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 25 September 2025 . Applicant's arguments and amendments to the claims have been fully considered but do not place the application in condition for allowance. All rejections not reiterated herein are hereby withdrawn.
Claim Status
3. Claims 1-4, 7-8, and 11-22 are pending.
Claims 11, 12, 14 and 15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 8 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1-4, 7, 13 and 16-22 read on the elected invention and have been examined herein. The claims have been examined only to the extent that they read on the elected species of the first RSV primer of SEQ ID NO: 100, the second RSV primer of SEQ ID NO: 115 and the RSV probe of SEQ ID NO: 102 The claims encompass non-elected species of primers and probes. 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.
Maintained / Modified Claim Rejections - 35 USC § 101
4. 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, 16 and 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 comprising naturally occurring nucleic acid sequences of RSV B virus. 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.
Regarding claim 2, this claim recites “wherein the first and/or second RSV B primer comprises a primer upstream region having a nucleotide sequence that is not complementary to a sequence present in the RSV B target nucleotide sequence.” However, claim does not define the RSV B target nucleotide sequence and does not limit what is encompassed by complementary. Claim 2 encompasses primers that contain naturally occurring flanking sequences that are not 100% complementary to another unspecified strain of RSV B. The claims do not require that a heterologous sequence is present upstream of the target hybridizing sequence.
New claim 22 recites that the reaction mixture further comprises one or more of a reverse transcriptase, DNA polymerase, buffer, and dNTPs. Reverse transcriptase, DNA polymerase, buffer, and dNTPs are naturally occurring products. The claim does not recite any structural properties or other attributes of these products to establish that the products have any markedly different structural properties as compared to their naturally occurring counterparts. To any extent that the reaction mixture is intended to encompass a single solution comprising the primers and one or more of the reverse transcriptase, DNA polymerase, buffer, and dNTPs, the presence of these components together does not alter the characteristics of the other components because the components need not interact with one another. For example, there is no requirement that the mixture is under conditions that cause primer extension of the primers by the DNA polymerase or reverse transcriptase.
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.
Moreover, it is noted that the claims as amended include the non-naturally occurring products of the RSV B probes recited in claims 1 and 16. However, the non-naturally occurring probes in the kit or reaction mixture does not have a functional relationship with or otherwise modify the primers (or other reagents) in the kit or reaction mixture.
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.
Regarding the probes of claims 1 and 16, the probes are recited at a high level of generality. The RSV B probes as broadly recited were well-known, routine and conventional in the prior art and do not add something significantly more to the recited kits and reaction mixtures. The specification (par [0012] states “Two nucleic acid sequences are “sufficiently complementary” when, their respective contiguous nucleic acid sequences are at least 70% complementary.” However, the claims do not define the amplicon in terms of a particular sequence. Nor do the claims define the amplicon in terms of the conditions under which they are produced. Under low stringency conditions, the primers “comprising” the recited sequences (and thereby having any number of nucleotides of any identity at their 3’ and 5’ ends) can amplify a broad genus of sequences and the probe is required to only be “substantially complementary” - e.g., have 70% complementarity with the unspecified amplicon. Further, probes for RSV B labeled with a chemiluminescent moiety, a fluorophore moiety, a quencher moiety, and both a fluorophore moiety and a quencher moiety were well-known, routine and conventional in the prior art. See, for example, Chen et al discussed in detail below. Note that the specification states at para [0024] “Labels and related detections methods are well known (see e.g., U.S. Pat. No. 6,627,748 (B1); Styer and Haugland, (1967), Proc. Natl. Acad. Sci. U.S.A. 98:719; U.S. Pat. Nos. 5,591,578; 5,491,063; 5,201,015).” See also paragraph [0025] regarding labels). Thus, the broadly recited probes do not add something significantly more to the recited judicial exception.
