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 the Claims
Claims 1-15, 17-26, and 37-42 are pending. Claims 1-3, 7-8, 22-26, and 37-42 are the subject of this FINAL Office Action. Claims 4-6, 9-15, and 17-21 have been withdrawn. Claims 37-42 are new.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 08/19/2025 has been entered.
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.
Response to Arguments –112 Rejections
Applicant’s amendments to the claims have overcome the 112(b) rejections previously set forth in the Final Office Action of 07/12/2024. The 112(b) rejections have been withdrawn.
Claim Interpretation
Claim 1 has been amended to recite the limitation “individually contacting only a random subset of the library of SNAs with a cell.” This limitation is interpreted as any random subset of any size. The limitation does not exclude performing the method of claim 1 multiple times or in parallel.
The claims do not require any particular method of choosing which members of the library comprise the random subset of the library. The claim is therefore interpreted as encompassing any method or rationale of splitting up a library into random portions.
The claims do not require a particular library of oligonucleotide-functionalized SNAs, and do not require a particular library size. The claim will be interpreted as encompassing any library of oligonucleotide-functionalized SNAs, where the library consists of at least two SNAs such that the library can be dividing into subsets consisting of one SNA.
Claim 1 recites “thereby assessing the SAR of the library of SNAs.” This statement is interpreted as stating the result of the method, but does not impart any additional requirements or limitations on the method of the claims. The claim is interpreted as only requiring correlating the product signal intensity to the substrate signal intensity to determine the extent of product formation, with no additional method steps required.
Maintained - 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.
Claim(s) 1-3, 7-8, and 22-26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Radovic-Moreno et al. (Immunomodulatory spherical nucleic acids. PNAS. 112, 2015, 3892-3897; cited on the 8 pg. IDS filed 03/28/2024 beginning with Mrksich) in view of Gurard-Levin et al. (High-throughput screening of small molecule libraries using SAMDI mass spectrometry. ACS Comb. Sci. 13, 2011, 347-350; cited on the 10 pg. IDS filed 03/28/2024).
Regarding claim 1, Radovic-Moreno teaches a method of screening a library of oligonucleotide-functionalized spherical nucleic acids (Abstract).
Radovic-Moreno teaches a library of oligonucleotide-functionalized spherical nucleic acids (SNAs) (pg. 3892, right col., par. 2; pg. 3893, right col., par. 1). Radovic-Moreno then teaches contacting each SNA of the library with a cell (Fig. 1; pg. 3893, left col., par. 2). Radovic-Moreno further teaches that the cell modulates expression of an enzyme in proportion to the activity of the SNA (pg. 3893, left col., par. 1; Fig. 2; Supporting Information, pg. 1, left col., par., 2).
Radovic-Moreno describes various experiments using the library of SNAs (pg. 3894, right col., par. 3; Fig. S2; S3A), and states that the activity of SNAs were tested in the STAM mouse model, which were randomized into groups of 8 (pg. 3897, right col., par. 3). The use of the SNAs in various experiments indicate that the library can be divided into separate portions for different experiments. Additionally, as the STAM mouse model test required the mice to be randomized into groups of 8, this fulfills the limitation of “only a random subset of the library of SNAs.”
Radovic-Moreno does not teach the contacting of the expressed enzyme with a substrate to transform the substrate to a product, immobilizing the product and the substrate on a self-assembled monolayer on a surface, and subjecting the immobilized substrate and product to mass spectrometry.
Gurard-Levin teaches a method of high-throughput screening of small molecule libraries using a combination of self-assembled monolayers and mass spectrometry (Abstract).
Gurard-Levin teaches contacting an expressed enzyme with a substrate to transform the substrate to a product, wherein the product has a mass different from the substrate (pg. 348, left col., par. 3; pg. 348, right col., par. 1-3; Fig. 1)
Gurard-Levin teaches separating the library into 40 plates, each comprising 2560 compounds out of a total of 102,400 compounds (pg. 348, left col., par. 3), which is 2.5% of the total library. This would therefore fulfill the limitation using only a random subset of the library.
Gurard-Levin teaches immobilizing the product and the substrate on a self-assembled monolayer on a surface (Fig. 1; pg. 347, left col., par. 2; pg. 347, right col., par. 1).
Gurard-Levin teaches subjecting the immobilized substrate and product to mass spectrometry to produce a mass spectrum having a product signal and substrate signal (pg. 348, right col., par. 2).
