DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
2. Applicant's response filed on January 28, 2026 has been entered.
Claims 1-18 and 20 are pending. Claims 1-15 and 20 are under examination. Claims 16-18 remain withdrawn from consideration as being drawn to a non-elected invention.
Response to Arguments
3. Applicant’s arguments filed on January 28, 2026 have been fully considered.
Request for Rejoinder
Applicant requests rejoinder of the withdrawn claims when claim 1 and its dependent claims are allowable (Remarks, page 12).
Applicant’s request is acknowledged. Claim 1 and its dependent claims are not yet allowable, so this request is moot. It is also noted that withdrawn product claims are not necessarily eligible for rejoinder per the guidance set forth in MPEP 821.04.
Objections to the Drawings
Applicant argues that the objections should be withdrawn in view of the replacement drawings filed with the response (Remarks, page 12).
This argument was persuasive. The objections made previously have been withdrawn.
Objections to the Specification and the Abstract
Applicant argues that the objections should be withdrawn in view of the amendments to the specification and abstract filed with the response (Remarks, pages 12-13).
This argument was persuasive. The objections made previously have been withdrawn.
Claim Objections
Applicant argues that the objections to claims 1, 3, 7, and 10 should be withdrawn in view of the amendments to those claims (Remarks, page 13).
This argument was persuasive. The objections have been withdrawn.
Rejection of claim 19 under 35 U.S.C. 101
Applicant argues that the rejection is moot in view of the cancellation of claim 19 (Remarks, page 13).
This argument was persuasive. The rejection has been withdrawn.
Rejection of claims 1-15 and 19 under 35 U.S.C. 112(b)
Applicant argues that the rejection should be withdrawn (Remarks, pages 13-14). More specifically, Applicant argues that the issues raised in the rejection concerning claims 1, 6, 7, 10, and 15 are moot in view of the claim amendments (Remarks, pages 13-14). Applicant also argues that the rejection is moot with respect to claim 19 since that claim has been canceled (Remarks, page 14).
These arguments were persuasive in part. The claim amendments and cancellation of claim 19 address all of the previously raised issues except for the “broad-narrow” issue in claim 1. Accordingly, the claims remain rejected under 35 U.S.C. 112(b) since not all of the issues raised previously have been addressed. As well, the amendments also create new indefiniteness issues, which are discussed below in the modified rejection.
Rejection of claims 1-8, 10, and 13 under 35 U.S.C. 102(a)(1) as being anticipated by Frey
Applicant argues that the rejection should be withdrawn because Frey fails to teach all of the elements of the rejected claims (Remarks, pages 14-16). More specifically, Applicant argues that Frey fails to teach amplification of two nucleic acid sequences, A and B, using a primer set for each nucleic acid sequence as required by independent claim 1 (Remarks, pages 14-15). Instead, Applicant argues, Frey teaches the use of two primer sets to amplify a single nucleic acid sequence (Remarks, pages 14-15). Applicant also argues that Frey fails to teach primers with the 5’ portion required by the last clause in independent claim 1 (Remarks, pages 15-16).
These arguments have been fully considered, but they were not persuasive.
In response to Applicant’s first argument, the two primer pairs of Frey do amplify two different target nucleic acids, A and B, as required by the claims. It is true that the two nucleic acids amplified by the primers of Frey are related, but they are not identical since the nucleic acid amplified by the second set of primers has different termini compared to the nucleic acid amplified by the first set of primers. Therefore, the two primer pairs used by Frey meet the requirement in independent claim 1 to be used to amplify two different nucleic acids, especially since the neither the claims nor an explicit definition in the specification requires anything narrower (e.g., for nucleic acids A and B to be present in the sample at the start of the method or for nucleic acids A and B to not share any significant degree of sequence similarity).
Applicant’s second argument was also unpersuasive because the second primer pair in Frey (i.e., the “first set primers” shown in Figure 1 and also described in para. 12 of Frey) meets the requirements of the concluding “wherein” clause in independent claim 1. As can be seen in Figure 1, the forward primer and reverse primer in the first set primers of Frey each contain a 5’ portion that corresponds to the 3’ portion of the forward or reverse primer, respectively, in the second set forward primer of Frey. And, as noted in the rejection, the presence of the additional 5’ portion of the second set primers of Frey is optional (para. 13). Therefore, in this embodiment of Frey, the primers in the first set primers of Frey contain the 5’ portion required by the instant claim 1. It is further noted that neither the claim language nor an explicit definition in the specification excludes a 5’ portion as disclosed in Frey. In other words, neither the claims nor an explicit definition in the specification prevents the 5’ portion from being a sequence that targets an artificial sequence rather than a natural sequence.
