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 .
Status of Claims
Applicant's amendment filed 08/11/2025 is acknowledged. Claims 1, 3, 9, 10, and 12 have been amended. Claims 1-12 are pending in the instant application and the subject of this final office action.
All of the amendments and arguments have been reviewed and considered. Any rejections or objections not reiterated herein have been withdrawn in light of amendments to the claims or as discussed in this office action.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Previous Rejection
Status of Prior Rejections/Objections:
The 112(b) rejections to claims 1-12 are withdrawn in view of the amendments to the claims.
The 112(d) rejections to claims 4-6 are withdrawn in view of the amendments to the claims.
The prior art rejection(s) under 35 USC 103 directed to claims 1-7 and 10-11 as being unpatentable over Fu in view of Rosati, Ruggiero, and Tong; claim 8 over Fu in view of Rosati, Ruggiero, and Tong and in further view of Livak; claim 9 over Fu in view of Rosati, Ruggiero, and Tong and in further view of Brennan; and claim 12 over Fu in view of Rosati, Ruggiero, and Tong and in further view of James@cancer are maintained.
Specification
The use of the terms Illumina® and SPRI®, which are a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trade marks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Interpretation
Regarding claim 1, as recited in the instant specifications, the term “oligo-dT” refers to a homopolymer typically consisting exclusively of thymidines (para [0015]).
Claim Rejections - 35 USC § 103
Claim(s) 1-7 and 10-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fu (WO 2016/138500 A1; published 09/01/2016) in view of Rosati (Rosati E, et al. Overview of methodologies for T-cell receptor repertoire analysis. BMC Biotechnol. 2017 Jul 10;17(1):61), Ruggiero (Ruggiero E, et al. High-resolution analysis of the human T-cell receptor repertoire. Nat Commun. 2015 Sep 1;6:8081), and Tong (Tong C, Guo B, He S. Bead-probe complex capture a couple of SINE and LINE family from genomes of two closely related species of East Asian cyprinid directly using magnetic separation. BMC Genomics. 2009 Feb 19;10:83).
Regarding claims 1 and 4-7, Fu teaches a method comprising:
mRNAs barcoded with molecular labels (MI) [i.e., molecular barcode] (instant claim 7) and sample labels (SI) during reverse transcription using either a TCR C-region reverse sequence or poly(A) tail for universal mRNA capture; and
2 multiplex PCRs are performed to enrich targets using gene-specific primers and to attach sequencing adapters (para [0057]) wherein they can be designed to target can be designed to target the V region of the VDJ combination, the D region of the VDJ combination, and/or the J region of the VDJ combination (para [0219])
wherein the forward multiplex PCR primers bind upstream of the CDR3 region in the TCR V(D)J sequence and the reverse primer of the multiplex reaction binds in the anchor region on the 5’ of the sequence added by the reverse transcription primer (Fig. 38). Fu teaches that the method is used to characterize the TCR alpha chain and beta chain (para [0287]).
Fu further teaches a generic method comprising a reverse transcription step using a first oligonucleotide comprising a universal PCR primer and a poly(dT) and a second extension step using a second oligonucleotide comprising a target-specific sequence and a universal adaptor primer (para [0029]; Fig. 10; para [0117]).
Fu also teaches the use of beads, including probe beads wherein some embodiments, the target binding region is the same for all stochastic barcodes attached to a given bead or wherein the target binding regions for the plurality of stochastic barcodes attached to a given bead may comprise two or more different target binding sequences (para [0103]). Fu likewise teaches that in any of the above-mentioned embodiments, any of the oligonucleotide may be attached to a solid support, such as a bead (para [0111]), wherein the bead may comprise a magnetic bead (para [0016]) and further teaches exemplary primers designed to bind to a C-region [i.e., constant gene region] of one or both of the alpha chain and beta chains of the TCR (para [0218];[ 0287]).
Fu teaches capturing targets on beads (e.g., Fig. 23).
