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 .
2. This action is in response to the amendment filed on 02/26/2026. Applicant's arguments and amendments to the claims have been fully considered but do not place the application in condition for allowance. All rejections and objections not reiterated herein are hereby withdrawn.
Election/Restrictions
3. In the reply of 09/15/2025, Applicant elected without traverse of Group I and the species of the combination of Flu A (a), Flu A (b), Flu B (c), RSV A (d), and RSV B (e); and the species of the particular primers and probes of SEQ ID NOs:23, 25, and 8 (Flu A (a)), SEQ ID NOs: 24, 26, and 18 (Flu A (b)), SEQ ID NOs: 67, 68, and 64 (Flu B), SEQ ID NOs:79, 92, and 75 (RSV A), and SEQ ID NOs:100, 115, and 102 (RSV B) in the reply filed on 15 September 2025 is acknowledged.
Claim Status
4. Claims 1-2, 4-10, 13-15, and 17-22 are pending.
Claims 14-15 and 18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Note that claim 18 depends from canceled claim 16, but is still; directed to the non-elected invention of Group II.
Claims 1, 2, 4-10, 13, 17 and 19-22 read on the elected invention and have been examined herein to the extent that they read on the elected species.
As stated in the Office action of 11/25/2025, the elected species recited in claim 1 - i.e., kits and compositions comprising the combination of each of the first Flu A primers comprising SEQ ID NO: 23 and 25; the second Flu A primers comprising SEQ ID NO: 24 and 26; the Flu B primers of SEQ ID NO: 67 and 68; the RSV A primers comprising SEQ ID NO: 79 and 92 and the RSV B primers comprising SEQ ID NO: 100 and 115 - is allowable over the prior art. Examination has been extended to the next species of the combination of Flu B and RSV B, and the particular primers for Flu B comprising SEQ ID NO: 67 and 68 and the RSV B primers comprising SEQ ID NO: 100 and 115, as well as the Flu B probe comprising SEQ ID NO: 64 and the RSV B probe of SEQ ID NO: 102. This species has been rejoined with the elected species and fully examined herein.
Each of the claims encompasses the non-elected species of the additionally recited combinations of viruses and primers and probes; and claim 13 encompasses non-elected primers and probes (e.g., the first Flu A primers of SEQ ID NO: 1 and 28). Prior to the allowance of claims, any non-elected subject matter which has not been rejoined with the elected subject matter will be required to be removed from the claims.
Terminal Disclaimer
5. The terminal disclaimer filed on 02/26/2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of any patent granted on U.S. Application Nos. 18625354 and 18625370 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Maintained / Modified Claim Rejections - 35 USC § 101
6. 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 1-2, 4, 9-10, 13, 17 and 19-22 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a natural phenomenon / naturally occurring product without significantly more. The judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Applicant’s attention is directed to MPEP 2106 “Patent Subject Matter Eligibility” and particularly 2106.04(b)II and 2106.04(c) “Examples of Products Lacking Markedly Different Characteristics.”
Regarding Step 1 of the analysis, the claims are directed to the statutory category of a product.
Regarding Step 2A, prong one, the claims recite the judicial exception of a natural phenomenon – i.e., a naturally occurring product.
Pursuant to the Supreme Court decision in Association for Molecular Pathology v. Myriad Genetics, Inc. (June 2013), a naturally-occurring nucleic acid or fragment thereof, whether isolated or not, is not patent-eligible subject matter. Specifically, the Supreme Court held that “a naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated.”
In the present situation, the claims recite primers and probes comprising naturally occurring nucleic acid sequences of influenza A (flu A), influenza B (flu B), Respiratory Syncytial Virus (RSV) A and RSV B. Claim 13 also recites amplicons that comprise naturally occurring nucleic acid sequences. Naturally occurring nucleic acid segments do not have markedly different characteristics from their naturally occurring counterparts because the nucleic acid segments convey the same genetic information.