It is also noted that the primers of Frey do not anneal to one another as Applicant argues on page 15 of the Remarks. As can be seen in Figure 1 and Tables 1-3 of Frey, the primers do not anneal to one another. For example, as can be seen in Tables 1 and 3, the 5’ portion of SEQ ID NO: 1 is identical to rather than complementary to the 3’ sequence of SEQ ID NO: 63. Similarly, as can be seen in Tables 2 and 3, the 5’ portion of SEQ ID NO: 32 is identical to rather than complementary to the 3’ portion of SEQ ID NO: 64. In other words, neither SEQ ID NOs: 1 and 63 nor SEQ ID NOs: 32 and 64 are designed to anneal to one another.
Since Applicant’s arguments were not persuasive, the rejection has been maintained.
Rejection of claims 1-4, 7, 8, 10, and 11 under 35 U.S.C. 102(a)(1) as being anticipated by Favaro
Applicant argues that the rejection should be withdrawn because the primers in the second primer pair of Favaro lack the 5’ portion required by the last clause of independent claim 1 (Remarks, pages 16-17). Instead, Applicant argues that page e71 of Favaro teaches that the 5’ tails of the DIP-targeting primer pairs anneal to the universal reporter primers (Remarks, page 16). Applicant also argues that “[A]ll targets will be amplified with a chimeric primer in Favaro et al., whereas the present method uses a non-chimeric primer for target[ing] the sequence A” (Remarks, page 17).
These arguments have been fully considered, but they were not persuasive for the following reasons.
In response to Applicant’s first argument regarding the teachings of Favaro on page e71, Applicant is correct that Favaro states that the 5’ tail sequences in the locus-targeting primers “anneal to universal reporter primers.” This description is an apparent error in Favaro, though, for at least the following reasons. First, the method of Favaro would not function to generate the amplification products shown in Figure 1 if this was the case. More specifically, if the universal reporter primers annealed to 5’ tail sequences in the locus-specific primers rather than their complementary sequences, the universal reporter primers would only copy the 5’ tail portion and would not generate the amplicons shown in Figure 1 of Favaro.
Second, in the first paragraph of section 2 on page e71, Favaro states that “DIP loci were amplified by PCR using locus-specific primers which are tailed with ‘universal’ sequences at their 5’ ends, as described by Asari et al.” As can be seen in Asari, a copy of which is provided with this Office action, the locus-specific primers contain a 5’ tail sequence that is identical to a universal reporter sequence (see, e.g., Table 1 on page 86 of Asari). Therefore, it is reasonable to conclude that the locus-specific primers of Favaro contain a 5’ tail sequence that is identical (i.e., not complementary to) one of the universal reporter sequences shown in Table 1 of Favaro. This conclusion is further supported by the second paragraph in section 2 of Favaro on page e71, where the reference describes various loci as being “amplified with the uni11 tail sequence” or “amplified with the uni9 tail sequence.” These statements in Favaro, especially when considered in the context of Asari, make clear that the locus-specific primers contain a 5’ tail that is identical to one of the universal reporter sequences shown in Table 1 of Favaro.
Applicant’s second argument was unpersuasive because the claims do not require using a non-chimeric primer to amplify sequence A. The claims encompass this, but it is not currently required by the claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Since Applicant’s arguments were not persuasive, the rejection has been maintained.
Rejections of claims 5, 6, 9, and 12-15 under 35 U.S.C. 103 citing Favaro as the primary reference
Applicant argues that the rejections should be withdrawn because none of the secondary references cited in the rejections remedies the deficiencies of Favaro with respect to independent claim 1 (Remarks, page 17).
This argument was not persuasive because Favaro is not deficient for the reasons set forth above. The rejections have been maintained with modifications to address the amendments to claim 15.
