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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-12, 33, 44, 52, and 62, in the reply filed on July 10, 2026 is acknowledged.
Claims 63, 69, 76, 84, 85, 87, and 88 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 10, 2026
Priority
While Figure 17 of U.S. Provisional Application 63/273,053 teaches increased oxygen consumption in CAR-CXCR2 expressing T cells in the presence of IL-8 compared to CAR expressing T cells in the presence of IL-8, there is no disclosure of increase mitochondrial mass nor increased ATP production until Example 14 of the instant Specification filed on April 14, 2022.
Claim 44 is examined with the priority date of PCT/US2022/024917, filed on April 14, 2022. Should Applicant disagree with the analysis above, he or she must point to the precise page and line of U.S. Provisional 63/278,428; 63/273,053; or 63/175,457 where increased mitochondrial mass and ATP production are disclosed.
Claim Rejections - 35 USC § 112(a)
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 1-12, 33, 44, 52, and 62 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1, from which claims 2-12, 33, 44, and 62 ultimately depend, recite two genera: any chemokine receptor, and any scFv CAR which is “able to bind to B7H3”. Claim 2 recites the polynucleotide encoding the CAR, a protein with a particular function, comprises a partial polynucleotide sequence, and thereby, a partial protein structure. Similarly, claim 5 recites the polynucleotide encoding the chemokine receptor, a protein with a particular function, comprises a comprises a partial polynucleotide sequence, and thereby, a partial protein structure. Further, claim 3 recites the genus of midkine receptors, which is not encompassed in chemokine receptors. As evidenced by Figure 2 of Aller et al. (International Journal of Molecular Sciences. 26(10): 4809; Published: May 17, 2025), reproduced below. Midkine has various functions – not limited to chemotaxis – and signals through a variety of receptors not known to be part of the art recognized group of chemokine receptors.
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Additionally, claims 3 and 4 recite that the polynucleotide encoding the chemokine receptor may encode “a biologically active fragment thereof”. Claim 52 recites two genera: any CAR encoded by the first polynucleotide and any chemokine receptor encoded by the second polynucleotide.
Regarding the genus of any chemokine receptor, the genus of chemokine receptor is described in the prior art; see Hughes er al. (The FEBS Journal. 285: 2944-2971; Published: April 10, 2018) and Kohli et al. (Cancer Gene Therapy. 29: 10-21; Published: February 18, 2021). One could not readily envisage the members of this genus and their sequences because what one of ordinary skill in the art would consider as encompassed in this genus appears to differ from what Applicant considers a chemokine receptor; see Midkine receptor above and section 112b. Further, combinations of CARs with a representative number of chemokine receptors are taught in the prior art; see Wang et al. (Frontiers in Immunology. 12: 628906; Published: March 10, 2021), Muller et al. (Journal of Immunotherapy. 38 (5): 197-210; Published: June 2015), and Di Stasi et al. (Blood. 113(25): 6392-6402; Published: June 18, 2009), for example.
Regarding genera of any anti-B7H3 scFv CAR or any CAR, these genera require an antigen binding domain, the structure of which confers specific binding. One skilled in the art cannot visualize or recognize the identities of the members of these genera that exhibit this functional property (binds to B7H3 or an antigen). The characteristics defining the genus of antibodies that bind B7H3 or an antigen unknown as this only sets forth what the antigen binding domains of the CARs do and not what they are. One would need to conduct further testing to see whether a given antibody was a member of the genus.
The claim scope is potentially enormous depending on how many of the products that meet the structural requirements would also meet the functional requirements (binding to B7H3 or an antigen); by contrast, the scope of the description which only includes a single species, is extremely narrow. Furthermore, the specification fails to disclose sufficient identifying characteristics of the genus, as discussed in more detail below.
It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date. Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 964 (Fed. Cir. 2002).
However, the record here does not indicate such an established correlation. The claims attempt to claim a polynucleotide sequence or cell comprising every anti-B7H3 scFv CAR or every CAR that would achieve a desired result, i.e. of binding to B7H3 or an antigen. However, the instant application only describes a polynucleotide sequence or cell comprising the anti-B7H3 scFv CAR comprising SEQ ID NO: 1 per se. The specification fails to identify what structural features would be responsible for conferring these desired properties and as such, fails to disclose a correlation between structure and function.
