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 .
This action is in response to the amendment filed 03/18/2026, in which claims 1 and 15-20 were amended and claims 21-30 and 32-34 were previously withdrawn due to a restriction requirement mailed 11/03/2025. Claims 1 and 15-20 are currently pending.
Applicant’s arguments have been thoroughly reviewed, but are not persuasive for the
reasons that follow. Any rejection and objections not reiterated in this action have been
withdrawn. This action is FINAL.
Response to Amendments - Claim Objections
The previous rejection of claim 1 has been withdrawn in view of Applicant’s amendments to the claims filed on 03/18/2026.
Response to Amendments - Claim Rejections - 35 USC § 112
The previous rejection of claims 15 and 16 under 35 U.S.C. 112(b), second paragraph, has been withdrawn in view of Applicant’s amendments to the claims filed on 03/18/2026.
Claim Rejections - 35 USC § 102
The previous rejection of claims 1 and 15-18 under 35 U.S.C. 102(a)(1) as being anticipated has been withdrawn in view of Applicant’s amendments to the claims filed on 03/18/2026.
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.
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.
Claims 1 and 15-20 are rejected under 35 U.S.C. 103 as being unpatentable over Qin et al (Molecular Therapy, Vol. 27 No. 7, Pgs. 1262-1274; July 2019) in view of Glucksmann et al (WO 2015/048577 A2) and as evidenced by Sanjana et al (Nat Methods 11, 783–784; 2014) and Jinek et al (Science337,816-821; 2012). This is a previous rejection made in an Office Action mailed on 11/03/2025 and re-written to address specific amendments made by Applicant filed on 03/18/2026.
Qin teaches expressed on the surface of a variety of hematologic neoplasms, the interleukin-3 (IL-3) receptor alpha subunit (IL3Ra), also known as CD123, has been under investigation as a therapeutic target for hairy cell leukemia, acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL) (Page 1263, Column 1). Qin teaches the targeting CD123 via CRISPR by transducing the cells with LentiCRISPRv2 transfer vector containing the guide RNA for targeting CD123 where the guide RNA is 5’-AGTTCCCACATCCTGGTGCG-3’ (Page 1270, Column 2) (See PREVIOUS Appendix I) where the guide RNA is capable of targeting the target domain listed in instant Table 1 such as instant SEQ ID NO: 9 (See PREVIOUS Appendix II). Qin teaches the gRNA sequence as 5’-AGTTCCCACATCCTGGTGCG-3’ (Page 1270, Column 2). Sanjana is only cited to provide that the guide RNA of lenticrisperv2 is a single guide RNA (sgRNA) (i.e., it is one piece and not a separate crRNA and tracrRNA) (Page 783, Table 1). Because Qin teaches that the guide RNA is a single guide RNA, it would also teach the limitations of claim 17 as evidenced by Jinek which teaches the known structure of Cas9 sgRNA comprising a first complementarity domain, a linking domain and a second complementarity domain complementary to the first complementarity domain, and a proximal region wherein the first and second domains hybridize to form a stem-loop structure with GAAA as the loop or linking domain of the claim and the sequence that hybridizes to the target is the proximal region of the claim (Page 820, Figure 5).
Qin does not teach the specific gRNA sequence of SEQ ID NO: 50 which is capable of targeting its respective target site of instant SEQ ID NO: 44.
Glucksmann teaches optimization of guide RNA by analyzing specific parts of the genome that would increase the efficiency of genome editing wherein cleavage efficiency at each off-target sequences can be predicted and guide RNAs with increased off-targeting effects can be avoided [0456]. Glucksmann teaches the guide RNA is preceding an NGG PAM within the genome [0456]. Glucksmann teaches the gRNA is 20 nucleotides in length [0604]. Glucksmann teaches the target position may comprise one or more nucleotides that are altered, e.g., corrected, by a template nucleic acid and the target position is within a target sequence (e.g., the sequence to which the gRNA binds) [0573].
The gRNA provided by the instant application is shown within the human genome of the X chromosome at positions 1352337 to 1352356 (See alignment below; See Appendix III).
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43
687
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Greyscale
Wherein position 1 corresponds to position 1352301 within the genome, the underlined portion is the gRNA as claimed in the instant application and directly following is the required PAM sequence of CGG (highlighted for clarity) for the construction of the guide RNA to the target gene with increased specificity.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the guide RNA of Qin by utilizing the computational gRNA selection process to select gRNAs that would provide increased efficiency of on-target events as well as reduced interactions with off-target events as taught by Glucksmann, wherein the relevant artisan would have determined, with a reasonable expectation of success through routine screening/optimization assays, the guide RNA sequence of instant SEQ ID NO: 50 for targeting of the corresponding target site identified as instant SEQ ID NO: 44 in view Qin’s teachings that include the targeting of CD123 using a gRNA CRISPR cas system and Glucksmann’s teaching of the gRNA design methods that are known in the art.
One of ordinary skill in the art would have been motivated to do so to increase the efficiency of the guide RNA used for targeting CD123, also referred to as IL3RA, by targeting the specific sequence of instant SEQ ID NO: 50 because guide RNA for targeting CD123 as well as guide RNA design methods and techniques are known in the art as evidenced by Qin and Glucksmann.
