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 .
Claims Status
The Amendment filed on 05Nov2025 canceled claims 33-38 and added new claims 51-58.
Claim(s) 39-58 is/are currently pending and presented for examination on the merits.
Response to Amendment
The objection(s) to the drawings, and/or the specification have been withdrawn in view of the Amendment filed on 05Nov2025.
All previous rejections of claim(s) 33-38 are moot in view of claim cancelation. Any arguments pertaining only to canceled claims 33-38 are not discussed herein.
The previously set forth rejection(s) of claim(s) 44-46 under 35 U.S.C. § 112(a), of claim(s) 42, 44-48, 50 under 35 U.S.C. § 112(b), and of claim(s) 39-46, 49-50 under 35 U.S.C. § 103 have been withdrawn in view of the recent claim amendment filed on 05Nov2025, which added new limitations to the claims that were not considered in the previous rejections, necessitating new rejection(s).
Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
New Rejections Necessitated by Claim Amendments
Claim Rejections - 35 USC § 112(b)
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 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.
Claim(s) 39-58 is/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.
Regarding instant claim(s) 39 (and dependent claims 40-58), claim 1 recites the phrase “wherein the CAR comprises a SIRPy fusion protein and CAR1…wherein the CAR1 comprises an extracellular domain recognizing a tumor antigen, a hinge region, a transmembrane domain and an intracellular signaling domain…”, which renders the claims indefinite. Specifically, it is unclear what CAR1 is referring to. In the instant speciation, CAR1 is described as comprising different sequences and structure, including:
(a) preferred embodiment 1 comprising: (i) an scFv, (ii) a hinge (SEQ ID NO: 24), (iii) a transmembrane (Tm) (SEQ ID NO: 7 or 8), (iv) CD3z (SEQ ID NO: 11), and (v) SIRPy fusion protein comprising SIRPy (SEQ ID NO: 1), CD28 Tm (SEQ ID NO: 7), CD28 ICD (SEQ ID NO: 9) [e.g., pg. 5, ¶ 5];
(b) preferred embodiment 2 comprising: (i) an anti-CEA scFv, (ii) a CD8 hinge, (iii) a CD8 Tm, (iv) a CD137-CD3z dual stimulus signal, and (v) SIRPy fusion protein comprising SIRPy (SEQ ID NO: 1), CD28 Tm (SEQ ID NO: 7), CD28 ICD (SEQ ID NO: 9) [e.g., pg. 6, ¶ 3];
(c) preferred embodiment 3 comprising: (i) an anti-CD19 scFv, (ii) a CD8 hinge, (iii) a CD8 Tm, (iv) a CD28-CD137-CD3z dual stimulus signal, and (v) SIRPy fusion protein comprising SIRPy (SEQ ID NO: 1), CD28 Tm (SEQ ID NO: 7), CD28 ICD (SEQ ID NO: 9) [e.g., pg. 6, ¶ 6];
(d) preferred embodiment 4 comprising: (i) an anti-PSCA scFv, (ii) a hinge, (iii) a CD8 Tm, (iv) a CD137-CD3z dual stimulus signal, and (v) SIRPy fusion protein comprising SIRPy (SEQ ID NO: 1), CD28 Tm (SEQ ID NO: 7), CD28 ICD (SEQ ID NO: 9) [e.g., pg. 7, ¶ 2]; or
(e) preferred embodiment 5 comprising: (i) an scFv, (ii) a hinge (SEQ ID NO: 24), (iii) a transmembrane (Tm) (SEQ ID NO: 7 or 8), (iv) CD3z (SEQ ID NO: 11), (v) SIRPy fusion protein comprising SIRPy (SEQ ID NO: 1), CD28 Tm (SEQ ID NO: 7), CD28 ICD (SEQ ID NO: 9), and (vi) a hypoxia-inducible promotor [e.g., pg. 7, ¶ 6].
Thus, it is unclear what CAR1 is referring to.
For the purposes of compact prosecution, the recitation of CAR1 in claim 39 is considered to refer to preferred embodiment 1. This rejection may be overcome by amending claim 39 to (1) replace “CAR1” with “CAR”, or (2) clearly define which embodiment of CAR1 is claimed. Dependent claims 40-58 can overcome this rejection by amending claim 39 as indicated above.
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) 39-41, 49-56 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0044404 A1 (hereinafter “US404”) and Piccio et al. (BLOOD, 15ar2005, Vol 105, No 6; hereinafter “Piccio”) as evidenced by GeneCards (Signal Regulatory Protein Gamma, website accessed 29Jul2025; hereinafter “GeneCards”).
