DETAILED ACTION
Claims 1-4, 6, 8, 10-13, 15-19,21, 23, 29, 49, 51 and 58 are currently pending.
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 without traverse of Invention Group 1 (Claims 1-4, 6, 8, 10-13, 15-19, 21, and 23) in the reply filed on 4/6/2026 is acknowledged.
Claims 29, 49, 51 and 58 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/6/2026.
Priority
Acknowledgement is made of the instant application being a national stage entry under 35 USC 371 of international application PCT/US2021/029714, filed April 28, 2021, which claims the benefit of provisional application No. 63/016,841, filed April 28, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 4/6/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
It is further noted the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code, for example at page 53. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 15 is objected to because of the following informalities: abbreviation.
Claim 15 recites the phrase “GSG linker”. It is noted the abbreviation GSG (glysine-serine-glysine) should first be spelled out upon its first usage in a claim.
It is further suggested the specification is amended accordingly.
Appropriate correction is required.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-4, 6, 8, 10-12, 17, 19, 21 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Ports et al., (US 2020/0054673; previously cited) (“Ports”), as evidenced by New England Biolabs (Furin- Product Information, retrieved from the internet; see PTO-892) (“New England Biolabs”) and Jensen et al., (US 2015/0306141; see PTO-892) (“Jensen”).
Ports is directed to methods of treatment involving immunotherapy, wherein the method includes a combination therapy that involves administration of engineered T cells, such as chimeric antigen receptor (CAR)-expressing cells, and the engineered cells have modified expression of a molecule involved in the kynurenine pathway (Abstract).
Regarding claims 1, 6, 8, 10-12, Ports teaches embodiments wherein the kynurenine pathway modulator is a nucleic acid (RNA/DNA, claim 19) molecule ([0019]) that is effective for genetic disruption that reduces expression of said molecule ([0069], [0072]).
Ports teaches [0073] the disruption involves introducing:
(a) a fusion protein that includes a DNA-targeting protein and a nuclease or
(b) an RNA-guided nuclease, and the RNA-guided nuclease includes a zinc finger protein (ZFP), a TAL protein, or a clustered regularly interspaced short palindromic nucleic acid (CRISPR) specific for the gene. Ports teaches the disruption is caused by introducing an agent into the cell including one of the RNA-guided nucleases that specifically recognizes/hybridizes to the gene encoding the molecule involved in the kynurenine pathway, specifically the agent is a CRISPR-Cas9 combination and the CRISPR-Cas9 combination includes a guide RNA (gRNA) containing a guide sequence that is complementary to, and/or capable of hybridizing to, a target sequence in the gene ([0073]) (claims 10-12, 19).
It is noted that Ports teaches the nucleic acid encoding the molecule or agent for modifying the expression of the molecule can be contained in one, or more, polynucleotides and contained in vectors ([0100], [0154], [0702]), and the nucleic acid encoding the recombinant receptor and the nucleic acid encoding the molecule or portion thereof or an agent that is capable of modifying the expression of the molecule can each be operably linked to a promoter for expression, or can be operably linked to one promoter, in one polynucleotide. The polynucleotides can be multicistronic. The polynucleotides can also encode one or more marker, such as a surface marker, e.g., truncated epidermal growth factor (tEGFR) (claim 1).
Ports further teaches the nucleic acid encoding the marker (tEGFR) is operably linked to a polynucleotide encoding a linker sequence, such as a cleavable linker sequence T2A (self-cleaving peptide, claims 1, 6 and 8) ([0589]), and wherein the T2A linker is located between the polynucleotide encoding the tEFGR and the antigen receptor, thus two proteins are expressed from the same construct, and the tEGFR marker can be used to detect the modified cells ([0600]).
Thus, Ports’ teaching encompasses a nucleic acid construct comprising a polynucleotide encoding an RNA-guided gene editing agent (CRISPR/CAS or TAL), a polynucleotide encoding a linker peptide, e.g., T2A, and a polynucleotide encoding a truncated epidermal growth factor receptor (tEGFR), as recited in claim 1.
Further regarding claim 1 and the limitation “wherein the polynucleotide encoding the linker peptide is located between the polynucleotide encoding the tEGFR and the polynucleotide encoding the gene editing agent”, it is noted however, that although Ports teaches the linker is located between the polynucleotide encoding the tEGFR and the antigen receptor, Ports does not specifically comment on whether or not the gene editing polynucleotide is located near the antigen receptor polynucleotide and thus the linker is located between the gene editing polynucleotide and the tEGFR polynucleotide.
However, given that Ports teaches the nucleic acid encoding the molecule or agent for modifying the expression of the molecule can be contained in one polynucleotide construct for expression of each of the antigen receptor, the gene editing agent and tEGFR marker and that self-cleaving linkers can be located between the polynucleotides intended for expression of individual peptides, it is reasonable to consider that the self-cleavable linker would be located between the gene editing polynucleotide and the tEGFR polynucleotide, thus permitting cleavage and expression of each peptide.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ a self-cleavable linker between the gene editing agent and the tEFGR marker.
