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 .
Election/Restrictions
2. Applicant’s election without traverse of “small molecules” as the species of blocking agent for examination in the reply filed on March 20, 2026 is acknowledged.
As noted by Applicant, all of the pending claims (i.e., claims 182-201) read on the elected species. They are the subject of this Office action on the merits.
As well, the search will be extended to non-elected species if a generic claim is found to be allowable.
Information Disclosure Statement
3. Applicant’s submission of an Information Disclosure Statement (IDS) on June 18, 2023; July 31, 2023; February 9, 2024; August 21, 2024; December 12, 2024; and March 24, 2026 is acknowledged.
Two citations were lined through and not considered on the IDS filed on February 9, 2024 because the copy required by 37 CFR 1.98(a)(2) was not provided.
Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e) or 37 CFR 1.98(a)(4). See MPEP § 609.05(a).
Drawings
4. Applicant’s submission of replacement drawing sheets on July 10, 2023 is acknowledged.
The replacement drawings are objected to because each of Figures 13-17 and 29 contains multiple parts, but the “Brief Description of the Drawings” section only refers to each figure as a whole. To illustrate, Figure 13 contains parts (A)-(C), but the “Brief Description of the Drawings” section only refers to “Figure 13.” As noted in MPEP 608.01(f), when a figure contains multiple parts, the “Brief Description of the Drawings” section must describe each part.
The replacement drawings are also objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference character(s) not mentioned in the description: 210, 212, and 522.
The original drawings filed on February 28, 2023 are objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference character(s) not mentioned in the description: 330, 1862b, 2107, and 2208.
To address the objections for failing to comply with 37 CFR 1.84(p)(5), corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to add the reference character(s) in the description in compliance with 37 CFR 1.121(b) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objections to the drawings will not be held in abeyance.
Substitute Specification
5. The substitute specification filed on July 10, 2023 has been entered.
The substitute specification is objected to because it contains a typographical error in para. 184 of the clean copy of the substitute specification where “029 (phi29) DNA polymerase” is recited for “Φ29 (phi29) DNA polymerase.”
Claim Objections
6. Claim 185 is objected to because the word “a” should be inserted before “biotin analog.”
Claim Rejections - 35 USC § 112
7. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 186 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 186, which is a new claim added in a preliminary amendment submitted after the filing date of the application, requires a blocking agent selected from biotin, biocytin, and a biotin analog to be provided at a concentration of at least 100 picomolar.
Applicant’s response filed with the preliminary amendment points to at least Example 13, the original claims, and paras. 105, 309, 397, and 401-404 of the specification as providing support for the subject matter of the new claims filed with the preliminary amendment. See the first page of the Remarks filed on August 6, 2024.
The original disclosure, including the portions cited by Applicant, has been reviewed, but support was not found for the full scope of claim 186. More specifically, the original disclosure only provides support for the claimed concentration range when the blocking agent is biocytin (see, e.g., para. 105 on page 11 of the clean copy of the substitute specification filed on July 10, 2023), but claim 186 also encompasses providing biotin or a biotin analog as the blocking agent at a concentration of at least 100 pM. The original disclosure fails to support providing a blocking agent other than biocytin at a concentration of at least 100 pM. Accordingly, claim 186 contains new matter.
Claim Rejections - 35 USC § 112
8. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 182-201 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 182
Regarding claim 182, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 182 recites the broad recitation “a plurality of capture moieties that has affinity to the affinity tag” in step (b), and the claim also recites “free-floating capture moieties” in step (c), which is the narrower statement of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. In other words, the structural requirements of the plurality of capture moieties is not entirely clear.
Claims 183-201
Claims 183-201 are also indefinite since they depend from claim 182 and do not correct its indefiniteness issue.
Claims 184-186
Each of claims 184-186 is also indefinite for an additional reason. Specifically, each of these claims recites “the blocking agent,” but claim 182 recites “a plurality of blocking agents.” This inconsistency in claim terminology creates uncertainty as to whether all or just some of the blocking agents used in claim 182 must satisfy the requirements of claims 184-186.