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 that claim 1 has been amended to recite that the kit comprises a probe linked to a chemiluminescent moiety, a fluorophore moiety, a quencher moiety, and both a fluorophore moiety and a quencher moiety. The response points to Example 7 of the USPTO’s guidance on Nature-based products in which it was determined that an isolated nucleic acid comprising a fluorescent label is not a product of nature. Applicant concludes that the present claim is also not directed to a product of nature.
This argument and the amendment to claim 1 have been fully considered but are not persuasive. Claim 1 has been amended to recite “an RSV B probe molecule species that is substantially complementary to a sequence in the RSV B amplicon, wherein the RSV B probe molecule species is linked to a chemiluminescent moiety, a fluorophore moiety, a quencher moiety, and both a fluorophore moiety and a quencher moiety.” It is acknowledged that the RSV probe comprising one of the recited labels is not a product of nature. However, the presence of this non-nature based product in the kit does not render the claimed kit patent-eligible.
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.”
Herein, the claim recites the naturally occurring products of the RSV B primers. The presence of the non-naturally occurring products of the RSV B probes in the kit does not modify the primers (or other reagents) in the kit or reaction mixture. In a kit, the primers and probes may be packaged separately. No interaction need occur between the probe and primers so as to change the structural attributes of the primers in a manner which materially distinguishes the primers over their naturally occurring counterparts. With respect to the reaction mixture of claim 16, the claim does not require that the primer and probe are present under any particular conditions which cause the primer and probe to interact in a manner which alters the primers such that the primers have a markedly different characteristic as compared to their naturally occurring counterpart.
Modified Claim Rejections - 35 USC § 103
5. 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, 3, 4, 7, 13, 16, 17, and 22 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. AF013254, 30 September 1999, National Library of Medicine, NIH, available via URL: <ncbi.nlm.nih.gov/nuccore/AF013254>), and Sigma-Aldrich (qPCR Technical Guide. 2008 Available via url: <gene-quantification.com/SIAL-qPCR-Technical-Guide.pdf>).
Chen teaches methods, compositions and kits for detecting human RSV B, as well as human RSV A, and influenza A and influenza B (e.g., para [0060]).
Chen 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 [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 teaches that the probes are labeled with a fluorescent moiety or both a fluorescent moiety and quencher (e.g., para [0030-0032] and [0042]).
Chen does not teach reaction mixtures or kits comprising 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]).
Chen provides guidance for the selection of additional RSV 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 RSV B matrix protein was well known in the prior art and Chen specifically exemplifies designing primers to the gene encoding the matrix protein present within GenBank Accession No. AF013254. Each of present 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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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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SEQ ID NO: 102:
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Moreover, the prior art provides extensive guidance, direction and motivation to select primers to amplify 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 RSV 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 RSV B, including the primers comprising or consisting of present SEQ ID NO: 100 and 115 and the probe of 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 primers of SEQ ID NO: 100 and 115 and the probe of SEQ ID NO: 102 in a reaction mixture or kit for the advantage that the primers and probe could be used in amplification reactions to assay for RSV B nucleic acids in test samples.
Regarding claims 3 and 4, Chen teaches that the probes can be up to 60 nucleotides in length (e.g., para [0076]).
Regarding claim 7, Chen teaches that the primers can be peptide nucleic acid primers, locked nucleic acid primers, or phosphorothioate modified primers (e.g., para [0029]) and thereby the primers can include a nucleotide analogue.
Regarding claim 13, the use of the modified compositions of Chen as set forth above in an amplification assay in which a target RSV B nucleic acids were present would have resulted in a composition comprising a first RSV B primer comprising SEQ ID NO: 100, a second RSV B primer comprising SEQ ID NO: 115, an RSV B probe comprising SEQ ID NO: 102, and an amplicon comprising RSV B sequences amplified by the first and second RSV B primers.
Regarding claim 22, Chen further teaches that the reaction mixtures containing the primers also contain reagents for performing the amplification assays, including DNA polymerase and dNTPs (e.g., para [0082] and [0126], and [0127] / Table 3).
