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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 3/7/2025 has been entered.
Election/Restrictions
Applicant’s election without traverse of SEQ ID NO: 1 for the spiked primer and SEQ ID NO: 98 for the probe in the reply filed on 2/29/2024 is acknowledged. The election does not read on claims 35-37; thus, claims 35-37 are withdrawn from examination. Thus, claims 1-3, 5-13, 16-17, 19, 21, 23, 27-30, 32-34, 39-40, 42, 44-45, and 47-52 are presently under examination.
Application Status
This action is written in response to applicant’s correspondence received on 10/30/2025. Claims 1-3, 5-13, 16-17, 19, 21, 23, 27-30, 32-37, 39-40, 42, 44-45, and 47-52 are pending. Claims 1, 12-13, 16, 21, 27-28, 33-37, 45, and 50-52 have been amended. Claims 35-37 are withdrawn as they are drawn to non-elected species. Claims 1-3, 5-13, 16-17, 19, 21, 23, 27-30, 32-34, 39-40, 42, 44-45, and 47-52 are currently under examination. Any claim rejections not reiterated herein have been overcome by amendment.
Any rejection of record in the previous office actions not addressed herein is withdrawn. New grounds of rejection are presented herein that were not necessitated by applicant’s amendment of the claims since the office action mailed 5/30/2025. Therefore, this action is not final.
Claim Objections
Claim 27 is objected to because of the following informalities:
Claim 27 recites “wherein the set of spiked primers comprise nucleotide sequence selected from,” which should be amended to read “wherein the set of spiked primers comprise a nucleotide sequence selected from” to fix the typo (i.e., the deletion of “a” should be changed to include “a”).
Appropriate correction is required.
Claim Rejections - 35 USC § 112 – New Rejection
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 1-3, 5-13, 16-17, 19, 21, 23, 27-30, 32-34, 39-40, 42, 44, and 50-52 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.
Regarding claim 1, claim 1 recites “(ii) partitioning the MSA-aligned genomes into overlapping 300-nucleotide to 600-nucleotide (nt) segments with at least a 150-nt overlap.” Thus, claim 1 is claiming that the overlapping segments overlap at 300-600 nt segments, but also that the segments are at least 150 nts. This claim language is confusing because the length of overlapping segments appears to be recited with two separate parameters: 300-600 and “at least 150” nts. It is unclear what the length of the overlapping segments are meant to be because a segment that is 150 nts is not 300-600 nts. It is unclear if segments ranging from 150-299 nts are meant to be included in the range, as step (ii) seems to recite, which contradicts the “overlapping” range of 300-600 nts.
Claims 2-3, 5-13, 16-17, 19, 21, 23, 27-30, 32-34, 39-40, 42, 44, and 50-52 ultimately depend from claim 1 and do not resolve this 112(b) issue and are therefore also rejected.
Similarly, claim 11 recites that the segments are partitioned into 500-600 nt overlapping segments, with 200-300 nt overlap. It is unclear what length of overlap is meant to be recited in claim 11, as claim 11 recites that the overlap is “500-600” and also “200-300.”
112(d) – Maintained
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.
Claim 50-51 is 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.
Regarding claim 50, claim 50 depends from claim 1 and recites that the primer sequences in step vii (referring to claim 1) are “6 to 50 nucleotides” in length. However, the primers recited in claim 1 are recited to be between 11 and 17 nucleotides in length. Thus, claim 50 fails to limit the scope of claim 1 because it in fact expands the scope by increasing the length of the primers.
Regarding claim 51, claim 51 recites that the primers are between 11-17 nucleotides in length. However, this limitation is already a part of claim 1; claim 51 therefore does not further limit claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Response to Arguments
The Applicant argues that the amendments to claim 50 obviate the previous 112(d) rejection. However, claims 50 and 51 still appear to suffer from 112(d) issues, as claim 50 appears to expand the length of primers which can be made (e.g., as short as 6 nucleotides, where claim 1 is drawn to primers which are between 11-17 nucleotides, where step vii of claim 1 does not appear to limit the length of primers recited in step iii of claim 1). Furthermore, claim 51 does not appear to further limit claim 1 because it recites the same length of primers recited in step iii of claim 1 (i.e., 11-17 nts in length).