One of ordinary skill in the art would have been further motivated to incorporate the basic design rules of guide RNAs, including a single gRNA comprising a first complementarity domain, a linking domain, a second complementarity domain which is complementary to the first complementarity domain, and a proximal domain, wherein the guide RNA is a single guide RNA (sgRNA) and comprises one or more 2'O-methyl nucleotide and one or more phosphorothioate or thioPACE linkages, as taught by Glucksmann in paragraphs [0188, 0362, 0915 and 0946] in order to target the CD123 gene, also known as IL3RA, for gene manipulation. Regarding claims 15-20, although Qin teaches expressed on the surface of a variety of hematologic neoplasms, the interleukin-3 (IL-3) receptor alpha subunit (IL3Ra), also known as CD123, has been under investigation as a therapeutic target for hairy cell leukemia, acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL) (Page 1263, Column 1) as well as targeting CD123 via CRISPR by transducing the cells with LentiCRISPRv2 transfer vector containing the guide RNA (Page 1270, Column 2), Qin does not teach the specific gRNA sequence of instant SEQ ID NO: 50. Glucksmann futher teaches the guide RNA as unimolecular such as having a single RNA molecule [0188]. Glucksmann teaches IL3RA as a target gene that the gRNA can be used to target for gene manipulation ([0846] and Table IX, Page 445). Glucksmann teaches a gRNA that has the following structure: 5' [targeting domain]- [first complementarity domain]- [linking domain]- [second complementarity domain]- [proximal domain]- [tail domain]-3' [0362]. Glucksmann teaches the guide RNA as a modified guide such as all, or substantially all, of the phosphate groups of a unimolecular or modular gRNA molecule are replaced with phosphorothioate groups [0915]. Glucksmann teaches the guide RNA are 2'-sugar modified, such as, 2-F 2'-0-methyl [0946].
In view of the foregoing, claims 1 and 15-20 taken as a whole would have been prima facie obvious at the time the invention was made.
Response to Arguments - Claim Rejections - 35 USC § 103
The previous rejection of claims 1 and 15-20 under 35 U.S.C. 103 has been maintained in view of Applicant’s amendments filed on 03/18/2026. Applicant’s arguments have been fully considered but are not found to be persuasive.
Applicant argues the combination of cited prior art references fails to provide all of the elements of the claimed invention and fails to provide a reasonable expectation of success. Applicant continues to argue that instant SEQ ID NO: 50 is not taught in the combination of cited references, therefore, the combination of cited references fails to support a prima facie case of obviousness since all of the elements of the claimed invention are not disclosed. Specifically, Applicant argues that instant SEQ ID NO: 9 which is also taught by Qin is not similar to instant SEQ ID NO: 50 and therefore, a skilled person would not have had any expectation of success in obtaining SEQ ID NO: 50 by “optimizing” the sequence of SEQ ID NO: 9, let alone the requisite reasonable expectation of success.
However, it is found that SEQ ID NO: 44, which corresponds to what would be the gRNA of SEQ ID NO: 50, is found within the human genome, specifically within the interleukin-3 (IL-3) receptor alpha subunit (IL3Ra), also known as CD123 gene. Therefore, it would be obvious to try to target other sequences within the interleukin-3 (IL-3) receptor alpha subunit (IL3Ra), also known as CD123, gene by using the general gRNA design and engineering as taught by Glucksmann as well as because it is already known in the art that Qin has already constructed a gRNA, specifically instant SEQ ID NO: 9, for targeting the interleukin-3 (IL-3) receptor alpha subunit (IL3Ra) gene. The current combination is not meant to infer that the instant SEQ ID NO: 50 can be “optimized” from instant SEQ ID NO: 9 but rather, it would be obvious to try and create other gRNAs, such as SEQ ID NO: 50, due to knowing that other gRNAs have been created to target the same gene as well as knowing that SEQ ID NO: 44 is also within the gene and could be used to engineer a gRNA which would result in the gRNA sequence of instant SEQ ID NO: 50.
Applicant argues the motivation to modify the teaching of Qin is insufficient. Specifically, Applicant argues that the Examiner alleges that the motivation to obtain SEQ ID NO: 50 was to increase the efficiency of the guide RNA of Qin by using the guide RNA design methods and techniques that are known in the art as evidenced by Qin and Glucksmann. Applicant continues to argue that, as previously discussed, instant SEQ ID NO: 9 and 50 are not similar and therefore, fails to describe why and how SEQ ID NO: 9 would have been modified sufficiently to arrive at the sequence of SEQ ID NO: 50 without any guidance to do so in the combination of cited references.
However, MPEP § 2143.01(I)(E) states an obvious to try rationale that includes “a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem” as well as “a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success” due to already knowing that it is possible to generate a gRNA possible of targeting the interleukin-3 (IL-3) receptor alpha subunit (IL3Ra) gene as well as knowing the position and features of the the interleukin-3 (IL-3) receptor alpha subunit (IL3Ra), also known as CD123, gene within the human genome as shown and discussed above. The current combination is not meant to infer that the instant SEQ ID NO: 50 can be “optimized” from instant SEQ ID NO: 9 but rather, it would be obvious to try and create other gRNAs, such as SEQ ID NO: 50, due to knowing that other gRNAs have been created to target the same gene as well as knowing that SEQ ID NO: 44 is also within the gene and could be used to engineer a gRNA which would result in the gRNA sequence of instant SEQ ID NO: 50.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDRA ROSE LIPPOLIS whose telephone number is (703)756-5450. The examiner can normally be reached Monday-Friday, 8:00am to 5:00pm EST.
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/ALEXANDRA ROSE LIPPOLIS/Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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