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 arguments and amendments have been thoroughly reviewed and considered. Claims 16-17 have been added. Claim 5 has been canceled. Claims 12-14 remain withdrawn. Claims 1-4, 6-11, and 15-17 are pending and are examined on the merits herein.
Response to Applicant’s Amendments
Nucleotide and/or Amino Acid Sequence Disclosures
The specification was objected to because the Sequence Incorporation by Reference paragraph was missing. In light of Applicant’s amendments to the specification submitted 9/25/2026, this objection has been withdrawn.
35 USC 112(b) Rejections
Claims 1-11 and 15 were objected to due to various indefiniteness issues. The rejection over claim 1 has been maintained-in-part – see the 35 USC 112(b) Rejections below. The individual rejections for claims 2 and 15 have been withdrawn. Thus, overall, the rejections for all currently pending claims have been maintained-in-part. Claim 5 has been canceled, and so this rejection has been rendered moot. It is noted that Applicant has not provided any substantive arguments against these rejections.
35 USC 101 Rejections
Claims 1-9 and 15 were rejected for reciting natural products without significantly more. Applicant’s arguments and amendments have been thoroughly reviewed and considered. The rejections have been maintained for all currently pending claims. See “Response to Applicant’s Arguments” below. Claim 5 has been canceled, and so this rejection has been rendered moot.
35 USC 103 Rejections
Claims 1-11 and 15 were rejected under 35 U.S.C. 103 as being unpatentable over Mitsuo et al. (WO 2018/038232) in view of Ezaki et al. (US 2010/0075305 A1).
Applicant’s arguments and amendments have been thoroughly reviewed and considered. The rejections have been maintained for all currently pending claims. See “Response to Applicant’s Arguments” below. Claim 5 has been canceled, and so this rejection has been rendered moot. See also new grounds of rejection below for added claims 16-17.
Response to Applicant’s Arguments
Regarding the 35 USC 101 Rejections, Applicant argues that the combination of the first, second, and third primer as recited in claim 1 is markedly different than a natural product, as the primer set does not exist in nature. Furthermore, Applicant states that the purpose of the tags on the first primer and second primers are intended to allow the primers to be attached to a solid support, and thus are specifically designed to allow the invention to operate “outside the scope of any natural phenomenon,” (Remarks, page 9). On pages 10-11 of their Remarks, Applicant further describes how no primer set that acts as described in the instant claims exists in nature.
Regarding the combination of primers in the instant claims, MPEP 2106.04(c) discusses the markedly different characteristics analysis. In section I (A), which Applicant cites in their arguments, it is stated that the markedly different characteristics analysis does apply to a resultant combination, rather than component parts. However, the actual markedly different characteristics analysis in II (A) states, “When there are multiple counterparts to the nature-based product, the comparison should be made to the closest naturally occurring counterpart…When the nature-based product is a combination produced from multiple components, the closest counterpart may be the individual nature-based components of the combination. For example, assume that applicant claims an inoculant comprising a mixture of bacteria from different species, e.g., some bacteria of species E and some bacteria of species F. Because there is no counterpart mixture in nature, the closest counterparts to the claimed mixture are the individual components of the mixture, i.e., each naturally occurring species by itself. See, e.g., Funk Bros., 333 U.S. at 130, 76 USPQ at 281 (comparing claimed mixture of bacterial species to each species as it occurs in nature); Ambry Genetics, 774 F.3d at 760, 113 USPQ2d at 1244 (although claimed as a pair, individual primer molecules were compared to corresponding segments of naturally occurring gene sequence),” (emphasis added). Then, in section II (C) 2, primers are specifically stated to lack markedly different characteristics.
