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 .
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-17 in the reply filed on 05/12/2026 is acknowledged. The traversal is on the ground(s) that claim 18 has been amended to depend from claim 1 and claim 20 has nbeen amended to recite the corresponding technical feature of claim 1. This is not found persuasive because this application was not filed under 35 USC 371 but is a Continuation. Lack of Unity practice is not germane.
The requirement is still deemed proper and is therefore made FINAL.
Claims 18-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 05/12/2026.
Claim Objections
Claim 10 is objected to because of the following informalities: The term “a” should be inserted at line 3 between “of” and “5’”. Appropriate correction is required.
Claim 17 is objected to because of the following informalities: The phrase “the sequence of the Cas9 mRNA is shown in SEQ ID NO:3” should read “the sequence of the Cas9 mRNA is is the sequence set forth by SEQ ID NO:3”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 10-17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 10 is unclear. The phrase “the homologous recombination vector” recited in lines 1-2 lacks antecedent basis. The phrase “the 3’ homology arm” art line 4 also lacks antecedent basis. Claims 11-17 are unclear based on their dependency from claim 10.
Claim 15 is unclear. It is unclear if the “and” and the end of line 5 is intended to read as a “wherein” clause or if the gRNA of line 6 is an additional component added in addition to the gRNA recited in line 3. Also, only a portion of SEQ ID NO:4 appears to correspond to a gRNA so it is not clear if it is intended to read on a portion of SEQ ID NO:4 or all of it. Claims 16 and 17 are unclear based on their dependency from claim 15.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-3 and 5-8 is/are rejected under 35 U.S.C. 102a1 as being anticipated by Maruyama (VOLUME 33 NUMBER 5 MAY 2015 Nature Biotechnology, pages 538-542) as evidenced by Strijbis (Traffic 2012; 13: 780–789).
Claim 1 is drawn to a method of constructing a vertebrate model, the vertebrate model is used to produce an antibody carrying a universal site-directed coupling interface; the method comprises the step of inserting a nucleic acid encoding a specific recognition sequence of a certain ligase A at a certain position A of a certain coding gene A of an immunoglobulin in the genome of a recipient animal, to obtain the vertebrate model.
With regard to claims 1-3, Marayuma taught making a mouse (vertebrate model) by using the CRISPR/Cas9 system (claim 7) to insert a sortase recognition sequence (coding gene of a specific recognition sequence of a certain ligase A into the 3’ end (at a certain position A) of the Igkc gene (of a certain coding gene A of an immunoglobulin). The sortase recognition sequence was LPETG (claim 6), which is the canonical sortaseA recognition motif from Staphylococcus aureus (Sortasestaph enzyme, claim 5), as evidenced by Strijbis. With regard to claim 8, the ligase recognition sequence is inserted at position A based on the gRNA and cleavage by Cas9 occurs within the gRNA sequence, which is within 500nt of position A.
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.
Claim(s) 1 and 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Maruyama (VOLUME 33 NUMBER 5 MAY 2015 Nature Biotechnology, pages 538-542) in view of Ward (Life Sci Space Res, 2018 February ; 16: 63–75. doi:10.1016/j.lssr.2017.11.003).
Maruyama meets the limitations of claim 4 as set forth above. Maruyama does teach insertion of the sortase recognition sequence at the 3’ end of the Igkc gene. However, Maruyama does not teach that the position A (insertion site) is between 70726754 and 70726755 of the Igkc gene on chromosome 6.
Ward, however, taught that Igk locus spans nucleotides 67555636 to 70726754, thus establishing 70726754 as the last codon of the IGk gene.
It would have been obvious to insert the sortase recognition sequence just after position 70726754 of the Igk gene as taught by Maruyama and Ward to prevent disruption of the Igk coding region to arrive at the invention as claimed. One would be motivated to make such a choice of 3/ position given the teachings of Ward that this site would be just downstream but not disruptive of the Igk coding sequence. One would have had a reasonable expectation of success in making the combination as it was well within the skill of the ordinary artisan at the time of filing to engineer the site as claimed. .
Claim(s) 1,7-9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Maruyama (VOLUME 33 NUMBER 5 MAY 2015 Nature Biotechnology, pages 538-542) in view GenBank Accession AJ487682 (NCBI, Mus musculus IGKC gene for immunoglobulin kappa light chain, strain C5 - Nucleotide - NCBI, accessed 5/20/2026, printout attached).
Maruyama meets the limitations of claim 1 as set forth above. Maruyama teaches insertion of the sequence encoding the sortaseA ligation site at the 3’ end of the Igkc gene, which is the same as the instant invention. Claim 9 requires the target sequence cleaved by Cas9 be that set forth by SEQ ID NO:1. This sequence is nucleotides 4318-4340 of the mouse IgkC gene set forth by GenBank Accession AJ487682. This places the cleavage site just after the stop codon of the Igkc gene. Maruyama also used a gRNA targeting the 3’ end of the Igkc gene but this gRNA starts 5 nucleotides downstream of the 3’ end of the gRNA set forth by the sequence of SEQ ID NO:1 and thus is a slightly different 3’ location following the gene, the sequence of which was known given GenBank Accession AJ487682. Maruyama teaches a cleavage site (AGACAA) just 3’ to the PAM (TAG) within the gRNA and the PAM of the invention (AGG) is adjacent the cleavage site (AGA*CAA; spec at page 8).