Gurard-Levin then teaches correlating the product signal intensity to the substrate signal intensity to assess activity (pg. 347, left col., par. 2; pg. 348, right col., par. 2).
It would have been obvious to one of ordinary skill in the art at the time to filing to use the method of Gurard-Levin to analyze the activity of the SNAs used in Radovic-Moreno. Radovic-Moreno teaches the screening of SNAs in contact with a cell, wherein the cell modulates expression of an enzyme in proportion to the activity of the SNA (pg. 3893, left col., par. 1; Fig. 2; Supporting Information, pg. 1, left col., par., 2).
Gurard-Levin teaches a high-throughput screening method for identifying molecules that modulate enzymatic activities (pg. 347, left col., par. 1). Gurard-Levin further teaches that this method eliminates steps associated with installing and observing fluorescent labels, which can perturb enzyme activities, and teaches that mass spectrometry methods can observe each of the species present in a reaction and therefore provides a more complete assessment of activity (pg. 347, left col., par. 1-2).
It therefore would be obvious to one of ordinary skill in the art to use the method of Gurard-Levin to assess the activity of the SNAs as taught by Radovic-Moreno, as Gurard-Levin teaches that this method provides the benefits of eliminating the inclusion of fluorescent labels which can perturb enzyme activities and providing a more complete assessment of activity (pg. 347, left col., par. 1-2), with no evidence of unexpected results.
Furthermore, it would be obvious to one of ordinary skill in the art to perform the method of claim 1 with a random subset of the library of SNAs, as one of ordinary skill in the art would recognize that a large library can be divided into smaller portions. For example, 384 well plates, such as taught by Gurard-Levin (Fig. 2), would limit the amount of library members that can be screened. Other limitations which would lead to using a subset of a library would include time constraints e.g. Gurard-Levin teaches the screening of over 100,000 compounds was completed in 24 hours (pg. 349, left col., par. 2). Reducing the size of library to be screened would thus reduce the time of the screening.
As the claims do not require a method of choosing the subset of the library, and does not require interactions between the library members, one of ordinary skill in the art would have a reasonable expectation of success in performing the method with any random subset of the library.
Regarding claim 2, Radovic-Moreno teaches that at least one SNA in the library further comprises an antigen (pg. 3895, left col., par. 5).
Regarding claims 3 and 7, Radovic-Moreno teaches that the SNAs of the library differ in at least one structural parameter, and the structural parameter is an antigen composition (pg. 3895, left col., par. 5).
Regarding claim 8, Radovic-Moreno teaches the antigen composition comprises ovalbumin (pg. 3895, left col., par. 5).
Regarding claim 22, Radovic-Moreno does not teach that each SNA in the less than or equal to 25% of the library of SNAs is in a separate well of a multiwell plate. Radovic-Moreno does teach plating cells in a multi-well plate (Supplemental Information, pg. 2, right col., par. 2). Gurard-Levin teaches organizing a compound library into pools of eight molecules in 384-well plates (pg. 348, left col., par. 3).
It would have been obvious to one of ordinary skill in the art to have each SNA in the less than or equal to 25% of the library in a separate well, as it would allow for the comparison and analysis of each individual SNA of the less than or equal to 25% of the library, with no evidence of unexpected results.
Regarding claims 23-25, Gurard-Levin teaches the self-assembled monolayer comprises an immobilizing moiety that interacts with and immobilizes the substrate and the product, wherein the immobilizing moiety comprises a maleimide and the substrate and the product each comprise and alkane thiol (Fig. 1).
Regarding claim 26, Radovic-Moreno teaches that the cell line used expresses a secreted alkaline phosphatase (Supplemental Information, pg. 1, left col., par. 2).
Claim(s) 37-42 is/are rejected under 35 U.S.C. 103 as being unpatentable over Radovic-Moreno et al. (Immunomodulatory spherical nucleic acids. PNAS. 112, 2015, 3892-3897; cited on the 8 pg. IDS filed 03/28/2024 beginning with Mrksich) in view of Gurard-Levin et al. (High-throughput screening of small molecule libraries using SAMDI mass spectrometry. ACS Comb. Sci. 13, 2011, 347-350; cited on the 10 pg. IDS filed 03/28/2024).