Thus, in analyzing the instant claims under 35 USC 101, the primers of the primer set would each be individually compared to corresponding segments of their naturally occurring gene sequence. Though tags can exist on the primers, as noted in the initial 35 USC 101 rejection, there is no requirement for what the structure of the tag must be – only that said tag is not amplified in a nucleic acid amplification reaction. Although it is Applicant’s intention that the tag be used to attach the associated polynucleotides to a solid support, this is not actually required by the rejected claims. Thus, as pointed out in the 35 USC 101 Rejection, how the tag may be independent of an amplification is not specified, and so “may be a sequence that has a particular secondary structure (e.g. a stem-loop) or a sequence that has an affinity for binding to a protein that blocks amplification. In both of these instances, the first polynucleotide would still remain a nucleic acid with a particular sequence, where said sequence could exist in nature,” (see para. 18 of the Non-Final Rejection). Then, regarding the label substance for the second polynucleotide, as stated in para. 21 of the Non-Final Rejection, “A “label substance” is not defined by the instant specification. Para. 63 notes that, “A label substance is not particularly limited, provided that it does not inhibit a nucleic acid amplification reaction.” Para. 24 notes that tags can be used for labeling, and para. 68 specifically states that a second polynucleotide tag (on the second polynucleotide) can be a tag for labeling. Thus, the use of an additional tag sequence can be considered to be encompassed by a “label substance,” where such a tag label has no restrictions on the type of sequence that it may be. Thus, this tag may simply be an extension of the sequence of the second primer, with no structural or functional components that would render it markedly different from a natural product.”
Therefore, in examining each of the claimed primers in claims 1-4, 6-9, and 15, each primer is analyzed separately under the markedly different characteristics analysis, and none of the primers have any characteristics that would render them markedly different from their corresponding natural products, as all the primers simply amount to a corresponding natural nucleic acid sequence with natural features.
Thus, Applicant’s arguments are not considered persuasive, and the 35 USC 101 Rejections are maintained for all relevant currently pending claims.
It is noted that Applicant has provided arguments against the application of 35 USC 101 to the kit claims of the instant invention (claims 10-11 and 16-17), but claims 10-11 were not rejected in the Non-Final Rejection under this statute.
Regarding the 35 USC 103 Rejections, Applicant argues that the amendments to claim 1 in the second wherein clause, specifically that the first, second, and third primer are “to be used in combination in a nucleic acid amplification reaction,” overcome the prior art rejections, as neither Mitsuo nor Ezaki teach the use of three of the claimed primers together in a reaction.
As claim 1 is a product claim, the use or performance of an amplification reaction is not actually required by the claim. Thus, this limitation is interpreted as requiring the first, second, and third primers to be generally capable of use together in an amplification reaction, with no particular efficacy requirements. As the primers of Mitsuo in view of Ezaki would have such capabilities, as the combination is drawn to multiple primer pairs with the same target annealing sequences, they are considered to meet this limitation.
Thus, Applicant’s arguments are not considered persuasive.
Mitsuo in view of Ezaki also taught the limitations of previous claim 5, which has now been incorporated into instant claim 1. Mitsuo also teaches the use of double-stranded target nucleic acids (para. 15). Thus, these references are considered to meet all of the limitations of the newly amended claims. This is the basis for the maintaining of the rejections for claims 1-4, 6-11, and 15. It is noted that Mitsuo in view of Ezaki was already stated to teach the newly added limitation of instant claim 15.
Newly added claims 16 and 17 are not taught by the combination of Mitsuo in view of Ezaki, and so new grounds of rejection are required and presented below.
Claim Objections
Claim 1 is objected to because of the following informalities: in the newly added first wherein clause, “the target nucleic acid comprising” should read “the target nucleic acid comprises.” Additionally, in the description of the first polynucleotide, “the 5’ terminus of a target nucleic acid” should read “the 5’ terminus of the target nucleic acid.” Appropriate correction is required.
Claim 2 is objected to because of the following informality: the phrase “the same complementary strand of the partial polynucleotide A’ of the target nucleic acid” should read “the at the 5’ terminus of the target nucleic acid” for better clarity. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 1-4, 6-11, and 15-17 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.
Claim 1 is rejected because the scope of the claim is indefinite relative to the hybridization of the set of primers and the target nucleic acid. Though the target nucleic acid is now specifically described as being double-stranded, the specific strands that the described polynucleotides hybridize to is not entirely clear.
In the instant claim, the first primer hybridizes, at its 3’ end, to a “complementary strand of partial polynucleotide A’ at the 5’ terminus of a target nucleic acid.” As the target is double-stranded, the first primer may hybridize to the second strand that is complementary to partial polynucleotide A’, which would be a 3’ end that would thus allow for extension, but the use of either the first or second strand of the target nucleic acid is not specified.