Regarding instant claim(s) 39-41, 49-50, 53-56, US404 teaches a P2A (self-cleaving peptide) polycistronic vector that links a CAR and a fusion protein, and uses thereof including cancer therapy [e.g., title, abstract, ¶ 0039, 0223; fig. 7a]. US404 further teaches that (1) the CAR T cell comprises an scFv antigen-binding domain, [e.g., ¶ 0003, 0053], a hinge region, a transmembrane domain [e.g., ¶ 0011, 0050], and (2) a SIRPa fusion protein comprising a SIRPa extracellular component, a CD28 transmembrane (Tm) and a CD28 intracellular signaling domain (ICD) which are the same as instant SEQ ID NOs: 7, 38, respectively (see alignment below) [e.g., fig. 8A]. US404 further teaches that (1) such immunomodulatory fusion proteins are useful in treating cancers [e.g., abstract; ¶ 0028-0030], (2) that the extracellular portion of the fusion protein can be readily substituted (e.g., SIRPa, CD200R, PD1, Fas, Lag3, Tim3) [e.g., figs. 1A, 8A, 9A, 11A, 12A, 13A], and (3) that the fusion protein binding to a target can generate a modulatory signal in a host cell, such as a T cell [e.g., title and abstract].
Alignment of instant CD28 Tm (SEQ ID NO: 7) with US404 SEQ ID NO: 27:
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86
310
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Alignment of instant CD28 ICD (SEQ ID NO: 38) with US404 SEQ ID NO: 28:
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Regarding instant claim(s) 51, US404 further teaches that the vector (e.g., polycistronic vector) is transfected into a host cell [e.g., ¶ 0051, 0164-0171].
Regarding instant claim(s) 52, US404 further teaches methods and compositions comprising the invention (e.g., fusion protein and CAR expressing T cells) for the treatment tumors including non-Hodgkin’s lymphoma, Hodgkin’s disease, prostate cancer, breast cancer, ovarian cancer, cervical cancer, lung cancer [e.g., ¶ 0175].
US404 does not expressly teach (1) a CAR-P2A-SIRPy fusion expressing T cell for cancer therapy, or (2) a CAR-P2A-SIRPy fusion expressing T cell for cancer therapy wherein the cancer treated is Hodgkin’s lymphoma, Hodgkin’s disease, prostate cancer, breast cancer, ovarian cancer, cervical cancer, lung cancer.
Piccio teaches adhesion of T cells to APCs through SIRPB2-CD47 interaction co-stimulates T cell proliferation, that SIRPB2 is expressed on T cells and activated NK cells, and that SIRPB2 binding to CD47 mediates cell-cell adhesion [e.g., title and abstract]. SIRPB2 is the same as SIRPy, as evidenced by GeneCards [e.g., pg. 1, "Aliases for SIRPG Gene"]. Piccio further teaches materials and methods for constructing and expressing SIRP fusion proteins [e.g., pg. 2422,, "cDNAs ... ", "SIRP-lgG fusion ... ", table 1]. Piccio teaches that SIRPB2 is a unique member of the SIRP receptor family in that it is the only SIRP detected on T cells and activated NK cells, and that SIRPB2 binds CD47 providing T and NK cells with the ability to interact with CD47, but that wildtype SIRPB2 doesn't have an intracellular signaling domain, and therefore cannot deliver activating or inhibitory signals, but rather mediates strong cell-cell adhesion, supporting T cell-APC contact and thereby enhancing antigen presentation, T cell proliferation, and cytokine secretion [e.g., pg. 2425-2426, Discussion]. Piccio further teaches that SIPRB2 enhanced T-cell proliferation was induced by suboptimal concentrations of T cell receptor ligand, and whether SIRPB2 acts as a costimulatory similar to CD28 or synergizes with TCR signaling by other mechanisms is unknown [e.g., pg. 2426, Discussion].