Further, Applicant recites a B7H3 scFv CAR encoded by the polynucleotide comprising 85% to 100% identity to SEQ ID NO: 1. Indeed, this encompasses substitutions, insertions, and deletions or truncations anywhere in SEQ ID NO: 1. The scFv comprises critical residues or CDRs conferring the function of binding to B7H3 and the CAR comprises structures necessary to convey intracellular activation. Applicant has not described the structure of variants having 85% to 100% identity to SEQ ID NO: 1 which are capable of binding B7H3 and activating the cell which expresses the polynucleotide comprising 85% to 100% identity to SEQ ID NO: 1. There is no teaching in the Specification regarding which up to 15% of the structure can be varied while retaining these abilities. Further, there is no art-recognized correlation between any structure (other than SEQ ID NO: 1) and the activity of binding B7H3 and activating the cell, based on which those of ordinary skill in the art could predict which amino acids can vary from SEQ ID NO: 1 without losing the function of binding B7H3 and activating the cell.
Regarding the genus of biologically active fragments of chemokine receptors, the limitation is indefinite as it is unclear what function or functions must be retained for the fragment to be considered biologically active. For the purpose of compact prosecution, the limitations are interpreted as encompassing any chemokine receptor having at least one binding site. Thus, this genus encompasses atypical chemokine receptors or receptor decoys and truncated chemokine receptors such that they retain at least one binding site. The scope of this limitation is extensive as it encompasses truncations of any chemokine receptor. Further, many chemokine receptors are promiscuous and bind a variety of ligands at differing affinities.
Kleist et al. (Biochemical Pharmacology. 114: 53-68; Published: April 19, 2016) teaches that chemokine and receptor interactions occur by a two-step/two-site mechanism whereby site 1 provides affinity and specificity, followed by site 2 which elicits receptor activation and where site 1 refers to interactions between the CKR N-terminus (a.k.a., chemokine recognition site 1, CRS1) and the chemokine globular core, and site 2 refers to contacts between residues in the receptor transmembrane (TM) domain (a.k.a., CRS2) and the unstructured chemokine N-terminus. Kleist et al. states, “[t]he recent crystal and NMR structures of chemokine-CKR complexes provide clues that far from following a two-site convention, interactions are diverse and highly specific for each individual chemokine-CKR pair at the extracellular surface.” Kleist et al. adds that “[s]tudies of CXCR1 and CXCR2 in the 1990s established a number of important principles concerning CKR recognition and activation as they relate to the receptor extracellular surface, including: 1) different chemokines utilize unique combinations of extracellular domains for the binding and activation of a single CKR [85, 86], 2) a single chemokine may utilize unique combinations of extracellular domains when binding different CKRs [85], and more generally 3) CKR binding and activation is a consequence of multiple, interdependent variables, particularly the identity of the chemokine and the simultaneous interactions it makes with all adjacent extracellular domains (i.e. N-terminus, ECLs 1–3) (Fig. 2A, B) [83–86].” In summary, Kleist et al. teaches that the chemokine receptor structure or critical residues necessary for binding varies depending on the ligand. With chemokine receptors binding more than one ligand, as illustrated in Figure 1 of Hughes et al. (reproduced below), the identity of the chemokine receptor structures necessary to confer binding rapidly becomes convoluted. Further adding to the complexity, chemokine-chemokine receptor pairings are species specific; see the red and blue lines in Figure 1 of Hughes et al. below.
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In contrast to the great complexity of what structure may be a biologically active fragment of a chemokine, Applicant has only exemplified making the claimed products with CXCR1 and CXCR2 encoded by the polynucleotides comprising SEQ ID NOs: 11 and 2, respectively.
Similarly, Applicant claims a partial sequence of CXCR2 encoded by a polynucleotide having 85% to 100% identity to instant SEQ ID NO: 2. This variation encompasses substitutions, insertions, and deletions or truncations anywhere in SEQ ID NO: 2. As above, chemokine receptors are promiscuous, and indeed, Figure 1 of Hughes illustrates that CXCR2 has seven known binding partners depending on the species. Kleist et al. teaches the significance of the chemokine receptor structures providing two binding sites and the complexity of chemokine receptor – chemokine pairings being mediated by specific structures.
