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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/4/2025 has been entered.
Applicant’s arguments and amendments have been thoroughly reviewed and considered. Claim 41 has been canceled. Claims 1, 4, 17, 29, 34-38, 43, 46, and 48 remain withdrawn. Claims 2, 40, 42, and 47 are pending and are examined on the merits herein.
Response to Applicant’s Declarations
The declaration from Derek K. Leung submitted 12/4/2025 has been reviewed and considered. Mr. Leung states that when designing primers or probes via the teachings of Kwon, there is no indication that any particular designed oligonucleotide will work in a particular assay, and the oligonucleotides designed rely heavily on input parameters that may change depending on the user (points 11 and 12). Mr. Leung used the teachings of Kwon to determine the number of possible primer pairs derivable from SEQ ID NOs: 45 and 53 of Kwon, which are cited in the Final Rejection as comprising SEQ ID NOs: 1 and 3. This generated a very large number of primer sequences (point 16 and Tables 1 and 2).
The declaration from Dr. Sree Panuganti submitted 12/4/2025 has been reviewed and considered. Dr. Panuganti states that a person of ordinary skill in the art would interpret the oligomer design of instant claim 2 as comprising target-hybridizing sequences, where additional nucleotides may be added as additional non-target-hybridizing sequences, but would not allow for additional target-hybridizing sequences, which is allegedly supported in the instant specification at para. 118 (point 12). Dr. Panuganti explains that the unexpected results of the instant invention are allegedly commensurate in scope with the claimed invention, stating that non-target hybridizing sequences can be added to the claimed oligomers without substantially negatively impacting their performance, and that “This would be particularly evident to an ordinary skilled artisan since any non-target-hybridizing sequence would be added to the 5’ (i.e. non-priming) end of the oligomer,” (points 13 and 14). Dr. Panuganti cites prior art (Nazarenko et al.) to support this notion (point 15). Prior art is also cited to support the idea that additional oligonucleotides could be added to the claimed method with no change in sensitivity (points 16-18). Dr. Panuganti also comments on the declaration of Mr. Leung, and adds that the teachings of Kwon alone would not render the design of the claimed oligonucleotides routine or predictable, particularly in view of their in silico analyses (points 22-24). Dr. Panuganti also states that Kwon is drawn to primers that include common subsequences, while the instant primers are specific to S. pyogenes, and therefore Kwon teaches away from the claimed invention (points 26-27). Finally, Dr. Panuganti reiterates the allegedly unexpected results of the claimed invention (points 33-34).
Regarding point 12 of this latter declaration, the Examiner does not agree with Dr. Panuganti’s interpretation of claim 2 (this also applies to claim 40, which describes the amplification oligomers in the same manner). The claims do not prohibit the use of multiple target-hybridizing sequences on each amplification oligomer. Such an additional region could be directly next to the explicitly claimed hybridization regions, on either the 5’ or 3’ end of the existing region. MPEP 2111.03 I states, “The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004).” The claim also does not prohibit the use of additional amplification oligomers that may contain entirely different target-hybridization sequences. Though claims must be given their broadest reasonable interpretation in light of the specification, the instant specification does not limit all embodiments of the invention to only containing a single target-hybridizing and non-target-hybridizing region. Para. 118, cited by Dr. Panuganti, even begins with the phrase “In some embodiments,” and similar language is used throughout the paragraph.
Regarding the allegedly unexpected results of the instant invention, Dr. Panuganti states that non-hybridizing sequences can be added to the claimed amplification oligomers without degrading their performance in amplification reactions, using Nazarenko as a reference, and that additional oligonucleotides can be added to a reaction mixture without degrading the performance of amplification oligomers, using Butler and Kim as references (points 14-17). Nazarenko appears to focus on the use of 5’ hairpin structures in primers, where the 5’ end is complementary to the 3’ end of a primer (Figure 1). Thus, the 5’ end would be similar in sequence to a target nucleic acid, and may even be complementary to a portion of a double-stranded target. Because of this, it is not clear that the teachings of Nazarenko are relevant to the instant invention and arguments at hand. Even if the 5’ hairpin forming sequences were non-target-hybridizing, this would only represent a particular species in the genus of possible non-target-hybridizing 5’ ends. It is not clear that the efficiency results described by Nazarenko would extend to solely linear 5’ non-target-hybridizing sequences.