Therefore, regarding claim 9, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to choose the gRNA sequence of the invention, ending just at the end of the coding sequence, to insert the ligase recognition sequence immediately at the end of the protein coding sequence as taught by GenBank Accession AJ487682. One of ordinary skill would not have considered the slight adjustment to placement of the gRNA be inventive because the sequences clearly target the same genetic region and the cleavage sequence remained identical and adjacent the PAM. One would have been motivated to make the change to provide a ligation site immediately at the end of the Igkc protein.
Claim(s) 10-12,15-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Maruyama (VOLUME 33 NUMBER 5 MAY 2015 Nature Biotechnology, pages 538-542) in view of GenBank Accession AJ487682 (NCBI, Mus musculus IGKC gene for immunoglobulin kappa light chain, strain C5 - Nucleotide - NCBI, accessed 5/20/2026, printout attached), as applied to claims 1,7-9 above, and further in view of Li (2014, PLOS One, 9:8, e105779, 10 pages) and Poueymirou (NATURE BIOTECHNOLOGY VOLUME 25 NUMBER 1 JANUARY 2007, pages 91-99).
With regard to claim 10, Maruyama teaches a recombination vector having a 79nt 5’homology arm and a 64 nt 3’ homology arm, flanking a coding region for a ligase recognition site. Claim 10, however, requires the homology arms be 120 and 150 bp, respectively. Aligning the homology arms of the invention and those of Maruyama with the genomic sequence for Igkc shown by GenBank Accession AJ487682, the 120bp 5’homogy arm of the invention is an obvious extension of that of Maruyama and also not inventive. Likewise, the 3’ homology arm of Maruyama aligns with that of claim 10 with that of claim 10 being longer.
Li taught that increasing the length of the homology arms of the homology-directed repair template strongly enhanced targeting efficiency.
With regard to claims 15-16, which depends from claim 10 and requires the method be carried out by injecting cas9 and the gRNA and the homologous recombination vector into a fertilized egg cytoplasm to generate F0 mice with further mating to generate heterozygous and homozygous mice, it is obvious to cross the F0 mice that are somewhat chimeric to generate heterozygous animals (see legend Fig 2b) and mating the F1s to generate homozygotes, as is taught by Poueymirou.
It would have been obvious at the time of filing to combine the teachings of Maruyama regarding use of Crispr/Cas9 to insert a ligase recognition site at the 3’ end of the Igkc gene with those of Li regarding Crispr/Cas9 homology dependent recombination and extension of homology arms because longer homology arms led to higher targeting efficiencies. One would have been motivated to breed the F0 to generate stable lines that could be perpetuated as taught by Poueymirou. One would have had a reasonable expectation of success in carrying out the combination as it was well withing the skill of the ordinary artisan to extend the homology arms given the sequence provided by GenBank Accession AJ487682. This combination would have provided the sequences of claims 11-12 because that is the sequence provided by AJ487682 which aligns with the sequences of the instant invention as well as those of Maruyama.
Claim(s) 13-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Maruyama (VOLUME 33 NUMBER 5 MAY 2015 Nature Biotechnology, pages 538-542) in view of GenBank Accession AJ487682 (NCBI, Mus musculus IGKC gene for immunoglobulin kappa light chain, strain C5 - Nucleotide - NCBI, accessed 5/20/2026, printout attached), and further in view of Li (2014, PLOS One, 9:8, e105779, 10 pages) and Poueymirou (NATURE BIOTECHNOLOGY VOLUME 25 NUMBER 1 JANUARY 2007, pages 91-99) as applied to claims 10-12 above, and further in view of Mauro (Trends Mol Med. 2014 November ; 20(11): 604–613. doi:10.1016/j.molmed.2014.09.003).
Maruyama, GenBank Accession AJ487682 and Li taught the method of claim 10 with the homology arms recited in claims 11 and 12 along with an intervening coding sequence for the same LPETG ligase recognition sequence. The coding sequence for the recognition sequence differed from that of claim 13, but would readily be arrived at through employing the degeneracy of the code as set forth below. Claim 14 is a combination of the homology arms with the recognition sequence coding nucleic acid in between and is obvious to the same extent as claim 13.
Mauro discusses the degeneracy of the genetic code and reasons the skilled artisan might change the code, while maintaining the sequence of the encoded protein, to optimize protein expression for a desired outcome. Thus, it would have been obvious to alter the coding sequence to optimize its translation or mRNA stability based on species-specific characteristics given the finite number of substitutions based on the degeneracy of the code.
The combination of prior art cited above in all rejections under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. ___, 82 USPQ2d 1385 (2007)): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
In the present situation, rationales A,B and E are applicable. The claims merely require the combining of known prior art methods as taught by Mauro to improve protein production. The application of Mauro would lead to a predictable result absent results to the contrary. Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VALARIE BERTOGLIO whose telephone number is (571)272-0725. The examiner can normally be reached M-F 6AM-2:30PM.
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, Peter Paras can be reached at 571-272-4517. 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.
VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632 fstri
Prosecution Insights