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 .
DETAILED ACTION
Status of Application/Amendment/Claims
Applicant's response filed 09/15/2025 has been considered. Rejections and/or objections not reiterated from the previous office action mailed 06/13/2025 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
With entry of the amendment filed on 09/15/2025, claims 414, 416, 426 and 434-444 are pending in the application.
With the claim amendments, claims 414 and 416 are rejoined and claims 414, 416, 426 and 434-444 are examined.
The 103 rejection has been withdrawn in view of a new rejection herein.
The 112(a) rejection has been withdrawn in response to claim amendments.
The statement that SEQ ID No. 323 is free of the art has been withdrawn and a new rejection is below.
New Claim Rejections
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 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 414, 416, 426 and 435-444 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US 20160153005 of record cited on IDS filed 12/07/2022), Maslakova et al. (Moscow University Biological Sciences Bulletin, 2015, Vol. 70, No. 3, pp. 127–131 of record cited on IDS filed 12/07/2022), Human Z type alpha-1-antitrypsin gene, complete cds (exons 2-5) Nucleotide NCBI 12/16/2025 and
Zhu, Lihua Julie. ("Overview of guide RNA design tools for CRISPR-Cas9 genome editing technology." Frontiers in Biology 10.4 (2015): 289-296).
Regarding claims 414, 416 and 426-444, Zhang et al. teach methods of altering liver cells by contacting the cells with CRISPR-Cas system comprising a gRNA to a target gene SERPINA1 that encodes the protein called Alpha-1 Antitrypsin (A1AT) (see 1274, 1282 and claims). Zhang et al. teach using Cas9 enzymes with improved liver-targeting specificity and teach a nucleic acid encoding the gRNA (see 0010). Zhang et al. teach the use of nanoparticles to deliver the CRISPR enzyme or mRNA or guide RNA (see 0397). Zhang et al. teach delivery can be in cells or in vivo (0609). Zhang et al. does not teach
Zhang et al. does not teach the gRNA sequence having SEQ ID No. 323 or teach the gRNA is configured to target Exon V of the SERPINA1 gene.
Regarding claim 414, 416 and SEQ ID No. 323, Maslakova et al. teach it was known in the art that SERPINA1 gene contains four coding exons, exons 2-5, in several cell types such as liver cells Hep2 (see page 127, Fig 2). Maslakova et al. teach Alpha1-antitrypsin (A1AT) is encoded by the SERPINA1 gene, AIA T is found elevated in some tumors and diseases and found to have high levels in Hep2 cells and high relative expression levels with respect to exons 5 (see Figs. 1 and 2).
It would have been obvious to make a gRNA targeted to the SERPINA1 gene, particularly in the region comprising exons 2-5 and especially exon 5 given Maslakova et al. teach exon 5 had the highest expression of SERPINA1 which encodes A1AT. One of skill in the art would have wanted to try targeting this region in efforts to find a gRNA to use in the CRISPR-Cas system. SEQ ID No. 323 is defined in the instant specification at targeting Exon V of the SERPINA1 gene (see Tables 7 and 8).