In contrast to this complexity, Applicant has only exemplified making the polynucleotides encoding an anti-B7H3 scFv CAR and a CXCR2 encoded by a polynucleotide comprising 100% identity to SEQ ID NO: 2. There is no guidance in the instant Specification regarding critical residues of the CAR or CXCR2, or which chemokine pairings are critical to the intended function.
One of ordinary skill in the art would reasonably conclude that applicant was not in possession of polynucleotide constructs or vectors comprising the following:
1. Any chemokine receptor or biologically active fragment thereof,
2. Any anti-B7H3 scFv CAR,
3. Any CAR,
4. An anti-B7H3 scFv CAR encoded by a polynucleotide comprising 85%-100% identity to SEQ ID NO: 1, nor
5. A CXCR2 encoded by a polynucleotide comprising 85%-100% identity to SEQ ID NO: 2;
nor the resulting polypeptides, cells expressing or comprising the polynucleotide constructs or vectors, nor pharmaceutical compositions comprising cells expressing or comprising the polynucleotide constructs or vectors.
Claim Rejections - 35 USC § 112(b)
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 1-12, 33, 44, and 62 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 1 recites “[a] polynucleotide construct encoding a polypeptide comprising at least one chimeric antigen receptor (CAR) and at least one chemokine receptor”. It is unclear of the polynucleotide construct may comprise elements beyond polynucleotide sequences encoding at least one CAR and at least one chemokine receptor. Because the instant Specification defines constructs has having regulatory elements (see paragraph 0050), the claim is interpreted as reciting “[a] polynucleotide construct comprising a polynucleotide sequence encoding at least one chimeric antigen receptor (CAR) and a polynucleotide sequence encoding at least one chemokine receptor; wherein the CAR comprises a single-chain fragment (scFv) able to bind to B7H3 (B7 Homolog 3, CD276).” Additionally, this suggested language softens the shift to “the CAR polynucleotide” and “the polynucleotide encoding the chemokine receptor” in claims 2-5 by providing clearer antecedent basis.
Claims 2-12, 33, 44, and 62 are rejected for depending from claim 1 and failing to remedy the indefiniteness.
Claims 3 and 4 recite “biologically active fragments” of chemokine receptors. There is no definition provided in the instant Specification as to what functions the fragments must retain in order to be considered biologically active. Kleist et al. (Biochemical Pharmacology. 114: 53-68; Published: April 19, 2016) teaches that chemokine and receptor interactions occur by a two-step/two-site mechanism whereby site 1 provides affinity and specificity, followed by site 2 which elicits receptor activation and where site 1 refers to interactions between the CKR N-terminus (a.k.a., chemokine recognition site 1, CRS1) and the chemokine globular core, and site 2 refers to contacts between residues in the receptor transmembrane (TM) domain (a.k.a., CRS2) and the unstructured chemokine N-terminus. It is unclear whether fragment needs both sites 1 and 2, or just one of those to be biologically active? Bonecchi et al. (Cytokine. 87: 37-45; Published: August 4, 2016) teaches that there are soluble and seven-transmembrane domain chemokine decoy receptors, including atypical chemokine receptors, which are unable to elicit migration or conventional signaling while they are still able to sequester and scavenge inflammatory chemokines. Are these biologically active fragments? If one modifies a typical chemokine receptor to comprise site 1, but not receptor activation site 2 so that it functions as a decoy, then is that biologically active? For the purpose of compact prosecution, the claims are interpreted as encompassing any chemokine receptor having at least one binding site.
Additionally, claim 3 recites midkine receptor. A midkine receptor is not a chemokine receptor; see section 112a. It is unclear how a polynucleotide encoding the chemokine receptor can comprise a polynucleotide encoding a midkine receptor.
Claim 4 recites “[t]he polynucleotide construct according to claim , wherein […]”. The claim number has been deleted. It is unclear from which claim, claim 4 depends. For the purpose of compact prosecution, claim 4 is interpreted as depending from claim 1.