Fu teaches that a sensitive method to detect mRNAs can utilize a targeted approach, especially useful when the mRNA transcript level is less abundant as the efficiency of a multiplex PCR reaction can enrich targeted regions for a higher number of sequencing reads (para [0283]). Fu further teaches that in genes that can mutate, primer design can be targeted towards regions with the least variation [i.e., the constant region of IgG] (para [0283]).
Fu further teaches that the methods may further comprise amplifying a nucleotide sequence using a pair of PCR primers, such as universal PCR primers (para [0111]) and that the PCR amplification primer or target-specific sequence [i.e., in the generic method of para [0029]] may be selected from the group consisting of a V region of a TCR alpha chain or beta chain, the junction of a V and D region of a TCR alpha chain or beta chain, or any combination thereof (para [0111]).
Fu does not specify if the oligo-dTs are intended to consist exclusively of thymidines.
Fu does not explicitly describe an embodiment in which an oligo-dT primer is used for RT followed by a multiplex primer with a forward primer located in the TCR alpha and/or beta chain V(D)J regions and a reverse primer that binds to a universal sequence added by an engineered sequence of the 5’ of the oligo-dT primer.
Fu does not explicitly teach using probe beads to capture amplicons comprising TCR alpha chain and beta chain V(D)J sequences from a multiplex amplification using a target-specific forward primer and a reverse primer that binds to a sequence on the 5’ end of the oligo-dT primer. Fu further does not teach washing the sample or eluting the amplicons from the beads.
Rosati partially rectifies the matter of probe beads by teaching three principal methodologies for TCR library preparation including multiplex PCR and target enrichment, wherein in the target enrichment RNA is first processed with a standard sequencing library preparation kit, followed by incubation of the samples with custom designed RNA baits, complementary to the sequences of interest that tolerate a few different bases compared to the target, hybridize with the cDNA target, allowing for capture of it, and submitting the captured cDNA to a further amplification step of the wanted sequence (pg. 5, Target Enrichment, spanning pg. 6). Rosati teaches that the RNA baits, after hybridizing with molecules in the library, are retrieved using magnetic beads (Fig. 2).
Rosati teaches that target enrichment requires fewer PCR cycles and thus is less susceptible to PCR bias and also teaches that alpha and beta chains can be processed together whereas the other methods may require separate processing to increase the quality of the outcome (pg. 5, Target Enrichment, spanning pg. 6).
Rosati also teaches a similar multiplex PCR approach to Fu wherein additional non-interfering multiplex primers were included, enabling the parallel study of the expression level of phenotypic traits related to T cells (pg. 8, Outlook: Single cell methods, para 1).
Ruggiero further rectifies the matter of probe beads by teaching a biotinylated primer located in the constant (C) gene of the TCR chains wherein amplicons comprising the biotinylated primers were magnetically captured on streptavidin beads (Fig. 1).
Ruggiero teaches that even small amount of cDNA processed via this method enabled reliable representation of the existing TCR repertoire diversity, including rare cells (pg. 2, Results, para 2).
Tong fully rectifies the matter of probe beads by teaching a method of attaching biotinylated probes to magnetic beads (pg. 3, B. Preparation of bead-probe complex; Fig. 2) to capture complementary DNA via hybridization, washing the hybridized sample and beads, and releasing the DNA from the beads by elution, wherein the eluted DNA is used in a PCR (pg. 3, Capture of target sequences, spanning pg. 5; Fig. 2). Tong teaches applying this method to PCR enriched DNA (pg. 3, col 2, PCR enrichment).
Tong teaches that the widely used magnetic bead-based isolation system is technically straightforward and permits isolation of a large number of targets in less time consumption and less cost and effort than is required to execute traditional protocol involving rounds of filter hybridization (pg. 12, Some aspects about the new retroposons enrichment strategy, para 1).
Regarding oligo-dT primer sequence composition, it is held to have been obvious to exclude any anchor nucleotides (e.g., N or NV) that may be used in oligo-dT primers in the art to reduce complexity and thus the cost of synthesis under MPEP 2144.04(II).