Claims 198 and 199
Claims 198 and 199 are also indefinite for an additional reason. These claims depend from claim 191 and recite “a second cleavable moiety,” but none of claims 191, 198, and 199 recites “a first cleavable moiety.” This creates uncertainty for two reasons. First, it is not clear whether claims 198 and 199 were intended to depend from, e.g., claim 195, which recites a cleavable moiety. Second, it is not clear whether claims 198 and 199 intend to require the second adapter to contain two cleavable moieties.
Claims 200 and 201
Claims 200 and 201 are also indefinite because the ratios recited in each claim are unclearly defined. This is because line 2 of each claim uses “and” rather than “to” to separate “the first plurality of supports” and “the first plurality of template nucleic acid molecules.” The use of “and” rather than “to” creates uncertainty as to whether the ratio in each claim refers to first plurality of supports:first plurality of template nucleic acid molecules or first plurality of template nucleic acid molecules:first plurality of supports.
Claim Rejections - 35 USC § 103
9. 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.
10. 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.
11. Claims 182-201 are rejected under 35 U.S.C. 103 as being unpatentable over Hindson et al. (US 2014/0378322 A1) in view of Jayasena et al. (US 2004/0248299 A1).
The instant claims are drawn to a method for recycling solid supports used in a nucleic acid analysis method. As noted above, Applicant has elected “small molecules” as the species of blocking agent for examination.
Regarding claims 182, 183, and 187, Hindson discloses a method that comprises the following steps (see Fig. 4 and the accompanying description in paras. 183-192):
(a) contacting a first plurality of solid supports with a first plurality of template nucleic acid molecules to generate a first mixture of supports comprising a first plurality of positive supports and a first plurality of negative supports, wherein each of the first plurality of solid supports comprises a template nucleic acid molecule of the first plurality of template molecules bound to a support of the first plurality of solid supports, and wherein each of the first plurality of negative supports comprises a support of the first plurality of supports unbound to the first plurality of template nucleic acid molecules (see Fig. 4b, where the nucleic acid containing elements 404, 405, and 407 is the template nucleic acid; see also paras. 183-184 and 187);
(b) modifying the first plurality of positive supports to contain an affinity tag (Figs. 4d-4e and paras. 184-187, where biotin-labeled capture primer 406 is used to obtain positive supports in which the nucleic acid attached thereto contains biotin);
(c) isolating the first plurality of positive supports from the first mixture of supports using a plurality of capture moieties with affinity to the affinity tag (Figs. 4f-4g and para. 187, where beads lined to streptavidin 409 are taught); and
(d) contacting the first plurality of negative supports with a second plurality of template nucleic acid molecules to generate a second mixture of supports comprising a second plurality of positive supports and a second plurality of negative supports (see, e.g., paras. 187 and 192, where Hindson describes reprocessing negative beads “to generate additional positive beads”).
Further regarding claims 182, 183, and 187, in Figure 23, Hindson also teaches a method in which a double-stranded barcode-containing template nucleic acid (element 2306 in Fig. 23) is attached to beads via hybridization and ligation (Fig. 23B and paras. 212-213). Hindson goes on to teach using affinity capture to separate beads with barcodes (i.e., positive beads) from beads that lack barcodes (i.e., negative beads) (paras. 237-238, where biotin-containing positive beads are separated from negative beads using streptavidin) and also that a “capture moiety” (e.g., biotin) may be attached “to an internal sequence” or added via PCR or ligation (para. 241).
Hindson is not anticipatory for the following reasons. First, in the embodiment shown in Figure 4, the template nucleic acid (i.e., the nucleic acid containing elements 404, 405, and 407) does not contain an affinity tag that is later captured via a capture moiety as required by steps (a) and (b) of independent claim 182. Instead, the affinity tag (biotin) is added to a nucleic acid generated from the template nucleic acid (see Figs. 4d-4e and paras. 184-187, where capture primer 406 is used to incorporate biotin) and that affinity tagged nucleic acid is captured with the capture moiety (streptavidin). Second, it is not entirely clear that the embodiment shown in Figure 23 comprises forming the mixture of solid supports required by step (a) of claim 182 and then using affinity capture to separate positive beads from negative beads as also required by claim 182. Third, the method of Hindson does not use a blocking agent as required by step (c) of independent claim 182.
