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
Claims 1- 13, 20, 23, 24, 26, 33- 36 are pending.
Claims 1- 13, 20, 23, 24, 26, 33- 36 are subject to restriction requirement/ election of species.
Claims 1- 11, 13, 20, 23, 24, 26, 33- 35 are considered on the merits.
Claims 12, 36 are withdrawn.
Claims 1- 11, 13, 20, 23, 24, 26, 33- 35 are rejected.
No claims are allowed.
Election/Restrictions
Applicant's election with traverse of invention Group I, and election with traverse of species ZF, CTFR, and SEQ ID No 21 in the reply filed on April 8, 2026 is acknowledged. The traversal is on the ground(s) that “the Office Action has not shown that a serious burden.” This is not found persuasive because the argument doesn’t specifically address the reasons that were provided for why there is a burden. Therefore, the applicant’s argument regarding lack of search burden is merely a conclusory statement.
The multiple groups of inventions present a search burden because they fall within different CPC classifications and search for one would not likely yield results for the other. Furthermore, the requirement for election of species presents a search burden because the species of each group lack sufficient structural similarity and activity as described in the restriction requirement, “the common structure is not a significant structural element because it represents only a small portion of the compound structures and does not constitute a structurally distinctive portion… each of the targets have different sequences and activities… the compounds of these groups do not belong to a recognized class of chemical compounds..”.
The requirement is still deemed proper and is therefore made FINAL.
Claims 12 and 36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on April 8, 2026.
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 1- 11, 13, 20, 23, 24, 26, 33- 35 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.
Those claims included in the statement of rejection but not otherwise discussed are rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
Claim 1 recites “An engineered retroviral integration complex comprising an engineered prototype foamy virus (PFV) integrase (IN), two or more non-naturally occurring flanking nucleic acid sequences, and a cargo nucleic acid sequence.” The term “flanking” does not sufficiently describe the structural relation of the “two or more non-naturally occurring … nucleic acid sequences” in relation to either the “engineered prototype foamy virus (PFV) integrase (IN)” or the “cargo nucleic acid sequence. Multiple specific disclosures within the specification indicates these “two or more non-naturally occurring flanking nucleic acid sequences“ flank the cargo nucleic acid sequence, however, the claim as written does not make this clear. Example disclosures are found on Page 2, bottom (paragraph 10), Background of the specifications recites “The cargo nucleic acid sequence is flanked by the flanking nucleic acid sequences. In some examples, the cargo nucleic acid sequence is linked to at least one flanking nucleic acid sequence through a polynucleotide linker sequence.” Additionally, Figures 13 and 15 support the recited text.
Claim 26 recites, “wherein the polynucleotide linker sequence comprises a blunt end linked to the flanking nucleic acid sequence and a sticky end linked to the cargo nucleic acid sequence.” It is unclear how a nucleotide linkage may be either “blunt end” or “sticky end”. The terms “blunt end” and “sticky end” are reserved for termini of nucleic acids. Therefore, it is unclear how the structure of a linkage allows for either blunt or sticky ends.
Claim Rejections - 35 USC § 102
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 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) 1-4, 20, 23, 24, 33, and 35 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sweeney (Sweeney et al. Sci Rep. 2017 Aug 14;7(1):8085.), as evidenced by Jackson (Jackson et al. J Virol. 2013 Jan;87(2):1252-4.). The rejections of claims 2-4 is evidenced by Hare (Hare et al. Nature. 2010 Mar 11;464(7286):232-6.) The rejections of claims 20 is evidenced by Jackson (Jackson et al. J Virol. 2013 Jan;87(2):1252-4.) and further evidenced by Anderson (Anderson_US_20210363509_A1. Effective filing date October 22, 2018).
Regarding claims 1, 23, 24, and 33, Sweeney teaches a prototype foamy virus integrase “We inserted increasing lengths of the dystrophin open reading frame in a [prototype] foamy virus vector and quantified packaged vector RNA and integrated DNA”(Abstract). Sweeney teaches their cargo with flanking sequences in Table 1 “[EFS-GFP-dys7a] Table 1. FVV transfer plasmid inserts and the resulting provirus size.”(legend).