While claims 1, 2, 4, 9, 10, 13, 17 and 22 have been amended to recite that the probe comprises a detectable label, this recitation does not distinguish the claimed nucleic acids over their naturally occurring counterparts. Regarding detectable labels, the specification (para [0024]) states “(t)he terms “label” or “detectable label” are used interchangeably herein and refer to one or more atoms that can be specifically detected to indicate the presence of a substance to which the one or more atoms is attached.” As broadly recited, the claims encompass detectable labels that are nucleotides or fragments of nucleic acids. The nucleotides present in nucleic acids are detectable, e.g., using 260nm UV light or via their binding properties, and thereby nucleotides and nucleic acid fragments are considered to be “detectable moieties.” Thereby, the claims read on probes having any number of additional nucleotides present adjacent to the recited sequences, which additional nucleotides are part of the naturally occurring Flu A, Flu B, RSV A and RSV B nucleic acids.
Additionally, dependent claim 10 recites that the reaction mixture further comprises the naturally occurring products of reverse transcriptase, a DNA polymerase, a buffer, and dNTPs. These naturally occurring products that do not have any markedly different structural properties as compared to their naturally occurring counterparts.
Regarding claim 4, this claim recites “wherein one or more of the primers in one or more of the primer pairs further comprises a primer upstream region having a nucleotide sequence that is not complementary to the primer' s target nucleotide sequence.” However, the claim does not define the target nucleotide sequence and does not limit what is encompassed by complementary. The claim encompasses primers that contain naturally occurring flanking sequences that are not 100% complementary to another unspecified strain of Flu A, Flu B, RSV A and/or RSV B. The claim does not require that a heterologous sequence upstream of the target hybridizing sequence.
Regarding the recitation of kits, the packaging of the natural products in a kit does not change their characteristics. The products may exist separately from one another and need not interact with one another in a manner which would change their characteristics from their natural counterparts.
Further, regarding kits per se, MPEP 2106.04(c)IA states “Where the claim is to a nature-based product in combination with non-nature based elements (e.g., a claim to "a yogurt starter kit comprising Lactobacillus in a container with instructions for culturing Lactobacillus with milk to produce yogurt"), the markedly different characteristics analysis should be applied only to the nature-based product limitation.”
Thereby, herein the markedly different characteristics analysis is applied to the nature-based product limitations.
Claim 17 recites that “the two or more primer pairs are suitable for use with an automated system.” However, neither the specification nor the claim provides a limiting definition of primers that are suitable for use with an automated system. The recited naturally occurring nucleic acid fragments / primers are considered to have the attribute that they would be suitable for use with an automated system. Accordingly, the claim does not recite any limitations regarding the structure of the primers which would distinguish the primers over naturally occurring nucleic acids.
Regarding Step 2A, prong two, having determined that the claims recite a judicial exception, it is then determined whether the claims recite additional elements that integrate the judicial exception into a practical application.
Herein, the claims do not recite additional elements that integrate the recited judicial exceptions into a practical application of the exception(s).
Regarding Step 2B, the next question is whether the remaining elements – i.e., the non-patent-ineligible elements - either in isolation or combination, amount to significantly more than the judicial exception.
As discussed above, the reagents in the kit are the judicial exception of natural products and thereby not something in addition to the recited judicial exception.
Regarding the recitation of a kit, in the absence of any recitation in the claims or any direction in the specification to the contrary, the recitation of kit reads on component parts capable of being assembled or a plurality of elements grouped together as a kit. Accordingly, the word “kit” does not impart any additional special structural or functional features.
To any extent that the term “kit” is intended to encompass a box or other container, boxes and containers used to package laboratory reagents were well-known, routine and conventional in the prior art. For example, Ahern, H. (The Scientist. July 1995. 9(15): 20-25; see, e.g., p. 22) discloses the conventionality of kits for performing detection methods and discloses that kits provide the advantage of pre-assembling the specific reagents required to perform an assay and ensure the quality and compatibility of the reagents to be used in the assay.
Thereby, the kit (box or container) does not add something significantly more to the recited judicial exceptions.
For the reasons set forth above, the claims are not considered to recite something significantly different than a judicial exception and thereby are not directed to patent eligible subject matter.Response to Remarks:
The response states:
“Applicant has amended claims 1 and 13 to incorporate elements of claims 3 and 5, respectively. Applicant notes that claim 5 was not included in the rejection.”
