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 1-6, 8-9, 11, 15, 19, 25-27, 38-42, 45-47, 49, 62-63, 67, 79, 82, 85-86, 90-91, 93, 96, 99-101, 124, 149, 182, 192-193, 198, 201, 203, and 218 are pending. Claims 1, 4, 6, 9, 11, 19, 25, 26, 27, 38-42, 46-47, 49, 62-63, 67, 79, 82, 85, 86, 90, 91, 93, 96, and 99-101 are rejected. Claims 2-3, 5, 8, 15, 45, 124, 149, 182, 192-193, 198, 201, 203, and 218 are withdrawn.
Information Disclosure Statement
The Information Disclosure Statement (IDS) submitted on 5/10/2024 was considered by the Examiner.
Election/Restrictions
Applicant’s election of Group I and the following species:
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, in the reply filed on 7/27/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). **Examiner corrected and is including claim 79 in Group I.
Claims 1, 4, 6, 9, 11, 19, 25, 26, 27, 38-42, 46-47, 49, 62-63, 67, 79, 82, 85, 86, 90, 91, 93, 96, and 99-101 embrace Applicant’s elected species and are therefore under examination. The elected species is free of the art. As per MPEP 803.02, “Following election, the Markush claim will be examined fully with respect to the elected species and further to the extent necessary to determine patentability.” The search and examination have been expanded to included non-elected species rejected below under 35 USC 103.
Claims 2-3, 5, 8, 15, 45, 124, 149, 182, 192-193, 198, 201, 203, and 218 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claim Objections
Claim 27 is objected to because of the following informalities: Line 1 should read: “A compound selected from the group consisting of:”. Appropriate correction is required.
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.
Claim(s) 1, 4, 6, 9, 11, 19, 25, and 26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Finlay et al. (WO2018114999- as disclosed on 5/10/2024 IDS). (REJECTION “A” OVER FINLAY).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Finlay et al. disclose the following DNA-PK inhibitor useful in the treatment of cancer (see abstract) with Example 6 on p. 71:
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, which is similar to a compound of instant Formula I:
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, wherein R1 = C1 alkyl (methyl); R2= cycloalkyl substituted with one R6, R6 = methoxy; x1= N; R4 = H; R5 = C1 alkyl (methyl); R7 = H.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art compound differs from the instant claims in that R1 = methyl instead of “R1 = C2-C3 alkyl”.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Regarding instant claims 1, 4, 6, 9, 11, 19, 25, and 26, the prior art is a homolog of the instant claims, wherein the instant R1 location may differ by one carbon chain (i.e., ethyl vs. methyl). “Structural relationships may provide the requisite motivation or suggestion to modify known compounds to obtain new compounds. For example, a prior art compound may suggest its
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homologs because
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homologs
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often have similar properties and therefore chemists of ordinary skill would ordinarily contemplate making them to try to obtain compounds with improved properties.” In re Deuel 34 USPQ2d 1210 at 1214. Furthermore MPEP 2144.09 (II) states: “Compounds which are […] homologs (…) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).” A PHOSITA would have had a reasonable expectation of success in arriving at the instant claims because the properties of the homologs would have been similar as a result of their similar chemical structure (both DNA-PKI).
Claim(s) 1, 4, 6, 9, 25, 26, and 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Finlay et al. (WO2018114999- as disclosed on 5/10/2024 IDS). (REJECTION “B” OVER FINLAY).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Finlay et al. teach the following DNA-PK inhibitor useful in the treatment of cancer (see abstract) with Example 3 on p. 63:
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, which is similar to a compound of instant Formula I:
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, wherein R1 = C1 alkyl (methyl); R2 = heterocyclyl,
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; x1 = N; R4 = H; R5 = C1 alkyl (methyl); R7 = H.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art compound differs from the instant claims in that R1 = methyl instead of “R1 = C2-C3 alkyl”.
Regarding specifically instant claim 27, the prior art differs by one hydrocarbon group from the first compound listed in instant claim 27:
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(arrow added by Examiner).
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Regarding instant claims 1, 4, 6, 9, 25, 26, and 27, the prior art is a homolog of the instant claims, wherein the instant R1 location may differ by one carbon chain (ethyl vs. methyl). “Structural relationships may provide the requisite motivation or suggestion to modify known compounds to obtain new compounds. For example, a prior art compound may suggest its
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homologs because
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homologs
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often have similar properties and therefore chemists of ordinary skill would ordinarily contemplate making them to try to obtain compounds with improved properties.” In re Deuel 34 USPQ2d 1210 at 1214. Furthermore MPEP 2144.09 (II) states: “Compounds which are […] homologs (…) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).” A PHOSITA would have had a reasonable expectation of success in arriving at the instant claims because the properties of the homologs would have been similar as a result of their similar chemical structure (both DNA-PKI).