Drawings
4. Applicant’s submission of replacement drawings on January 28, 2026 is acknowledged.
The replacement drawings are objected to because Figures 6-8 appear to contain a typographical error where the sizes of the marker bands are given in “pb” rather than “bp.”
The replacement drawings are also objected to because Figure 4 contains a typographical error where the reverse primer for Target DNA B is labeled “RT2 + RT2” instead of “RT2 + RT1.” This typographical error also causes Figure 4 to contain new matter because the original disclosure does not provide support for use of an “RT2 + RT2” reverse primer for Target DNA B. The original disclosure only provides support for an “RT2 + RT1” reverse primer or an “RT2 + FW1” reverse primer (see page 4 of the originally filed specification).
Appropriate correction is required.
Specification
5. The specification is objected to because it contains a typographical error on pages 40 and 41, where “pb” is recited for “bp.” There are three instances of this typographical error.
The specification is also objected to because it fails to provide support for the subject matter of original claim 3. As discussed in MPEP 2163.06 III, this is not a new matter issue since the original claims are part of the original disclosure. And, more specifically, the subject matter in claim 3 that lacks support in the specification is “wherein the second primer in primer pair 1 contains, at its 5’ end, the sequence of the first primer of primer pair 1, and wherein said sequences are adjacent.” It is noted that claim 3 may have been intended to recite “second primer of the primer pair 2” in line 2 since this is supported by the specification, e.g., at page 4.
Claim Interpretation
6. Applicant has provided explicit (i.e., limiting) definitions for some of the terms used in the claims. These definitions include the following:
(i) pair of primers or pair of oligonucleotides = two oligonucleotides which make it possible to amplify a target sequence within the context of PCR (p. 9, last para. – p. 10, first para.);
(ii) pair of primers capable of amplifying a nucleic acid sequence of interest = a pair of primers comprising a sense primer and an antisense primer capable of amplifying a specified sequence of interest, by means of PCR (p. 10); and
(iii) amplification = the amplification of the target sequence during a PCR reaction (p. 10).
Claim Objections
7. Claim 1 is objected to because of the following minor informality. Replacing “the pair of primers being formed of” in steps (a)(i) and (a)(ii) of claim 1 with “the pair of primers is formed of” is suggested to improve the claim language.
Claim 3 is objected to because it appears to contain a typographical error in line 2. More specifically, as discussed above in the “Specification” section, it appears that “second primer of the pair of primers 2” was intended in line 2 of claim 3. As well, “the pair 1” in line 3 should be replaced with “the pair of primers 1” to maintain consistency with claim 1.
Claim 15 is objected to because “the microorganisms” in line 2 should be replaced with “the microorganism(s)” or “the at least one microorganism” to maintain consistency with claim 14.
Claim Rejections - 35 USC § 112
8. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 20 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 20, which is a new claim, depends from claim 1 and requires the use of particular amplification primers. The claim states that the first and second primers in each of the primer pair 1 and the primer pair 2 “comprise” a particular nucleotide sequence. For example, lines 6-7 in claim 20 recite “the first primer in the pair of primers 1 comprises SEQ ID NO: 14 or SEQ ID NO: 15.” All of the other primers recited in the claim are also described using open, “comprising” language.
This open language encompasses a first primer that consists of SEQ ID NO: 14 or SEQ ID NO: 15 as well as longer primers, provided that the longer primers include SEQ ID NO: 14 or SEQ ID NO: 15. The same analysis applies to all of the other primers recited in the claim.
Applicant’s response does not identify any particular portion(s) of the original disclosure that provide support for the subject matter of new claim 20.1
The original disclosure, including the originally filed claims, has been reviewed, but support was not found for the full scope of new claim 20. In particular, support was not found for the open-ended, “comprising” language used to describe the primers. The original disclosure provides support for “consisting of” language to describe the sequences of the primers (page 21). The original disclosure also provides support for the broader language used on page 23, but it does not provide support for the recited “comprising” language, which imposes no limits on the length or sequence content of the primers, so long as they are capable of functioning as primers and contain one of the required sequences.
Thus, claim 20 contains new matter.