6. Claim 2 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. AF013254, (30 September 1999, National Library of Medicine, NIH, available via URL: <ncbi.nlm.nih.gov/nuccore/AF013254>), and Sigma-Aldrich (qPCR Technical Guide. 2008 Available via url: <gene-quantification.com/SIAL-qPCR-Technical-Guide.pdf>), and further in view of Mullis et al (U.S. Patent No. 4,683,202).
The teachings of Chen, NCBI Database GenBank Accession No. AF013254 and Sigma-Aldrich are presented above.
The combined references do not teach that the primers include a 5’ sequence that is not complementary to the RSV B target nucleic acid.
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 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.
7. Claim(s) 18 and 19 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. AF013254, 30 September 1999, National Library of Medicine, NIH, available via URL: <ncbi.nlm.nih.gov/nuccore/AF013254>), and Sigma-Aldrich (qPCR Technical Guide. 2008 Available via url: <gene-quantification.com/SIAL-qPCR-Technical-Guide.pdf>), and further in view of Thermo Fisher Scientific (“Thermo Scientific Modified Nucleoside Phosphoramidites,” 2007. 2 pages, available via URL: <assets.thermofisher.com/TFS-Assets/LSG/brochures/Modified-Nucleoside-Phosphoramidites.pdf>) and Shafer, D. (U.S. 20040053275).
The teachings of Chen, NCBI Database GenBank Accession No. AF013254 and Sigma-Aldrich are presented above.
In particular, Chen teaches that the primers can be phosphorothioate modified primers (e.g., para [0029]), and thereby the primers may include nucleotide analogues. Chen does not teach that the primers or the primers and probes each include the nucleotide analogue of 5-me-dC.
However, Thermo Fisher Scientific teaches oligonucleotides for use as probes or primers that incorporate 5-Methyl dC (i.e., 5-Me-dC; see p. 1). It is disclosed that the stability and melting temperature of oligonucleotide duplexes can be improved by the incorporation of 5-Methyl dC into oligonucleotide primers and probes (p. 1).
Further, Shafer (para [0216]) teaches that incorporation of 5-Me-dC into oligonucleotides “can significantly raise melt temperature (Tm) by several degrees, and can diminish non-specific binding of these components.”
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 primers and probes of Chen so as to have incorporated the nucleotide analog of 5-Methyl dC into the primers and probes in order to have increased the melting temperature of the primers and probes and the stability of duplexes formed with the primers and probes, thereby improving the specificity of binding of the primers and probes in amplification and detection assays.
10. Claims 20 and 21 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. AF013254, 30 September 1999, National Library of Medicine, NIH, available via URL: <ncbi.nlm.nih.gov/nuccore/AF013254>)and Sigma-Aldrich (qPCR Technical Guide. 2008 Available via url: <gene-quantification.com/SIAL-qPCR-Technical-Guide.pdf>), and further in view of Shen et al (U.S. Patent No. 5834254).
The teachings of Chen, NCBI Database GenBank Accession No. AF013254 and Sigma-Aldrich are presented above.
The combined references do not teach that one or more of the primers or probes are in a lyophilized form and that the kit includes a salt as a rehydration reagent.
However, Shen teaches providing the reagents used to perform amplification assays in lyophilized form, including the reagents of primers and reverse transcriptase (e.g., Example 6 at col. 21 lines 1-26). Shen (col. 7, lines 31-55) discloses:
“the present invention comprises a component of a kit for the amplification and specific identification of nucleic acids belonging to one or more phylogenetic groupings of organisms, for example for the specific detection of one or more species within a genus or one or more genera within a family. The invention provides a reconstitutable dried formulation comprising a reverse transcriptase, an RNA polymerase, ribonucleotide triphosphates, deoxyribonucleotide triphosphates, zinc and/or magnesium salts, and a reducing agent in a single container. Amplification primers and an aqueous reconstitution solution may be supplied as one or more additional separate components of the kit. Alternatively, amplification primers may be comprised in the dried formulation. Target sequence-specific nucleic acid hybridization assay probes and any desired unlabeled helper oligonucleotides may be included in the dried formulation or provided in a separate reagent. Upon reconstitution of the dried formulation and addition of the oligonucleotide primers (if not already present), the mixture is contacted with a partially or wholly single-stranded target nucleic acid. If the target nucleic acid has nucleotide sequences complementary to the primer(s) (or the primer portion of a promoter-primer(s)), the reaction will proceed upon incubation of the reaction mixture at a temperature sufficient for nucleic acid amplification.”