Sweeney’s data (see Fig. 2, 3) indicating incorporation of the cargo and flanking sequences into the plasmid is evidence of “engineered retroviral integration complex” but Sweeney is silent on the formation of the integration complex (intasome).
However, Jackson provides the evidence that the PVF vector expresses the PFV integrase intasome as a matter of fact, “FV Pol expression occurs independently of Gag from a spliced mRNA… The Pol precursor is also cleaved only once between reverse transcriptase (RT) and integrase (IN), resulting in IN and a PR-RT fusion protein”(Abstract). Therefore, it is inherent to Sweeney’s [prototype] foamy virus vector that is has PFV integrase intasome.
Regarding claim 35, Sweeney teaches “The transfer plasmids shown in Table 1 were cotransfected with Gag, Pol and Env expression constructs into 293 T cells to produce FVV”(page 8085, Results section, last paragraph).
Therefore, Sweeney, as evidenced by Jackson, teaches all of the elements of claim 1, 23, 24, 33, and 35.
Therefore, Sweeney anticipates claim 1, 23, 24, 33, and 35.
Regarding claim 20, Sweeney teaches all of the elements of claim 1 as described above.
Sweeney is silent on the flanking nucleic acid sequences comprise two blunt ends, one sticky end, or two sticky ends.
However, Anderson provides the evidence that the flanking nucleic acid sequences comprise two blunt ends as a matter of fact. Anderson teaches the general lentiviral lifecycle in their Fig 14 “Following viral transduction, lentiviral RNA genomes are copied as blunt-ended dsDNA by viral Encoded reverse transcriptase (RT) and inserted into host genomes by Integrase I(IN).” [0035]. Sweeney uses the lentivirus; therefore it follows the same lifecycle.
Therefore, it is inherent that the flanking nucleic acid sequences of The engineered retroviral integration complex comprise two blunt ends.
Therefore, Sweeney, as evidenced by Jackson, and Anderson teaches the embodiment “wherein the flanking nucleic acid sequences comprise two blunt ends” and therefore teaches all of the elements of claim 20.
Therefore, Sweeney anticipates claim 20.
Regarding claims 2- 4, Sweeney teaches “The transfer plasmids shown in Table 1 were cotransfected with Gag, Pol and Env expression constructs into 293 T cells to produce FVV”(page 8085, Results section, last paragraph).
However, regarding claims 2 and 3, Sweeney is silent regarding the PFV integrase comprises at least one inner PFV IN protomer and at least one outer PFV IN Protomers; the PFV integrase comprises two inner PFV IN protomers and two outer PFV IN protomers; and the outer PFV IN protomer comprises a nucleic acid binding domain.
However, Hare provides the crystal structure evidence that the PFV IN is a tetramer, and comprises two inner and two outer IN protomers as a matter of fact “The inner subunits of the tetramer … the outer subunits…”(page 232, 2nd column, bottom) and “Previous retroviral IN CCD structures showed a conserved dimeric interface, and this interface is retained between the inner and outer IN subunits of the intasome”(page 233, 1st column, top).
Regarding claim 4, Hare further show as a matter of fact the PFV IN protomer outer DNA binding domain “Each CTD makes contact with the phosphodiester backbone of both viral DNA molecules”(page 233, 2nd column, top).
Therefore, it is inherent to the integration complex of Sweeney that the PFV integrase comprises at least one inner PFV IN protomer and at least one outer PFV IN Protomers; the PFV integrase comprises two inner PFV IN protomers and two outer PFV IN protomers; and the outer PFV IN protomer comprises a nucleic acid binding domain.
Therefore, Sweeney, as evidenced by Hare, teaches all of the elements of claims 2, 3, 4.
Therefore, Sweeney anticipates claims 2, 3, 4.
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.
Claim(s) 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sweeney (Sweeney et al. Sci Rep. 2017 Aug 14;7(1):8085.), as evidenced by Jackson (Jackson et al. J Virol. 2013 Jan;87(2):1252-4.) as applied to claim 1 above, and further in view of Anderson (Anderson_US_20210363509_A1. Effective filing date October 22, 2018).
Regarding claims 5 and 6, Sweeney teaches all of the elements of claims 1.