Regarding reverse transcription and the first amplification, it would have been obvious to one of ordinary skill before the effective filing date to utilize the TCR target-specific primers in the amplification with the reverse transcription using oligo-dT as taught in the two embodiments of Fu if a practitioner desired to amplify (and sequence) the constant region, transmembrane region, and/or cytoplasmic tail. The artisan would have been so motivated if performing studies interested in how SNPs in the structural regions influenced the selection of the variable regions in T-cell maturation or for studies monitoring how T-cell malignancy therapies targeting these regions caused mutations in patients to better improve therapies. Fu further teaches the motivation of designing primers directed towards regions with the least variation, wherein the multiplex PCR enables efficiently enriching for less abundant sequences. There would be a strong expectation of success as oligo-dT primers are widely used in the art for generating cDNA, the RT oligo-dT primers with universal primer sequence are provided, and the multiplex TCR-specific primers and universal primers for the subsequent amplification are provided.
Further, regarding the probe beads, in the method of Fu, it would have been obvious to one of ordinary skill before the effective filing date to utilize either or both the primers sequences for the constant region taught by Fu (instant claims 4-6) or that of Ruggiero with the biotinylation of the primer taught by Ruggiero with the method of attaching biotinylated probes to magnetic beads for DNA capture, washing, and eluting for subsequent amplification of Tong with the second amplification of Fu/subsequent amplification of Rosati, motivated by the teachings of Rosati that it is beneficial to utilize probe bead-based target enrichment in order to reduce the number of PCRs and thereby reduce PCR bias in results; of Tong that the widely known method is straightforward and cheaper/faster than other similar methods; and of Ruggerio that such a method enables reliable representation of TCR repertoire diversity. It would further be obvious to improve enrichment for the sequences of interest so as to reduce the amount of sequencing depth required to obtain adequate coverage of sequences of interest.
It would have been obvious to choose probe bead primers configured to choose only one of the TCR alpha or beta if a practitioner wished to focus their sequencing depth on a study of only one or likewise on both if simplicity of practice were, informed by Rosati that target enrichment may better allow processing a combination whereas it was recommended to separate under multiplex methods; given that this method is a hybrid of both techniques, it would be obvious that the relative advantages may depend on the objectives of the practitioner and on routine optimization of the method.
There would have been a strong expectation of success the conditions for the probe beads are taught by Tong and multiple sequences are provided as options; further, it would be well within the skill set of an ordinary artisan and within routine optimization to design alternative oligos in the regions based on design objectives and desired conditions. In addition, all are directed to means of nucleic acid enrichment and represent the application of known techniques to known methods.
Regarding claim 2, in the method of Fu in view of Rosati, Ruggiero, and Tong, Fu teaches that an amplified target may be subjected to sequencing (para [0196]), methods of adding sequencing primers (para [0219]; [0278]; Fig. 38-39), and sequencing of TCR mRNAs amplified with a target-specific amplification method (para [0287]). Further, the title of Fu is “Methods and Compositions for Barcode Nucleic Acids for Sequencing”.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to sequence the amplicons that resulted from the method Fu in view of Rosati, Ruggiero, and Tong as doing so would enable counting and identifying of the sample TCR alpha and beta chain sequences to which barcodes had been added, enabling downstream analysis. There would have been a strong expectation of success as sequencing samples at this time was routine and Fu provides method of preparing for sequencing.
Regarding claim 3, in the method of Fu in view of Rosati, Ruggiero, and Tong, Fu teaches evaluating the sequences to count the molecular indices for TCR alpha chain and beta chain mRNAs (para [0288]; Fig. 40).
Likewise, Rosati shows the most abundant TCR sequence detected across various method for alpha and beta chains in one patient (Fig. 3).
Ruggiero also shows the TCR alpha and beta repertoires for healthy donors and Sézary patients (Fig. 3).
Therefore, it would have been obvious to one ordinary skill before the effective filing date to evaluate the sequences to determine the frequency of TCR alpha chain and TCR beta chain V(D)J sequences to determine if the selection works as elected, there are differences between patients, etc. There would have been a strong expectation for success as this is a standard technique utilized with many options a practitioner can choose from in the art depending on their desired intricacy of analysis.
