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 .
Applicant’s arguments and amendments have been thoroughly reviewed and considered. Claims 1-35 are pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 9/1/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Applicant’s Amendments
Claim Objections
Claims 11 and 19 were objected to for various informalities. In light of Applicant’s amendments to the claims submitted 8/27/2025, these objections have been withdrawn. However, see new grounds of objection below.
35 USC 102 Rejections
Claims 1, 5-6, 8-11, 13, 21-28, and 35 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by Seitz et al. (WO 2013/038010 A2). Applicant’s arguments and amendments have been thoroughly reviewed and considered. These rejections have been maintained, and see “Response to Applicant’s Arguments” below.
35 USC 103 Rejections
Claims 2-4, 7, 12, 14-19, 20, and 29-34 are rejected under 35 U.S.C. 103 as being unpatentable over Seitz et al. (WO 2013/038010 A2). Applicant’s arguments and amendments have been thoroughly reviewed and considered. These rejections have been maintained, and see “Response to Applicant’s Arguments” below.
Response to Applicant’s Arguments
Regarding the prior art rejections, Applicant argues that Seitz does not teach the newly added limitation to claim 1, wherein the identification sequence remains single stranded when the adapter hybridizes to the elongation stopper. Applicant further states that this would not be possible in the methods of Seitz, because the reference allegedly teaches that the 5’ end of the sequence tag is hybridized to the stopper to position it near the 3’ end of the elongation product, and the reference does not teach the ligation of a free adapter (Remarks, pages 7-8).
Firstly, it is noted that in the Non-Final Rejection mailed 5/14/2025, Seitz is not stated to teach that part of the adapter hybridizes to the elongation stopper. The adapter is double-stranded, with L2 hybridizing to L2rc (it is noted that the sequence analogous to the identification sequence of the instant claim is the 5’ end of the L2 sequence). The elongation product is then ligated to the adapter, and both L2 and L2rc are incorporated into the final products. In Figure 4, which is used in the 35 USC 102 rejections, note that elongation stopper Sm is never hybridized to L2 and/or L2rc, and is not present in the final products. Sm is only connected to the adapter sequence at the 3’ end of the L2rc sequence. This connection is considered to be encompassed by the word “bound” in the instant claims, while the term “hybridized” is interpreted to refer to complementary binding of nucleotide sequences. Neither of these terms is specifically defined by the instant specification, and so are considered under their broadest reasonable interpretations in view of their use in the prior art. Thus, the adapter of Seitz never hybridizes to the elongation stopper.
Furthermore, even though the adapter of Seitz is double-stranded with the L2 and L2rc sequences, the identifier sequence (the 5’ end of L2), is a portion of a single strand, as defined by claim 1 (“an adaptor nucleic acid that comprises an identification sequence on its 5’ end”). This claim language encompasses utilizing the 5’ end of a single strand of a double-stranded adapter for the identification sequence. In this embodiment, this portion of a single strand would remain the same throughout the method of claim 1, as no step is recited to alter its structure. Therefore, the “identification sequence remains single stranded” is simply a normal function of this embodiment of the method of claim 1, and thus is a normal function of the teachings of Seitz in relation to the method of instant claim 1.
Thus, the amendments to claim 1 do not change how the teachings of Seitz relate to the limitations of the claim. The prior art rejections presented in the Non-Final Rejection are therefore maintained and are reiterated below.
Claim Objections
Claim 1 is objected to because of the following informality: in the newly amended portion of the claim, “and wherein in case a part” should read “and wherein in the case where part.” Appropriate correction is required.
Claim 14 is objected to because of the following informality: the spacing of the claim should be consistent with the spacing presented throughout the claim set. Currently, the body of the claim appears further indented compared to that of the other claims. Appropriate correction is required.
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, 5-6, 8-11, 13, 21-28, and 35 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Seitz et al. (WO 2013/038010 A2).
Seitz teaches methods for generating an amplified nucleic acid portion of a template nucleic acid (Abstract). One such method (on page 7, para. 2) comprises:
Providing a template nucleic acid.
Annealing a first oligonucleotide primer to said template nucleic acid.
Annealing at least one further oligonucleotide primer to said template nucleic acid.
Elongating the first oligonucleotide primer in a template specific manner until it reaches the further oligonucleotide primer. Here, the further oligonucleotide primer can act as a stopper, and can be elongated itself, also acting as a primer.
Additionally, sequence tags may attached to either or both of the primers. These sequence tags function as labels that can be used to detect particular sequences, and do not hybridize to the template nucleic acid (page 18, para. 5). The tag may be hybridized to a complement strand, where said complement is ligated to the 5’ end of the stopper oligonucleotide (thereby acting independently of the stopper annealing sequence; page 19, para. 1; instant claim 23). This allows said tag and complement to form a double-stranded adapter (page 39, para. 2 and Figure 4, reference characters L2 and L2rc). After elongation of the oligonucleotide primer reaches the stopper, the tag can be ligated to the 3’ end of the elongation product (page 19, para. 1 and Figure 4, reference character L2; instant claims 1 and 35).
