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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 June 29, 2026 has been entered.
Applicant previously canceled claims 6-7 and 23-24. Applicants make no amendments. Claims 1-5, 8-22, and 25-26 are under examination.
Any objection or rejection of record in the previous Office Action, mailed December 29, 2025, which is not addressed in this action has been withdrawn in light of Applicants’ amendments and/or arguments.
Specification
The disclosure is objected to because of the following informalities:
At page 6, line 24, “BRIEF” should be inserted before “DESCRIPTION.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-5, 8-17, 21-22, and 25-26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for insertions into the albumin, RHO, and β-actin genes, does not reasonably provide enablement for insertion into any gene or treating any genetic disease in a subject. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Wands states, on page 1404:
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex part Forman. They include (1 the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of these in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
The claims are broadly drawn to a method of treating a genetic disease in a subject by administration of a first and second insertion template and a first and second rare-cutting endonuclease. After administration of the first insertion template and first rare-cutting endonuclease, integration of the template into the genome of the cells occurs. Following integration of the first insertion template the second insertion template and second rare-cutting endonuclease are administered and integrated into the genome of the cells.
The state of the art, the unpredictability of the art, and the relative skill of the ordinary artisan
It is well established in the art that administration of mRNA vaccines can reduce the symptoms of some infectious diseases in a subject and the insertion of transgenes in certain sites can improve certain genetic diseases. However, the delivering any biologically active polypeptide to a subject via a CRISPR nuclease is unpredictable. In addition, the skill of those in the relative art is high, but still, given the state and unpredictability of the art, undue experimentation would be required to determine if an in vivo administration of an RNA encoding any biologically active polypeptide is able to treat any genetic disease by administration of any transgene to a subject. Therefore, expression of any biologically active protein via administration of a transgene via a CRISPR nuclease to a subject cannot be predictably accomplished.
Amount of experimentation required and the direction or guidance presented
The specification does not enable using CRISPR nucleases, as broadly embraced by the breadth of the base claims that requires integration of any insertion template into any endogenous locus. The specification is limited to inserting a gene of interest using Cas9 that target intron 1 of the albumin gene, intron 4 of the rhodopsin (RHO) gene, or the β-actin gene (see Examples). The specification fails to correlate obtaining expression by targeting any other site of any other endogenous gene that would integrate the insertion template in vitro or in vivo resulting in production of functional protein deficient in the cells. The art teaches vector, promoter, route of administration, mode of delivery and target cells were unpredictable and neither instant specification nor prior art provided in any predictable outcome. There is no reasonable co relation of in vitro results to in vivo effect. Further, prior to filing of instant application, reported cleavage without a introducing a polynucleotide comprising exogenous sequence results in mutations such as insertions and/or deletions and short duplications. Thus, integrating a gene of interest into a target site in the genome of a cell required delivery of the nuclease as well as the nucleic acid for recombination to the appropriate cells in vivo at a level sufficient to support homologous recombination while balancing the negative side effects of nonhomologous recombination. The art also shows significant on-target mutagenesis, large deletions, and DNA breaks introduced through gRNA/Cas9 have been reported to result in deletions extending over many kilobases leading to pathogenic consequences (Kosicki et al., 36 Nature Biotechnology 765-771 (2018)).
Applicants fail to teach systemic expression of any integrated gene using the method claimed was obtained and of a level similar to treating any disease. The lack of guidance in the specification would force the skilled practitioner to establish how to construct such a insertion template or to functionally integrate any insertion template into any endogenous gene using any rare-cutting endonuclease targeted to any site within the endogenous gene. Given the unpredictability of gene therapy taken with the lack of guidance in the specification and the art at the time of filing, it would have required those of skill undue experimentation to try making and/or using the invention, without reasonable expectation of success. Such guessing would require extensive and undue experimentation. Applicant should note that “case law requires that the disclosure of an application shall inform those skilled in the art how to use applicants’ alleged discovery, not to find out how to use it for themselves.” Jn re Gardner 166 USPQ 138 (CCPA) 1970. Consequently, due to the high unpredictability in the relevant art and the lack of specific guidance and working examples for the breadth of embodiments embraced by the claims, undue experimentation would be required to carry out the invention as broadly as it is claimed without reasonable expectation of success.