Sweeney does not teach “wherein the flanking nucleic acid sequences are derived from a virus” nor does Sweeney teach “wherein the flanking viral nucleic acid sequence is DNA.”
Anderson teaches a PFV IN-Cas fusion complex by showing a drawing of the engineered integration complex in Fig. 17C and providing descriptions of embodiments, “the fusion protein comprises a retroviral integrase (IN), or a fragment thereof having a first amino acid sequence; a CRISPR-associated (Cas) protein having a second amino acid sequence… the retroviral IN is selected from the group consisting of… Prototype foamy virus (PFV) IN,”[0008].
Anderson further teaches their integration complex comprises viral derived IRES and 2A flanking DNA sequences “FIG. 15B depicts a diagram showing a dsDNA Donor template containing an IGR IRES-mCherry-2A-Puromycin (puro) cassette flanked by U3/U5 viral motifs” [0036].
It would have been obvious to a person having ordinary skill in the art (PHOSITA) at the time of filing to have started with the expression cassette of Sweeney and substituted the expression cassette comprising flanking DNA sequences of Anderson to arrive at the instant integration complex with flanking nucleic acid sequences because it is simply combining prior art elements according to known methods to yield predictable results. Both Sweeney and Anderson use fluorescent proteins as exemplary cargo nucleic acids. A PHOSITA would recognize an IRES sequence and a 2A sequence each provide benefits to protein expression by allowing cap-independent translation and generating polyproteins from a single ORF, respectively. These flanking inclusions allow for a simpler translation mechanism for the cargo sequence followed by a mechanism to ensure the cargo protein is not linked to downstream proteins. Therefore a PHOSITA would recognize and predict their cargo nucleic acid would achieve enhanced expression and subsequently include these flanking sequences with a reasonable expectation of success.
Claim(s) 7, 8, 9, 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sweeney (Sweeney et al. Sci Rep. 2017 Aug 14;7(1):8085.), as applied to claim 4 above, and further in view of Anderson (Anderson_US_20210363509_A1. Effective filing date October 22, 2018); and Jones (Jones et al. Sci Rep. 2019 Jan 15;9(1):132.). Sweeney is evidenced by Hare (Hare et al. Nature. 2010 Mar 11;464(7286):232-6.) as applied to claim 4 above; and Anderson is evidenced by Engelman (Engelman et al. J Virol. 1994 Sep;68(9):5911-7.).
Regarding claim 7, Sweeney teaches all of the elements of claim 4.
Sweeney does not teach “wherein a carboxyl terminus domain (CTD) region of the outer PFV IN protomer is replaced with the nucleic acid binding domain.”
Anderson teaches a PFV IN-Cas fusion complex as described above. Anderson further teaches “the retroviral IN fragment comprises the IN N-terminal domain (NTD), and the IN catalytic core domain (CCD).”[0010]. Furthermore, Anderson teaches replacement of the CTD domain (non-specific DNA binding domain) “Replacement of the non-specific DNA binding domain of Integrase with the programmable DNA binding domain of dCas9 allows for targeted integration of dsDNA donor templates via delivery in lentiviral particles. Alternative DNA binding domains (such as TALENs) may be utilized for targeted integration as fusions to viral Integrase.”[0044].
Anderson is silent regarding the integrase CTD is a non-specific DNA binding domain.
However, Engelman provides evidence the integrase CTD is a non-specific DNA binding domain, “Both the core and C-terminal domains of integrase therefore contribute to core nonspecific DNA binding.”(Abstract).
Therefore, it is inherent that the integrase CTD is a non-specific DNA binding domain.
Jones provides motivation for replacing the CTD by citing improved performance where the CTD is absent, “Truncation mutants reveal that integration to a supercoiled plasmid increases without the outer monomer CTDs present. Deletion of the outer CTDs enhances the lifetime of the intasome compared to full length (FL) IN” and “the outer CTDs contribute to aggregation of PFV intasomes”(Abstract).