Claim Rejections - 35 USC § 112
9. 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 1-15 and 20 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
Regarding claim 1, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 1 recites the broad recitation “the pair of primers 1…capable of amplifying a nucleic acid corresponding to the first sequence (A)” in step (a)(i), and the claim also recites “a pair of primers 1 capable of amplifying a first nucleic acid sequence of interest (A)” in lines 1-2 of step (a), which is the narrower statement of the limitation. More specifically, the use of “corresponding” in step (a)(i) causes that portion of the claim to be broader than the language in lines 1-2 of step (a) concerning primer pair 1.
Claim 1 also recites the broad recitation “the pair of primers 2…capable of amplifying a nucleic acid corresponding to the second sequence (B)” in step (a)(ii), and the claim also recites “a pair of primers 2 capable of amplifying a second nucleic acid sequence of interest (B)” in lines 2-3 of step (a), which is the narrower statement of the limitation. As above, the use of “corresponding” in step (a)(ii) causes that portion of the claim to be broader than the language in lines 2-3 of step (a) concerning primer pair 2.
Claim 1 is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Put another way, it is not clear whether the claim is limited to the narrower language in lines 1-3 of step (a) concerning the primer pairs or if it is not so limited and encompasses the broader language in parts (i) and (ii) of step (a).
Claims 2-15 and 20
Claims 2-15 and 20 are also indefinite since they depend from claim 1 and do not correct its indefiniteness issue.
Claim 2
Claim 2 is further indefinite because its requirements are unclear in view of the amendments to claim 1.
Claim 1 has been amended to require the first primer in the pair of primers 2 to contain, at its 5’ end, the sequence of the first primer of the pair of primers 1 and for the second primer in the pair of primers 2 to contain, at its 5’ end, the sequence of the second primer of the pair of primers 1.
Claim 2, though, states that the first primer in the pair of primers 2 may contain either the sequence of the first primer in the pair of primers 1 or the sequence of the second primer in the pair of primers 1. Claim 2 also states that the second primer in the pair of primers 2 may contain either the sequence of the first primer in the pair of primers 1 or the sequence of the second primer in the pair of primers 1.
In view of the amendments to claim 1, it appears that claim 2 should have been amended to narrow structure of the primers in primer pair 2 in the same way that they were narrowed in amended claim 1. Claim 2 was not amended, though, and this raises the question of whether the primers recited in claim 2 are intended to be substituted for those recited in claim 1 or if claim 2 was intended to be amended to include the changes set forth in claim 1. If the first interpretation is correct, claim 2 is not further limiting because not all options for the primers in primer pair 2 include all of the structural features required by claim 1. If the second interpretation is correct, claim 2 appears to contain an error for the reasons set forth previously with respect to claim 1.
Claim 15
Claim 15 is also indefinite for an additional reason. The claim has been amended to state that “subsequent to the amplification, the microorganisms are further identified by performing…reverse transcription PCR.” As noted above in the “Claim Interpretation” section, the specification defines “amplification” to mean “PCR.” Therefore, the amplification step referenced in line 2 of claim 15 is a PCR amplification, which would produce DNA amplicons. It is unclear as to how those amplicons could then be further identified by performing RT-PCR as recited in the claim since RT-PCR requires an RNA template. Clarification is required.
Claim Rejections - 35 USC § 112
10. 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 2 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.
Claim 2 depends from claim 1 and states that the first primer in the pair of primers 2 may contain either the sequence of the first primer in the pair of primers 1 or the sequence of the second primer in the pair of primers 1. Claim 2 also states that the second primer in the pair of primers 2 may contain either the sequence of the first primer in the pair of primers 1 or the sequence of the second primer in the pair of primers 1.
In view of the amendments to claim 1, claim 2 is not further limiting because it encompasses options that would not include all of the elements required by claim 1. In particular, claim 1 requires the first primer in the pair of primers 2 to contain, at its 5’ end, the sequence of the first primer of the pair of primers 1 and for the second primer in the pair of primers 2 to contain, at its 5’ end, the sequence of the second primer of the pair of primers 1. When the first primer of primer pair 2 in claim 2 contains, at its 5’ end, the sequence of the second primer of the pair of primers 1 and/or when the second primer in primer pair 2 in claim 2 contains, at its 5’ end, the sequence of the first primer of primer pair 1, claim 2 would use a primer(s) excluded by claim 1. Accordingly, claim 2 is not further limiting because not all of the options contain all of the elements required by claim 1.