Nature of the invention, the presence or absence of working examples, and the breadth of the claims
While the specification does provide potential for the integration of insertion templates and expression of albumin, rhodopsin, and β-actin in mice, it fails to disclose how to administer first and second insertion templates and first and second CRISPR nucleases that encode any biologically active polypeptide in a subject, as encompassed by the claims. Because the invention requires that a biologically active peptide is expressed upon administration to a subject and integration of the insertion templates into the genome of the subject’s cells, rather than expression of only albumin integrated at intron 1 of the albumin gene site, rhodopsin integrated at intron 4 of the rhodopsin gene site, and B-actin at the actin gene site, the specification does not provide any disclosure to enable the claims over their full scope.
In view of the lack of the predictability of the art to which the invention pertains, undue experimentation would be required to make and use the claimed invention to integrate any biologically active polypeptide in a subject via administration of an insertion template encoding the polypeptide, with a reasonable expectation of success. Because the specification does not contain a detailed description of how to make and use the method based on administration of a first and second insertion template encoding any biological polypeptide to a subject, according to the invention, and absent working examples that provide evidence that is reasonably predictive of the ability of expressing a biologically active polypeptide by administration of insertion templates and rare-cutting endonucleases to a subject, the claims are not enabled commensurate in scope with the claimed invention.
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 1-5, 8-18, 20-22, and 25-26 are rejected under 35 U.S.C. 103 as being unpatentable over Baltes (U.S. Patent Application Publication No. 2023/0190962, published June 22, 2023, and cited in the Information Disclosure Statement filed April 25, 2025) in view of Kerr et al. (U.S. Patent Application Publication NO. 2022/0175970, published June 9, 2022, and cited in the Information Disclosure Statement filed April 25, 2025).
Regarding claim 1, Baltes discloses methods of modifying the expression of endogenous genes and their coding sequences (abstract). Baltes discloses that the methods can be used for correcting gene expression from gain-of function disorders (paragraph [0006]). Baltes discloses first and second alleles of an endogenous gene can be modified by administration (paragraphs [0007]-[0008]). Baltes discloses that the endogenous gene can be albumin (paragraphs [0089]). Baltes discloses that the targeting can use a rare-cutting endonuclease to cleave an intron in both alleles of an endogenous gene, which is interpreted as the intron being the same for both the first and second target site, and which can include a transgene having two target sites having different sequences (paragraphs [0092] and [0095]-[0097]). Baltes discloses that the rare-cutting enzyme can be a CRISPR nuclease (paragraph [0097]). Baltes discloses that the transgene is integrated into a mutant or wild type allele (paragraphs [0006]-[0010])
Regarding claim 8, Baltes discloses that the CRISPR nuclease can be Cas9 (paragraphs [0165] and [0170]).
Regarding claims 9-10, Baltes discloses that the targeting can use a CRISPR nuclease to cleave an intron in both alleles of an endogenous gene and at two different target sites (paragraphs [0092] and [0095]-[0097]).
Regarding claim 11, Baltes discloses that the targeting can use a CRISPR nuclease to cleave an intron in both alleles of an endogenous gene, which is interpreted as the intron being the same for both the first and second target sites (paragraphs [0092] and [0095]).
Regarding claims 12-17, Baltes discloses that the transgenes can be inserted at introns 1 or 13, which is interpreted as having target sites upstream/downstream of each other, as well as being separated by at least 1000 nucleotides (paragraphs [0026], [0089], [0118], [0147], [0208]-[0209], and Figure 12).
Regarding claim 18, Baltes discloses that the target site can be in intron 1 of albumin (paragraphs [0026] and [0147]).
Regarding claim 20, Baltes discloses that the target site can be in the RHO gene intron 4 (paragraphs [0028] and [0079]s).
Regarding claim 21, Baltes discloses that the insertion templates can be operably linked to a splice acceptor sequence (paragraphs [0009], [0050], and [0099]).
Regarding claim 22, Baltes discloses that the insertion can be operably linked to a splice donor sequence (paragraphs [0009], [0051], and [0096]).
Regarding claims 25-26, Baltes discloses that a defective coding sequence can be corrected by insertion of the transgene (paragraph [0100]).