Regarding claims 37-42, Radovic-Moreno required the mice to be randomized into groups of 8, which would result in each mouse in a single group receiving at most 12.5% of the library (pg. 3897, right col., par. 3). Gurard-Levin teaches separating the library into 40 plates, each comprising 2560 compounds of a total of 102,400 compounds, which is 2.5% of the total library (pg. 348, left col., par. 3).
Response to Arguments – 103 Rejections
Applicant states that neither Radovic-Moreno nor Gurard-Levin disclose or suggest a method of assessing structure-activity relationships of a library of SNAs, where only a random subset of the library of SNAs is analyzed in order to assess the SAR of the entire library of SNAs. This is not found persuasive for the reasons detailed above.
Both Radovic-Moreno (pg. 3894, right col., par. 3; Fig. S2; S3A; pg. 3897, right col., par. 3) and Gurard-Levin (pg. 348, left col., par. 3) teach separating a large library into smaller portions. Additionally, it would be obvious to one of ordinary skill in the art to use a random subset of a library of SNAs, as one of ordinary skill in the art would recognize that a large library can be divided into smaller portions due to limitations such as the equipment (e.g. 384 well plates, such as taught by Gurard-Levin (Fig. 2), would limit the amount of library members that can be screened) or time constraints (e.g. Gurard-Levin teaches the screening of over 100,000 compounds was completed in 24 hours (pg. 349, left col., par. 2); reducing the size of library to be screened would thus reduce the time of the screening).
Applicant further states that par. 0091 of the application teaches that one advantage of the claimed method is that a small number of randomly selected SNAs can predict structure-activity relationships (SARs) of a large SNA library. Applicant states this teaching was unpredictable and allows one to study and predict the SAR of tens of thousands of SNAs with a much smaller subset of SNA structures, therefore there could not have been a reasonable expectation of success at arriving at the method of amended claim 1.
This is not found persuasive. Claim 1 does not require any analysis of the library as a whole. Step (e) requires correlating the product signal intensity to the substrate signal intensity to determine the extent of product formation and thereby assay the activity of each SNA in the random subset of the library of SNAs, thereby assessing the SAR of the library of SNAs. The method is performed on each SNA in the library individually and does not describe any additional method steps to achieve the assessing the SAR of the library of SNAs.
The claims do not require prediction of structure-activity relationships of a large SNA library from a small number of randomly selected SNAs. The claims only require correlating the product signal intensity to the substrate signal intensity to determine the extent of product formation, which does not require examining the relationship between different library members.
Furthermore, par. 0091 describes using an xgboost model to identify the point of diminishing returns by balancing the minimum number of SNAs with maximum Q2. The paragraph further states that “[c]ombined with high-throughput SNA synthesis described above, the machine learning analysis showed that a combined experimental/computational method can probe and predict the SAR of tens of thousands of SNAs with a much smaller subset of structures.” The claims do not require analysis of the structure-activity relationship of a library, and do not require any machine learning analysis or prediction. As the asserted unpredictable teachings are relevant to features not recited in the claims, this argument is not persuasive.
Additionally, par. 0091 states “this external Q2 (prediction of non-synthesized SNAs) cannot be measured with a randomized sub-sample, but an internal Q2 can be measured by cross-validating within the randomized sub-sample. It is shown herein that the internal and external Q2 are highly correlated (Figure 7d and Figure 9), suggesting that the point of diminishing returns can be identified as SNAs are continually synthesized from an arbitrary library size.”
From this statement, it is not clear that the teaching that a random subset of a library of SNAs can predict structure-activity relationships of a large SNA library is applicable every possible SNA library. The machine learning model was trained on a random selection of SNAs from the library and was tested on the remaining unselected SNAs within the three subsets of the library (par. 0091). While these results are applicable to the library used in the specification, the claim encompasses any library of oligonucleotide-functionalized SNAs.
Finally, the statement “the point of diminishing returns can be identified as SNAs are continually synthesized from an arbitrary library size” does not indicate that a random subset of a library of SNAs can predict structure-activity relationships of a large SNA library is applicable to every possible SNA library. Rather, this statement is interpreted as indicating that while a smaller subset of SNAs can be used to predict structure-activity relationships of a large SNA library, this analysis must be performed for every library used and does not guarantee that every possible random subset of every possible SNA library can be used.
Therefore, Applicant’s arguments are not found persuasive.
Conclusion
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.
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/R.L.B./Examiner, Art Unit 1684 /AARON A PRIEST/Primary Examiner, Art Unit 1681