Prior to the effective filing date of the claimed invention, though, it would have been prima facie obvious for the ordinary artisan to practice the method of Hindson using a biotin-labeled template nucleic acid that is subsequently captured via streptavidin binding to separate positive supports containing the biotinylated template nucleic acid from negative supports that lack the template nucleic acid and are destined to be recycled/reprocessed. As discussed above, Hindson clearly teaches using biotin-streptavidin capture to separate positive supports from negative supports and then further processing the negative supports to obtain additional positive supports. The ordinary artisan in possession of the teachings of Hindson would have appreciated that the biotin affinity tag could be added to positive supports in a variety of ways, recognizing that what is important is that biotin is present on the positive supports to permit their separation from negative supports destined for further processing (i.e., recycling as recited in the last step of claim 182). Accordingly, the ordinary artisan would have had motivation and a reasonable expectation of success in practicing the method of Hindson using any of the following ways of adding a biotin affinity tag to the positive supports: (i) via a primer as disclosed in Figure 4, (ii) via a capture probe hybridized to a template nucleic acid attached to a positive support, or (iii) placing the affinity tag in the initial template to be attached to the positive support (e.g., to nucleic acid 2306 in Fig. 23). Thus, the teachings of Hindson suggest a method comprising steps (a), (b), and (d) of claim 182.
The above method suggested by Hindson does not use a blocking agent as required by step (c) of claim 182, but this also would have been an obvious modification in view of the teachings of Jayasena. In particular, Jayasena teaches that free biotin, which is a small molecule as recited in claims 184 and 185, may be used to block excess streptavidin (para. 194). The ordinary artisan practicing the method suggested by Hindson, which uses biotin-streptavidin binding to separate positive and negative supports, would have recognized that leftover capture moiety (streptavidin) could be present in the mixture containing the negative supports and lacking the positive supports. To prevent this leftover streptavidin from interfering with the further processing (recycling) of the negative supports, the ordinary artisan would have been motivated to add a blocking agent (i.e., free biotin as disclosed in para. 194 of Jayasena), recognizing that the teachings of Jayasena would apply to other methods that use biotin-streptavidin binding. Thus, it also would have been prima facie obvious to practice the method suggested by Hindson using a blocking agent as recited in claim 182 and further defined in claims 184 and 185.
Thus, the methods of claims 182-185 and 187 are prima facie obvious over Hindson in view of Jayasena.
Further regarding claim 186, it also would have been prima facie obvious to perform routine experimentation to determine the optimal concentration of the blocking agent (free biotin) used in the method suggested by Hindson in view of Jayasena. As discussed in MPEP 2144.05 II, it is prima facie obvious to conduct routine experimentation to optimize known results-effective variables, such as concentrations, in the absence of unexpected results. In this case, the ordinary artisan would have recognized that the blocking agent (i.e., free biotin) concentration should be optimized to maximize the ability to bind any leftover/remaining capture moiety (i.e., streptavidin) in the mixture comprising the negative supports while not interfering with the further processing steps taught in para. 192 of Hindson. Therefore, the ordinary artisan would have been motivated to conduct routine experimentation to determine the ideal concentration for the blocking agent and would have had a reasonable expectation of success since only routine experimentation would be required. Then, since no evidence of unexpected results has been presented with respect to the claimed concentration range of at least 100 pM, the claimed concentrations are prima facie obvious in view of the foregoing.
Further regarding claims 188-190, it also would have been prima facie obvious to repeat the steps set forth in claim 188, which describe multiple rounds of recycling negative supports to generate additional positive supports, as many times as desired (e.g., at least three times or at least five times as recited in claims 189 and 190, respectively) when practicing the method suggested by Hindson in view of Jayasena. Hindson teaches one round of “recycling” negative supports to obtain additional positive supports in para. 192. The ordinary artisan would have recognized that this recycling step could be performed as many times as desired (i.e., using the steps set forth in claim 188) to reduce the amount of waste (i.e., negative supports) at the end of the method. The ordinary artisan would have had a reasonable expectation of success since simply repeating the steps suggested by Hindson in view of Jayasena would be required. Thus, the methods of claims 188-190 are also prima facie obvious.