Baltes fails to explicitly disclose or suggest administration of a first and second composition comprising first and second insertion templates (i.e., transgenes) and first and second CRISPR nucleases and waiting for integration of the first composition before administering the second composition. Baltes fails to explicitly disclose the locations of the first and second target sites.
Regarding claim 1, Kerr discloses methods for genome using a transgene (i.e., an insertion template) where the expression level is sustained or increased with one or more subsequence administration (i.e., a redose) (abstract and paragraphs [0013]-[0017]). Ker discloses that the nuclease can be a CRISPR/Cas9 protein (paragraph [0004]). Kerr discloses that the transgenes can be inserted into a safe harbor locus, such as albumin (paragraph [0216]). Kerr discloses that the administration can be redosed at a time period of at least 30 days and up to 18 months, in order to maintain or increase expression of the transgene (paragraphs [0013]-[0017] and [0050]-[0052]). Kerr discloses that the transgene can be administered with an editing molecule, such as a nuclease, which may be a CRISPR nuclease (paragraph [0378]).
Regarding claim 1, Kerr discloses that the vectors can contain elements that permit integration of a donor sequence into the host cell’s genome (paragraphs [0308] and [0324]).
Regarding claim 8, Kerr discloses that the CRISPR nuclease can be Cas9 (paragraph [0143]).
Regarding claims 25-26, Kerr discloses that the transgene can replace a defective protein, or one that is not expressed or is underexpressed (paragraph [0054]).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to use Kerr’s redosing schedule for the method of Baltes for treating a disease by targeting an intron of a gene at two locations with CRISPR nuclease, such as albumin intron 1 or RHO intron 4, in order to provide sustainable gene expression or increase gene expression by redosing according to Kerr. One of ordinary skill in the art would have been motivated to use Kerr’s redosing schedule in order to obtain sustained or increased transgene expression in order to a subject’s genetic disease or disorder to be treated over time, thus avoiding a potential relapse of the disease or condition.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Baltes in view of Kerr, as applied to claims 1-18 and 20-22 above, and further in view of Brooks (U.S. Patent Application Publication No. 2019/0247517, published August 15, 2019, and cited in the Information Disclosure Statement filed April 25, 2025).
Baltes and Kerr disclose and suggest a method of treating a genetic disease by administering first and second insertion templates/rare-cutting endonucleases into first and second target sites, as discussed above.
Baltes and Kerr fail to explicitly disclose or suggest the sequence of the first target site.
Regarding claim 19, Brooks discloses methods for gene editing for hemophilia (abstract). Brooks discloses that a therapeutic gene can be inserted into a target genome site using a CRISPR endonuclease (paragraph [0011]). Brooks discloses that the CRISPR endonuclease can be Cas9 (paragraph [0012]). Brooks discloses that the guide RNA can target a genomic sequence at or near endogenous albumin (paragraph [0006]). Brooks discloses that the gene editing can employ targeting the insertion of a gene into intron 1 of the albumin gene (paragraph [0060]). Brooks discloses that the sequence of the target site can be identical to the sequence of instant SEQ ID NO: 6 (SEQ ID NO: 21) (see Appendix I).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to administer the insertion templates/rare-cutting endonucleases to a subject using Brooks’ guide RNA targeting intron 1 of albumin because, as disclosed by Brooks, intron 1 of albumin can be used to provide genes for integration and expression in a genome in order to treat a genetic disease or condition. One of ordinary skill in the art would be motivated to use Brooks’ albumin intron 1 as an integration site because such integration at an intron would not cause unintended expression of the gene being inserted.
Response to Amendments and Arguments
Regarding the entry of “BRIEF” before “DESCRIPTION,” Applicant states that a substitute specification this deficiency. However, no substitute specification was filed with the June 29, 2026 reply. Therefore, this objection is maintained. In addition, the previous amendment to the specification, inserting the Sequence Listing Incorporation by Reference paragraph, is acknowledged.
Regarding the rejection under 35 U.S.C. § 112(a)/first paragraph, Applicant’s amendments and arguments have been fully considered, but are not deemed to be wholly persuasive.
