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 .
This application is in response to the papers filed 03/02/2026.
Election/Restrictions
Applicant’s election of group I, SID 1-3 in the reply filed on 03/02/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 12-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/02/2026.
Claims 1-11 are under examination. Claim 9 is under examination with respect to SEQ ID NO 2. Claim 10 is under examination with respect to SEQ ID NO 1. Claim 11 is under examination with respect to SEQ ID NO. 3
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3-4, 6-7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Prchal (US 2010/0068712 A1).
With regard to claim 1, 4, and 7, Prchal teaches an first oligonucleotide complementary to a target polynucleotide that comprises an LNA unit, a mismatch nucleobase, and an allele -specific nucleobase corresponding to a first allele of the target oligonucleotide. Prchal teaches a second oligonucleotide complementary comprising a LNA unit, mismatch nucleobase and allele specific nucleobase corresponding to the second allele of the target polynucleotide (see para 20 and 21). Prchal teaches the allele specific nucleobase is at the 3’ terminal position, the LNA base is at -2 position relative to the nucleobase and the mismatch nucleotide is -1 positive relative to the allele specific nucleobase (see para 32). Prchal teaches the oligonucleotide is a primer (see para 34). Prchal teaches a universal primer and allele specific primer (see para 35 and fig 1). Prchal teaches a reverse extension primer that is complementary to the target sequence that is common to both the gene of the target allele and variant allele at a position downstream from the genetic locus of interest (see para 113).
With regard to claim 3 and 6, Prchal teaches oligonucleotides that are prepared synthetically to include thioester bonds. Prchal teaches synthetic oligonucleotides that contain phosphorothioates (see para 60-61).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 2 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Prchal (US 2010/0068712 A1) in view of Chan (WO2018085584A1)
Prchal teaches an first oligonucleotide complementary to a target polynucleotide that comprises an LNA unit, a mismatch nucleobase, and an allele -specific nucleobase corresponding to a first allele of the target oligonucleotide. Prchal teaches a second oligonucleotide complementary comprising a LNA unit, mismatch nucleobase and allele specific nucleobase corresponding to the second allele of the target polynucleotide (see para 20 and 21). Prchal teaches the allele specific nucleobase is at the 3’ terminal position, the LNA base is at -2 position relative to the nucleobase and the mismatch nucleotide is -1 positive relative to the allele specific nucleobase (see para 32). Prchal teaches the oligonucleotide is a primer (see para 34). Prchal teaches a universal primer and allele specific primer (see para 35 and fig 1). Prchal teaches a reverse extension primer that is complementary to the target sequence that is common to both the gene of the target allele and variant allele at a position downstream from the genetic locus of interest (see para 113). Prchal does not teach a mismatch nucleotide at the 3rd position relative to the 3’ in the allele specific primers.
However, it was well known in the art to use a mismatch at the third position relative to the 3’ end in allele specific primers. Chan teaches allele specific extension primer having a sequence complementary at its 3’ nucleotide to the target allele and variant allele (see pg. 4). Chan teaches the third nucleotide from the 3’ end of the allele specific primer is changed to a different nucleotide from the normal sequence to enhance discrimination of the two alleles (see pg. 4) (claim 2 and claim 5). Chan teaches two allele specific primers for both alleles and a common primer (see fig 2).
Therefore it would have been prima facie obvious to modify the allele specific primers of Prchal to replace the mismatch at the 1st position with a mismatch at the 3rd position relative to the 3’ as taught by Chan to enhance discrimination of the two alleles. The ordinary artisan would have been motivated with an expectation of success to replace the mismatch position of Prchal at the 1st position with a mismatch at the 3rd position in the allele specific primers of Prchal because Chan teaches a mismatch at the 3rd position relative to the 3’ in allele specific primers increase specificity of the primers.
Claims 2 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Prchal (US 2010/0068712 A1) in view of Bosamia (Agrobios, 2014, vol XIII, p 31-32)
Prchal teaches an first oligonucleotide complementary to a target polynucleotide that comprises an LNA unit, a mismatch nucleobase, and an allele -specific nucleobase corresponding to a first allele of the target oligonucleotide. Prchal teaches a second oligonucleotide complementary comprising a LNA unit, mismatch nucleobase and allele specific nucleobase corresponding to the second allele of the target polynucleotide (see para 20 and 21). Prchal teaches the allele specific nucleobase is at the 3’ terminal position, the LNA base is at -2 position relative to the nucleobase and the mismatch nucleotide is -1 positive relative to the allele specific nucleobase (see para 32). Prchal teaches the oligonucleotide is a primer (see para 34). Prchal teaches a universal primer and allele specific primer (see para 35 and fig 1). Prchal teaches a reverse extension primer that is complementary to the target sequence that is common to both the gene of the target allele and variant allele at a position downstream from the genetic locus of interest (see para 113). Prchal does not teach a mismatch nucleotide at the 3rd position relative to the 3’ in the allele specific primers.
Bosamia teaches allele specific primer design. Bosamia teaches addition of artificial mismatch at the third base from the 3’ end of the primer might add to increase reliability of discrimination between two alleles. Bosamia teaches rules for selection of a nucleotide for a secondary mismatch. Bosamia teaches a strong mismatch (G/A) at the 3’ end of allele specific primer will likely need a weak second mismatch (G/T) (see pg. 31, last para can’t to pg. 32). Bosamia teaches adding a secondary mismatch is simple, versatile and does not require expensive probes or equipment and easily established in any molecular biology laboratory.