Regarding Butler and Kim, it is noted that both of these references discuss singleplex and multiplex amplification of viral sequences. Because both references still utilize PCR techniques, which is the focus of the examples in the instant specification and is recited in instant claim 2, the teachings of these references are still considered relevant to the arguments at hand. Thus, these references demonstrate that sensitivity is not significantly changed when primers associated with designed assays are used with additional oligonucleotide sequences.
However, considering this in the context of Applicant’s allegedly unexpected results, and the explanation of the Examiner’s interpretation of the claimed method described above, the results and accompanying explanations are not yet enough to be persuasive. Examples 1 and 6 of the instant specification are focused on by Dr. Panuganti. According to MPEP 716.02, in order to sufficiently prove such results, the burden is on Applicant to describe why the results are unexpected and significant. As pointed out in the previous Final Rejection, the ordinary artisan would anticipate that some amplification oligomers would work better than others for detecting GAS sequences, which is currently shown by Applicant’s results. In Table 3, which concerns Example 1, the results for mix 1 for both cell suspensions and lysate groups are similar to the values shown in other groups (e.g. values for mix 2 lysate, mix 3 lysate, and mix 4 lysate). Though the values are slightly higher for mix 1, it is not clear that the degree of difference indicates superior or unexpected performance. It is noted that, Table 8, which concerns Example 5, shows data for mixes 8.2 (SEQ ID NOs: 30 and 28) and 11 (SEQ ID NOs: 37 and 38), and these appear to be grouped with mixes 5.2, 8.1, and 9 in Applicant’s statements regarding the shown results (para. 181). Thus, it is not clear what in particular concerning the results of mixes 8.2 and 11 warrant would be unexpected over the other indicated mixes. Example 6 only uses mixes 5.2, 8.2, and 11, and the choice to use these mixes alone is not made clear. Mixes 8.2 and 11 do appear to more often align with negative culture results, though positive results were similar for all three mixes. It is not clear from a single comparison point alone that mixes 8.2 and 11 significantly outperform other primer mixes in terms of detecting both true positives and true negatives. It is possible that additional comparisons that show similar trends to those shown in Example 6 may indicate superior performance of the primers in these mixes.
Additionally, as noted previously, the results demonstrated by Applicant are not commensurate in scope with the claimed invention, particularly as the instant claims state that the amplification oligomers can comprise one of the pairs of the listed SEQ ID NOs, and thus may also include additional sequences, including target or non-target-hybridizing sequences. The oligomers of the described examples appear to consist of the stated SEQ ID NOs (see Table 2).
Thus, these points are not persuasive.
Regarding both declarations and their points concerning the Kwon reference, it is noted that in the Final Rejection, Kwon teaches SEQ ID NOs: 45 and 53, which contain instant SEQ ID NOs: 1 and 3, as well as primer design teachings and the general method steps presented in the instant claims.
Dr. Panuganti states that Kwon teaches away from the claimed invention because the reference teaches the creation and use of primer sets with multiple Streptococcus species and common subsequences (points 26-27). MPEP 2145 X (D) 1 states, “‘the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….’ In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023) ("a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed.") (internal quotations omitted) (quoting DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009)).” Kwon does not disparage the detection of a single species, and so does not teach away from the detection of S. pyogenes singularly.
Both declarations also appear to be concerned with primer length, and in particular, the general length of the primers taught by Kwon relative to the claimed SEQ ID NOs. The Panuganti declaration at point 28 and the Leung declaration at point 17 both state that the pair of instant SEQ ID NOs: 30 and 28 fall outside the length range of Kwon’s 18-25 bp. It is unclear where this length range in Kwon is stated as a requirement – in para. 38 of the reference, it is stated that when hybridization temperatures are in a certain range, primer or probe base sequences may be set at 18-25 bp. There is not requirement that all primers encompassed by the reference (or rendered obvious via the teachings of the reference) need be this length. Furthermore, Kwon is not used to render obvious the use of instant SEQ ID NOs: 30 and 28. Only instant SEQ ID NOs: 1 and 3 are discussed in the obviousness rejection. The claims only require the use of one pair of the listed sequences.
Both declarations also discuss preparation of a subsequence based on Kwon’s SEQ ID NOs: 45 and 53, which relates to the obviousness rationale used in the Final Rejection. In Table 2 of the Leung declaration, experimentation with primer design created large numbers of possible primer pairs. Though the Leung declaration approximates parameters based on teachings of Kwon and typical values associated with PCR, it is not clear that all parameters used were the same as those of Kwon.