The template nucleic acid is preferably RNA, which is elongated via reverse transcriptase (page 7, para. 3 and page 8, para. 3; instant claims 8 and 24).
Anywhere from 1-50 oligonucleotide primers may be used, where elongation of said additional primers may also be stopped with an elongation stopper (page 13, para. 2; instant claim 13). Anywhere from 1-50 oligonucleotide stoppers may be used, and these different stoppers may differ in their annealing sequences. The annealing sequence may be random (page 14, para. 2; instant claims 5-6 and 21-22).
In a preferred embodiment where the template nucleic acid is specifically mRNA, oligo dT primers can be used to anneal to the poly A tail of the mRNA. The oligo dT primer can include anchored oligonucleotides (page 32, para. 5 through page 33, para. 1; instant claims 10 and 26).
Regarding claims 9 and 25, the instant specification states that “a universal sequence means that it is the same for all primers, stoppers or adapters, respectively,” (page 17, line 38 through page 18, line 2). The oligonucleotide primers and stoppers of Seitz can each share the same sequence tags that can be used for amplification, thus meeting this definition and the limitations of instant claims 9 and 25 (page 13, para. 2 and page 14, para. 2).
Seitz teaches that the ligation reaction can include PEG and Tween (page 17, paras. 2-3) and also teaches that oligonucleotides may be modified to increase their melting temperature (page 27, para. 2; instant claims 11 and 27). These modifications specifically refer to oligonucleotides that bind to the template strand, and therefore encompass the elongation stopper and oligonucleotide primer (page 27, para. 2; instant claim 28).
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 2-4, 7, 12, 14-19, 20, and 29-34 are rejected under 35 U.S.C. 103 as being unpatentable over Seitz et al. (WO 2013/038010 A2).
Regarding claims 2 and 17-19, Seitz teaches the method of claim 1, as described above. Seitz also teaches the creation of a cDNA library that does not include an elongation stopper, where the elongation of at least one oligonucleotide primer is able to reach the 5’ end of the template nucleic acid (page 38, description of Figures 2 and Figure 2). Ligase is also shown to be involved in these methods (Figure 2). Seitz also notes that linkers can be ligated to any amplified nucleic acids of their invention (page 22, para. 2), and generally teaches that linkers can be ligated to elongated nucleic acid products (page 22, para. 3). In this latter teaching, though an elongation stopper is used as an example, it is not required. These linkers can thus be analogous to the adapters in the instant claims, and specifically the adapter formed in the rejection of claim 1 described above. This reference also teaches that M-MLV reverse transcriptase can be used, and that terminal transferase activity can add nucleotides to amplified fragments resulting from the invention (page 35, paras. 2 and 4). Therefore, it would be prima facie obvious for one of ordinary skill in the art to combine these aspects to create an embodiment of Seitz where no elongation stopper is required, an adapter is added after elongation, and oligonucleotides are added to fragments after amplification. The ordinary artisan would be motivated to do this because the exclusion of the oligonucleotide stopper would mean less resources are required for the overall method, and Seitz teaches that by adding nucleotides to amplified fragments, single-stranded products can more quickly and efficiently hybridize to a template, which would be useful for downstream analyses (page 35, para. 4). In adding the adapters, Seitz teaches that linkers are particularly useful for amplification and next generation sequencing methods, and so including these adapters even in the absence of an elongation stopper would aid in downstream analyses (page 22, para. 2).
Thus, claims 2 and 17-19 are prima facie obvious over Seitz.
Regarding claims 3 and 20, Seitz teaches the method of claim 1, as described above. Because the sequence tags are taught to be attached to the oligonucleotide stopper, and at least 50 distinct stoppers and 50 distinct oligonucleotide primers can exist, then at least 50 sequence tags can exist and be ligated in the method of claim 1 (page 13, para. 2 and page 14, para. 2). Sequence tags are unique, pre-selected nucleic acid sequences that can be used to detect, recognize, or amplify a sequence labelled with said tag (page 18, para. 5). Therefore, it would be prima facie obvious to one of ordinary skill in the art to create several unique sequence tags in order to only detect or amplify particular sequences. This would be particularly useful if the ordinary artisan wanted to only detect or amplify fragments from a particular region of a template nucleic acid.
Thus, claims 3 and 20 are prima facie obvious over Seitz.
Regarding claim 4, Seitz teaches the method of claim 1, as described above. Seitz also teaches that the oligonucleotide primer sequences may be random sequences, and also teaches the synthesis of random sequences (page 13, para. 2 and page 14, para. 2). Therefore, it would be prima facie obvious for one of ordinary skill in the art to additionally randomly synthesize the sequence tag, as the method for doing so was well-known in the art. Because the sequence tag is pre-selected (page 18, para. 5), the ordinary artisan would still know what the nucleotide sequence of the tag is - the actual generation of the said sequence would just be random. This would likely aid in detection of the sequence tag during downstream analysis, as the pre-selected random sequence could be chosen for its variance in relation to the sequences of the oligonucleotide primer, stopper, and template nucleic acid.