This argument and the amendment to claims 1 and 13 have been fully considered but do not obviate the rejection. Claim 5 recites “each probe molecule species comprises a detectable label selected from the group consisting of: a chemiluminescent moiety, a fluorophore moiety, a quencher moiety, and both a fluorophore moiety and a quencher moiety.” This limitation was not added to claims 1 and 13. Rather, claims 1 and 13 were amended to recite that the probes comprise a (i.e., any) detectable label. For the reasons set forth in the above rejection, the broad recitation of “detectable label” (see para [0024 of the specification for the definition of “detectable label”) does not distinguish the claimed probes over their naturally occurring nucleic acid counterparts.
The rejection is maintained.
Maintained / Modified Claim Rejections - 35 USC § 112(d) / Fourth paragraph
7. 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 10 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 10 recites a “reaction mixture comprising the two or more combinations of claim 1.” However, claim 3 is drawn to a “kit for analysis of two or more of Influenza A (Flu A), Influenza B (Flu B), Respiratory Syncytial Virus A (RSV A), and/or Respiratory Syncytial Virus B (RSV B) that may be present in a biological sample.” Claim 1 is not limited to only combinations of two or more primers and probes per se. Thus, claim 10 does not include all of the limitations of claim 1 from which it depend.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Response to Remarks:
The response states “The Rejection is moot in view of the amendments to the claim.”
However, the amendment does not obviate the rejection because claim 10 as amended still does not include all of the limitations of claim 1, from which it depends. Claim 1 is drawn to a kit comprising two or more combinations of primer pairs and probe molecule species. Claim 1 is not limited to “two or more combinations” per se or two or more combinations of primer pairs and probes.
Maintained / Modified Claim Rejections - 35 USC § 103
8. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-2, 5-10, 13 and 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al (U.S. 20090181360) in view of NCBI Database (GenBank Accession No. AY581980, 2004, National Library of Medicine, NIH, available via URL: <ncbi.nlm.nih.gov/nuccore/AY581980>), Baptista (U.S. 20080003565), Rowlen et al (WO 2008086094) and Sigma-Aldrich (qPCR Technical Guide. 2008 Available via url: <gene-quantification.com/SIAL-qPCR-Technical-Guide.pdf>), Shirato et al (J Virological Methods. 2007. 139: 78-84) and NCBI Database (GenBank Accession No. AF013254, 30 September 1999, National Library of Medicine, NIH, available via URL: <ncbi.nlm.nih.gov/nuccore/AF013254>).
Chen teaches methods, compositions and kits for detecting human Influenza B and RSV B, as well as human influenza A and RSV A (e.g., para [0005] and [0060]).
Regarding (c) of Claim 1 and Influenza B primers, Chen teaches primers for amplifying human Influenza B Matrix gene (M gene) sequences and probes for detecting the amplified sequences, wherein the primers and probes comprise Matrix 1 (M1) gene sequences from the Human Influenza B virus (B/Nebraska/1/01) M1 matrix (M1) protein provided at GenBank Accession No. AY581980 (SEQ ID NO:6 therein; see, e.g., para [0009-0010], [0036-0038], [0040], [0053] and [0060]).
Chen exemplifies primers for specifically amplifying Influenza B Matrix (M) gene sequences consisting of SEQ ID NO: 17, 18, and 19 therein, and a probe for detecting the amplified Influenza B nucleic acid sequences consisting of SEQ ID NO: 20 therein, preferably wherein the probe is labeled with a fluorescent moiety (e.g., para [0040] and Table 1). See also Table 2 which provides the location of primer and probe sequences complementary to the M gene for amplifying and detecting Influenza B in GenBank Accession No. AY581980.
Chen does not teach kits or reaction mixtures comprising the presently claimed first Flu B primer of SEQ ID NO: 67 and the second Flu B primer of SEQ ID NO: 68, alone or in combination with the Flu B probe of SEQ ID NO: 64.
However, Chen teaches that additional primers and probes can be readily prepared for amplifying and detecting Influenza B, which primers and probes comprise a fragment of the Influenza B Matrix gene (e.g., para [0110] and [0121]).