Applicant may cancel the claim, amend the claim to be in proper dependent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Rejections - 35 USC § 102
11. 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.
12. Claims 1-8, 10, and 13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Frey et al. (US 2013/0045894 A1).
The instant claims are drawn to an amplification method that uses a first and second pair of primers.
Regarding claim 1, Frey discloses an amplification method that comprises the use of a first and second primer pair (see, e.g., the abstract, Figures 1-2, and paras. 12-13). The amplification method may be PCR conducted using the two primer pairs, PCR reagents, and PCR conditions (see, e.g., Figures 1-2, paras. 12-13, 29, and 44; see also Examples 1, 3, and 4).
Further regarding claim 1 and also regarding claims 2 and 3, the “second set” primers of Frey correspond to the claimed first pair of primers, and the “first set” primers of Frey correspond to the claimed second pair of primers for the following reasons. First, as can be seen in Figure 1, the two primer pairs used by Frey are capable of amplifying two distinct sequences of interest, (A) and (B). As well, the primers of Frey have the structural features required by the last clause in claim 1 (see, e.g., Figs. 1-2 and paras. 12-13). More specifically, regarding the claimed first primer pair, the “second set primers” of Frey (i.e., the primers described in, e.g., para. 13 and depicted as elements 105 and 107 in Figure 1 and elements 225 and 230 in Figure 2) have a sequence that hybridizes to a sequence of interest (black or cross-hatched boxes in Figures 1 and 2) as required by the claimed first primer pair. It is further noted that the additional 5’ sequence shown in Figures 1 and 2 is optional (see, e.g., para. 13). And, regarding the claimed second primer pair, the “first set primers” of Frey (i.e., the primers described in in para. 12 and depicted as elements 100 and 103 in Figure 1 and elements 200-205 and 210-215 in Figure 2) have a 3’ portion that hybridizes to a different sequence of interest and a 5’ portion that is adjacent to the 3’ portion and the same as one of the primers in the “second set primers” of Frey (see Figures 1 and 2 and paras. 12-13; see also Tables 1-3).
Regarding claims 4-6, Frey teaches that the concentration of the second primer pair may be less than or equal to the concentration of the first pair of primers (see, e.g., para. 15). (As noted above, the first and second primer pairs of Frey respectively correspond to the claimed second and first primer pairs. Frey also teaches particular concentration ratios for the first primer pair and the second primer pair that lie within the claimed ranges (see para. 15; see also Examples 1, 3, and 4 at paras. 71, 78, and 83).
Regarding claims 7 and 10, Frey additionally teaches that the sample may be contacted with third and fourth primer pairs, each of which is capable of amplifying a third or fourth nucleic acid sequence, (C) or (D), and each of which contains at the 5’ end the sequence of the first or second primer of the first primer pair. See Tables 1 and 2 on pages 4-6 and also Table 4 on page 7, where Frey discloses a plurality of forward primers and reverse primers, that may be used as primer pairs to amplify different target nucleic acids. As can be seen in Tables 1 and 2, the primers of Frey contain the sequence of one of the primers in the first primer pair (i.e., one of the sequences in Table 3 on page 6). See also para. 51. Frey teaches amplification with these primer pairs in, e.g., paras. 57-59 and Examples 1 and 3. It is further noted that claims 7 and 10 do not require amplification in the presence of primer pairs 1-3 or primer pairs 1-4 and encompass the teachings of Frey in which separate mixtures comprising primer pairs 1-2, 1-3, or 1-4 are used.
Regarding claim 8, as noted above, Frey teaches that the concentration of the first primer pair may be greater than that of the second primer pair (see, e.g., para. 15).
Regarding claim 13, Frey further teaches that the amplification products may be sequenced (see, e.g., Example 4 at para. 92; see also paras. 13, 28, 60, and 62).
13. Claims 1-4, 7, 8, 10, and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Favaro et al. (Forensic Science International: Genetics Supplement Series 2011; 3: e71-e72).
The instant claims are drawn to a multiplex amplification method that uses a first and second pair of primers.
Regarding claims 1, 7, and 10, Favaro discloses an amplification method that comprises the use of a first, second, third, and fourth primer pair (see section 2 on page e71, where the second, third, and fourth primer pairs are any of the tailed DIP-targeting primer pairs and the first primer pair is the universal reporter primer pair). The amplification method is PCR conducted using the primer pairs, PCR reagents, and PCR conditions (see section 2 on page e71).