Shen (col. 3, lines 41-59) further states:
“A method of storing and shipping reverse transcriptase and RNA polymerase without the need for refrigeration would obviate the necessity for refrigerated transport and/or methods of cold storage such as dry ice, wet packs, dry packs, or styrofoam shipping containers. Such methods would also be more cost effective, since the production overhead associated with these methods of maintaining enzyme activity would be unnecessary. Methods of storing enzymes which would allow the enzyme preparation to tolerate a limited exposure to higher temperatures would eliminate the losses in enzyme activity which could result if the enzyme preparation sits on a loading dock or in a truck during shipment. Such a method would have to be highly reproducible. Moreover, if the enzymes could be provided in a single container in a form compatible with their intended use (such as in a formulation containing all or most of any necessary co-factors and substrates) such a preparation would be more economical to manufacture and more convenient to use.”
Shen teaches that the reconstitution buffer comprises MgCl2 (e.g., col. 10, lines 9-15).
In view of the teachings of Shen, 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 provided one or more of the primers or probe, in a lyophilized form in the kit, as well as to have included the salt of magnesium chloride for rehydrating the amplification reagents. One would have been motivated to have done so to achieve the advantages set forth by Shen of providing an economical and convenient means for performing amplification reactions, and obviating the need for refrigerated transport and cold storage of the amplification reagents.Response to remarks regarding the rejections under 35 U.S.C. 103:
The response states that Genbank Accession No. AF013254 disclosed the complete 15225 nucleotide sequence of the RSV B virus. It is asserted that “the number of possible primer combinations for a pair of 20-nucleotide primers that bind to AF013254 and produce an amplicon 50-150 nucleotides in length is more than 1.5 million.”
This argument has been fully considered but is not persuasive because it does not address the rejection of record. All teachings in Chen et al are limited to primers and probes that target / hybridize to the gene encoding the matrix protein. Genbank Accession No. AF013254 clearly identifies the gene encoding the matrix protein of RSV B as occurring at nucleotides 3263-4033:
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Applicant argues that even if the skilled artisan was motivated to limit the RSV B target sequence to the B gene, there would be more than 69,000 primers of 15-40 nucleotides in length. Applicant notes that the Office action cited para [0121] of Chen and concludes that “one skilled in the art would not be motivated to limit the target nucleic acid to the M gene of RSV B. “
These arguments have been fully considered but are not persuasive. Applicant’s rationale for this opinion is not understood. Again, all teachings of Chen are limited to primers and probes that target the gene encoding the matrix protein. Chen provides several GenBank accession numbers for the gene encoding the matrix protein from RSV B, as well as RSV A, Flu A and Flu B (Table 2 - entitled “M Gene Nucleotide Sequences from GenBank”). Chen states at para [0121] “Using methods similar to the ones described below, 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.” There is nothing in Chen which suggests that one should use any gene other than the gene encoding for the matrix protein to design additional primers and probes. The fact that the gene encoding for the matrix protein is 771 nucleotides in length would not motivate the ordinary artisan to select another gene to generate primers and probes for amplifying and detecting RSV B.