Chen provides guidance for the selection of additional Flu B primers and probes, and particularly states:
[0074] The skilled artisan is capable of designing and preparing primers that are appropriate for amplifying a target sequence in view of this disclosure. The length of the amplification primers for use in the present invention depends on several factors including the nucleotide sequence identity and the temperature at which these nucleic acids are hybridized or used during in vitro nucleic acid amplification. The considerations necessary to determine a preferred length for an amplification primer of a particular sequence identity are well known to the person of ordinary skill in the art.
[0075] Primers that amplify a nucleic acid molecule can be designed using, for example, a computer program such as OLIGO (Molecular Biology Insights, Inc., Cascade, Colo.). Important features when designing oligonucleotides to be used as amplification primers include, but are not limited to, an appropriate size amplification product to facilitate detection (e.g., by electrophoresis or real-time PCR), similar melting temperatures for the members of a pair of primers, and the length of each primer (i.e., the primers need to be long enough to anneal with sequence-specificity and to initiate synthesis but not so long that fidelity is reduced during oligonucleotide synthesis). Typically, oligonucleotide primers are 15 to 40 nucleotides in length.
[0076] Designing oligonucleotides to be used as hybridization probes can be performed in a manner similar to the design of primers. As with oligonucleotide primers, oligonucleotide probes usually have similar melting temperatures, and the length of each probe must be sufficient for sequence-specific hybridization to occur but not so long that fidelity is reduced during synthesis. Oligonucleotide probes are generally 15 to 60 nucleotides in length.
Chen teaches that the sequence of the gene encoding for the Flu B matrix protein was known in the prior art and Chen specifically exemplifies designing primers to the gene encoding the matrix protein present within GenBank Accession No. AY581980. GenBank Accession No. AY581980 teaches that the Matrix 1 (M1) gene is present at positions 1-747 therein. As shown in the alignments below, the nucleotide sequences of each of SEQ ID NO: 67, 68 and 64 are present within the sequence of GenBank Accession No. AY581980, as shown in the alignments below, wherein “Query” is the sequence of GenBank Accession No. AY581980 and “Sbjct” is the sequence of one of the present primers and probes:
SEQ ID NO: 67:
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192
880
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SEQ ID NO: 68:
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218
908
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SEQ ID NO: 64:
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200
866
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The prior art also teaches oligonucleotides which target / hybridize to the same region as that of present SEQ ID NO: 67, 68 and 64.
For example, Baptista teaches probes for detecting Influenza B virus and microarrays comprising these probes (e.g., para [0007-0008]; Example 9 at para [0094-0097] and the Sequence Listing).
Baptista (see abstract) states:
“The present invention relates generally to viral nucleic acid microarrays and methods of detecting and identifying Known and unknown viruses using the microarrays containing known viral nucleotide sequences. The methods can further include the sequencing of nucleic acids that hybridize to the microarrays and analysis of the hybridized sequences with existing databases, thus identifying existing or new subtypes of viruses.”
Baptista exemplifies the probe of SEQ ID NO: 7659 (“Db”) therein which comprises the full length sequence of present SEQ ID NO: 67 (Qy”):
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150
706
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Baptista also teaches the probe of SEQ ID NO: 7662 (“Db”) therein which comprises nucleotides 1-28 of the 29mer of present SEQ ID NO: 64 (Qy”):
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172
480
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Rowlen (e.g., para [0009] and Sequence Listing) also teaches probes for detecting Influenza B and particularly exemplifies the probe of SEQ ID NO: 113 (“Db”) therein which comprises the full length sequence of the inverse complement of present SEQ ID NO: 68 (“Qy”):
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154
726
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Thus, the prior art provides extensive guidance and motivation to generate additional primers to the Influenza B Matrix gene.
Regarding (e) of claim 1 and primer pairs for detecting RSV B, Chen also teaches primers for amplifying human RSV B Matrix gene (M gene) sequences and probes for detecting the amplified sequences, wherein the primers and probes comprise Matrix (M) gene sequences from the Human Respiratory Syncytial Virus B nucleotide sequence provided at GenBank Accession No. AF013254 (SEQ ID NO:11 therein; see, e.g., para [0006],[0036-0038], [0042], [0058] and [0060]).