Further regarding claim 1 and also regarding claims 2, 3, 7, and 10, the tailed DIP-targeting primer pairs of Favaro correspond to the claimed second, third, and fourth pairs of primers, and the universal reporter primer pair of Favaro corresponds to the claimed first pair of primers for the following reasons. First, as discussed in section 2 of Favaro, all of the primer pairs used by Favaro are capable of amplifying distinct sequences of interest. As well, the primers of Favaro have the structural features required by the last clause in claim 1 (see section 2 on page e71). More specifically, regarding the claimed first primer pair, the universal reporter primer pair of Favaro has a sequence that hybridizes to a sequence of interest as required by the claimed primer pair. And, regarding the claimed second, third, and fourth primer pairs, the tailed DIP-targeting primer pairs of Favaro have a 3’ portion that hybridizes to a different sequence of interest and a 5’ portion that is adjacent to the 3’ portion and the same as one of the universal reporter primers of Favaro (see section 2 on page e71).
Thus, Favaro anticipates the methods of claims 1-3, 7, and 10.
Regarding claim 4, Favaro teaches that the concentration of the second primer pair is less than the concentration of the first primer pair (see page e71, where the concentration of the second primer pair (i.e., a tailed DIP-targeting primer pair) is lower than the concentration of the first primer pair (i.e., the universal reporter primer pair)).
Regarding claim 8, Favaro teaches that the concentration of the first primer pair is greater than the concentration of the second and/or third primer pair (see page e71, where the concentration of the second and third primer pairs (i.e., the tailed DIP-targeting primer pairs) is lower than the concentration of the first primer pair (i.e., the universal reporter primer pair)).
Regarding claim 11, Favaro teaches that the concentration of the fourth primer pair is less than the concentration of the first primer pair (see page e71, where the concentration of the fourth primer pair (i.e., a tailed DIP-targeting primer pair) is lower than the concentration of the first primer pair (i.e., the universal reporter primer pair)).
Thus, Favaro anticipates the methods of claims 1-4, 7, 8, 10, and 11.
Claim Rejections - 35 USC § 103
14. 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.
15. Claims 5, 6, 9, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Favaro et al. (Forensic Science International: Genetics Supplement Series 2011; 3: e71-e72) in view of Frey et al. (US 2013/0045894 A1).
As discussed above, Favaro anticipates the methods of claims 1-4, 7, 8, 10, and 11.
Regarding claims 5, 6, 9, and 12, Favaro teaches that the concentration of the tailed DIP-targeting primers in the PCR is 130 nM (p. e71, col. 2). The concentration of the universal reporter primers in the PCR is 260 nM (p. e71, col. 2). As noted above, the different tailed DIP-targeting primer pairs correspond to the claimed second, third, and fourth primer pairs, and the universal reporter primer pair corresponds to the claimed first primer pair. It is not clear from Favaro whether each different tailed DIP-targeting primer pair is provided at a concentration of 130 nM in the PCR or if the total concentration of all DIP-targeting primer pairs is 130 nM. As a result, it cannot be determined whether Favaro meets the requirements of claims 5, 6, 9, and 12.
Prior to the effective filing date of the claimed invention, though, it would have been prima facie obvious to conduct routine experimentation to determine optimal relative amounts of the different primer pairs used in the method of Favaro. As discussed in MPEP 2144.05 II, concentration differences between claims and the prior art typically do not support patentability unless there is evidence that the claimed concentrations are critical. In this case, there is nothing to indicate that the claimed relative amounts of the different primer pairs are critical, and the prior art of Frey teaches that different concentration ratios may be used with success in a similar amplification method (see, e.g., Example 1 of Frey at para. 71). Thus, the claimed relative amounts of the different primer pairs recited in claims 5, 6, 9, and 12 are prima facie obvious.
16. Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Favaro et al. (Forensic Science International: Genetics Supplement Series 2011; 3: e71-e72) in view of Bus et al. (Electrophoresis 2016; 37: 3039-3045).
As discussed above, Favaro anticipates the methods of claims 1-4, 7, 8, 10, and 11.
