DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 8/20/2026 has been entered.
Status of Claims
Currently, claims 1-13, and 15-22 are pending in the instant application. Claims 1-12 are withdrawn from consideration as being drawn to a non-elected invention. Claims 13 and 15-22 are currently under examination. All the amendments and arguments have been thoroughly reviewed but are deemed insufficient to place this application in condition for allowance. The following rejections are reiterated. They constitute the complete set being presently applied to the instant Application. Response to Applicant's arguments follow. This action is FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejections - 35 USC § 103
Claims 13 and 15-22 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Rohlfs (Rohlfs et al; US 2011/0230365; citations within this rejection are made with regard to US Patent 8,728,731, which is identical in disclosure) in view of Bareil (Bareil et al; Human Mutation, vol 31: 2010, pages 1011-1019), Mizuki (Mizuki, Psalm; Thesis, Rochester Institute of Technology, 2010) and Vorkas (Vorkas et al; Journal of Molecular Diagnostics, vol 12, pp 697-704; 2010), further in view of Mori (Mori et al; Clinical Biochemistry, vol 33, pages 323-327, 2000) and May (May et al; US Patent 8,691,509).
Rohlfs teaches methods for testing a sample obtained from a subject to determine the presence of one or more mutations in the CFTR gene (see abstract). Rohlfs teaches the CFTR genomic sequence (SEQ ID NO: 1) and cDNA sequence (SEQ ID NO: 2). Rohlfs teaches that the presence of mutations can be determined by PCR and sequencing (see col 21). Rohlfs teaches targeting different segments of the CFTR gene. Rohlfs teaches kits containing reagents for carrying out analysis including reagents for primer directed amplification and sequencing (see para bridging cols 28-29). Rohlfs teaches identifying new CFTR mutations (tables 1-5) by sequencing the full coding sequence or individual exons (different target regions) (see example 5) after PCR amplification of the desired target region.
Rohlfs does not teach a primer with the sequence of SEQ ID NO: 9, for example (or SEQ ID NO: 61, 109, and/or 143), however
the claimed primer sequences are 100% identical to the CFTR gene and cDNA sequences taught by Rohlfs (SEQ ID NOS 1 and 2 respectively).
Bareil teaches that the number of sequence variations in the CFTR gene is constantly rising. Bareil teaches constructing a database listing 301 known CFTR sequence variations (see page 1016, col 2).
Vorkas teaches methods of detecting hotspot mutations in the PIK3CA gene (see abstract). Vorkas teaches that the primers were designed so that mutation sites were included within the amplified region but excluded from primer sites (see page 699, col 1).
Mizuki teaches a program designed for constructing primers to highly polymorphic mtDNA (see abstract). Mizuki teaches that PCR is a key component of genotyping methods but can be problematic for mtDNA due to the highly polymorphic nature of the source DNA, preventing primers from annealing properly. Mizuki teaches that the program allows design of primers that avoid polymorphic areas.
Therefore, it would have been prima facie obvious to one having ordinary skill at the time the invention was made to construct kits comprising different primer pairs, the primer pairs comprising a forward primer and a reverse primer, including SEQ ID NO: 9, which do not hybridize to known mutated sites taught by Rohlfs and Bareil, for sequencing individual portions of the CFTR gene, for the purpose of providing reagents in kit format for sequencing the CFTR gene to detect known and new mutations. The ordinary artisan would be motivated to construct primers that do not hybridize over positions known to be mutated because Mizuki taches that PCR can be problematic with highly polymorphic sequences because primers designed to anneal over mutant sites may not do so properly due to the presence of mutations that differ from the sequence the primer was designed to hybridize to. Given that the CFTR gene was known to contain a large number of mutant sites (see Rohlfs and Bareil), the art exemplifies designing primers in mutation sequencing assays that do not hybridize over sites that contain known mutations (Vorkas), and the art exemplifies primer design that avoids constructing primers that hybridize to known mutated sites (Mizuki) the instantly claimed SEQ ID NOS are considered obvious in view of the teachings of Rohlfs, Bareil, Vorkas, and Mizuki.
Rohlfs, Bareil, Vorkas, and Mizuki do not teach kits comprising a primer consisting of SEQ ID NO: 9 which is fluorescently labeled. However, Mori teaches constructing fluorescently labeled primers for amplification and sequencing the LPL gene using different primer pairs to cover and span all exons and exon/intron boundaries. Therefore, it would have been prima facie obvious to the ordinary artisan at the time the invention was made to construct fluorescently labeled primers in the kits of Rohlfs, Bareil, Vorkas, and Mizuki, because Mori teaches the successful sequencing of a gene’s exons using these primers.