The Examiner does not dispute that the design and choosing of primer pairs is a process that may arrive at several different results in terms of final primer sequences chosen for use in an assay. In the Final Rejection, it is not stated that instant SEQ ID NOs: 1 and 3 would be the only potential primer sequences that would result from an analysis of SEQ ID NOs: 45 and 53 of Kwon. The Final Rejection states in para. 19, “The teachings of Kwon detail methods of designing primers and probes that are more efficient than comparable methods, and because these methods can be written as computer programs, the ordinary artisan would be able to utilize them to obtain primers and probes for amplifying and detecting known sequences, respectively. Because Kwon also teaches streptococcus species that are related to sepsis or bacteremia, such as S. pyogenes, the ordinary artisan would be motivated to detect these species in samples in medical settings to improve patient outcomes (para. 67). In view of the above, the ordinary artisan would have been motivated to use the primer and probe design methods and the known S. pyogenes sequences described by Kwon to design primers and probes for use in the method of Kwon, and in the absence of unexpected results, the claimed amplification oligomers (instant SEQ ID NOs: 1 and 3) simply represent the result of an obvious series of steps.” This rejection provides rationale for using the teachings of Kwon to design primers and probes and to target S. pyrogenes specifically. In the absence of unexpected results associated with any particular primers that may result from the use of SEQ ID NOs: 45 and 53 to design S. pyogenes primer sequences, any resulting primer created would be prima facie obvious. Kwon specifically teaches the use of primer/probe design methods in Examples 1-2 where the sequences to choose from regarding S. pyogenes were SEQ ID NOs: 45-69, and the reference showed success in creating resulting primers. Thus, the presence of a large number of potential sequences for choosing a primer is clearly not a limiting factor in the method of Kwon, and would not dissuade the ordinary artisan from following the primer design methodology of Kwon with a smaller pool of starting sequences (i.e. SEQ ID NOs: 45 and 53).
In considering primer design, Dr. Panuganti provides the Henriques reference that states that it is difficult to rely on in silico analyses when developing primers, and that in silico analysis can be a poor predictor of in vitro specificity (point 23). This reference appears to be used to argue that Kwon’s method of primer design would not be motivating for the ordinary artisan.
MPEP 2143.01 I states that prior art suggestion of the claimed invention is not necessarily negated by the presence of desirable alternatives, and section V states, “[a] given course of action often has simultaneous advantages and disadvantages, and this does not necessarily obviate motivation to combine’" (quoting Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165, 77 USPQ2d 1865, 1870 (Fed. Cir. 2006).” Thus, though Kwon presents a computer-driven analysis that Henriques states may not be the most effective primer design method, this does not obviate the obviousness rejection. In silico methods also provide advantages over in vitro methods in terms of being less time and resource intensive. It is also noted that the instant claims do not require or prohibit any particular primer design.
Therefore, the points provided by the declarations of Mr. Leung and Dr. Panuganti are not persuasive to overcome the 35 USC 103 Rejections presented in the Final Rejection mailed 3/3/2026.
Response to Applicant’s Amendments and Arguments
Regarding the 35 USC 103 Rejections, Applicant argues the points initially stated in the declarations of Mr. Leung and Dr. Panuganti, which are addressed above.
Additionally, Applicant argues that with regard to unexpected results, the comparison of the claimed primer pairs with other, non-claimed primer pairs in Examples 1 and 6 is sufficient for comparison under MPEP 716.02(e). Applicant argues that “the instant rejection does not point to or otherwise identify any GAS-specific oligomer pairs in the cited art,” (Remarks, page 18). MPEP 716.02(e) I states that a comparison with the closest prior art need not be with the prior art that is relied upon by the Examiner, and so Applicant need not use cited references present in a rejection to meet this point. However, the Examiner agrees that the additional primer pairs evaluated by Applicant in their examples could be sufficient for comparison with the claimed primer pairs. In Example 1, a sufficient number of primer pairs are provided for comparison to meet this burden. This alone does not render the results persuasive to prove unexpected results however (see the response above in the response to Applicant’s Declarations). Furthermore, in Example 6, as noted above, only one additional primer pair is used, and so this is not currently considered sufficient for comparison n the context of an unexpected results evaluation.
Taken together, Applicant’s arguments and amendments are not persuasive to over the 35 USC 103 Rejections. Therefore, these rejections have been maintained for all currently pending claims. Claim 41 has been canceled, and so this rejection has been rendered moot.