The second primer is described as binding to “partial polynucleotide B’ at the 3’ terminus of the target nucleic acid” at the 3’ end of the primer. It is unclear if “partial polynucleotide B’” is on the same strand as “partial polynucleotide A’” or is on a different strand. If they are on different strands, then the primers would potentially be acting upon the same strand (as the first primer is potentially hybridizing to the complement of partial polynucleotide A’), and in this scenario, one strand of the double stranded target would not be amplified.
Thus, the scope of the claim is indefinite as the structure and function of the primers unclear relative to the double-stranded target. It will be interpreted as though the primers are acting as shown in Figures 1-1 and 1-2, and Applicant is encouraged to amend the claim to more clearly recite how the primers bind relative to the target nucleic acid strands.
Claims 2-4, 6-11, and 15-17 are rejected due to their dependence on rejected claim 1.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-4, 6-9, and 15 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claims recite natural products.
Claim 1 is drawn towards a set of primers for target nucleic acid amplification. The second and third primers are particular nucleic acid sequences. The first primer must contain a tag that is independent of an amplification reaction. According to para. 31 of the instant specification, a sequence that is “independent of an amplification reaction” is not used as a template in said reaction, though how this may be accomplished is not specifically defined by the instant specification. Thus, the tag may be a sequence that has a particular secondary structure (e.g. a stem-loop) or a sequence that has an affinity for binding to a protein that blocks amplification. In both of these instances, the first polynucleotide would still remain a nucleic acid with a particular sequence, where said sequence could exist in nature. Additionally, the final wherein clause recites the use of a label substance linked to the second polynucleotide. A “label substance” is not defined by the instant specification. Para. 63 notes that, “A label substance is not particularly limited, provided that it does not inhibit a nucleic acid amplification reaction.” Para. 24 notes that tags can be used for labeling, and para. 68 specifically states that a second polynucleotide tag (on the second polynucleotide) can be a tag for labeling. Thus, the use of an additional tag sequence can be considered to be encompassed by a “label substance,” where such a tag label has no restrictions on the type of sequence that it may be. Therefore, this tag may simply be an extension of the sequence of the second primer, with no structural or functional components that would render it markedly different from a natural product.
Thus, though it is not clear that oligonucleotides having the features recited in claim 1 exist in nature, the claimed oligonucleotides are, nevertheless, judicial exceptions because they are derived from naturally occurring molecules and are not required to possess any structural or functional differences relative to their naturally occurring counterparts. For example, the oligonucleotides of claim 1 are not required to include a fluorescently detectable label. As well, the oligonucleotides do not have a function that differs from that of the naturally occurring counterparts since, like the naturally occurring counterparts, the claimed oligonucleotides hybridize to specific nucleic acid sequences. MPEP 2106.04(c) II specifically notes that primers are considered products of nature that lack markedly different characteristics because they share the same sequence as their naturally occurring counterparts, and the ability of the primers to act as starting material is innate to DNA itself, and is not created or altered by the creation of the primers. See also “Response to Applicant’s Arguments” above, which discusses the evaluation of combinations of natural products in the context of the markedly different analysis. As the primers of instant claim 1 currently encompass natural products, the claim as a whole is directed to a group of products that are not markedly different from their naturally occurring counterparts.
Claim 2 depends on claim 1 and provides additional sequence limitations for the third primer. These additional limitations (being a certain percentage in common with a target sequence) still encompass natural products, and so the claim is directed to a judicial exception without significantly more for the same reasons described above for claim 1.
Claims 3-4 depend on claim 1 and specify proportion amounts of each of the primers to be included in the set of primers. These claims do not alter the structure or functions of the primers, and so the claims are directed to a judicial exception without significantly more for the same reasons described above for claim 1.
Claim 6 depends on claim 1, adds a second tag with the same functional requirements as the first tag of claim 1 (in that it is independent of nucleic acid amplification reactions), and adds a fourth primer. No additional structures or functions of the primers are recited that differ from those of claim 1. Thus, this claim is directed to a judicial exception without significantly more for the same reasons described above for claim 1.
Claim 7 depends on claim 6 and provides additional sequence limitations for the fourth primer. These additional limitations (being a certain percentage in common with a target sequence) still encompass natural products, and so the claim is directed to a judicial exception without significantly more for the same reasons described above for claims 1 and 6.