Claim Rejections - 35 USC § 103 – New Rejection
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 1-3, 5-6, 11-13, 16-17, 19, 21, 23, 28-30, 32, 39-40, 42, 44, and 50-51 are rejected under 35 U.S.C. 103 as being unpatentable over Gardner 1 (Gardner SN et al. Adv Bioinformatics. 2014;2014:101894) in view of Greninger (Greninger AL et al. Genome Med. 2015 Sep 29;7:99) and Gardner 2 (Gardner SN et al. Nucleic Acids Res. 2009 Oct;37(19):6291-304). The rejection of claims 3 and 5-6 is further evidenced by Gosh (Ghosh D et al. PLoS Negl Trop Dis. 2009 Sep 29;3(9):e437).
Regarding claim 1, Gardner 1 is a research article that is focused on developing multiplex PCR reactions for targeted sequencing/amplification of multiple viruses (Title, Abstract, and throughout). Regarding step (i) of instant claim 1, Gardner 1 teaches a general method and strategy for designing multiplex degenerate primers for viral samples using multiple sequence alignments:
“The method here differs in that it takes the full multiple sequence alignment as input rather than a consensus, and it seeks to automatically design a minimal, degenerate set of multiplex compatible primers to amplify all the strains for a given region in a single reaction,” (page 2, left column, first paragraph).
Furthermore, Gardner 1 teaches that such primer design methods as they teach were used for pathogenic viruses such as South American hemorrhagic fever viruses (Abstract). Gardner 1 therefore teaches that the method comprises performing multiple-sequence alignment (MSA) on a plurality of genomes from a set of one of more reference genomes from a taxa of pathogenic microorganisms (step (i), instant claim 1).
Regarding step (ii) of instant claim 1, Gardner 1 teaches that a range of user-designed overlapping segments can be input into their primer design algorithm, with ranges including 500 nt (page 4, left column, final paragraph, step (ii) of instant claim 1).
Regarding steps (iii)-(vi) of instant claim 1, Gardner 1 teaches that, when performing primer design using their method:
“Some regions of high conservation may have only one primer pair predicted to amplify all strain variants, while other regions may require many primers to cover all known variants,” (page 2, left column, final paragraph)
Thus, Gardner 1’s method includes the ranking and selection of multiple primers, where degenerate primers for a given region can comprise as few as 1 primer while regions of the MSA with higher divergence can require additional selection of more primers (i.e., ranking). Gardner 1’s method therefore reasonably includes ranking and selecting primers based upon their frequency amongst the aligned reference genomes, where furthermore a threshold is established (i.e., 1 primer for highly conserved regions).
Furthermore, Gardner 1 teaches that the primers are selected from the ends of the overlap, which reasonably includes a region that is 30-70 nts from the ends of the segments (Figure 1, reproduced below):
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Thus, given that Gardner 1’s method involves selecting different primers/different numbers of primers based upon sequence alignment of partitioned regions, the method can broadly be said to encompass ranking and selecting such primers. For instance, Gardner 1 teaches that:
The run tiled primers process can be summarized as follows: split a multiple sequence alignment into overlapping regions, and for each region design a degenerate multiplex set of primers that in combination amplify that region in all strains with as few primers as possible. Run tiled primers takes as input a multiple sequence alignment (MSA). Run tiled primers splits the alignment into regions of size “𝑠” bases that overlap by “𝑥” bases (Figure 1),” (page 3, left column, second paragraph).
Thus, Gardner 1’s method teaches partitioning MSA into overlapping regions and systematically designing degenerate primers for the regions in as few primers as possible (i.e., a lower threshold). Thus, Gardner 1’s algorithm and approach appear to read broadly on the presently recited steps (see “Implementation” section of Gardner 1, beginning, pages 3-4).
Gardner 1 teaches that the primers at 18 nt in length (Table 2).
Regarding step vii, Gardner 1 teaches selecting for sequences that minimize self-dimerization, have optimum Tm values, and do not comprise homopolymer regions (e.g., page 3 final paragraph to page 4 first paragraph).
Regarding step ix, Gardner 1 teaches that the primer designs were tested, and therefore inherently teaches that the primers were chemically synthesized (e.g., caption of Figure 2).
Gardner 1, while teaching that the primers were 18 nt in length does not teach that they were between 11-17 nts in length. Gardner 1 does not teach attaching an adapter comprising SEQ ID NO: 97 to the primers.