Further regarding claims 191 and 192, in the embodiment shown in Figure 23 of Hindson, the solid supports comprise surface primer molecules (element 2302, para. 212), and the template nucleic acids (element 2306, para. 212) are double-stranded molecules that comprise an overhang that is complementary to (and hybridizes to) the surface primer (Fig. 23B, paras. 212-213). The template nucleic acids may also contain an adapter at each end (paras. 212-215). More specifically, the partial P5 sequence in template 2306 is an adapter as is the short overhang at the other end of the nucleic acid. Therefore, the first adapter sequence in template 2306 contains the required overhang that hybridizes to the surface primer. Thus, the method suggested by Hindson in view of Jayasena includes the requirements of claims 191 and 192.
Further regarding claim 193, Hindson further teaches that the first adapter may be ligated to the surface primer to generate positive supports (Fig. 23 and para. 213). Thus, the method of claim 193 is also suggested by Hindson in view of Jayasena.
Further regarding claim 194, it also would have been prima facie obvious to place the affinity tag (biotin) within the second adapter in the template nucleic acid 2306 of Hindson. As discussed above with respect to claim 182, the ordinary artisan would have recognized from the teachings of Hindson that the affinity tag could be placed within a template nucleic acid, especially when the method does not include amplification. Accordingly, the ordinary artisan would have been motivated to include the affinity tag at the end of template nucleic acid 2306 furthest from the surface primer (i.e., in the second adapter portion of the template) to facilitate separation of positive supports from negative supports in the subsequent affinity capture step. Thus, the method of claim 194 is also prima facie obvious.
Further regarding claims 195, 196, 198, and 199, the first and second adapter in the template nucleic acid of Hindson may contain a cleavable moiety. Hindson teaches that X at each end of template 2306 may be a C3 spacer (para. 212). As evidenced by the specification of the instant application in para. 110 on page 11 of the clean copy of the substitute specification, a C3 spacer is a cleavable moiety. As well, further regarding claims 196 and 199, the teachings in, e.g., paras. 23, 26, 151, 211, 214 of Hindson also suggest that uracil may be included in the first and/or second adapter in template 2306.
Further regarding claim 197, it also would have been prima facie obvious to cleave the cleavable moiety in the template nucleic acid of Hindson. First, the presence of a cleavable moiety in a nucleic acid suggests a subsequent cleavage step. Hindson also provides motivation to perform a cleaving step by teaching that a cleavable moiety may be cleaved to release a nucleic acid of interest from a bead (see, e.g., paras. 5, 98, and 255). The ordinary artisan also would have recognized that one appropriate time to cleave the cleavable moiety, thereby releasing a nucleic acid of interest from a bead, would be after isolating positive supports containing said nucleic acid of interest. Therefore, the method of claim 197 is also prima facie obvious.
Further regarding claims 200 and 201, as discussed above in the indefiniteness rejection, the required ratios are not entirely clear, but it would nevertheless have been prima facie obvious to perform routine experimentation to determine the optimal relative amounts of the first plurality of supports and the first plurality of template nucleic acids when practicing the method suggested by Hindson in view of Jayasena. As discussed in MPEP 2144.05 II, it is prima facie obvious to conduct routine experimentation to optimize known results-effective variables, such as concentrations, in the absence of unexpected results. In this case, the ordinary artisan would have recognized that relative amounts of the first plurality of supports and the first plurality of template nucleic acids should be optimized to maximize the number of positive supports resulting from combining the supports and template nucleic acids while minimizing nonspecific binding or other undesired reaction events. Therefore, the ordinary artisan would have been motivated to conduct routine experimentation to determine the ideal relative amounts of the first plurality of supports and the first plurality of template nucleic acids and would have had a reasonable expectation of success since only routine experimentation would be required. Then, since no evidence of unexpected results has been presented with respect to the claimed ratios, they are prima facie obvious in view of the foregoing.
Conclusion
12. No claims are currently allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Angela Bertagna whose telephone number is (571)272-8291. The examiner can normally be reached 8-5, M-F.
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/ANGELA M. BERTAGNA/Primary Examiner, Art Unit 1681
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