Claims 8-9 depend on claim 6 and specify proportion amounts of each of the primers to be included in the set of primers. These claims do not alter the structure or functions of the primers, and so the claims are directed to a judicial exception without significantly more for the same reasons described above for claims 1 and 6.
Claim 15 recites a multiplex set of primers as claimed in claim 1, where the primers are specific to distinct target sequences. This claim does not add to or alter the structures or functions of the set of primers of claim 1, and so the claim is directed to a judicial exception without significantly more for the same reasons described above for claim 1.
Claim Interpretation
As the pending claims 1-4, 6-11, and 15-17 are directed to or contain a “set of primers,” it is noted that the instant specification provides no specific definition for this term, and so this term confers no particular structure onto the primers of the set, nor a particular means of keeping the primers of a set together (e.g. packaged together in a kit or reagent mixture).
With regard to the penultimate wherein clause of claim 1, where polynucleotide C must be capable of hybridizing competitively with polynucleotide A, the instant specification states that “when one of polynucleotide A of the first primer and polynucleotide C of the third primer hybridizes to the complementary strand of the target nucleic acid, the other cannot hybridize…” (para. 75). This paragraph goes on to state that this may occur when the third polynucleotide can bind to 50% or more nucleotides of the same target as polynucleotide A. Thus, though polynucleotide A and polynucleotide C may be identical, this is not required, and any polynucleotide meeting this 50% or more requirement will be considered to meet the competitive requirements of the instant claim.
This same competitive interpretation will be applied to claim 6, which requires that polynucleotides D and B be competitive, and a similar explanation is provided for these polynucleotides in para. 93 of the instant specification.
In claim 1, a “label substance” is not defined by the instant specification. Para. 63 notes that, “A label substance is not particularly limited, provided that it does not inhibit a nucleic acid amplification reaction.” Para. 24 notes that tags can be used for labeling, and para. 68 specifically states that a second polynucleotide tag (on the second polynucleotide) can be a tag for labeling. Thus, any substance that can be linked to the second polynucleotide will be considered to be encompassed by a “label substance,” including the use of an additional polynucleotide tag.
Further regarding a “label substance,” in claim 11, which recites that a label substance must be capable of binding to a polynucleotide tag, para.116 states, “The step of labeling is performed when the second primer of the set of primers contains the second polynucleotide tag or when the second primer of the set of primers contains a label substance capable of binding to another substance detectable via a secondary reaction. In such a case, the second polynucleotide tag or the label substance is added in the nucleic acid for detection containing the target nucleic acid. In the step of labeling, the reaction product is brought into contact with a label substance or a detectable substance, and thereby binding the label substance or the detectable substance to the second polynucleotide tag in the nucleic acid for detection containing the target nucleic acid.” This does not necessarily further limit the structure of the “label substance” in the claim. Thus, the “label substance” here will be interpreted as any substance capable of binding to the second tag and a solid-phase support, where the label substance can be used for detection.
Similarly, a “capture substance” as recited in claims 10-11 is stated in the instant specification to be “not particularly limited, provided that it can bind to the first polynucleotide tag. A preferable capture substance is a polynucleotide capable of hybridizing to the first polynucleotide tag,” (para. 112). Thus, in the context of the claims, any substance that can bind to the first polynucleotide tag while also being bound to a solid-phase support will be considered to be encompassed by a capture substance. It is noted that some embodiments of capture substances under this interpretation may overlap with those described for the label substance above.
Furthermore, the claims currently being examined are product claims, and have no requirement that the primers in the primer set be used simultaneously. Additionally, though components (such as the first polynucleotide tag) are specified to be “independent of the nucleic acid amplification reaction,” the actual performance of an amplification reaction is not required by the claims.
It is noted that in claim 1, the second wherein clause now states that the set of primers are “to be used in combination in a nucleic acid amplification reaction.” As the actual use of an amplification reaction is not required, this limitation is interpreted as the primers being capable of use together in an amplification reaction. See also “Response to Applicant’s Arguments” above.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-4, 6-11 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Mitsuo et al. (WO 2018/038232) in view of Ezaki et al. (US 2010/0075305 A1).