Greninger is a research article which focuses on the rapid metagenomic identification of viral pathogens by sequencing (Title, Abstract, and throughout). Gardner 1 and Greninger therefore directly overlap in subject matter and field of endeavor because they both relate to the sequencing of viral pathogens using metagenomic approaches. Furthermore, regarding sequencing techniques in this field of endeavor, Greninger teaches Primer B/adapter sequence, which is a 100% identical match to the instantly recited SEQ ID NO: 97 (below):
GTTTCCCACTGGAGGATA (Primer B, page 4 left column, Greninger)
GTTTCCCACTGGAGGATA (Instant SEQ ID NO: 97)
Thus, as taught by Greninger, Primer B and by extension an adapter which could be used in sequencing reactions to generate cDNA libraries, is a known sequence used in viral sequencing technologies (Greninger, page 4, left column, second paragraph). Furthermore, given that Greninger and Gardner 1 overlap in subject matter and objectives, combining such known elements of a sequencing adapter to the methods of Gardner 1 would yield predictable results.
Regarding the limitation that the primers are between 11-17 nts in length, Gardner 2 is a research article which focuses on multiplex primer designs for viral targets (Title, Abstract, and throughout). Thus, Gardner 1 and Greninger overlap in subject matter and field of endeavor, as each of these references is directed to the sequencing of viral samples using targeted primers. Gardner 2 teaches that such viral primers can be as short as 17 nts for target amplification in pathogenic microorganism (e.g., page 6293, right column, paragraphs 2 and 3). Furthermore, Gardner 2 also teaches the method of ligating adapters onto shorter primers for viral amplification, and therefore provides additional teachings regarding predictability and motivation to combine adapters such as those taught by Greninger onto shorter primers when amplifying viral genomes (e.g., page 6303, left column, first paragraph).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the MSA primer design method/algorithm of Gardner 1 and the adapter/shorter primer teachings of Greninger/Gardner 2, as such a combination is simply the combination of known prior art elements with predictable results. In the present case, a practitioner would be motivated to use shorter primers such as those taught by Gardner 2, as such shorter primers are known to be useful and reduced to practice when amplifying viral genomes. Furthermore, Greninger has also taught and reduced to practice the use of such primer/adapters as SEQ ID NO: 97, which would be furthermore useful in the methods of sequencing as taught by Greninger and Gardner 2. Additionally, the results are predictable because each of Gardner 1, Gardner 2, and Greningner relate to the same field of endeavor and use similar reagents and methods. The combination would therefore render predictable results.
Regarding claim 2, Gardner 1 teaches that the method was applied to pathogenic viruses (Abstract).
Regarding claims 3 and 5-6, Gardner 1 teaches the Japanese encephalitis virus (Abstract), which belongs to the Flaviviridae taxa as evidenced by Gosh (Abstract).
Regarding claim 11, as discussed in the 112(b) rejection above, it is unclear what length the overlapping region is meant to be in claim 11. Claim 11 is broadly interpreted to include regions which are, for instance, 500 bp. Gardner 1 teaches that the overlap region can be 500 nt (page 4, left column, final paragraph). Furthermore, even if claim 11 were interpreted to require regions that were 200-300 nts, Gardner 1 also teaches that such designs are modular and can accommodate the design of a practitioner, where the overlapping region can be shortened (page 4, left column, final paragraph). As such, the ranges recited in claim 11 would be obvious given the teachings of Gardner 1.
Regarding claim 12, Gardner 2 teaches that primers for viral sequencing can be as short as 10-mers (e.g., page 6302 right column, final paragraph). Thus, Gardner 2 teaches a range of primers in lengths from 10-17 nts, where such lengths include 13-15 nts (page 6302, right column, final paragraph, page 6293, right column, paragraphs 2-3).
Regarding claim 13, Gardner 1 teaches that the primers are designed for the ends of the overlapping regions/segments (Figure 1), which reasonably includes regions which are 40-60 nts from the ends (Figure 1).
Regarding claim 16, Gardner 1 teaches that the primers can be applied to a sequencing assay to detect a target pathogen which further comprises random primers, where sequencing detects the presence of absence of a target pathogenic taxa (page 6, left column, first two paragraphs).
Regarding claim 17, Gardner 1 teaches that the sample is obtained from a subject (a mouse, page 6, left column, first paragraph).
Regarding claim 19, Gardner teaches that the sample was collected as a bronchoalveolar lavage, which can broadly be interpreted to be a tissue sample, biopsy sample, and/or DNA sample/RNA sample, as such a sampling method would reasonably include DNA and RNA (page 6, left column, first paragraph).