Regarding claim 10-11, in the method of Fu in view of Rosati, Ruggiero, and Tong, Fu teaches Fu teaches multiplexed amplification (para [0186]: “Amplification may be performed in a multiplexed manner, wherein multiple target nucleic acid sequences are amplified simultaneously”; Fig. 38; para [0210]: "The forward primers for the N1 and N2 multiplex PCR steps (as shown in Figure 38)”), wherein amplification reactions may be used to add sequencing adaptors (para [0186]). Fu further teaches a multiplex PCR with an engineered sequence (N2) (Fig. 32; Table 2). Fu further teaches that the reverse transcription primers can be gene-specific, e.g., gene-specific for one or more alpha chains of a TC~ one or more beta chains of a TCR (para [0249]). However, Fu fails to explicitly teach that a majority are of the multiplex primers are configured to bind to one or more TCR alpha chain or, alternately, TCR beta chain V(D)J sequences.
Rosati teaches that it is suggested to separate the processing of the two chains for [multiplex] methods in order to increase the quality of the outcome (pg. 5, Target enrichment, spanning, pg. 6), specifically, treating them as two different samples increases precision and specificity of the outcome (pg. 4, Choosing target sequences: Chains and CDR regions).
Therefore, it would have been obvious to one of ordinary skill before the effective filing date to make a variant of the method of Fu in view of Rosati, Ruggiero, and Tong, informed by Rosati and the use of alpha- or beta-specific RT primers of Fu, wherein a majority (e.g., all) of the multiplex primers target either TCR alpha or TCR beta chain sequences so as to improve the precision and specificity of the assay. These are accordingly held to be obvious variants under 2144.04(I)(b).
Claim(s) 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fu (WO 2016/138500 A1; published 09/01/2016) in view of Rosati (Rosati E, et al. Overview of methodologies for T-cell receptor repertoire analysis. BMC Biotechnol. 2017 Jul 10;17(1):61), Ruggiero (Ruggiero E, et al. High-resolution analysis of the human T-cell receptor repertoire. Nat Commun. 2015 Sep 1;6:8081), and Tong (Tong C, Guo B, He S. Bead-probe complex capture a couple of SINE and LINE family from genomes of two closely related species of East Asian cyprinid directly using magnetic separation. BMC Genomics. 2009 Feb 19;10:83) as applied to claims 1-7 and 10-11 above, and further in view of Livak (WO 2018/013723 A1; as cited in the IDS dated 02/14/2022).
Regarding claim 8, in the method of Fu in view of Rosati, Ruggiero, and Tong, Fu teaches multiplexed amplification (para [0186]: “Amplification may be performed in a multiplexed manner, wherein multiple target nucleic acid sequences are amplified simultaneously”; Fig. 38; para [0210]: "The forward primers for the N1 and N2 multiplex PCR steps (as shown in Figure 38)”), wherein amplification reactions may be used to add sequencing adaptors (para [0186]). Fu further teaches a multiplex PCR with an engineered sequence (N2) (Fig. 32; Table 2) but fails to teach its use for the first set of amplicons.
Livak rectifies this by teaching a set of primers binding to the TCR alpha and beta chain V region (Fig. 4B) comprising a target-binding region a universal binding region (Rd1, wherein Rd1 is the Illumina TruSeq Read 1 sequence) (Fig. 4B; para [0179-180]).
Rosati further rectifies this by teaching that multiplex PCR methods are subjected to amplification biases, which lead to better amplification of some alleles compared to others, thereby distorting the relative abundances of the resulting products (pg. 5, Multiplex PCR).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to combine the method of Fu in view of Rosati, Ruggiero, and Tong with the idea of utilizing a 5’ engineered sequence comprising a universal binding site of Livak so as to enable any subsequent amplifications to be performed with a single set of primers, thereby avoiding further amplification bias and potential distortion of results, informed by Rosati. There would be a strong expectation for success as Fu discloses barcoding primers utilized for amplifying the 3’ that include such an adapter and additional components so synthesis of oligos of the required length would not be an issue before the effective filing date and one of ordinary skill would easily be able to design such primers by appending sequence from one to another.