Claim(s) 49 is/are rejected under 35 U.S.C. 103 as being unpatentable over Finlay et al. (WO2018114999- as disclosed on 5/10/2024 IDS) [Finlay rejection “B” supra], as applied to claims 1, 4, 6, 9, 25, 26, and 27 above, and further in view of Su et al. (Scientific Reports, 6:20070, 2016, 1-13).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Finlay rejection “B” teaches a DNA-PKI compound which renders a compound of claim 27 obvious (see 103 rejection “B” supra). Finlay fails to teach a composition also comprising a DNA cutting agent.
Su et al. teach CRISPR Cas 9 as a genome editing tool: “The CRISPR-Cas9 system conferring targeted gene editing by small RNAs that guide the Cas9 nuclease to the target site through base pairing has been demonstrated as an easy-handle, highly specific, efficient approach for engineering eukaryotic genomes. In our previous work we had achieved efficient gene targeting in mice and rats by co-injection of one-cell-stage embryos with Cas9 mRNA and sgRNAs [single guide RNA]….” (see p. 2, first full para.) (DNA cutting agent). Su’s study found the importance of CRISPR-Cas9 genome editing for the disruption of immune inhibitory checkpoints and the potential in adoptive T-cell [immune cell] transfer therapy of cancer (see p. 2, second full paragraph).
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
There is not a single embodiment in the prior art of a specific DNA protein kinase inhibitor of instant claim 27 with a DNA cutting agent.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Regarding instant claim 49, it would have been obvious to a PHOSITA to combine both a DNA-PKI of instant claim 27 with a DNA cutting agent, such as CRISPR/Cas 9 nuclease, as both have been found useful in the treatment of cancer. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072. See MPEP 2144.06(I). A skilled artisan would have been motivated to combine DNA-PKI of the instant claims with a DNA cutting agent, such as CRISPR/Cas 9 nuclease, in an effort to enhance and improve cancer treatment, with a reasonable expectation of success.
Claim(s) 38, 39, 40, 41, 42, 46-47, 62-63, 67, 79, 82, 85, 86, 91, and 93 is/are rejected under 35 U.S.C. 103 as being unpatentable over Finlay et al. (WO2018114999- as disclosed on 5/10/2024 IDS), in view of Su et al. (Scientific Reports, 6:20070, 2016, 1-13), and further in view of Rhun et al. (RNA Biology, 2019, 16:4, 380-389).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Finlay et al disclose the following DNA-PK inhibitor useful in the treatment of cancer (see abstract) with Example 6 on p. 71:
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, which is embraced by a compound of instant Formula I:
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, wherein R1 = C1 alkyl (methyl); R2= cycloalkyl (cyclohexyl) substituted with one R6, R6 = methoxy; x1= N; R4 = H; R5 = C1 alkyl (methyl); R7 = H. Finlay does not teach a composition also comprising a DNA cutting agent nor an immune (eukaryotic) cell or guide RNA.
Su et al. teach CRISPR Cas 9 as a genome editing tool: “The CRISPR-Cas9 system conferring targeted gene editing by small RNAs that guide the Cas9 nuclease to the target site through base pairing has been demonstrated as an easy-handle, highly specific, efficient approach for engineering eukaryotic genomes. In our previous work we had achieved efficient gene targeting in mice and rats by co-injection of one-cell-stage embryos with Cas9 mRNA and sgRNAs [single guide RNA]….” (see p. 2, first full para.) (DNA cutting agent). Su’s study found the importance of CRISPR-Cas9 genome editing for the disruption of immune inhibitory checkpoints and the potential in adoptive T-cell [eukaryotic immune cell] transfer therapy of cancer (see p. 2, second full paragraph). “In our study, we described, for the first time, a new approach of inhibiting PD-1/PD-L1 co-stimulation by directly disrupting genome PD-1 expression on human primary T cells through the Cas9:sgRNA gene knock out system” (see p. 9, second full para.). “Interestingly, our approach to disrupt PD-1 expression on human T cells was successfully utilized on several cancer patients and healthy donors…” (see p. 9, bottom para.) Su does not teach a Cas9 nuclease specifically derived from S. pyogenes.
Rhun et al. teach a review of CRISPR-Cas in S. pyogenes (see title), particularly a CRISPR-Cas9 system (see abstract). “Despite the fact that most applications emerged after the discovery of the type II-A CRISPR-Cas9 system of Streptococcus pyogenes, its biological importance in this organism has received little attention. Here, we provide a comprehensive overview of the current knowledge about CRISPR-Cas systems from S. pyogenes” (see abstract).