Regarding claim 21, Gardner 1 teaches that their method should be applied to environmental samples (page 3, left column, first paragraph).
Regarding claim 23, Gardner 1 teaches tick-born pathogens (Abstract). As such, a practitioner could immediately envision measuring such a pathogenic vector to track a pathogen (Abstract).
Regarding claim 28, Greninger teaches sequencing reads between 10-100,000 reads with respect to a pathogenic taxa (e.g., Table 1). Furthermore, such read values as those recited are dependent upon factors such as viral load in a given subject or environmental sample which are subject to change dependent upon sample. In a given sample, such a method as that of Gardner 1 could detect, for instance, 10 – 100,000 reads absent any evidence to the contrary.
Regarding claim 29, Gardner 1 teaches that the primers they designed, which were based on reference genomes, were capable of targeting sequence regions within a given sample (e.g., page 6, left column).
Regarding claims 30 and 32, these claims relates to an inherent property of a given clinical and/or environmental sample. Given that Gardner 1 teaches that their method is to be used with clinical and/or environmental samples, such a method would inherently read on a sample of any pathogenic titer, where such a titer of pathogenic microorganism could be between 1,000 and 100,000 genome copies per mL (page 3, left column, first paragraph). Gardner 1’s method, in other words, could be applied to any such sample with any titer of genomes per mL, absent evidence to the contrary.
Regarding claim 39, as Gardner 2 (page 6303, left column, first paragraph) and Greninger (page 5, left column, second paragraph) teach adapters to be used in their methods of sequencing, a practitioner of ordinary skill in the art could at once envision that the adapter is at the 5’ end, as the practitioner would be selecting from only one of two ends (i.e., the 5’ and 3’ end of a primer sequence).
Regarding claim 40, Gardner 1 teaches that their method comprises random hexamer primers (page 6, left column, first two paragraphs).
Regarding claim 42, as Gardner 1 teaches both the components of random hexamer primers and a set of designed primers, where such primer sets are used within the same method, a practitioner could arrive at a given ration simply by routine laboratory optimization and testing different primer ratios for a desired result. As MPEP 2144.05, IIA states:
“Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.”
As such, the concentration of known primer elements can simply be viewed as routine laboratory optimization for a sequencing reaction.
Regarding claim 44, Gardner 2 teaches that such amplified products can be used in conjunction with probes for further downstream characterization (e.g., page 6292, left column, second paragraph).
Regarding claim 50, Gardner 1 teaches that the primer length can be 18-25 nucleotides (Table 2).
Regarding claim 51, the combination of Gardner 1, Gardner 2, and Greningner renders obvious the claim limitations wherein the primer is between 11-17 nts in length, as discussed in the rejection of claim 1 (above).
Claims 7 and 52 is rejected under 35 U.S.C. 103 as being unpatentable over Gardner 1 (Gardner SN et al. Adv Bioinformatics. 2014;2014:101894), Greninger (Greninger AL et al. Genome Med. 2015 Sep 29;7:99) and Gardner 2 (Gardner SN et al. Nucleic Acids Res. 2009 Oct;37(19):6291-304), as applied to claims 1-3, 5-6, 11-13, 16-17, 19, 21, 23, 28-30, 32, 39-40, 42, 44, and 50-51, above, and further in view of Robins-Browne (Robins-Browne RM et al. Front Cell Infect Microbiol. 2016 Nov 18;6:141).
Regarding claims 7 and 52, a discussion of Gardner 1, Gardner 2, and Greninger is given above. Gardner 1 teaches that their method of pathogen detection is useful for identifying pathogens such as viruses.
Gardner 1 does not specifically teach that the pathogen to be detected is a bacteria such as Escherichia (claim 7), a pathogenic bacteria (claim 52).
Robins-Browne is a research article which focuses on the importance of whole genome sequencing of E. coli in order to generate relevant information concerning pathotype as well as individual strain tracking and spread (Abstract). Thus, Robins-Browne teaches that it is known that performing sequencing on pathogenic bacteria such as Escherichia strains is important in order to generate useful information (Abstract).
It would have been obvious to a person of ordinary skill in the art to combine the sequencing/primer design methods of Gardner 1/Gardner2/Greninger to pathogenic bacteria such as Escherichia in view of Robins-Browne; a practitioner would be motivated to apply such sequencing techniques because it is known in the art that sequencing of pathogenic bacterial strains provides useful information for strain tracking (Robins-Browne, Abstract) and is thus clinically relevant).