Rohlfs, Bareil, Vorkas, Mizuki, and Mori do not teach kits comprising a primer consisting of SEQ ID NO: 9 and a sequencing adapter sequence selected from SEQ ID NO: 1 or 2. However, May teaches a method of PCR amplification and sequencing using primers with tags with the sequences of SEQ ID NOS 1 and 2 (see SEQ ID NO: 163 and 164 of May) ligated to the 5’ end of the primer sequence (see example 4). Therefore, it would have been prima facie obvious to the ordinary artisan at the time the invention was made to substitute the amplification and sequencing taught by Rohlfs, to construct kits with primers with the ligated adapter sequences taught by May because May teaches that using these tagged primers results in amplification and sequencing of target nucleic acids.
Although the claims have been amended to recite that the one or more primers is suitable for determining the presence or absence of base changes, gene deletions, and gene duplications, these are intended use limitations which do not structurally distinguish the claimed primers from the teachings of the prior art. The claims are directed to products (kits and oligonucleotides), not to methods of detection.
Response to Arguments
The response traverses the rejections under 35 USC 103 from the previous office action and asserts that the claim amendments have overcome the rejections. This argument has been thoroughly reviewed but was not found persuasive because these are intended use limitations which do not structurally distinguish the claimed primers from the teachings of the prior art. The claims are directed to products (kits and oligonucleotides), not to methods of detection.
The response asserts that the office action acknowledges the lack of teaching of the prior art to arrive at the instantly claimed kits by asserting that “Rohlfs does not teach primers with the sequence of SEQ ID NO: 9…” The response asserts that Rohlfs does not teach any of the claimed primer sequences and that the secondary references do not provide for any of the specifically recited primers. With regard to Mizuki, the response again argues that Mizuki teaches design of primers to mtDNA, not to CFTR. These arguments have been thoroughly reviewed but were not found persuasive. Armed with the teachings of the prior art, the ordinary artisan would have recognized that there are many known mutations throughout the CFTR gene (Bareil) and that when constructing primers for sequencing a known polymorphic gene, primers should be designed to avoid the mutated sites (Vorkas, Mizuki). It is routine for ordinary artisans in the field of mutation detection to continually construct new primers with improved properties, even given the complexities of the human genome, particular genes, etc. If the complexity of a gene were enough to deter an ordinary artisan from attempting to design new primers, the art would not be replete with references where practitioners design new primers. However, this is not the case, as illustrated by the prior art cited in the office action. Further, Mizuki even teaches modifying a “popular online primer design program, Primer3… to create primers for mtDNA…”, illustrating the availability of online primer design programs. Mizuki demonstrates the routine nature of designing primers to avoid polymorphic sites and exemplifies the application with regard to mtDNA using a web-based primer design program. The office action does not state that CFTR primers can be designed using specific mtDNA primer software, but rather that the programming of software to design primers to known polymorphic regions has been carried out with a reasonable expectation of success. Not only would it have been obvious to design primers to the CFTR gene which avoid polymorphic sites, but the ordinary artisan would have been motivated to do so in view of the teachings of the prior art. The fact that Mizuki teaches doing so with regard to mtDNA, does not indicate that this technology was only applicable to mtDNA, but rather teaches a problem which is broadly applicable to any highly polymorphic gene target, and how to remedy the problem. The response does not provide any scientific reasoning or evidence that designing primers that do not hybridize over a polymorphic position of a known DNA sequence would be different for mitochondrial DNA sequencing vs CFTR gene sequencing. Again, as already noted, the nature of primers is that they hybridize to complementary target nucleic acid sequences as a first step of a reaction to construct the exact same nucleic acid sequence as the relevant portion of a target nucleic acid. The fact that the mtDNA sequence and the CFTR gene sequence are different does not render the claimed primers nonobvious because primers used for sequencing mtDNA and primers used for sequencing CFTR DNA both utilize the innate ability of DNA to hybridize to itself. The principle of designing primers that do not hybridize over a polymorphic position, that is are completely complementary to a target, regardless if it is mutated or not, is universal to any polymorphic sequence. What is needed is knowledge of the target DNA sequence and which positions are polymorphic, which the art teaches (Rohlfs and Bareil). Both Vorkas and Mizuki illustrate that one of ordinary skill in the art would have had a reasonable expectation of success in designing such primers. Any arguments pertaining to Mori and May are not found persuasive for the reasons already made of record. The rejections are maintained.
Conclusion
No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 examiner Jehanne Sitton whose telephone number is (571) 272-0752. The examiner is a hoteling examiner and can normally be reached Mondays-Fridays from 8:00 AM to 2:00 PM Eastern Time Zone.
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/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
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