The sequence of the SERPINA1 gene encoding A1AT is known as shown below:
Human Z type alpha-1-antitrypsin gene, complete cds (exons 2-5)
GenBank: J02619.1
>J02619.1 Human Z type alpha-1-antitrypsin gene, complete cds (exons 2-5)
GACAATGCCGTCTTCTGTCTCGTGGGGCATCCTCCTGCTGGCAGGCCTGTGCTGCCTGGTCCCTGTCTCCCTGGCTGAGGATCCCCAGGGAGATGCTGCCCAGAAGACAGATACATCCCACCATGATCAGGATCACCCAACCTTCAACAAGATCACCCCCAACCTGGCTGAGTTCGCCTTCAGCCTATACCGCCAGCTGGCACACCAGTCCAACAGCACCAATATCTTCTTCTCCCCAGTGAGCATCGCTACAGCCTTTGCAATGCTCTCCCTGGGGACCAAGGCTGACACTCACGATGAAATCCTGGAGGGCCTGAATTTCAACCTCACGGAGATTCCGGAGGCTCAGATCCATGAAGGCTTCCAGGAACTCCTCCGTACCCTCAACCAGCCAGACAGCCAGCTCCAGCTGACCACCGGCAATGGCCTGTTCCTCAGCGAGGGCCTGAAGCTAGTGGATAAATTTTTGGAGGATGTTAAAAAGTTGTACCACTCAGAAGCCTTCACTGTCAACTTCGGGGACACCGAAGAGGCCAAGAAACAGATCAACGATTACGTGGAGAAGGGTACTCAAGGGAAAATTGTGGATTTGGTCAAGGAGCTTGACAGAGACACAGTTTTTGCTCTGGTGAATTACATCTTCTTTAAAGGCAAATGGGAGAGACCCTTTGAAGTCAAGGACACCGAGGAAGAGGACTTCCACGTGGACCAGGCGACCACCGTGAAGGTGCCTATGATGAAGCGTTTAGGCATGTTTAACATCCAGCACTGTAAGAAGCTGTCCAGCTGGGTGCTGCTGATGAAATACCTGGGCAATGCCACCGCCATCTTCTTCCTGCCTGATGAGGGGAAACTACAGCACCTGGAAAATGAACTCACCCACGATATCATCACCAAGTTCCTGGAAAATGAAGACAGAAGGTCTGCCAGCTTACATTTACCCAAACTGTCCATTACTGGAACCTATGATCTGAAGAGCGTCCTGGGTCAACTGGGCATCACTAAGGTCTTCAGCAATGGGGCTGACCTCTCCGGGGTCACAGAGGAGGCACCCCTGAAGCTCTCCAAGGCCGTGCATAAGGCTGTGCTGACCATCGACAAGAAAGGGACTGAAGCTGCTGGGGCCATGTTTTTAGAGGCCATACCCATGTCTATCCCCCCCGAGGTCAAGTTCAACAAACCCTTTGTCTTCTTAATGATTGAACAAAATACCAAGTCTCCCCTCTTCATGGGAAAAGTGGTGAATCCCACCCAAAAATAACTGCCTCTCGCTCCTCAACCCCTCCCCTCCATCCCTGGCCCCCTCCCTGGATGACATTAAAGAAGGGTTGAGCTGGACTGCCTCTCGCTCCTCAACCCCTCCCCTCCATCCCTGGCCCCCTCCCTGGATGACATTAAAGAAGGGTTGAGCTGG
Zhu teach an overview of guide RNA design tools for use in the CRISPR-Cas9 genome editing technology and teach finding target sites in generally quite easy and teach many computational tools have been developed to aid in finding an optimal gRNA (see abstract and page 90).
It would have been obvious for one of ordinary skill in the art to try the known computational tools to make gRNA targeted to the SERPINA1 gene to use in the CRISPR-Cas9 genome editing technology targeting Exon V of the gene. Given the prior art of Zhang et al. teach gRNA can be used to target the SERPINA1 gene and Maslakova et al. teach Alpha1-antitrypsin (A1AT) is encoded by the SERPINA1 gene and found high levels in Hep2 cells and high relative expression levels with respect to exons 5, one of skill in the art would have wanted make a gRNA targeted to Exon V. SEQ ID No. 323 is complementary to a region in the gene as highlighted above and given Zhu et al. teach how to use tools to design and test for gRNA and given the region of Exon V is known, it would have been obvious to make SEQ ID No. 323 differing by no more that 3 nucleotides as claimed. There is a finite number of sequences within the range of Exon V that can be identified given the size of the gene above and therefore a person of ordinary skill has good reason to make the gRNA within their technical grasp.
Moreover, because there was a known association between Exon V and high expression levels of the SERPINA1 gene and known association with high expression levels and conditions or diseases, there is a predictable outcome of success at reducing expression levels and treatment. There is an expectation of an advantage for making a gRNA targeted to Exon V of the SERPINA1 and thus a motivation to combine the prior art references for treatment of fibrosis (see MPEP 2144). Conclusive proof of efficacy is not required to show a reasonable expectation of success and obviousness does not require absolute predictability, but at least some degree of predictability is required (MPEP 2143.02).
Thus in the absence of evidence to the contrary, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kimberly Chong at (571)272-3111. The examiner can normally be reached Monday thru Friday between M-F 8:00am-4:30pm.
If attempts to reach the examiner by telephone are unsuccessful please contact the SPE for 1636 Neil Hammell at 571-272-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KIMBERLY CHONG/
Primary Examiner Art Unit 1636