoinder will be considered when all elected claims are found allowable.
The requirement is still deemed proper and is therefore made FINAL.
Claim Rejections - 35 USC § 112
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 1-6 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 1 and 4 recite “the probes are complementary to the target nucleic acids” and it is unclear if this means that the probes are complementary to all target nucleic acids (as in some sort of universal probe) of if this means that each probe is complementary to a particular target nucleic acid.
Claims 1 and 4 recite “the ΔG of the probes is greater than -3kcal/mol.” This is a relative term, and there is no basis for comparison to define the claims. Gibbs free energy, or ΔG is a function of temperature and salt strength, in addition to probe and target site sequences. Therefore, the phrase ΔG is a relative term for which there is no clear understanding or universal way to calculate it for a given nucleic acid sequence. It does not impart a particular structural requirement on the claimed oligonucleotides, and it is unclear how to determine the ΔG in isolation from the other necessary conditions for calculating the property.
Claims 1 and 4 recite “the distance between” the upstream primers and the probes and this is indefinite because the claims do not previously require any distance or placement of the primers and probes relative to one another. The claims encompass probes and primers which may be in a common composition but they do not require that they are. They could also be in separate compositions. It appears that applicant is trying to define the primers and probes in terms of a hypothetical target, but the target is not present in the claimed primers and probes and could be assigned as anything. That is, the requirement goes to how the molecules might be used but it is unclear what definite structure is implied by the limitation. Furthermore, since, claims 3 and 6 the required probes have GC sequences at the 5’ end of the probes, and these would not be expected to hybridize to the pathogen targets, it is unclear what it means to require these claimed 5’ ends to be that close to the probe. This limitation is related to how the primers and probes would be used, and absent any knowledge of the system in which they will be employed, it is unclear how to know that the ΔG of any particular probes are, because fundamentally ΔG is a relative term.
Furthermore, the claims 1 and 4 recite that different target nucleic acids “in the same fluorescence channel” which is indefinite because there is no requirement previously mentioned in the claim about any fluorescent labels or channels and so it is not clear from the claim what it means for target nucleic acids to be in channels.
Furthermore, the claims recite that the target nucleic acids “are amplified,” which is a process limitation in a product claim. As the limitations of the claim are drawn to how a user would administer the compounds, and not to formulations of the compounds, there is confusion as to when direct infringement occurs. See MPEP 2173.05(p). Furthermore, the claim sets forth that the targets are amplified “by different probes with the same fluorescent group” which is indefinite because (1) it is unclear in view of the specification how the probes would be considered to “amplify” target and (2) it is unclear if these probes labeled with the same fluorescent group are the same or different as “the probes” previously mentioned in the claim and (3) there is no requirement in the claim anywhere that structurally requires the probes have labels of any kind. Again, this language goes to how the probes and primers could be used, but it is not clear what structure is required by this recitation which is not clearly tied to the previously mentioned primers and probes.
Claims 2, 3, 5, and 6 recited “enterovirus EV” and or “enterovirus EV gene” and it is not clear if the “EV” is meant to be an abbreviation of enterovirus or to designate a particular type or strain of enterovirus or a particular target within enterovirus genome.
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.
Claim(s) 1-2 and 4-5 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Liao et al. (Int J Mol Epidemiol Genet 2019;10(2):29-37), as evidenced by Li et al., of record in IDS.
Liao et al. teach primers and probes for detecting respiratory pathogen target nucleic acids. See Table 1.
The claims require that the primers are “recombinant polymerase amplification primers”- Li et al., of record in IDS. Li et al. teaches “Shorter PCR primers (typically between 18 and 25 nucleotides) can also be used in the RPA reaction but may decrease the reaction speed and sensitivity (section 2.3).” The requirement that the primers are RPA primers defines the intended use of the primers, and as evidenced by Li et al. the primers taught by Liao et al. could be used as intended.
Liao et al. teaches probes that comprise a loop region and a step region, wherein the loop region is 15bp to 33 bp in length. See probes for influenza-A and influenza-B, for example, which have annotated loop regions of 20 and 23 nucleotides in length, and that are complementary to target. Liao et al. tech the probes hybridize to targets specifically in mixed samples. With regard to the claim requirement about the ΔG of the probes, this limitation is indefinite absent definition of salt, temperature and target binding partner sequence. With regard to the distance between the 3’end of the upstream primers and the 5’end of the probe for INF-A, the distance is greater than 6bp when the probes and primers are in solution as disclosed. It is infinite. There is no requirement in the claim that the claimed molecules are hybridized to any target in any formation. Likewise, the language in the final paragraph of claim 1, and also repeated in claim 4, sets forth how the probes and primers might be used, and does not distinguish structurally from those taught by Liao et al.
With regard to claim 4, there is no definition of “kit” in the specification, and so the broadest reasonable interpretation of this claim includes a set of reagents. Liao et al. teaches a set of reagents that comprises a nucleic acid amplification reaction solution (mixture of all reactants set forth p. 31), a premix (premix: mixture of dNTP mixed together (p. 31)), a positive control (p. 30, first column) and a blank control (reaction buffer, p. 31). The reference additionally teaches probes and primers as required for the kit.
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.
Claim(s) 1-2 and 4-5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liao et al. in view of Li et al
This rejection is written to address an embodiment of the claims wherein the oligonucleotide primers are at least 30 nucleotides in length.
The teachings of Liao et al. as they relate to the rejected claims are given previously in this Office action and are fully incorporated here.
Laio et al. does not teach primers that are 30 nucleotides in length. Although this is not strictly required by any claims, in the interest of compact prosecution this embodiment is being addressed.
Li et al. teaches that recombinase polymerase amplification (RPA) reaction is a revolutionary method with prominence to eclipse PCR (p. 32, section 2). The reference teaches that the length of RPA primers is relatively long, having a recommended minimum of 30 nucleotides (section 2.3), and in Table 5 indexes many different applications of RPA.
It would have been obvious to have modified the primers taught in Laio et al. so as to have lengthened them in order to provide primers that could be employed in an RPA assay. One would have been motivated to do so because of the advantages of RPA as taught by Li: its true isothermal properties, simple reaction scheme, fast reaction time, and excellent reports of sensitivity (section 5).
Claim Rejections - 35 USC § 112
Claims 3 and 6 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of each of the different groups of probes and primers is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: Each probe and primer set has a different structural composition designed to hybridize to a different target.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Purdue iGEM-2020 taught that “To ensure the molecular beacon forms at all, it is extremely important that a negative ΔG is used. In addition, we generally want a molecular beacon with a ΔG between -1.5 kcal/mol and -2.0 kcal/mol, but this specific range is less important than the probe length, melting temperature, stem length, and stem composition of the beacon. It is most important that free energy is below 0.” (Molecular Beacon Documentation, Purdue iGEM 2020; 19 pages).
Probes and primers for multiplex detection of respiratory pathogen target nucleic acids comprising SEQ ID NO: 1-6, consonant with the election are free of the prior art. Additional probe and primer species have not been searched because the they do not share common structure or unity of invention with the elected set. A combinations which require SEQ ID NO: 1-6 as elected could be considered for rejoinder if presented.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Juliet Switzer whose telephone number is (571)272-0753. The examiner can normally be reached Monday to Thursday, 8:00 AM-3:30 PM.
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Juliet Switzer
Primary Examiner
Art Unit 1682
/JULIET C SWITZER/Primary Examiner, Art Unit 1682