Thus, claim 4 is prima facie obvious over Seitz.
Regarding claim 7, Seitz teaches the method of claim 1, as described above. This reference also teaches several embodiments in which the oligonucleotide stopper is ligated to elongated product nucleic acids (page 7, para. 1, page 8, para. 1). Stoppers can also be primers (page 10, para. 5). Seitz also teaches that stoppers can be labeled and the extension product ligated with said labeled stopper (page 12, para. 5). In Figures 3 and 5, the stopper is clearly shown connected to a linker (particularly the L2 sequence). Figure 7 also shows ways that L2 and L2rc may be connected in relation to the stopper sequence. Based on these teachings, it would be prima facie obvious that the stopper sequence taught by Seitz in the rejection of claim 1 could simply not be removed after elongation is stopped and L2 is ligated to the end of the elongation product. Thus, the stopper would be still be attached to L2rc, and therefore bound to the double stranded adapter. By not removing the stopper sequence, a step in the method would be removed, saving time and resources. L2 and L2rc would still be able to hybridize to one another, and L2rc would still be able to act as a primer in the subsequent amplification step, and thus the results of removing this step would be predictable.
Thus, claim 7 is prima facie obvious over Seitz.
Regarding claims 12 and 29-30, Seitz teaches the method of claim 1, as described above. As stated in the rejection of claim 3 above, it would be prima facie obvious to create at least 50 elongation stoppers, as well as at least 50 sequence tags that comprise different sequences. Because the sequence tags are ligated to the oligonucleotide primers, and there can be at least 50 primers (page 13, para. 2), this would generate at least 50 differently labelled amplification fragments. Because the sequence tags can be used to amplify a sequence labelled with said tag, it would be prima facie obvious to further amplify the labelled fragments (page 18, para. 5). Seitz also teaches creating a sequence library with the generated amplified fragments (page 8, para. 2), and that tags on amplification products may be used for identification in such a sequence library (page 14, para. 1).
Thus, claims 12 and 29-30 are prima facie obvious over Seitz.
Regarding claims 14 and 16, Seitz teaches a kit for performing their method (page 8, para. 3). This kit comprises a reverse transcriptase, a ligase, oligonucleotide primers, and oligonucleotide stoppers. Kits of the invention can also include carrier means and the necessary tools for holding reagents (e.g. vials), and can include oligo dT primers specifically (page 37, para. 3). Though this recitation does not explicitly include sequence tags, it would be prima facie obvious for the ordinary artisan to include them in order to create a kit that can fully perform the method of Seitz described by claim 1, and so that reaction products can be more easily detected and identified (page 18, para. 5).
Thus, claims 14 and 16 are prima facie obvious over Seitz.
Regarding claims 15 and 33, Seitz renders obvious the kit of claim 14, as described above. Seitz specifically teaches that the kits can have more than one primer or stopper (page 8, para. 3). This reference also teaches that the invention may comprise up to 50 primers and 50 stoppers (page 13, para. 2 and page 14, para. 2). In order to ensure each elongation product is labelled, the same number of sequence tags and primers would be needed. Therefore, it would be prima facie obvious for the ordinary artisan to also include up to 50 sequence tags in the kit of Seitz.
Thus, claims 15 and 33 are prima facie obvious over Seitz.
Regarding claim 31, Seitz renders obvious the kit of claim 14, as described above. Seitz also teaches that the elongation stopper can also act as an initiator of elongation itself, thereby acting as a primer (page 7, para. 2). This elongation would be at the 3’ end (see for example the orientation of the stopper Sm in Figure 4).
Thus, claim 31 is prima facie obvious over Seitz.
Regarding claim 32, Seitz renders obvious the kit of claim 14, as described above, and teaches that the sequence tag (i.e. the adapter) may be hybridized to a complementary strand, where said complement is ligated to the 5’ end of the stopper oligonucleotide (thereby acting independently of the stopper annealing sequence; page 19, para. 1). This allows said tag and complement to form a double-stranded adapter (page 39, para. 2 and Figure 4, reference characters L2 and L2rc) bound to the stopper oligonucleotide.
Thus, claim 32 is prima facie obvious over Seitz.
Regarding claim 34, Seitz renders obvious the kit of claim 16, as described above, and teaches that the oligo dT primer can include anchored oligonucleotides (page 32, para. 5 through page 33, para. 1).
Thus, claim 34 is prima facie obvious over Seitz.
Conclusion
No claims are currently allowable.
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 FRANCESCA F GIAMMONA whose telephone number is (571)270-0595. The examiner can normally be reached M-Th, 7-5pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gary Benzion can be reached at (571) 272-0782. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/F.F.G./Examiner, Art Unit 1681
/ANGELA M. BERTAGNA/Primary Examiner, Art Unit 1681