Claim 5 is rejected for depending from claim 4 and failing to remedy the indefiniteness.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 3, 4, 11, and 12 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 12 recites “[a] vector comprising a polynucleotide according to claim 1.” Claim 1 recites “[a] polynucleotide construct”. Paragraph 0050 of the instant Specification groups “vector” and “construct” as synonymous; stating that these terms refer to nucleic acid components used to introduce polynucleotides into a cell having regulatory element s to provide expression of the heterologous nucleic acids into a cell. In light of the instant definition, there appears to be no difference between a structure which is a polynucleotide construct and a vector. Additionally, claim 12 recites “a polynucleotide according to claim 1”, yet claim 1 recites a polynucleotide construct. “[A] polynucleotide according to claim 1” in claim 12 is interpreted as encompassing to a subsequence of the polynucleotide construct of claim 1. Claim 12 fails to further limit the scope of claim 1.
Claims 3 and 4 are interpreted as each depending from claim 1; see 112b section. Claim 1 recites a polynucleotide encoding a polypeptide comprising at least one chimeric antigen receptor and at least one chemokine receptor. Claims 3 and 4 recite that the polynucleotide encoding the chemokine receptor comprising a polynucleotide encoding a biologically active fragment thereof. Claim 1 recites a chemokine receptor – not a chemokine receptor or a fragment thereof. Claims 3 and 4 further expand and fail to limit the scope of claim 1. In the interest of compact prosecution, Examiner clarifies that amending claim 1 to include fragments thereof would not resolve the issues of indefiniteness and possession; see 112a and 112b sections.
Claim 3 recites the polynucleotide encoding the chemokine receptor comprises a polynucleotide encoding a list of receptors, including midkine receptor. Midkine receptor is not known in the art to be a singular receptor. Additionally, while midkine may have role in chemotaxis, it is not a chemokine, but rather is a small, heparin-binding protein that functions as a growth factor and cytokine. Midkine signaling is implicated in diverse functions, such as mitogenicity, inflammation, angiogenesis, metastases, and stem cell self-renewal and occurs through a variety of membrane receptors, including Notch2; as evidenced by Table 1 and Figure 2 of Aller et al. (International Journal of Molecular Sciences. 26(10): 4809; Published: May 17, 2025), the latter is reproduced in the rejection under 35 U.S.C. 112(a) above.
Indeed, one of ordinary skill in the art would not consider midkine to chemokine nor the various receptors involved in midkine signaling to be part of the family of chemokine receptors as further evidenced by Figure 1 of Proudfoot (Nature Reviews Immunology. 2: 106-115; Published: February 1, 2002). Thus, claim 3 fails to limit the claim 1 from which it depends.
Claims 5 and 11 are rejected for depending from claims 4 and 12.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 3, 6-12, and 62 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Li et al. (US 2021/0214418 A1; Filed: December 12, 2019; Published: July 15, 2021).
Regarding claims 1, 3, and 12, Examples 4 and 5 teach design CAR-CXCR5 fusions and construction of vectors for expressing the CAR-CXCR5 fusions. Regarding claim 10, Figure 4B depicts the resulting CAR and CXCR5 combining and anti-B7H3 scFv with CXCR5. Regarding claims 6-8, Figure 4B depicts the CAR-CXCR5 fusion protein linked via a polypeptide linker which is a 2A, self-cleaving peptide. Regarding claims 9 and 11, Example 6 teaches transfecting 293T cells with the vectors or constructs encoding the CAR-CXCR fusions and Example 7 and table 7 demonstrate that percent of cells expressing the CAR-CXCR fusions. Regarding claim 62, Li et al. claims 7 and 8 teach a pharmaceutical composition comprising the CAR-CXCR5 fusion.
Thus, Li et al. anticipates claims 1, 3, 6-12, and 62.
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.
Claims 1, 3, 4, 6-12, 33, 44, and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (US 2021/0214418 A1; Filed: December 12, 2019; Published: July 15, 2021) and of Jin et al. (Nature Communications. 10: 4016; Published: September 5, 2019).