Claims 8-10 are rejected under 35 U.S.C. 103 as being unpatentable over Gardner 1 (Gardner SN et al. Adv Bioinformatics. 2014;2014:101894), Greninger (Greninger AL et al. Genome Med. 2015 Sep 29;7:99) and Gardner 2 (Gardner SN et al. Nucleic Acids Res. 2009 Oct;37(19):6291-304), as applied to claims 1-3, 5-6, 11-13, 16-17, 19, 21, 23, 28-30, 32, 39-40, 42, 44, and 50-51, above, and further in view of Zhao (Zhao Y et al. J Clin Microbiol. 2015 Nov;53(11):3639-45).
Regarding claim 1, a discussion of Gardner 1, Gardner 2, and Greninger is given above. Gardner 1 teaches that their method of pathogen detection is useful for identifying pathogens such as viruses.
Gardner 1 does not specifically teach that the pathogen to be detected is a fungus (claim 8) that is resistant to an anti-pathogen treatment (claim 9) such as an antifungal (claim 10).
Regarding claims 8-10, Zhao is a research article which focuses on the clinically relevant fungus Yarrowia and characterization of its resistance to antifungal treatments (Title, Abstract, and throughout). Zhao therefore teaches that it was known that fungus such as those belonging to Yarrowia are known to be both pathogenic and resistant to antifungal treatments (Title). Zhao furthermore teaches that sequencing of such fungi is useful for diagnostics and characterization (e.g., Abstract).
It would have been obvious to a person of ordinary skill in the art to apply the sequencing methods and approaches of Gardner 1 to fungus such as Yarrowia, as such a combination of elements is the simple combination of known prior art elements to yield predictable results. Furthermore, a practitioner would be motivated to apply such sequencing methods as those taught by Gardner 1 because Zhao teaches that it is useful to characterize antifungal strains of Yarrowia by sequencing (Abstract). Furthermore, a practitioner would be motivated to sequence such strains of fungus because they are known to be clinically relevant, and would therefore be useful to sequence, characterize, and detect.
Claims 27, 33-34, 45, and 47-48 are rejected under 35 U.S.C. 103 as being unpatentable over Gardner 1 (Gardner SN et al. Adv Bioinformatics. 2014;2014:101894), Greninger (Greninger AL et al. Genome Med. 2015 Sep 29;7:99) and Gardner 2 (Gardner SN et al. Nucleic Acids Res. 2009 Oct;37(19):6291-304), as applied to claims 1-3, 5-6, 11-13, 16-17, 19, 21, 23, 28-30, 32, 39-40, 42, 44, and 50-51, above, and further in view of Green (WO 2017/205668).
A discussion of the teachings of Gardner 1, Gardner 2, and Greninger is given above. As discussed above, Gardner 1 teaches that their method is useful for sequencing viral pathogens.
Gardner 1 and 2 and Greninger do not specifically teach SEQ ID NO: 1 as a primer.
Green is a patent document focused on method of detecting the presence of pathogenic targets (Abstract) and therefore directly overlaps with the subject matter and field of endeavor as Gardner 1, Gardner 2, and Greninger, as each of these is directed to such detection methods. Furthermore, Green teaches that it is important to detect viruses during outbreaks such as the Zika virus (paragraphs 3-5). Furthermore, Green teaches SEQ ID NO: 293, the reverse compliment of which is 100% identical to instant SEQ ID NO: 1 (below):
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SEQ ID NO: 1 (top) aligned with the reverse compliment of SEQ ID NO: 293 of Green (bottom).
Hence, per Green, SEQ ID NO: 1 is simply the known sequence of a strain of Zika virus.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to include a primer in the primer sequencing methods such as those taught by Gardner 1, Gardner 2, and Greninger, such as a complimentary sequence to SEQ ID NO: 1 (applicant’s elected species) as SEQ ID NO: 1 and its compliment are simply known sequences of the Zika virus as taught by Green (Green SEQ ID NO: 293). Thus, a practitioner who was using the methods of Gardner 1, Gardner 2, and Greninger could arrive at a primer sequence such as SEQ ID NO: 1 simply by routine optimization of Gardner’s method (i.e., Gardner 1’s method, absent evidence to the contrary, could reasonably produce such a primer as SEQ ID NO: 1 because it relies on multiple-sequence alignment and the Zika virus, which comprises a complimentary sequence to SEQ ID NO: 1, would be within such genome reference databases which would be mined for primer design by the method of Gardner 1). Furthermore, Zika virus was known to be a part of outbreaks; a practitioner would therefore be motivated to apply the method of Gardner 1 to such available genomes as the Zika virus genome taught by Green to arrive at the presently recited primer.