Chen exemplifies primers for specifically amplifying RSV B Matrix (M) gene sequences consisting of SEQ ID NO: 25, 26, or 27 therein, and a probe for detecting the amplified RSV B sequences consisting of SEQ ID NO: 28 therein, preferably wherein the probe is labeled with a fluorescent moiety (e.g., para [0042] and Table 1). See also Table 2 which provides the location of primer and probe sequences complementary to the M gene for amplifying and detecting RSV B in GenBank Accession No. AF013254, as well as GenBank Accession No. NC_001781, AY353550.
Chen does not teach that the reaction mixtures or kits further comprise the presently claimed forward RSV B primer of SEQ ID NO: 100 and the reverse RSV B primer of SEQ ID NO: 115, alone or in combination with the RSV B probe of SEQ ID NO: 102.
However, Chen teaches that additional primers and probes can be readily prepared for amplifying and detecting RSV B (e.g., para [0121]).
As discussed above Chen provides extensive guidance for the selection of additional RSV B primers and probes comprising fragments of the RSV B Matrix gene, and teaches that software programs were well known for identifying fragments of known target sequences that can be used as primers (e.g., para [0074-0075]).
Chen teaches that the sequence of the gene encoding for the RSV B matrix protein was well known in the prior art and particularly discloses obtaining primers and probes which are fragments of the gene encoding the matrix protein present within GenBank Accession No. AF013254.
GenBank Accession No. AF013254 discloses that the Matrix gene is present at nucleotides 3263-4033 of the sequence disclosed therein. Each of SEQ ID NO: 100, 115 and 102 are present within the sequence of GenBank Accession No. AF013254, as shown in the alignments below, wherein “Query” is the sequence of GenBank Accession No. AF013254 and “Sbjct” is the sequence of one of the present primers and probes:
SEQ ID NO: 100:
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232
822
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Note that present SEQ ID NO: 100 includes a Y at position 12 and thereby includes either a “T” (as present in AF013254) or a C.
SEQ ID NO: 115:
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232
860
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SEQ ID NO: 102:
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224
788
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Thus, Chen provides the guidance, direction and motivation to generate additional primers and probes to the Influenza B Matrix gene comprising a fragment of the nucleotide sequence of the Matrix gene present at nucleotides 3263-4033 in GenBank Accession No. AF013254.
Additionally, Shirato teaches methods for designing primers to amplify and detect RSV B and to distinguish between RSV B nucleic acids and RSV A nucleic acids wherein the primers comprise fragments of the nucleotide sequence of the Matrix gene of RSV B (section “2.3” at p. 79; Table 1 and Fig. 1). Shirato provides an alignment of Matrix gene sequences from RSV B and RSV A, which includes the RSV B Matrix gene sequence of GenBank Accession No. AF013254. The alignment clearly identifies sequences of the Matrix gene of RSV B which are conserved between strains and sequences which differ between RSV B and RSV A. As shown in Fig. 1 of Shirato, present SEQ ID NO :100, SEQ ID NO: 102 (inverse complement) and SEQ ID NO: 115 are present in the conserved RSV B sequences (see the sequences with the solid underlines at lines beginning at nucleotides 3314, 3374 and 3434 of GenBank Accession Nol AF013254):
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648
698
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Moreover, the prior art provides extensive guidance, direction and motivation to select primers to amplify known target nucleic acids and probes to detect amplified nucleic acids.
For example, Sigma-Aldrich provides a review of the parameters which effect PCR sensitivity and specificity and discloses the parameters for the design of optimal PCR primer and probe sequences to be used in quantitative RT-PCR (e.g., p. 10). The reference teaches optimizing the primers selected for multiplex reactions in particular, and provides guidance for performing routine assays that may be performed to ensure the optimal design and performance of primers and probes (e.g., p. 17, and p. 25-26). It is further disclosed that software programs are available to assist with primer and probe selection (e.g., p. 11 and 18). Sigma-Aldrich also teaches using primers and probes to detect viruses in clinical samples (e.g., p. 1 p. 7, col. 2; p. 8, col. 1). For instance, it is stated that “For instance, qPCR can be used to measure viral load or bacterial pathogens in a clinical sample, to verify microarray data, for allelic discrimination or to determine RNA (via cDNA) copy numbers.”