Claim(s) 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fu (WO 2016/138500 A1; published 09/01/2016) in view of Rosati (Rosati E, et al. Overview of methodologies for T-cell receptor repertoire analysis. BMC Biotechnol. 2017 Jul 10;17(1):61), Ruggiero (Ruggiero E, et al. High-resolution analysis of the human T-cell receptor repertoire. Nat Commun. 2015 Sep 1;6:8081), and Tong (Tong C, Guo B, He S. Bead-probe complex capture a couple of SINE and LINE family from genomes of two closely related species of East Asian cyprinid directly using magnetic separation. BMC Genomics. 2009 Feb 19;10:83) as applied to claims 1-7 and 10-11 above, and further in view of Brennan (Brennan, D. et al. Incorporating asymmetric PCR and microarray hybridization protocols onto an integrated microfluidic device, screening for the Escherichia coli ssrA gene. Sensor Actuat B-Chem. 2018 Feb 28; 261:325-334).
Regarding claim 9, in the method of Fu in view of Rosati, Ruggiero, and Tong, Fu teaches multiplexed amplification as detailed and cited in claim 8 but fails to teach amplification favoring a specific strand.
Brennan rectifies this by teaching an asymmetric PCR protocol followed by hybridization, the ratio of forward to reverse primers addressed amplicon re-annealing prior to hybridization, removing the need for sample fragmentation (pg. 326, col 1, para 1), while still maintaining specific hybridization to microarray capture probes (pg. 331, Discussion, para 1). Brennan further teaches a primer ratios of 10 forward: 1 reverse, melt temperatures for each primer, optimal microarray hybridization conditions (pg. 328, col. 1, para 1), and that amplicons specifically bound to capture probes (pg. 331, col 1, para 1).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to combine the method of Fu in view of Rosati, Ruggiero, and Tong with the method of asymmetric PCR of Brennan including utilizing a higher ratio of forward primer to reverse primers [and in doing so favoring amplification of the sense strand given that the method of Fu in view of Rosati, Ruggiero, and Tong utilizes oligo-dT for RT, which provides an anti-sense template] in order to address product re-annealing prior to hybridization and thereby enhance hybridization efficiency to capture probes by creating a pool largely comprising ssDNA. Doing so would further enable a practitioner to create probes, for example, with only the anti-sense of the probe they wished they use with the expectation that they could still capture a majority of the targeted amplicons, thereby reducing complexity and while providing the potential for enhanced enrichment. There would be a strong expectation of success as one of ordinary skill could readily adopt the ratios as taught by Brennan for the target-specific and universal primers of Fu in view of Rosati, Ruggiero, and Tong and further optimize the ratios as needed within routine experimentation.
Claim(s) 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fu (WO 2016/138500 A1; published 09/01/2016) in view of Rosati (Rosati E, et al. Overview of methodologies for T-cell receptor repertoire analysis. BMC Biotechnol. 2017 Jul 10;17(1):61), Ruggiero (Ruggiero E, et al. High-resolution analysis of the human T-cell receptor repertoire. Nat Commun. 2015 Sep 1;6:8081), and Tong (Tong C, Guo B, He S. Bead-probe complex capture a couple of SINE and LINE family from genomes of two closely related species of East Asian cyprinid directly using magnetic separation. BMC Genomics. 2009 Feb 19;10:83) as applied to claims 1-7 and 10-11 above, and further in view of James@cancer (James@cancer, sbrumpton. How do spri beads work? [Internet]. CoreGenomics; 2012 [cited 2025 Feb 2]. Available from: https://core-genomics.blogspot.com/2012/04/how-do-spri-beads-work.html).
Regarding claim 12, in the method of Fu in view of Rosati, Ruggiero, and Tong, Fu teaches the use of AMPure [beads] (Fig. 29-31) but fails to teach the use of clean up/size selection beads after the first round of amplification. Fu teaches two rounds of multiplex amplification (Fig. 38) and a further amplification to add additional sequencing adapters/sequences (Fig. 31; Fig. 36).