Regarding claims 45 and 47-48, the present rejection is directed to Applicant’s elected SEQ ID NO: 1, where a primer such as SEQ ID NO: 1 is obvious given the known genome of Zika virus per Green in light of the primer design and sequencing methods of Gardner 1, Gardner 2, and Greninger, as discussed in the above rejection of claims 27 and 33-34. Furthermore, regarding claim 45, Greninger teaches SEQ ID NO: 97 to be used as an adapter (page 4 left column, second paragraph, Primer B, and page 5 left column, second paragraph, Primer B, see alignment in the rejection of claim 1, above). Additionally, given that Greninger teaches that the sequence of primer B can be an adapter sequence, a practitioner could immediately envision the adapter at the 5’ end because they would be selecting from only one of two ends (i.e., either the 5’ or 3’ end, claim 47). Furthermore, Gardner 1 teaches random hexamer primers (page 6, left column, first two paragraphs, claim 48). Thus, the combination of Gardner 1, Gardner 2, Greninger, and Green render obvious the kit components presently recited in claims 45 and 47-48 (with regards to Applicant’s elected SEQ ID NO: 1).
Claim 49 is rejected under 35 U.S.C. 103 as being unpatentable over Gardner 1 (Gardner SN et al. Adv Bioinformatics. 2014;2014:101894), Greninger (Greninger AL et al. Genome Med. 2015 Sep 29;7:99), Gardner 2 (Gardner SN et al. Nucleic Acids Res. 2009 Oct;37(19):6291-304), and Green (WO 2017/205668) as applied to claims 1-3, 5-6, 11-13, 16-17, 19, 21, 23, 28-30, 32, 39-40, 42, 44, 45, 47-48, and 50-51, above, and further in view of GenBank: MH061872.1 (GenBank Accession Number MH061872.1, published 4/15/2018).
The discussion of the rejection of claims 1-3, 5-6, 11-13, 16-17, 19, 21, 23, 28-30, 32, 39-40, 42, 44, 45, 47-48, and 50-51 is incorporated herein. As discussed above, Green teaches the known sequences of Zika viruses, as well as sequencing methods to detect Zika (Abstract, throughout). Furthermore, Gardner 2 teaches the incorporation of probes to be used with amplification strategies (e.g., page 6292, left column, second paragraph).
Gardner 1, Gardner 2, Greninger, and Green do not teach the specific probe sequence of SEQ ID NO: 98.
As shown in the alignment below of GenBank MH061872.1 and SEQ ID NO: 98, SEQ ID NO:98 is simply a known sequence of the Zika virus genome:
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SEQ ID NO:98 (top) aligned with GenBank MH061872.1 (bottom). Such a sequence could therefore be reasonably used as a probe for probe capture in a sequencing method such as that rendered obvious by Gardner 1, Gardner 2, Greninger, and Green, as the sequence was already known in the art per GenBank MH061872.1.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to combine the sequencing and primer design method rendered obvious by Gardner 1, Gardner 2, Greninger, and Green, to further comprise a probe comprising SEQ ID NO: 98 for downstream applications such as probe capture/hybridization as taught by Gardner 2, as SEQ ID NO:98 was already known in the art to be comprised by the Zika virus genome as taught by GenBank MH0601872. The combination can be viewed as the simple combination of known prior art elements to yield predictable results given that Green has taught methods of detecting Zika virus, where furthermore such methods of primer design, sequencing, and probe capture were already known in the art.
Response to Arguments
The Applicant’s arguments and amendments are sufficient to obviate the 112(a) enablement rejection previously issued. Upon amendment and further searching, a new 103 rejection is issued as discussed above. Although the Applicant has amended the independent claims, it is the position of the Office that the above 103 rejection could have been made prior to amendment. As such, the present action is a non-final action so that the Applicant can have a chance to respond to the newly issued 103 rejection.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DOUGLAS CHARLES RYAN whose telephone number is (571)272-8406. The examiner can normally be reached M-F 8AM - 5PM.
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/D.C.R./ Examiner, Art Unit 1635
/KIMBERLY CHONG/ Primary Examiner, Art Unit 1636