Regarding claims 1, 3, and 12, Examples 4 and 5 teach design CAR-CXCR5 fusions and construction of vectors for expressing the CAR-CXCR5 fusions. Regarding claim 10, Figure 4B depicts the resulting CAR and CXCR5 combing and anti-B7H3 scFv with CXCR5. Regarding claims 6-8, Figure 4B depicts the CAR-CXCR5 fusion protein linked via a polypeptide linker which is a 2A, self-cleaving peptide. Regarding claims 9 and 11, Example 6 teaches transfecting 293T cells with the vectors or constructs encoding the CAR-CXCR fusions and Example 7 and table 7 demonstrate that percent of cells expressing the CAR-CXCR fusions. Regarding claim 62, Li et al. claims 7 an 8 teach a pharmaceutical composition comprising the CAR-CXCR5 fusion.
Li et al. does not teach a polynucleotide construct comprising CXCR2.
Regarding claims 3, 4, 6-12, and 33, Jin et al. teaches transducing human T cells with a CAR-CXCR1 or CAR-CXCR2 vector wherein the CAR and CXCR are linked via a 2A peptide; see ‘Retroviral and lentiviral constructs’ and ‘Transduction of human T cells and tumor cell lines’ sections.
Like Li et al., the vector of Jin et al. comprises the CAR with the CXCR downstream and linked via a self-cleaving 2A peptide. Given the similarities between the two vectors and the shared use in the potential treatment of cancer, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to modify the vector of either Li et al. or Jin et al. to express the combination of a B7H3 scFv CAR and CXCR2. One would have been motivated to make such a combination because using the anti-B7H3 scFv CAR taught by Li et al., instead of the anti-CD70 CAR taught by Jin et al., allows for use in another wide range of malignancies; see Table 3 of Li et al. for example. The anti-B7H3 CAR + CXCR5 T cells of Li et al. demonstrate improved migration compared to B7H3 CAR T cells, yet there was no improvement on target lysis when treated with anti-B7H3 CAR + CXCR5 T cells compared to anti-B7H3 CAR T cells; see Li et al. Figures 6 and 8, respectively. While the migration of anti-B7H3 CAR + CXCR5 T cells of Lin et al. was approximately 3-fold that of anti-B7H3 CAR T cells at the highest CXCL13 dose, the migration of anti-CD70 CAR + CXCR2 T cells was approximately 5-fold greater than anti-CD70 CAR T cells at the highest dose of culture media with no notable deficiencies in cytolytic activity; see Li et al. Figure 7 and Jin et al. Figures 2f and 2g, respectively. In other words, one would have been motivated to use CXCR2 taught by Jin et al., in place of CXCR5 taught by Li et al., because CXCR2 demonstrated a stronger effect on chemotaxis compared to CXCR5.
Regarding claim 44, the increased ATP production and/or mitochondrial mass is an inherent property of the transduction of a human immune cell or human stem cell with the anti-B7H3 scFv CAR and CXCR.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the application, as evidenced by the references.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (US 2021/0214418 A1; Filed: December 12, 2019; Published: July 15, 2021) and Jin et al. (Nature Communications. 10: 4016; Published: September 5, 2019) as applied to claim(s) 1, 3, 4, 6-12, 33, 44, and 62 above, and further in view of Gaitanaris et al. (WO 2004/040000 A2; Published: May 13, 2004).
The teachings of Li et al. and Jin et al. as related to claim(s) 1, 3, 4, 6-12, 33, 44, and 62, from which these claims depend are given previously in this Office action and are fully incorporated here.
While Jin et al. teaches a polynucleotide construct comprising human CXCR2, the reference does not teach the sequence of CXCR2.
Gaitanaris et al. teaches the polynucleotide of human CXCR2, also known as IL8RB; see page 178. Nucleotides 1-1080 of SEQ ID NO: 1083, the polynucleotide sequence encoding human CXCR2 taught by Gaitanaris et al., is 100% identical to instant SEQ ID NO: 2.