Claim Objections
Claim 40 is objected to because of the following informality: in lines 2 and 3 of the claim, “the amplicon” should read “the GAS amplicon” to match the language used in claim 2. Appropriate correction is required.
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.
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 2, 40, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Kwon et al. (US 2006/0204996 A1).
Kwon teaches methods of designing primers and probes to identify target sequences by amplification and hybridization (Abstract). Such primers and probes are specific to particular Streptococcus species (para. 67). One such species is S. pyogenes, which is a Group A Streptococcus, as recited in the instant specification (e.g. para. 4, Kwon para. 67). Kwon specifically teaches SEQ ID NOs: 45 and 53, which are DNA sequences derived from the 16S rRNA sequence of S. pyogenes (Table 1) and comprise instant SEQ ID NOs: 1 and 3. In Examples 1-3 (Figure 5 and paras. 66-76), Kwon explains how their primers and probes were designed, how their methods can be written as computer programs, and how their programs can design primers and probes much faster than other commercially available programs (Table 2). The reference goes on to say “According to the present invention, primer and probe sets capable of identifying rapidly and accurately a number of target sequences can be readily designed,” (para. 77).
The primer and probe sets can be used to identify species of bacteria in a sample (paras. 9 and 24). This involves amplifying a target sequence using the designed primers, hybridizing a detectable probe to the amplicons, and detecting the fluorescent signal produced by said hybridization (para. 25). Kwon teaches that target sequence detection can include amplification via PCR and detection of a PCR product (para. 37).
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 Kwon to arrive at the claimed invention. The teachings of Kwon detail methods of designing primers and probes that are more efficient than comparable methods, and because these methods can be written as computer programs, the ordinary artisan would be able to utilize them to obtain primers and probes for amplifying and detecting known sequences, respectively. Because Kwon also teaches streptococcus species that are related to sepsis or bacteremia, such as S. pyogenes, the ordinary artisan would be motivated to detect these species in samples in medical settings to improve patient outcomes (para. 67). In view of the above, the ordinary artisan would have been motivated to use the primer and probe design methods and the known S. pyogenes sequences described by Kwon to design primers and probes for use in the method of Kwon, and in the absence of unexpected results, the claimed amplification oligomers (instant SEQ ID NOs: 1 and 3) simply represent the result of an obvious series of steps.
Thus, claims 2, 40, and 47 are prima facie obvious over Kwon.
Claim 42 is rejected under 35 U.S.C. 103 as being unpatentable over Kwon et al. (US 2006/0204996 A1) in view of Navarro et al. (Clinica Chimica Acta, 2015).
Kwon teaches the method of claim 2, as described above. However, though Kwon teaches that PCR may be used (para. 37), this reference does not teach the specifics of this process.
Navarro teaches various methods for real-time PCR (Abstract). Once such method involves use of the TaqMan system. This system utilizes a probe labeled with a fluorophore and quencher, as well as a polymerase with 5’ to 3’ exonuclease activity. During PCR extension, the Taq polymerase degrades the probe, generating fluorescence from the fluorophore, thereby reducing quenching (Table 1 and Figure 2A). Navarro teaches that the design of TaqMan probes is easy, that the production of fluorescence does not interfere with the exponential synthesis of PCR products, and that the probes have many applications, such as quantifying bacterial load (page 240, column 1, paras. 1-3).
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 Navarro in order to use the TaqMan system, including its probes and polymerase, for PCR in the method of Kwon. Navarro teaches advantages and uses of this method that would motivate the ordinary artisan, and Navarro teaches that this method was developed in 1991, meaning it would be well-known (Navarro pages 239, column 2, para. 2). Using TaqMan methods in the method of Kwon would involve using a probe labeled with a fluorophore and quencher, as well as using Taq polymerase. Kwon already teaches using fluorescent signals from probes (paras. 25 and 62) and probe design (e.g. Example 1), and Navarro teaches the design of the TaqMan probe (Table 1 and Figure 2A). Therefore, the ordinary artisan would have a reasonable expectation of success in designing a TaqMan probe for use in the method of Kwon. As for the Taq polymerase, this can be commercially obtained, and its mechanism of action is well-known, as evidenced by Navarro. Therefore it could also be easily utilized in the method of Kwon with a reasonable expectation of success.
Thus, claim 42 is prima facie obvious over Kwon in view of Navarro.
Conclusion
No claims are currently allowable.
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/F.F.G./Examiner, Art Unit 1681
/ANGELA M. BERTAGNA/Primary Examiner, Art Unit 1681
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