Applicant asserts that amending the claims to recite that the rare cutting endonuclease is a CRISPR nuclease is sufficient to overcome this rejection.
While Applicant is correct, in part, the amendment does not address the lack of enablement regarding the integration sites, integration of any transgene, and treatment of any genetic diseases. As noted previously, Applicant’s amendment to recite that the rare-cutting endonuclease is a CRISPR nuclease obviates the portion of the rejection relating to the types of endonucleases encompassed by the claims. As noted above, the specification is enabled for integration of a transgene into the albumin, rhodopsin, and β-actin. However, as noted previously and above, the specification is not enabled for other integration sites, since the claims encompass integration of a transgene into any sequence in the entire host cell genome.
However, as discussed previously and above, Applicant fails to teach systemic expression of any integrated gene for the treatment of any genetic disease using the method claimed was obtained and of a level similar to treating any disease. The lack of guidance in the specification would force the skilled practitioner to establish how to construct such a insertion template or to functionally integrate any insertion template into any endogenous gene using the CRISPR-Cas9 endonuclease targeted to any site within the endogenous gene. Given the unpredictability of gene therapy taken with the lack of guidance in the specification and the art at the time of filing, it would have required those of skill undue experimentation to try making and/or using the invention, without reasonable expectation of success. Such guessing would require extensive and undue experimentation. Consequently, due to the high unpredictability in the relevant art and the lack of specific guidance and working examples for the breadth of embodiments embraced by the claims, undue experimentation would be required to carry out the invention as broadly as it is claimed without reasonable expectation of success.
For all these reasons, and those listed above, this rejection is maintained as set forth above.
Regarding the rejections under 35 U.S.C. § 103, Applicant’s amendments and arguments have been fully considered by are not deemed to be persuasive.
Applicant asserts that neither Baltes nor Kerr suggests redosing with a different composition than the first composition. Applicants assert that Baltes does not disclose integration of a transgene. Applicants assert that Brooks does not cure this alleged deficiency. Applicants assert that Kerr does not disclose integration of a transgene.
However, as discussed above and previously, Baltes does disclose use of two different rare-cutting endonucleases, including CRISPR nucleases. Baltes also discloses first and second target sites, as well as cleaving an intron, allowing for integration of a transgene by replacement of the gene. This requires the ability to cleave the gene at both sides (i.e., two different sequences) and allowing insertion of the insertion template (i.e., transgene). Thus, Baltes does indeed disclose that two different sequences of an intron or gene can be targeted, which would require the use of CRISPR nucleases targeting two different sequences, and allowing the transgene to be integrated into the genome of the subject.
Regarding Kerr’s therapeutic nucleic acid construct being delivered episomally, it is noted that Kerr, while disclosing episomal delivery of transgenes, also clearly states that the vectors contain elements that provide for integration of the desired transgene into the genome of the host cell. Therefore, one of ordinary skill in the art would have been motivated to use Kerr’s Cas9 and integrative delivery of transgenes along with Baltes method of integrating transgenes into the genome of a host cell. Because both Baltes and Kerr disclose integration of transgenes into host cells’ genomes, one of ordinary skill in the art would have looked to both references and be led directly to the claimed invention.
Regarding Brooks, this reference is cited for the use of a target site having the same sequence as instant SEQ ID NO: 6. Because Brooks recites a method for gene editing hemophilia in subjects using CRISPR nucleases that can target a genomic sequence at or near endogenous albumin and insert a transgene into an intron of albumin. Thus, the method of Baltes and Kerr can be used to target specific introns into an albumin gene, and can use Brooks target sequence to treat a genetic disease by insertion of an insertion template into the desired genomic site.
In addition, Applicant has not provided any objective, factually supported evidence in support of the arguments. Applicants have provided only arguments of counsel, and arguments of counsel cannot take the place of factually supported objective evidence. See, e.g., In re Huang, 100 F.3d 135,139-40, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984).
For all these reasons and those listed above, the rejections based upon Baltes in view of Kerr (and Brooks), are maintained as set forth above.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NANCY J LEITH whose telephone number is (313)446-4874. The examiner can normally be reached Monday - Thursday 8:00 AM - 6:30 PM.
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NANCY J. LEITH
Primary Examiner
Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