It would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success using the polynucleotide sequence encoding human CXCR2 in the polynucleotide construct comprising polynucleotide sequences encoding an anti-B7H3 scFv CAR and CXCR2.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claim 52 is rejected under 35 U.S.C. 103 as being unpatentable over Jin et al. (Nature Communications. 10: 4016; Published: September 5, 2019) in view of Liu et al. (European Journal of Immunology. 50(5): 712-724; Published: February 10, 2020).
Jin et al. teaches transducing human T cells with a CAR-CXCR1 or CAR-CXCR2 vector wherein the CAR and CXCR are linked via a 2A peptide; see ‘Retroviral and lentiviral constructs’ and ‘Transduction of human T cells and tumor cell lines’ sections. Jin et al. teaches CAR-CXCR1 T cells demonstrated superior chemotaxis and better proliferation than CAR-CXCR2 T cells with similar cytolytic activity in vitro; see Figures 2e, 2f, 2g, and 2i. However, in vivo models of ovarian and pancreatic cancer, the CAR-CXCR2 T cells results in better survival outcomes than the CAR-CXCR1 T cells; see Figures 3k and 3p. Although, the inclusion of either CXCR1 or CXCR2 outperformed the sham CAR-EGFP T cells in survival outcomes.
Jin et al. states of the potential mechanism by which the inclusion of CXCR1 or CXCR2 improves survival:
IL-8 is considered to be a pro-cancer chemokine with a role in tumor immunosuppression, and we found that the 8R70CAR T cells appear to be able to siphon IL-8 in vitro. We hypothesize that these CAR T cells may act as a sink to neutralize or remove IL-8 from the intratumoral microenvironment after trafficking into the tumor, and provide an advantage for improved antitumor therapeutics by lowering the intratumoral IL-8, in addition to enhancing T-cell trafficking. Interestingly, we also found that CAR-R2 is superior to CAR-R1 in vivo, although CAR-R1 displayed better chemotaxis and increased proliferation in response to IL-8 in vitro.
Jin et al., in highlighting the distinct responses of CAR-CXCR1 and CAR-CXCR2 T cells, alludes to potential diverging mechanisms of the CAR-CXCR1 and CAR-CXCR2 T cells with a nexus around IL-8.
Liu et al. teaches that CXCR1 and CXCR2 have different ligands. In contrast to CXCR1, which primarily binds IL-8, also known as CXCL8, CXCR2 binds to several ligands, including CXCL1, CXCL2, CXCL5, and CCL2 in addition to IL-8; see Figure 1H.
Given that Jin et al. demonstrated that CAR-CXCR1 T cells demonstrated better chemotaxis and proliferation and CAR-CXCR2 T cells demonstrated superior survival outcomes and the Liu et al. teaches that CXCR1 and CXCR2 bind different set of ligands, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to produce a T cell comprising a polynucleotide encoding a CAR, a polynucleotide encoding CXCR1, and a polynucleotide encoding CXCR2. One would have been motivated to construct a T cell comprising polynucleotide sequences encoding a CAR, CXCR1, and CXCR2 in order to produce a CAR T cell with superior chemotaxis, proliferation, and survival outcomes.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Potentially Allowable Subject Matter
Presently, no claims are allowed.
The CAR polynucleotide comprising 100% identity to SEQ ID NO: 1 is not taught or rendered obvious by the prior art. In particular, the sequence of the B7H3 scFv portion of the CAR polynucleotide is not taught in the art. Additionally, the translated protein encoded by the B7H3 scFv portion of the CAR polynucleotide is not taught by the prior art.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Huang et al. (WO 2019/051047 A1; Published: March 14, 2019) teaches nucleic acids encoding CXCR1 or CXCR2 and a CAR and T cells expressing CXCR1 or CXCR2 and a CAR. Whilding et al. (Cancers 11: 674; Published: May 14, 2019) teaches T cells co-expressing a CAR and CXCR1 or CXC2. Peng et al. (Clinical Cancer Research. 16(22): 5458-5468; Published: November 15, 2010) teaches transgenic pmel-1 T cells which recognize gp100 in the context of H-2Db, that were transduced with luciferase and CXCR2 genes.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE ANN HOLTZMAN whose telephone number is (571)270-0252. The examiner can normally be reached Monday - Friday 8:30am - 5:00pm MT.
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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