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 Claims 4-6, 9-15, and 17-21 have been withdrawn.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/01/2026 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.
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 will be interpreted according to Applicant’s statement on pg. 7 of the Response:
“The plain meaning of ‘only’ limits the method to contacting the random subset and nothing more.”
The limitation will therefore be interpreted in accordance with Applicant’s admission that the method is limited to a single random subset, and excludes the performance of the method 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
Applicant argues that the interpretation reads the word “only” out of the claim. Applicant states that claim 1 recites “individually contacting only a random subset of the library of SNAs with a cell,” and that the plain meaning of “only” limits the method to contacting the random subset and nothing more. Applicant further states that if the method were performed multiple times on different subsets until the whole library is tested, the method would not contact “only” a random subset – it would contact the entire library.
This is not found persuasive. As described above, both Radovic-Moreno and Gurard-Levin show that the library can be separated into random subsets. Furthermore, it would be obvious to one of ordinary skill in the art to use only 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.
Applicant argues that the interpretation renders “thereby assessing the SAR of the library of SNAs” superfluous. Applicant states that claim 1 recites two distinct phrases: (i) “thereby assay the activity of each SNA in the random subset of the library of SNAs” and (ii) “thereby assessing the SAR of the library of SNAs.” Applicant states that if “assessing the SAR of the library” means nothing more than assaying the activity of the subset, then the second phrase adds nothing and is superfluous. Applicant states that the phrase “of the library of SNAs” as opposed to “of the random subset” must be given meaning and that it indicates that the SAR assessment extends to the library as a whole, not just the tested subject.
This is not found persuasive. As stated above, 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. Step (e) of the claim recites the active step of correlating the product signal intensity to the substrate signal intensity to determine the extent of product formation. The following limitations of “thereby assay the activity of each SNA in the random subset of the library of SNAs,” and “thereby assessing the SAR of the library of SNAs” do not impart additional structural limitations on the claim or recite additional steps required in the method. The limitations “thereby assay the activity of each SNA in the random subset of the library of SNAs,” and “thereby assessing the SAR of the library of SNAs” are merely reciting a description of the results achieved by the method. The limitation “correlating the product signal intensity to the substrate signal intensity to determine the extent of product formation” is interpreted as the structural limitation which necessarily results in the assaying the activity of each SNA in the random subset of the library of SNAs and results in the assessing the SAR of the library of SNAs. The claim does not require additional method steps to occur in order to assay the activity of each SNA in the random subset of the library of SNAs or to assess the SAR of the library of SNAs. Therefore, the argument is not persuasive.
Applicant states that the interpretation is internally inconsistent with the meaning of “SAR.” Applicant states that “structure-activity relationships” by definition requires examining the relationship between different structures and their activities. Applicant states that if the method does not require examining the relationship between different library members, then it cannot be “assessing the SAR” of anything. Applicant states that the interpretation contradicts the plain meaning of “SAR” as recited in the claim.
This is not found persuasive. As described above, the claims do not require additional method steps to occur in order to assay the activity of each SNA in the random subset of the library of SNAs or to assess the SAR of the library of SNAs. The claim as written only requires correlating the product signal intensity to the substrate signal intensity to determine the extent of product formation. The claim, as written, states “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.” As described above, this language indicates that the only steps required to assess the SAR of the library of SNAs is to correlate the product signal intensity to the substrate signal intensity to determine the extent of product formation.
The claim does not recite any specific limitation requiring the examination of the relationship between different structures and their activities beyond correlating the product signal intensity to the substrate signal intensity to determine the extent of product formation. Nor any specific method. Additional examination is not required. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
The claim, as written, indicates that only the correlation of the product signal intensity to the substrate signal intensity to determine the extent of product formation is needed to assay the activity of each SNA in the random subset of the library of SNAs and to assess the SAR of the library of SNAs. The claim, as written, does not require any examination, correlation, prediction, or analysis of the library as a whole, and does not state any additional steps needed to achieve the result of assessing the SAR of the library of SNAs. Therefore, the argument is not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant states that neither Radovic-Moreno nor Gurard-Levin disclose or suggests a method where only a random subset of an SNA library is tested while the remainer is left untested to assess the SAR of the entire library. Applicant states that Radovic-Moreno does not disclose contacting “only a random subset” of an SNA library, and that Radovic-Moreno describes randomizing mice into treatment groups and does not describe randomly selecting a subset of SNAs from a library. Applicant further states that Gurard-Levin does not disclose contacting “only a random subset” of a library and instead screens all 40 plates as a logistical step for handling the entire library, not a deliberate selection of only a random subset.
This is not found persuasive. The claim does not require a particular method of selecting the random subset or method of contacting the random subset with a cell. Randomizing the mice into groups of eight fulfills the limitation of “only a random subset of the library of SNAs” as the claim does not require any particular method of individually contacting only a random subset of the library of SNAs with a cell. Gurard-Levin separates the library into 40 plates, and each plate is analyzed. As the claim does not exclude performing the method of claim 1 multiple times, Gurard-Levin fulfills the limitations of the claim.
Applicant states that neither reference discloses or suggests a method where only a random subset of an SNA library is tested while the remainder is left untested. This is not found persuasive as the claim as written does not require the remainder of the library to be left untested.
However, if the claim did require the remainder of the library to be left untested, the prior art makes obvious only using a random subset of the library. 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).
Regarding the argument that the motivation is directed at the wrong goal, this is not found persuasive. Applicant states that the motivation to test a subset because of practical constraints, such as equipment limitations and time savings, leads to testing fewer compounds and obtaining less information, not to testing fewer compounds and obtaining the same SAR information as testing the whole library. This is not found persuasive. MPEP 2144(IV) states that rationale different from applicant’s is permissible. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. Furthermore, MPEP 2145(II) states that mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. As Radovic-Moreno in view of Gurard-Levin teaches the method of claim 1, the claims are obvious and the argument is not persuasive.
Applicant further argues that there would not be a reasonable expectation of success in achieving the claimed result. Applicant states “the Office has not established a reasonable expectation of success in achieving the claimed result. The Office has alleged that ‘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.’ Action pg. 8. However, this addresses only the expectation of success in physically performing the assay steps on a subset – not the expectation of success in achieving the claimed result of ‘assessing the SAR of the library of SNAs’ from only a random subset.” Applicant cites par. 0027 which states that “machine learning was utilized to quantitatively model the enzyme activation of SNAs, and then applied to identify the minimum number of SNAs needed to capture optimum structure-activity relationships for a given library. By doing so, one can reduce the number of nanoparticles to be tested by an order of magnitude, and still get the same information from screening the entire library.” Applicant states that this teaching demonstrates that the ability to assess library-wide SAR from a small random subset was an unexpected discovery, not an obvious result.
This is not found persuasive. As stated above, MPEP 2145(II) states that mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. Is it Applicant’s contention that limiting the assay to a subset is not within the skill of an artisan? The claims do not have an active, specific step of assessing the SAR of the entire library of SNAs. The claims only describe the assay steps, and state the result of the method without requiring additional limitations to assay the activity of each SNA in the random subset of the library of SNAs and to assess the SAR of the library of SNAs. Furthermore, the claims do not require the machine learning step in par. 0027 of the specification as cited by Applicant. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Randi L Beil whose telephone number is (571)272-1147. The examiner can normally be reached M-F 8:00 am - 5:00 pm.
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, Heather Calamita can be reached at 571-272-2876. 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.
/R.L.B./Examiner, Art Unit 1684 /AARON A PRIEST/Primary Examiner, Art Unit 1681
Prosecution Insights