Therefore it would have been prima facie obvious to modify the allele specific primers of Prchal to replace the mismatch at the 1st position with a mismatch at the 3rd position relative to the 3’ as taught by Bosamia to enhance discrimination of the two alleles. The ordinary artisan would have been motivated with an expectation of success to replace the mismatch position of Prchal at the 1st position with a mismatch at the 3rd position in the allele specific primers of Prchal because Bosamia teaches a mismatch at the 3rd position relative to the 3’ in allele specific primers increase specificity and allows for a versatile, simple, flexible method to improve allele specific primers.
Claims 8-11 are rejected under 35 U.S.C. 103 as being unpatentable over Prchal (US 2010/0068712 A1) in view of Bosamia (Agrobios, 2014, vol XIII, p 31-32), Untergasser (NAR, 2007, Vol 35, W71-W74) and Jacobson (Amyloid, 2015, 22:171-174).
Prchal teaches an first oligonucleotide complementary to a target polynucleotide that comprises an LNA unit, a mismatch nucleobase, and an allele -specific nucleobase corresponding to a first allele of the target oligonucleotide. Prchal teaches a second oligonucleotide complementary comprising a LNA unit, mismatch nucleobase and allele specific nucleobase corresponding to the second allele of the target polynucleotide (see para 20 and 21). Prchal teaches the allele specific nucleobase is at the 3’ terminal position, the LNA base is at -2 position relative to the nucleobase and the mismatch nucleotide is -1 positive relative to the allele specific nucleobase (see para 32). Prchal teaches the oligonucleotide is a primer (see para 34). Prchal teaches a universal primer and allele specific primer (see para 35 and fig 1). Prchal teaches a reverse extension primer that is complementary to the target sequence that is common to both the gene of the target allele and variant allele at a position downstream from the genetic locus of interest (see para 113). Prchal does not teach allele specific primers for transthyretin (TTR) 424G>A variant or primer SEQ ID NO 2, SEQ ID NO 1, or locus primer SEQ ID NO 4.
Jacobson teaches TTR V122I allele (424G>A variant) is one of the point mutations that is associated with systemic amyloidosis. Jacobson teaches it s a G to A transition at a CG dinucleotide of the gene. Jacobson teaches detection of TTR mutation by PCR (see methods).
Bosamia teaches allele specific primer design. Bosamia teaches addition of artificial mismatch at the third base from the 3’ end of the primer might add to increase reliability of discrimination between two alleles. Bosamia teaches rules for selection of a nucleotide for a secondary mismatch. Bosamia teaches a strong mismatch (G/A) at the 3’ end of allele specific primer will likely need a weak second mismatch (G/T) (see pg. 31, last para can’t to pg. 32). Bosamia teaches adding a secondary mismatch is simple, versatile and does not require expensive probes or equipment and easily established in any molecular biology laboratory.
Untergasser teaches a web interface for primer design. Untergasser teaches a program that allows primer design of a known target. Untergasser teaches the detection task that designs standard PCR primers to detect a given sequence and Primer List which generates all possible primers that can be designed ton a target sequence and meet current requirements (see pg. W73).
It would have been prima facie obvious to one having ordinary skill in the art to apply the allele specific primer design and locus primer design as taught by Prchal to detect known alleles, including the allele disclosed by Jacobson in order to detect amyloidosis. The ordinary artisan would have had an expectation of success that the SNP disclosed by Jacobson could be detected in the method of Prchal because Jacobson teaches detecting allelic variants of TTR 424G>A by PCR and Prchal teaches a more specific method of identifying allelic variants using allele specific primers with more specificity.
Additionally it would have been prima facie obvious to one having ordinary skill in the art to apply familiar primer design parameters to yield the primers of SEQ ID NO 1-3 with a reasonable expectation of success. As many primers were known at the time of filing to amplify the TTR 424G>A variant as taught by Jacobson. Because Prchal and Bosamia teach allele specific primers to amplify a SNP and teach modifications to allow for higher specificity, a skilled artisan would have applied familiar primer design parameters to yield primers to amplify TTR 424G>A, including SEQ ID NO 1-3. For example, based on the teaching of Bosamia a skilled artisan would have generated primers comprising SEQ ID NO 1 and 2 because Bosamia teaches allele specific primers detecting a G>A transition benefit from higher specificity by including a G to T mismatch at the 3rd base from the 3’ end of the primer. A skilled artisan based on the teaching of Prchal and Bosamia would have designed SEQ ID NO 1 and SEQ ID NO 2. To this end, a skilled artisan at the time of filing would have designed primers and probes to known sequences (such as the sequences disclosed in the above references) with a high expectation of success. To design such primers constituted routine and conventional optimization at the time of filing. See In re Aller, 220 F.2d 454, at 456 (CCAP 1955) (“where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.”). Numerous references describe how to design and optimize primers and probes for PCR applications. For example, Untergasser teach how to design primers and probes from known sequences using known online primer/probe design programs for use in PCR assays. Untergasser teaches how to use Primer3Plus online program to design primers and probes to known sequences (Untergasser at pgs. W71-74). In other words, Untergasser (as provide specific guidance and parameters to optimize primer, probe and PCR assay design to yield optimal results; thus, designing PCR assays for particular applications constitutes well-known routine optimization. As noted in In re Aller, 105 USPQ 233 at 235, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Routine optimization is not considered inventive and no evidence has been presented that the primer selection performed was other than routine, that the products resulting from the optimization have any unexpected properties, or that the results should be considered unexpected in any way as compared to the closest prior art. In sum, the claimed primers are prima facie obvious because there was clear motivation to design allele specific PCR primers to detect the same mutations in the TTR gene; and designing and optimizing such primers constitutes a well-known, routine and conventional technique which would yield the claimed primers with a reasonable expectation of success.
Conclusion
No claims are allowable.
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/SARAE L BAUSCH/Primary Examiner, Art Unit 1699
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