It is first noted that all of the references to teachings in the Mitsuo reference are referring to the provided English Translation.
Mitsuo teaches methods related to amplification (Abstract). Para. 15 states that the target nucleic acid can be double-stranded. Specifically, the reference mentions both PCR and LAMP amplification methods, which respectively require thermocycling and isothermal conditions (paras. 2 and 5). In the method described in para. 10, the reference describes tags placed on primers that are independent of the amplification reaction and are placed at the 5’ end of each primer (see step (5)). The tags utilize spacers that are capable of stopping nucleic acid synthesis via a polymerase, and thus do not participate in the actual amplification of a target sequence (see steps (6)-(7)). This method as a whole results in amplification that can occur without thermocycling, and can be performed under isothermal conditions (para. 22). Mitsuo teaches that the first and second primers (that contain the first and second tags) can be based on conventional PCR primers (para. 23). The tags that are independent of the amplification reaction are specifically noted to not be used as a template during said amplification (para. 26). These independent tags can be used for detection and labeling (paras. 28-29).
Additionally, Mitsuo teaches that at least one of the first and second primers can contain a marking element that is a labeling substance (para. 10, steps (8)-(9)). Para. 26 notes that the first and second primers can have, in addition to the tags that are independent of the amplification reaction, tags that may be involved in the amplification reaction. Para. 29 notes that either of these tags can be a labeling tag that is used to detect amplification products. These labeling tags can contain fluorescent or chromogenic substances (para. 74).
However, though Mitsuo does teach the use of additional primers such as a third and fourth primer that do not contain tag sequences (see Figure 1 and para. 48 for example), these additional primers are not competitive with the first and second primers as claimed. It is noted that fifth and sixth primers are used in some of their examples, but these also do not contain tag sequences or appear to act competitively (see paras. 102-103).
Ezaki teaches methods for detecting target nucleic acids (Abstract). These methods can involve multiplex PCR with a plurality of primer sets (para. 6). Generally, Ezaki notes that primers can have tags that do not anneal to a target nucleic acid sequence (paras. 33 and 130). Ezaki notes that the primers may have a linker sequence between the tag and the annealing sequence (para. 131), but the reference does not specifically note that the linker may stop amplification, and so the tags are likely not independent of the amplification reaction as in Mitsuo. The tags of the invention are intended to be on the 5’ end of the primer sequences, with the target annealing sequence on the 3’ ends of the primers (para. 126). These 3’ ends would then attach to the target nucleic acids in a 5’ to 3’ direction (see Figure 14). In Example 8 of the reference, a set of tagged forward and tagged reverse primers is used (para. 226). As a means of comparison, untagged primers were also used, where the untagged forward and reverse primers were the same in sequence as the tagged forward and tagged reverse primers, but without the use of the tag sequences (para. 227). This comparative method was used to confirm that the tag methods of their invention produced successful amplification and were superior to the untagged primers (para. 231 and Figure 16).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the comparative reasoning of Ezaki with the invention of Mitsuo to arrive at the set of primers of instant claims 1 and 6. Mitsuo teaches that their isothermal amplification methods are an improvement to the versatility and primer design constraints required by LAMP (paras. 7-9). However, as a check to the method/primers of Mitsuo, the ordinary artisan would recognize that it would be beneficial to also attempt amplification using the same primers of the Mitsuo, but without the tag sequences. This would allow for the benefits of the tags to become clear, or, in the case where tagged primer design is ineffective, to recognize this issue before the primers are used for practical application. In Ezaki, tagged primers were shown to produce much more amplification product compared to non-tagged primers (see Figure 16), and so the benefits of the tags here are clear. As Mitsuo also teaches that their general amplification method is based on a novel principle (Abstract and para. 8), the ordinary artisan would be motivated to check the efficacy of the reaction with known and thoroughly tested amplification methods, and if the results of Mitsuo produce less product or are prone to more errors than typical LAMP or other isothermal amplification methods, the adoption of these methods may not be suitable for particular applications. There would be a reasonable expectation of success in developing these comparative primers as they would be based on the known annealing sequence of the tagged primers, and methods of primer design and amplification are generally well-known in the art (see paras. 77 and 103 of Ezaki in particular, which teach the use of primer design software that would be accessible to the ordinary artisan).