Regarding claim 13, the method of Favaro does not include sequencing amplified nucleic acids. Instead, the method of Favaro uses electrophoresis to identify the different amplification products (see page e72).
Prior to the effective filing date of the claimed invention, though, it would have been prima facie obvious for the ordinary artisan to substitute sequencing for electrophoresis when practicing the method of Favaro. Bus provides motivation to do so by teaching that pyrosequencing can function as an “alternative and rapid tool for the analysis of biallelic InDel (insertion/deletion) markers for individual identification” (abstract; see also pp. 3043-3044). Bus provides additional motivation by noting that “[M]ultiplex InDel pyrosequencing offers a cost-effective alternative for some applications” (p. 3044, col. 2). And, Bus further teaches, “In contrast to CE-based methods, sequencing allows detection of SNP(s) within or close to an InDel unit” (p. 3044, col. 1). The ordinary artisan practicing the method of Favaro would have been motivated by at least these teachings in Bus to sequence the amplification products to obtain the ability to detect SNP(s) in the amplification products and also to have a cost-effective alternative to the electrophoretic method taught by Favaro. The ordinary artisan would have had a reasonable expectation of success since Bus taught that sequencing could be used to analyze multiplex amplification products generated for InDel loci (see, e.g., pp. 3041-3042 and p. 3044). Thus, the method of claim 13 is prima facie obvious.
17. Claims 14 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Favaro et al. (Forensic Science International: Genetics Supplement Series 2011; 3: e71-e72 + Supplemental Material) in view of Ahmod et al. (Journal of Microbiological Methods 2011; 87: 278-285).2
As discussed above, Favaro anticipates the methods of claims 1-4, 7, 8, 10, and 11.
Regarding claim 14, Favaro does not teach applying the method to identification of at least one microorganism involved in at least one infectious disease.
Regarding claim 15, which depends from claim 14, Favaro also does not teach one of the recited detection methods for microorganism identification.
Prior to the effective filing date of the claimed invention, though, it would have been prima facie obvious for the ordinary artisan to use the method described in Favaro for the detection of other InDels of interest. The ordinary artisan would have been motivated to do so to increase the number of useful applications of the method. More specifically, since Ahmod discloses InDels that are useful for identifying disease-associated microorganisms (abstract, p. 280, pp. 282-283, and Fig. 3), the ordinary artisan would have recognized that these nucleic acids would be useful targets for use in a method containing the general steps set forth in Favaro, and accordingly, would have been motivated to use them in a multiplex PCR method containing the general steps of Favaro. In doing so, the ordinary artisan would have been motivated to use electrophoretic detection as taught in Favaro or the pyrosequencing (i.e., DNA sequencing) detection method disclosed in Ahmod (p. 280 and pp. 283-284), recognizing that either method would be suitable. The ordinary artisan would have had a reasonable expectation of success in view of the guidance provided in Favaro concerning PCR conditions and the guidance in Ahmod concerning the disclosed InDel loci and pyrosequencing (sections 2.3-2.4 and 3.2-3.3). Thus, the methods of claims 14 and 15 are prima facie obvious.
Prior Art
18. It is noted that claim 20 has not been rejected with prior art. The claim contains new matter for the reasons discussed above, but the prior art fails to teach or suggest a primer comprising or consisting of SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, or SEQ ID NO: 33. As can be seen in Table 1B on page 22 of the specification, these primers are chimeric primers comprising different portions of the variable region of the 16S gene. For example, as can be seen in Table 1B, SEQ ID NO: 28 contains a 5’ sequence consisting of SEQ ID NO: 14, which targets the V1 region of the 16S gene, linked to a 3’ sequence that targets the V4 region of the 16S gene. Since the prior art fails to teach or suggest the claimed chimeric primers, they are free of the prior art.
Conclusion
19. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Angela Bertagna whose telephone number is (571)272-8291. The examiner can normally be reached 8-5, M-F.
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/ANGELA M. BERTAGNA/Primary Examiner, Art Unit 1681
1 It is noted that page 12 of the Remarks states that new claim 20 is “based on claim 19,” but claim 19 did not recite any specific primer sequences.
2 It is noted that the effective filing date of the claimed invention is not the filing date of the foreign priority document (FR 2000902) because an English language translation of said document, which is in French, has not been provided. See MPEP 216 and MPEP 2152.06.
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