Ruggiero also teaches the use of AmPure beads after PCR amplification (pg. 5, TCR ligation-anchored-magnetically captured PCR, para 2; High-throughput sequencing of TCR-LA-MC PCR amplicons).
James@cancer rectifies this by teaching that Ampure beads are inherently SPRI beads (para 5: “You are most likely to come across SPRI beads labeled as Ampure XP from Beckman.”; para 7: “The binding capacity of SPRI beads is huge. 1ul of AmpureXP will bind over 3ug DNA.”). James@cancer further teaches that SPRI is great for low concentration DNA cleanup (para 7) and that they may be used for size-selection (pg. 8).
Therefore, it would have been obvious to one of ordinary skill before the effective filing date to combine the method of Fu in view of Rosati, Ruggiero, and Tong in light of the teachings of James@cancer in order to utilize SPRI beads such as Ampure beads to clean the first set of amplicons so as to perform clean up (e.g., to eliminate primers that might cause undesirable products in a subsequent amplification step if, say, nested PCR is performed). They could also be used to size select the products if some of the primers have some level of non-specific binding to other sequences, which specific SPRI bead selection sizes could reduce or eliminate. Thus, the order of when to perform such a clean-up/selection is held to be obvious under MPEP 2144.04(IV)(c).
Response to Arguments
Applicant's arguments filed 08/11/2025 have been fully considered but they are not persuasive.
Regarding the arguments on pgs. 7-8 regarding the number of PCRs performed in Fu, it is noted that the features upon which applicant relies (i.e., one multiplex amplification step) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
In particular, it is noted that the claims recite “A method comprising the steps of:” (emphasis added). Therefore, the argument that the instant claims differ from Fu because of an additional amplification step is not persuasive.
Further, it is noted 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). Applicant has not pointed out a specific deficiency of the mapping of the combination of Fu, Rosati, Ruggerio, and Tong.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
Motivation statements have been slightly modified to more emphasize/clarify motivations. Specifically, Fu teaches the reverse transcribing and producing a set of amplicons by amplifying; Ruggerio teaches capturing amplicons with a biotinylated primer located in the constant region of the TCR gene; and Tong teaches the specific steps (including order) amplifying DNA, washing, eluting, and a subsequent amplification. The artisan would have been motivated to combine these methods, at least because the motivating reference of Rosati teaches that is beneficial to utilize probe bead-based target enrichment in order to reduce the number of PCRs and thereby reduce PCR bias in results; Tong teaches that the widely known method [of probe enrichment] is straightforward and cheaper/faster than other similar methods; and Ruggerio teaches that such a method enables reliable representation of TCR repertoire diversity. It is noted that all are directed towards enrichment of nucleic acid sequences and represent the application of known techniques to a known method.
In addition, it is also noted that the Supreme Court ruling for KSR Int' l Co. v. Teleflex, Inc. (No 04-1350 (US 30 April 2007) forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See Ex parte Smith (USPQ2d, slip op. at 20 (Bd. Pat. App. & Interf. June 25, 2007).
Regarding the argument on pg. 10 regarding the order of steps for the SPRI bead clean up, as cited in the original rejection, it is noted that the courts have held that any order of performing process steps is prima facie obvious in the absence of new or unexpected results (In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930); Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959)). See MPEP §2144.04 IV C. Ruggiero teaches use of AmPure beads after amplification and James@cancer provides a motivation for such a DNA clean up. Therefore, performing the cleanup after the first amplification is held to be obvious at least for this reason, in addition to the teachings of Tong in the combination discussed above.
Applicant is advised that MPEP 716.01(c) makes clear that “[t]he arguments of counsel cannot take the place of evidence in the record” (In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965)). Thus, Applicant should not merely rely upon counsel's arguments in place of evidence in the record.
It is noted that the Response above should not be construed as an invitation to file an after final declaration. See MPEP 715.09.
Applicants remaining arguments rely on arguments already addressed above.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/EMMA R HOPPE/ Examiner, Art Unit 1683
/Robert T. Crow/Supervisory Patent Examiner Trainer, Art Unit 4100