This would thus result in the use of the primers of Mitsuo, where two tagged primers are present and the tags act independently of the amplification reaction (which are analogous to the first and second primers of instant claims 1 and 6), and two untagged primers that act as comparisons (which are analogous to the third and fourth primers of instant claims 1 and 6). As these third and fourth primers would have the same annealing sequences as the first and second primers, and Mitsuo teaches that their primers are fully hybridized to the target sequence (see para. 10, step (2) and at least Figure 1), these primers would also meet the limitations of instant claims 2 and 7. As noted above in the “Claim Interpretation” section, the primers of the instantly claimed set have no requirements to be used together, and so the primers generated by the combination of Mitsuo in view of Ezaki is considered to be analogous to the claimed set of primers.
Thus, claims 1-2 and 6-7 are prima facie obvious over Mitsuo in view of Ezaki.
Regarding claim 3, Ezaki states that their tagged forward and reverse primers are provided at 0.1µM each, and the untagged forward and reverse primers are also provided at 0.1µM each (see paras. 226-227). According to the tables of paras. 228-229, 2µL volume was used for each primer mixture, with a total reaction volume of 20µL for both reactions, and so each primer should have similar molarity. In claims 3-4, the percentages used are taken from the total amount of the third primer used to the total amount of the first and third primer used. The claims do not specify that the primers must be together in solution. Similar wording is provided for claims 8-9, where the amount of second primer provided is compared to the total amount of the second and fourth primers, without a requirement that they be together in solution. Thus, in Ezaki, the amount of an untagged forward primer provided relative to the tagged forward and untagged forward primers is 50 mol%, and the amount of an untagged reverse primer relative to the tagged and untagged reverse primers is 50 mol%. In the rejection of claims 1-2 and 6-7 described above, the comparative primer methods of Ezaki are employed to test the tagged primers of Mitsuo. As the teachings of Ezaki are used for comparison, and the reference shows successful data analysis resulting from their comparisons (e.g. Figure 16), it would be prima facie obvious to provide the first, second, third, and fourth primers described above in the combination of Mitsuo in view of Ezaki in the concentrations suggested by Ezaki (i.e. to have all the primers provided at the same concentration). This would ensure that the comparative methods are accurately reflecting the different amplification abilities of the primers given their tagged or untagged status, without additionally accounting for the confounding factor of primers being provided at different concentrations. Limiting such confounding is typical for comparative experiments, and so this design would be within the skill and knowledge of the ordinary artisan. There would be a reasonable expectation of success as manipulating reagent concentrations is well-known in the art, as evidenced by Ezaki (e.g. paras. 36, 141-142, and 153).
Thus, claims 3-4 and 8-9 are prima facie obvious over Mitsuo in view of Ezaki.
Regarding claims 10-11, the “detecting device” is not defined by the instant specification, and so is not required to be a part of any particular reaction type (e.g. amplification, sequencing), and must simply have the structural and functional features listed in the claims.
Mitsuo teaches that targets may be detected utilizing solid-phase support array-based methods with immobilized probes or beads with immobilized probes (paras. 93-94). The probes are designed based on specificity for hybridizing to an amplification product (para. 95). Detection can generally occur due to labeling elements placed on the first and second primers (para. 97), and paras. 26 and 28 state that the tags added to the primers that are independent of the amplification reaction can be designed to be hybridized to a detection probe. Para. 29 also notes that labeling tags that are independent of the amplification reaction are capable of hybridizing with labeling probes. Para. 91 also notes that target nucleic acids can be detected via hybridization of tags independent of the amplification reaction with probes. Mitsuo also teaches kits, where said kits can contain the primers of their invention, probes, and carriers that contain said immobilized probes (paras. 98-99).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the teachings of Mitsuo to arrive at the kits of claims 10-11 with the combination of Mitsuo in view of Ezaki. Mitsuo teaches that the tags on their primers that are independent of an amplification reaction may be used for detection and labeling, and both may be attached to probes. Probes may also be immobilized on a solid support. The ordinary artisan would be motivated to combine these aspects so that detecting of targets can occur on a solid support. Specifically, this would involve creating probes on the solid support capable of hybridizing to the detection/labeling tags on the first or second primer. Including both types of probes would ensure that both strands of a potential amplification product could be immobilized and detected. By using probes on a solid support, this would allow for easy downstream capture and manipulation of particular strands and easier washing steps to remove excess reagents. As Mitsuo already teaches that primers, probes, and elements for holding probes can be placed in kits, and teaches all of the structures and functions of the primers and the probes presented in this paragraph and the paragraph above, there would be a reasonable expectation of success.