Designing primers and probes to amplify and detect specific target nucleic acids identified in the prior art (including reverse complements), which are equivalents to those taught in the art was well-known in the prior art, as exemplified by the teachings of Chen, and requires only routine experimentation. The prior art teaches the parameters and objectives involved in the selection of oligonucleotides that function as primers and probes (see Sigma-Aldrich and Chen). The prior art is replete with guidance and information necessary to permit the ordinary artisan in the field of nucleic acid detection to design primers and probes to sequences identified in the prior art. As discussed above, the ordinary artisan would have been motivated to have designed and tested new primers and probes that function to amplify and detect Influenza B in view of the teachings of Chen.
For the reasons provided above, the ordinary artisan would have been motivated to have designed additional primers and probes and would have had more than a reasonable expectation of success of designing additional primers for Influenza B, including the primers comprising or consisting of present SEQ ID NO: 67 and 68 and the probe of SEQ ID NO: 64 and for RSV B, including primers comprising SEQ ID NO: 100 and 115, as well as probes comprising SEQ ID NO: 102.
Further, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have included the Influenza B primers of SEQ ID NO: 67 and 68 and the probe of SEQ ID NO: 64 and the RSV B primers comprising SEQ ID NO: 100 and 115 and the RSV B prove comprising SEQ ID NO: 102 in a reaction mixture or to have packaged the primers and probes into a kit for the advantage that the primers and probes could be used in amplification reactions to assay for Influenza B and RSV B nucleic acids in test samples.
Regarding the recitation in the amended claims that the probes comprise “detectable labels” and regarding claims 5-8, Chen teaches that the probes for detecting Influenza B and RSV B are differentially labeled so that they can be distinguished from one another and particularly teaches labelling the probes with a fluorescent moiety and quencher - i.e., a donor/acceptor label pair (e.g., para [0030-0032] and [0042]).
Regarding claim 9, Chen teaches that the probes can be up to 60 nucleotides in length (e.g., para [0076]), which is within the range recited in the present claims of up to about 100 bases in length.
Regarding claims 10, Chen further teaches that the reaction mixtures containing the primers also contain all of the reagents for performing the amplification assays, including reverse transcriptase, DNA polymerase, buffer and dNTPs (e.g., para [0082] and [0126], and [0127] / Table 3).
Regarding claim 13, modification of the compositions of Chen as set forth above would have resulted in compositions wherein the first Flu B primer comprises a nucleic acid sequence consisting of the nucleic acid sequence of SEQ ID NO:67, the second Flu B primer comprises a nucleic acid sequence consisting of the nucleic acid sequence of SEQ ID NO:68, and the Flu B probe comprises the nucleic acid sequence of SEQ ID NO: 64, and the first RSV B primer comprises the nucleic acid sequence of SEQ ID NO: 100, the second RSV B primer comprises the nucleic acid sequence of SEQ ID NO: 115, and the RSV probe comprises the nucleic acid sequence of SEQ ID NO: 102. Following amplification with Flu B primers and RSV B primers, the compositions would have included Flu B and RSV B amplicons generated using the first and second Flu B and RSV B primers.
Regarding claim 17, modification of the kits of Chen would have resulted in primer pairs comprising Flu B primers comprising SEQ ID NO: 67 and 68 and RSV B primers comprising SEQ ID NO: 100 and 115. It is considered to be a property of these primers that they would be suitable for use with an automated system. Note that claim 17 does not recite any structural features for primers which would be required for the primers to be suitable for use with an automated system and thereby does not recite any structural features for the claimed primers which distinguish the primers over those suggested by the combined prior art.9. Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Chen et al (U.S. 20090181360) in view of NCBI Database (GenBank Accession No. AY581980, 2004, National Library of Medicine, NIH, available via URL: <ncbi.nlm.nih.gov/nuccore/AY581980>), Baptista (U.S. 20080003565), Rowlen et al (WO 2008086094) and Sigma-Aldrich (qPCR Technical Guide. 2008 Available via url: <gene-quantification.com/SIAL-qPCR-Technical-Guide.pdf>), Shirato et al (J Virological Methods. 2007. 139: 78-84) and NCBI Database (GenBank Accession No. AF013254, 30 September 1999, National Library of Medicine, NIH, available via URL: <ncbi.nlm.nih.gov/nuccore/AF013254>), and further in view of Mullis et al (U.S. Patent No. 4,683,202; cited in the IDS).