It would have been obvious to a person having ordinary skill in the art (PHOSITA) at the time of filing to have started with the integration complex of Sweeney (comprising an IN CTD) and substituted the integration complex with the substituted nucleic acid binding domain of Anderson to arrive at the instant integration complex with nucleic acid binding domain substituted for the CTD because it is simply combining prior art elements according to known methods to yield predictable results. Jones provides motivation for replacing the CTD by citing improved performance where the CTD is absent, “Truncation mutants reveal that integration to a supercoiled plasmid increases without the outer monomer CTDs present. Deletion of the outer CTDs enhances the lifetime of the intasome compared to full length (FL) IN” and “the outer CTDs contribute to aggregation of PFV intasomes”(Abstract). Therefore, based on the performance enhancements taught by Jones, a PHOSITA would have been able to predict replacing the CTD of IN would have a reasonable expectation of success.
Regarding claim 8, Sweeney teaches all of the elements of claim 4 and, Sweeney, Anderson, and Jones teach all of the elements of claim 7.
In continuation of the analysis of claim 7, Anderson further teaches the limitation “wherein the nucleic acid binding domain is a zinc finger (ZF) domain” in paragraph [0110] “the present invention is based on the development of novel fusions of editing proteins and retroviral integrase” and embodiments includes “a zinc finger nuclease (ZFN) protein” [0143].
Therefore, Sweeney, Anderson, and Jones teach all of the elements of claim 8.
Regarding claim 9, Sweeney teaches all of the elements of claim 4 and, Sweeney, Anderson, and Jones teach all of the elements of claim 7.
In continuation of the analysis of claim 7, Anderson further teaches the limitation “wherein the nucleic acid binding domain targets a human gene.” Anderson teaches the nucleic acid binding domain containing Cas protein targets human genes in conjunction with the gRNA “Integrase-Cas-mediated gene delivery directs the sequence-specific integration of large DNA sequences into [human] mammalian genomic DNA (FIG. 2).”[0324] and (Fig 2).
Therefore, Sweeney, Anderson, and Jones teach all of the elements of claim 9.
Regarding claim 10, Sweeney teaches all of the elements of claim 4 and, Sweeney, Anderson, and Jones teach all of the elements of claim 7.
In continuation of the analysis of claim 7, Anderson further teaches the limitation “wherein the human gene is a cystic fibrosis transmembrane conductance regulator (CFTR) gene.” Anderson teaches “the disease includes, but is not limited to… Cystic Fibrosis (mutations occurring in CFTR)”[0293].
Therefore, Sweeney, Anderson, and Jones teach all of the elements of claim 10.
Claim(s) 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sweeney (Sweeney et al. Sci Rep. 2017 Aug 14;7(1):8085.), as evidenced by and Hare (Hare et al. Nature. 2010 Mar 11;464(7286):232-6.), and further in view of Anderson (Anderson_US_20210363509_A1. Effective filing date October 22, 2018), as evidenced by Engelman (Engelman et al. J Virol. 1994 Sep;68(9):5911-7.), and Jones (Jones et al. Sci Rep. 2019 Jan 15;9(1):132.) as applied to claim 8 above, and further in view of Kleinstiver (Kleinstiver et al. Proc Natl Acad Sci U S A. 2012 May 22;109(21):8061-6.).
Regarding claim 11, Sweeney, Anderson, and Jones teach all of the elements of claim 8.
However, Sweeney, Anderson, and Jones do not teach the limitation “wherein the ZF domain does not require dimerization.”
Kleinstiver teaches “Fusion of the GIY-YIG nuclease domain to three member zinc-finger DNA binding domains generated chimeric GIY-zinc finger endonucleases (GIY-ZFEs). Significantly, the I-TevI-derived fusions (Tev-ZFEs) function in vitro as monomers”(Abstract). Kleinstiver further provides a motivation for the creation of their monomer “One notable constraint imposed by the FokI nuclease domain is the requirement to function as a dimer to efficiently cleave DNA”(page 8061, 1st column, 1st paragraph).
It would have been obvious to a person having ordinary skill in the art (PHOSITA) at the time of filing to have started with the zinc finger nucleic acid binding domain of Sweeney-Anderson-Jones and substituted the monomer Tev-ZFEs of Kleinstiver to arrive at the instant claimed invention because it is simple substitution of one known element for another to obtain predictable results. A PHOSITA would recognize the Tev-ZFE monomer of Kleinstiver has similar functionality and capability as the zinc finger nucleic acid binding domain of Anderson (Sweeney-Anderson-Jones. Therefore, a PHOSITA would predict that the substitution of Tev-ZFE monomer for zinc finger nucleic acid binding domain would have a reasonable expectation of success.