The person of ordinary skill in the art would have been motivated to modify the composition of Ports to include a self-cleavable linker between the gene editing agent and the tEFGR marker, for the predictable result of successfully permitting expression of each peptide, thus meeting the limitation of claim 1.
Regarding claims 2-4, although Ports teaches the nucleic acid construct comprises the cleavable linker T2A, Ports does not further exemplify an embodiment wherein the nucleic acid construct further comprises an additional cleavage site (claim 2), wherein the cleavage site is a furin site (claim 3) or, wherein the furin cleavage site comprises the amino acid sequence of: (a) RXXR, wherein X is a naturally occurring amino acid residue, or the amino acid sequence is RRKR (claim 4).
However, Ports ([0718]) further teaches the open reading frame (ORF) of the nucleic acid construct which encodes the molecule involved in modulating a metabolic pathway and encoding the recombinant receptor can comprise protease recognition sites, such as furin sites, to permit separation of the encoded genes and processing of the individual proteins.
Thus, in view of Ports, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ protease recognition sites, such as furin sites, between various polynucleotides thus permitting separation of the encoded genes and processing of the individual proteins.
The person of ordinary skill in the art would have been motivated to modify the composition of Ports to include furin cleavage sites, for the predictable result of successfully permitting expression of the desired proteins, thus meeting the limitation of claims 2-3.
Further regarding claim 4, it is noted that New England Biolabs evidences that furin cleavage sites comprise the amino acid sequence RXXR. Thus, Ports’ teaching meets the limitation of claim 4.
Regarding claim 13, as discussed above regarding claim 1, Ports further teaches the T2A linker is located between the polynucleotide encoding the tEFGR and the antigen receptor, thus two proteins are expressed from the same construct, and the tEGFR marker can be used to detect the modified cells ([0600]). Thus, Ports renders obvious the placement of cleavable linkers 5’ of the various gene sequences for cleavage and processing to individual proteins, thus meeting the limitation of claim 13.
Regarding claim 17, it is noted that Ports teaches the polynucleotide encodes tEGFR. Ports disclosed tEFGR is identified as SEQ ID: NO 7, protein sequence. Ports does not further identify the nucleic acid sequence for the disclosed tEGFR, however US 2015/0306141 (14/422640) discloses the use of tEGFR as a marker protein for genetic modification of T-cells, identified as SEQ ID NO:9. Jensen evidences that Ports’ disclosed tEGFR comprises SEQ ID NO: 4 (see alignment below):
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Regarding claim 19, Ports teaches that viral and non-viral-based gene transfer methods can be employed to introduce the nucleic acid encoding the molecule or agent for modifying the expression of the molecule, wherein the vector delivery system comprises DNA plasmids or RNA ([0815], [0817]-[0818]), thus meeting the limitation of claim 19.
Regarding claim 21, Ports teaches expression vectors comprising the nucleic acid construct ([0100], [0154], [0702]), thus meeting the limitation of claim 21.
Regarding claim 23, Ports teaches introducing said nucleic acid constructs into cells (Abstract, [0072]-[0073] and [0100]), thus meeting the limitation of claim 23.
Claim(s) 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Ports, as evidenced by New England Biolabs and Jensen, as applied to claims 1-4, 6, 8, 10-12, 17, 19, 21 and 23 above, and further in view of Chng et al., (mAbs, Volume 7, Issue 2, pages 403-412, March/April 2015; see PTO-892) (“Chng”).
The teaching of Ports is set forth above.
Regarding claims 15-16, it is noted that Ports does not further teach the nucleic acid further comprises a nucleotide encoding a GSG linker (claim 15) or the GSG linker is 3’ of the polynucleotide encoding the cleavage site (claim 16).
However, Chng is directed to the use of cleavage efficient 2A peptides, e.g., T2A, in the construction of monoclonal antibody (mAb) cassettes, wherein expression was compared for constructs using different 2A peptides in the presence and absence of GSG linkers. Chng teaches that the inclusion of GSG linkers enhanced the cleavage efficiency resulting in enhanced the mAb expression level, and the highest cleavage efficiency was achieved using T2A with the GSG linker (GT2A) (Abstract). Chng’s Figure 1 illustrates the GSG linkers were located 3’ to the furin cleavage site (page 404).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include GSG linkers between the furin cleavage site and the T2A cleavage site (i.e., 3’ of the furin cleavage site), thus meeting the limitations of claims 15-16.
The person of ordinary skill in the art would have been motivated to modify the cleavage sites of Ports to include to include GSG linkers between the furin cleavage site and the T2A cleavage site, as taught by Chng, for the predictable result of successfully improving cleavage efficiency resulting in enhanced expression of the desired proteins.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Ports and Chng because each of these teachings are directed nucleic acid constructs for recombinant protein expression.
Allowable Subject Matter
Claim 18 appears to be free of prior art. The sequence search did not retrieve any results for a nucleic acid construct comprising SEQ ID NO: 1.
Claim 18 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.
Conclusion
No claim is allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to E. YVONNE PYLA whose telephone number is (571)270-7366. The examiner can normally be reached M-F 9am - 6pm.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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