The teachings of Chen, NCBI Database GenBank Accession No. AY581980 and GenBank Accession No. AF013254, Baptista, Rowlen, Sigma-Aldrich and Shirato are presented above.
The combined references do not teach that the primers include a 5’ sequence that is not complementary to the Flu B and RSV B target nucleic acids.
However, Mullis teaches methods for amplifying target nucleic acids. It is stated that:
“In addition, the primer can contain as part of its sequence a non-complementary sequence provided that a sufficient amount of the primer contains a sequence which is complementary to the strand to be amplified. For example, a nucleotide sequence which is not complementary to the template sequence (such as, e.g., a promoter, linker, coding sequence, etc.) may be attached at the 5' end of one or both of the primers, and thereby appended to the product of the amplification process. After the extension primer is added, sufficient cycles are run to achieve the desired amount of new template containing the non-complementary nucleotide insert.” (col. 13, lines 27-41).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the kits of Chen so as to have included in the primers a 5’ / upstream sequence that was not complementary to the target Flu B and RSV B nucleic acids so as to have facilitated including such a sequence in the amplification products, such that the additional 5’ / upstream sequence could be used to clone detected amplification products or otherwise modify the amplification products for further processing.
Response to remarks regarding the rejections under 35 U.S.C. 103:
In the reply of 02/26/2026, Applicant traversed the rejections under 35 U.S.C. 103.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Note that the rejections are based on what the references, when considered in combination would have suggested to one of ordinary skill in the art and not what the individual references teach in isolation.
The response states:
“Baptista does not teach SEQ ID NO:7659 as a region of the Flu B matrix gene which is useful for designing primers to amplify Flu B” and asserts that primers and probes have different properties.”
This argument has been fully considered but is not persuasive because the rejection is not based on a premise of using the probe of Baptista as a primer. Rather Baptista was cited for identifying regions within the influenza B Matrix gene, including a region which comprises present SEQ ID NO: 67 and a region comprising nucleotides 1-28 of the 29 mer of SEQ ID NO: 64, which can be targeted for detecting influenza B. Chen was cited as the primary reference and teaches primers for amplifying and detecting influenza B and for its teachings that additional primers and probes can be readily prepared for amplifying and detecting Influenza B, which primers and probes comprise a fragment of the Influenza B Matrix gene (e.g., para [0110] and [0121]).
The response states:
“Rowlen teaches probes for use in microarrays. The Examiner has failed to provide any evidence that one of ordinary skill in the art would look to modify a microarray probe for use as an amplification primer.”
These arguments are not persuasive because they are not directed to the rejection at hand. The rejection did not assert that one of ordinary skill in the art would use the probe of Rowlen as a primer. Rowlen was cited for its teachings of targeting the influenza B Matrix gene and a particular region therein that overlaps with the present primer of SEQ ID NO: 68 to detect Influenza B. Chen was cited as the primary reference and teaches primers for amplifying and detecting influenza B and for its teachings that additional primers and probes can be readily prepared for amplifying and detecting Influenza B, which primers and probes comprise a fragment of the Influenza B Matrix gene (e.g., para [0110] and [0121]).
The response states:
“Shirato also explicitly teaches primers that distinguish between RSV A and RSV B. Notably, the primers that Shirato teach as distinguishing between RSV A and RSV B are not the sequences claimed by the Applicant.” It is argued that “one skilled in the art would use the primers taught by Shirato and would not be motivated to search for other primers.”
These arguments have also been fully considered but are not persuasive. As discussed in the rejection, it was conventional in the prior art to design additional primers and pairs to a region that has been identified as useful for the detection of a virus and distinguishing that virus from other viruses. For instance, Chen (para [0121]) states “it would be possible for the skilled artisan to alter the parameters for the detection of additional target nucleic acids or use alternate probe/primer designs to the ones shown herein.”