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
There is not a single embodiment in the prior art of a specific DNA protein kinase inhibitor of instant claim 38 with a DNA cutting agent. Additional dependent limitations will be addressed below.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Regarding instant claims 38-42 and 46-47, it would have been obvious to a PHOSITA to combine both a DNA-PKI of the instant claims with a DNA cutting agent, such as CRISPR/Cas 9 nuclease, as both have been found useful in the treatment of cancer. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072. See MPEP 2144.06(I). A skilled artisan would have been motivated to combine DNA-PKI of the instant claims with a DNA cutting agent, such as CRISPR/Cas 9 nuclease, in an effort to enhance and improve cancer treatment, with a reasonable expectation of success.
Regarding instant claims 62-63, 67, 79, 82, 85-86, the prior art teaches the importance and potential of CRISPR/Cas9 nuclease technology (typically derived from S. pyogenes) in T-cell (immune eukaryotic cell) transfer therapy. It would have been obvious to a skilled artisan to include a eukaryotic immune cell, such as a human T cell, in the instantly claimed composition to find novel and effective ways to treat cancer. Additionally, a PHOSITA would have been motivated, prior to the effective filing date of the claimed invention, to utilize a Cas9 nuclease from S. pyogenes, with a reasonable expectation of success.
Regarding instant claims 91 and 93, co-injection of sgRNA (type of guide RNA nucleic acid) and Cas9 mRNA were successful in efficient gene targeting in mice and rats. A skilled artisan would have had a reasonable expectation of success in combining such components in a single composition for genome editing.
Claim(s) 90, 96, 99, 100, and 101 is/are rejected under 35 U.S.C. 103 as being unpatentable over Finlay et al. (WO2018114999- as disclosed on 5/10/2024 IDS), Su et al. (Scientific Reports, 6:20070, 2016, 1-13), and Rhun et al. (RNA Biology, 2019, 16:4, 380-389), applied to claims 38, 39, 40, 41, 42, 46-47, 62-63, 67, 79, 82, 85, 86, 91, and 93 above, and further in view of Lee et al. (eLife, 2017, 6:e25312, 1-17) and Rosenblum (Sci. Adv., 2020, 6: eabc9450, 1-12).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Finlay, Su and Rhun fail to disclose a modified (g)RNA, donor DNA, or lipid nanoparticle composition.
Lee et al. disclose that modified guide RNA (gRNA) (type of “modified RNA”) and donor DNA are a versatile platform for CRISPR-Cas9 engineering (see title). Lee demonstrates that gRNA’s of Cas9 and donor DNA can be chemically modified at their terminal positions without losing activity (see abstract). “The tolerance of the gRNA and the donor DNA to chemical modifications has the potential to enable new strategies for genome engineering” (see abstract). “Adding a ‘donor’ DNA molecule that contains the desired ‘edit’ can lead to the cell repairing the broken gene in a way that incorporates the desired change” (see p. 2, first para.) Lee additionally discloses a gRNA/donor DNA(“gDonor”)/Cas9 complex which can bind polycations and results in a nanoparticle formulation (see Figure 1) but does not specifically teach lipid nanoparticles.
Rosenblum teaches a targeted nonviral lipid nanoparticle delivery system for therapeutic genome editing and evaluates it in two aggressive and incurable cancer models (see p. 1, middle para, right column). Specifically, Rosenblum developed and characterized lipid nanoparticles encapsulating Cas9 mRNA and sgRNA (see p. 1, bottom right). Lipid nanoparticles are clinically approved nonviral nucleic acid delivery systems capable of delivering large payloads, such as Cas9 and sgRNA (see Introduction, p. 1).
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art fails to disclose a single embodiment of a DNA-PKI, DNA cutting agent, modified (g)RNA, donor DNA, or lipid nanoparticle composition. Additional dependent limitations will be addressed below.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Regarding instant claims 90 and 96, it would have been obvious to a skilled artisan to include modified (g)RNA in the instant composition in an effort to improve gene editing efficiency of CRISPR/Cas9 technology. The terminal positions modified and taught by the prior art are embraced by the “first five nucleotides” at the 5’ or 3’ end, such that a PHOSITA would have had a reasonable expectation of success in modifying the first five nucleotides at either end of an RNA strand and maintaining required activity. Regarding instant claims 99-100, a skilled artisan would have been motivated to incorporate a donor DNA that could code an “edit” for either a protein, regulatory sequence, or structural DNA with a reasonable expectation of success because DNA codes for RNA, which in turn codes for protein. Regarding instant claim 101, a skilled artisan would have been motivated to arrive at a lipid nanoparticle (LNP) composition in an effort to improve delivery and gene targeting of the instantly claimed composition, which is considered a large payload.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MEGHAN C HEASLEY whose telephone number is (571)270-0785. The examiner can normally be reached Monday - Friday 8:30-4:30 PM.
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/MEGHAN C HEASLEY/Examiner, Art Unit 1626
/MATTHEW P COUGHLIN/Primary Examiner, Art Unit 1626
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