While a large number of fragments of 15-40 nucleotides are present within the gene encoding for the matrix protein, the number of possible primers and probes is constrained by the well-known parameters that are taken into consideration when designing primers and probes. Chen clearly teaches aligning the sequences of target regions and particularly the M gene sequence, and using algorithms / software “known in the art” to identify oligonucleotides specific for a target sequence (para [0023]). Further, as set forth in the rejection, Chen at para [0074-0076] teaches the parameters that are considered when selecting primers and the use of computer programs, such as OLIGO, to select primers.
Applicant argues that the teachings of Chen at para [0074-0076] are generic and Chen only teaches “that the length be between 15 and 40 nucleotides for primers and 15 to 60 nucleotides for probes.” It is stated that “The Examiner fails to show how applying any of these vague teachings of Chen would lead the skilled artisan to Applicant's claimed primers.” Regarding the Sigma-Aldrich reference, Applicant asserts that the “instruction provides no guidance for selecting primers that will specifically detect multiple species of RSV A without detecting other species. Sigma-Aldrich teaches analyzing the primers for self-complementarity. However, such guidance, while possibly eliminating some possible primer sequences from Genbank Accession No. AF013254, provides no guidance for selecting primers that will specifically detect multiple species of FLU A without detecting other species.”
These arguments have also been fully considered but are not persuasive. First it is noted that the claims are not directed to RSV A or Flu A primers. Secondly, the teachings of Chen and Sigma-Aldrich are in fact sufficiently specific to guide the ordinary artisan to additional primers to RSV B. Both references teach the use of well-known software programs to select primers to known target sequences, as well as the parameters that effect primer and probe specificity.
The response argues Sigma-Aldrich does not provide “any direction on selecting primer sequences that will specifically detect multiple species of FLU A without detecting other species and do so in a multiplex assay.”
However, the present claims are drawn to primers “comprising” sequence ID NO: 100 and SEQ ID NO: 115 and a probe “comprising” SEQ ID NO: 102. The primers and probes may have any number of additional nucleotides, of any identity, at their 3’ end and at their 5’ end. The presence of any number of nucleotides of any identity at the 3’ end and/or 5’ end of the primers will affect their specificity, as well as their ability to be used in multiplex amplification assays. Applicant has not provided any evidence to establish that the broadly claimed primers and probes have the property that they detect multiple species / strains of RSV B and do not detect any other species. Nor has Applicant provided evidence that the broadly claimed primers have the property that they can be used effectively in a multiplex amplification assay with other unspecified primers to amplify and detect RSV B.
Applicant argues that the art does “not provide a finite number of identified, predictable potential solutions. Instead, the art provided thousands of possible solutions which would have required undue experimentation to arrive at the Applicant's claimed primed.” Regarding the dependent claims, Applicant states “the art might have provided guidance for designing additional experiments to identify additional solutions, but does not provide any known potential solutions.”
These arguments have also been fully considered but are not persuasive. First, the combined prior art when considered as a whole does suggest a finite number of primers and probes which are fragments of the RSV B matrix gene sequence disclosed in Genbank Accession No. AF013254. Secondly, Applicant has not established that the primers or probes are unobvious by stating that a large number of primers or probes could be generated to the RSV B Matrix gene. Selecting particular primers from known sequence information, which, in the absence of evidence to the contrary are equivalent to those in the prior art, is not inventive. Even though a large number of primers or probes may be theoretically possible, selecting particular primers or probes from a known sequence, especially those similar to prior art primers and probes, is a matter of routine experimentation. The ordinary artisan would have had more than a reasonable expectation of success at arriving at the claimed primers and probes “comprising” SEQ ID NO: 100, 115 and 102 given the fact that the sequence of the RSV B matrix gene was known in the prior art, as was the sequence of the matrix gene from RSV A, Flu A and Flu B (see Table 2 of Chen) and the prior art teaches the parameters that affect primer and probe selection and teaches that software programs were readily available for selecting additional primers and probes.
The rejections are maintained for the reasons of record.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng (Winston) Shen can be reached on 571-272-0731. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682
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