The response argues that Sigma-Aldrich doesn’t specifically provide guidance as to how to select the particularly claimed primers for FluB and RSV B. It is stated that:
“the Sigma- Aldrich guidance on multiplex reactions concerns optimizing amplification conditions and not primer sequence selection. The guidance provided by Sigma-Aldrich might be useful in optimizing previously selected sequences for used in a multiplex assay, but none of the suggestions provided by Sigma-Aldrich provides any direction on selecting primer sequences that will specifically detect multiple species of RSV B without detecting other species and do so in a multiplex assay. “
These arguments are not persuasive. Again, the rejection is not based on the isolated teachings of Sigma-Aldrich, but on the combination of teachings. When considered as a whole, the prior art teaches the sequences of Flu B and RSV B Matrix gene, identifies particular sequences within these genes that can be targeted to develop additional oligonucleotides for the detection of Flu B and RSV B, and provides extensive guidance, including well-known software programs for designing primers and probes to known target regions. Accordingly, it is maintained that the ordinary artisan would have been motivated to have designed additional primers and probes and would have had more than a reasonable expectation of success of designing additional primers for Influenza B, including the primers comprising or consisting of present SEQ ID NO: 67 and 68 and the probe of SEQ ID NO: 64 and for RSV B, including primers comprising SEQ ID NO: 100 and 115, as well as probes comprising SEQ ID NO: 102.
Regarding the arguments pertaining to multiplex assays, it is noted that the present claims are not drawn to multiplex assays. The claims are drawn to kits and compositions in which the primers and probes may be separately packaged. Only claim 10 relates to a mixture and this claim improperly depends from claim 1 which is drawn to a kit. None of the claims clearly requires a single reaction mixture comprising each of the primers and probes, as would be required for use in a multiplex amplification assay.
The response argues:
“The Examiner merely speculates that such programs might identify Applicant's claims primers and has provided no evidence that the unnamed programs will identify Applicant's claimed primers. Chen and Shirato-having had access to programs "available to assist with primer and probe selection" (including OLIGO and PrimerExplorer)-failed to teach or suggest Applicant's claimed primers.”
However, the fact that the combined references did not teach primers and probes identical to those claimed does not render the claimed primers and probes unobvious. The rejection was not made under 35 U.S.C. 102 and is based on what the combination of prior art, when considered as a whole, would have suggested to the ordinary artisan, absent evidence to the contrary. Note that Applicant has not established any unexpected results for the broadly claimed primers and probes which comprise the recited sequences flanked by additional nucleotides of any identity (and of any length for the primers).
The response states that Appendix 1 shows that the software program Primer3Plus did not identify the primers of SEQ ID NOs:67 and 68 or SEQ ID NOs: 99, 100-101, 104 and 115 for the detection of GenBank AY581980 and AF013254. It is asserted that “(t)wo additional programs-Primer-BLAST and Eurofins PCR Primer Design also failed to identify Applicants claimed primers.”
However, Applicant’s arguments pertaining to the software programs and Appendix 1 are not provided in declaratory form. See MPEP 716.01(c) “Arguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984).” The reason for requiring evidence in declaration or affidavit form is to obtain the assurances that any statements or representations made are correct, as provided by 35 U.S.C. 25 and 18 U.S.C. 1001. Note that this should not be construed as an invitation for providing a declaration or affidavits. See MPEP 716.01 regarding the timeliness of filing declarations/affidavits.
Additionally, the information in Appendix 1 is not clear. Appendix 1 refers to yellow, green and green/yellow alternating sequences (as well as pink and blue sequences at p. 10). However, the information provided is in black and white text. Also, it appears that Applicant limited the length of the primers to be identified to 20 nucleotides, whereas each of the presently claimed primers is of a length greater than 20 nucleotides. For example, the forward Flu B primer of SEQ ID NO: 67 is 23 nucleotides in length and the reverse Flu B primer of SEQ ID NO: 68 is 26 nucleotides in length. Also, the claims encompass primers of any length that comprise the 23 nucleotides of SEQ ID NO: 67 or the 26 nucleotides of SEQ ID NO: 68. It is not clear from the information provided that the search that was conducted would have fairly identified a primer comprising the longer length primers of SEQ ID NO: 67 and 68.
The rejections under 35 U.S.C. 103 are maintained for the reasons set forth above.
Conclusion
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 CARLA J MYERS whose telephone number is (571)272-0747. The examiner can normally be reached M-Th 6:30-5:00 EST.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682
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