Therefore, Sweeney, Anderson, Jones, and Kleinstiver teach all of the elements of claim 11.
Claim(s) 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sweeney (Sweeney et al. Sci Rep. 2017 Aug 14;7(1):8085.), as evidenced by and Hare (Hare et al. Nature. 2010 Mar 11;464(7286):232-6.) as applied to claims 2 above, and further in view of Li (Li et al. PLoS One. 2014 Aug 13;9(8):e105078.), Anderson (Anderson_US_20210363509_A1. Effective filing date October 22, 2018), and Jones (Jones et al. Sci Rep. 2019 Jan 15;9(1):132.).
Regarding claim 13, Sweeney teaches all of the elements of claim 2.
However, Sweeney does not teach the limitation “wherein the amino terminus of the outer PFV IN protomer is linked to a Sso7d solubility domain.”
Li teaches their HIV-I integrase-Sso7d fusion protein “fusing IN with a small non-specific DNA binding protein, Sulfolobus solfataricus chromosomal protein Sso7d (PDB: 1BNZ), we have engineered a highly soluble and hyperactive IN” (Abstract). Furthermore, Li’s Sso7d domain is attached to the amino terminus “We therefore tested whether fusing non-specific DNA binding domains to the N-terminus of HIV-1 IN would confer some of the favorable properties of PFV IN” (page 1, 2nd column, last paragraph). Li further provides motivation by describing the benefits of the fusion “Sso7d (PDB: 1BNZ), resulted in a hyperactive IN protein” (page 2, 1st column, top).
However, Li does not teach a PFV IN-Sso7d fusion.
As described above, Anderson teaches a PFV IN fusion. Anderson shows a drawing of the PFV IN-Cas fusion engineered integration complex in Fig. 17C and providing descriptions of embodiments, “the fusion protein comprises a retroviral integrase (IN), or a fragment thereof … the retroviral IN is selected from the group consisting of… Prototype foamy virus (PFV) IN,”[0008].
Anderson does not teach a particular protomer.
Jones teaches PFV IN protomers can be manipulated toward inner and outer locals “Elegant structural studies revealed that point mutations PFV IN(K120E) and PFV IN(D273K) can direct monomers to the inner and outer subunits of the intasome, respectively” (page 1, 2nd paragraph, middle).
It would have been obvious to a person having ordinary skill in the art (PHOSITA) at the time of filing to have started with the PFV In complex of Sweeney and generated a fusion with the Sso7d domain as taught by the combination of Li and Anderson. It would have been further obvious to a PHOSITA to have followed Jone’s teachings of PFV IN point mutations arrive at the instant amino terminus of the outer PFV IN protomer is linked to a Sso7d solubility domain because it is simply combining prior art elements according to known methods to yield predictable results. A PHOSITA would recognize fusion proteins. In particular, they would recognize integrase fusions, PFV integrase fusion, and Sso7d fusion proteins. Furthermore, a PHOSITA would recognize an Sso7d domain would incur benefits toward their PFV IN (hyperactivity). They would also recognize they could attach the Sso7d fusion to the N-terminus as well as direct the fusion protomer toward a preferred inner or outer local with known point mutations. Therefore, a PHOSITA would have recognized that the results of the combination were predictable and they would have had a reasonable expectation of success.
Allowable Subject Matter
Claim 34 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
This examiner was unable to find prior art of the limitation “wherein the polynucleotide sequence is at least 80% identical to SEQ ID NO: 21.” The most similar prior art was SEQ ID No 5 of US 20090203102 A1 sharing 73.9% identity to the instant SEQ ID No 21. Alternatively, the most similar prior art to the instant SEQ ID No 34 was SEQ ID No 23 of US 20130122562 A1, sharing 53.3% identity.
Conclusion
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/AARON DUREL WARD/ Examiner, Art Unit 1636
/NEIL P HAMMELL/ Supervisory Patent Examiner, Art Unit 1636
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