Thus, claims 10-11 are prima facie obvious over Mitsuo in view of Ezaki.
Regarding claim 15, Example 8 of Ezaki specifically notes that the method is multiplex amplification, where the tagged forward and reverse primers are all different sequences (the pairs are SEQ ID NOs: 1-18 for the forward primers and SEQ ID NOs: 19-36 for the reverse primers, which are different sequences, as noted in the Sequence Listing for the reference). Though these pairs are all designed to target portions of the Legionella pneumophila GTC 1279 DNA (para. 226), the exact nucleic acid sequences on the Legionella pneumophila GTC 1279 DNA amplified by each primer pair are different from one other, and so are considered different target nucleic acids. Ezaki also generally teaches multiplex amplification, and notes that multiplex amplification is useful for identifying pathogens (para. 6), and that primer specificity is important in such contexts (para. 19). Multiplex amplification can also be used for rapid detection (para. 20). Thus, with regard to the set of primers described by the combination of Mitsuo in view of Ezaki in the rejection of claim 1 above, it would be prima facie obvious that multiple sets of primers could be developed to amplify multiple targets. This would provide the benefit of being able to more quickly detect if a particular target is present in a sample, which would be particularly useful in diagnostic contexts. Ezaki teaches that multiplex amplification and primer design are well-known in the art (see paras. 77 and 103 of Ezaki in particular, which teach the use of primer design software that would be accessible to the ordinary artisan), and thus developing primers with specific target sequences to target multiple different nucleic acids would have a reasonable expectation of success.
Thus, claim 15 is prima facie obvious over Mitsuo in view of Ezaki.
Claims 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Mitsuo et al. (WO 2018/038232), in view of Ezaki et al. (US 2010/0075305 A1), and further in view of Provins et al. (US 2019/0226015 A1).
Mitsuo in view of Ezaki teach the products of claims 1-4, 6-11 and 15, as described above. And though Mitsuo teaches array-based methods, the reference does not specifically note the use of lateral flow methods. Ezaki does mention flow cytometry methods (paras. 92 and 156), but does not specifically describe flow methods in conjunction with array-based methods.
Provins teaches specific amplification methods (Abstract). Para. 58 states that amplification methods can be performed on solid supports with lateral flow methods. In para. 55, additional details are provided regarding lateral flow devices, in that they are well-known in the art and used for detection of target nucleic acids. Paras. 56-57 note general means of nucleic acid capture and detection, and teach that nucleic acid capture probes may be placed on lateral flow devices.
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the teachings of Provins to inform the solid-support aspects of the kits of Mitsuo in view of Ezaki. Specifically, though Mitsuo states that their assays may be performed on solid support arrays, the reference does not require a specific means or method for the use of the solid support. Provins notes that lateral flow methods are generally well-known in the art (providing a reasonable expectation of obtaining lateral flow components to include in a kit and a reasonable expectation of successful use of such components), and can operate with capture probes on a solid support for amplification and detection of nucleic acids. Thus, including such lateral flow components in the kits of Mitsuo in view of Ezaki would amount to simple substitution of the solid-support and associated components used in Mitsuo in view of Ezaki. MPEP 2143 I (B) states, “The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.” Using the lateral flow components described by Provins would allow for successful nucleic acid amplification and detection on a solid-support, which is the purpose of the solid-support array-based methods of Mitsuo in view of Ezaki as described above. Specifically, the tags on the polynucleotides of Mitsuo in view of Ezaki would still be capable of being captured, and the associated polynucleotides could be amplified and subsequently detected, and so the results of this substitution would be predictable.
Thus, claims 16-17 are prima facie obvious of Mitsuo, in view of Ezaki, and further in view of Provins.
Conclusion
No claims are currently allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/F.F.G./Examiner, Art Unit 1681
/ANGELA M. BERTAGNA/Primary Examiner, Art Unit 1681