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to substitute the SIRPa extracellular domain of the fusion protein of the CAR-P2A-SIRPa Fusion protein expressing T cell for treating cancer as taught by US404, with the SIRPB2 extracellular domain (same as SIRPy, as evidenced by GeneCards) as taught by Piccio, in the context of designing or developing a cancer therapeutic. A PHOSITA would have been motivated to substitute the SIRPy extracellular domain taught by Piccio for the SIRPa extracellular domain portion of the fusion protein taught by US404, because Piccio teaches SIRPy promotes T cell proliferation (e.g., beneficial for cancer therapy). There would have been a reasonable expectation of success for a PHOSITA to substitute the SIRPa extracellular domain of the fusion protein of the CAR-P2A-SIRPa Fusion protein expressing T cell for treating cancer as taught by US404 with the SIRPy extracellular domain taught by Piccio because US404 teaches that the extracellular portion of the fusion protein can be readily substituted (see above). This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Further, it would have been obvious to a PHOSITA to modify the modified method of treating cancer comprising administering CAR-P2A-SIRPy fusion protein expressing T cells as taught by US404 and Piccio (see above) to include that the cancers treated by CAR-P2A-SIRPy expressing T cell administration include Hodgkin’s lymphoma, Hodgkin’s disease, prostate cancer, breast cancer, ovarian cancer, cervical cancer, and lung cancer as taught by US404, because US404 and Piccio teach the administration of CAR-P2A-SIPRy fusion protein expressing T cells for cancer therapy, and US404 further teaches that cancers treated comprise Hodgkin’s lymphoma, Hodgkin’s disease, prostate cancer, breast cancer, ovarian cancer, cervical cancer, and lung cancer. Further, as discussed in Piccio above, both SIRPa and SIRPy interact with CD47. There is an expectation of success for a PHOPSITA to substitute the general treatment of “cancer” by administration of CAR-P2A-SIRPy fusion protein expressing T cells as taught by US404 and Piccio with specific cancer indications treatable thereby as taught by US404, because US404 and Piccio teach the administration of CAR-P2A-SIPRy fusion protein expressing T cells for cancer therapy, SIRPa and SIRPy both interact with CD47 (see Piccio above), and US404 further teaches specific cancer indications treatable with such therapeutics. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 43 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0044404 A1 (hereinafter “US404”) and Piccio et al. (BLOOD, 15ar2005, Vol 105, No 6; hereinafter “Piccio”) as evidenced by GeneCards (Signal Regulatory Protein Gamma, website accessed 29Jul2025; hereinafter GeneCards”) as applied to claim 39 above, and further in view of WO 2021/188599 A1 (hereinafter “WO599”).
The teachings of US404 and Piccio as recited above apply for claim 39.
US404 and Piccio do not expressly teach the CAR-P2A-SIRPy fusion protein wherein the CAR scFv recognizes (binds to) CD19, PSCA, or CEA.
Regarding claim(s) 43, WO599 teaches novel antigen binding domains of antibodies and CARs [e.g., title, abstract; ¶ 0002, 0004, 0007, 0027]. WO599 teaches that disclosed antigen binding domains such as anti-CD19, anti-PCSA, and anti-CEA are useful in treating cancer [e.g., ¶ 00287, 0033-0040, 0074, 0087, 00221-00222; tbls. B, 40].
Further, it would have been obvious to a PHOSITA to modify the modified method of treating cancer comprising administering CAR-P2A-SIRPy fusion protein expressing T cells as taught by US404 and Piccio (see above) to include the that the CAR scFv recognizes (binds to) CD19, PSCA, or CEA as taught by WO599, because US404 and Piccio teach the CAR-P2A-SIRPy structure, the method of treating cancer comprising administering CAR-P2A-SIRPy expressing T cells, and WO599 teaches specific target antigens for the treatment of cancer including CD19, PSCA, and CEA (see above). There is an expectation of success for a PHOPSITA to substitute the general scFv binding domain of the CAR in the modified method of treating cancer comprising administering CAR-P2A-SIRPy fusion protein expressing T cells as taught by US404 and Piccio (see above) with an anti-CD19, anti-PSCA, or anti-CEA scFv as taught by WO599, because US404 and Piccio teaches the basic structure of the CAR includes an scFv, as well as the treatment of cancer, and WO599 teaches scFvs of CARs, the treatment of cancer, that known cancer antigens include CD19, PSCA, and CEA, and teach anti-CD19, anti-PSCA, and anti-CEA scFv domains for cancer therapy. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Response to Arguments (for all 35 USC 103 rejections)
Applicant argues:
US404 and Piccio fail to provide motivation to modify SIRPy to obtain the SIRPy fusion protein of new claim 39 in terms of both structural and functional aspects: (1) STRUCTURAL DIFFERENCES: (a) SIRPa fusion protein of US404 contains ECD, Tm and ICD while WT SIRPy only comprises ECD, Ta and a 4 aa ICD, and therefore is not able to transduce an intracellular signal into a T cell; (b) the SIRPy fusion protein of Piccio is secreted, while the SIRPy fusion protein of the instant invention is bound to the ECM, thus the SIRPy fusion protein of Piccio and the SIRPy fusion protein of the instant application are two types of SIRPy fusion proteins; (c) none of the references provide motivation for making the SIRPy fusion protein of the present invention; and (2) FUNCTIONAL DIFFERENCES: (a) different affinity to T cells – SIRPy shows a 10-fold lower affinity for CD47, relative to SIRPa, and is unlikely to generate intracellular signaling because no recognizable signaling motifs; (b) WT SIRPy does not deliver activating or inhibitory signals on its own. Therefore, based on these differences it can be seen that (1) the SIRPy protein in Piccio shows SIRPy does not deliver activating or inhibitory signals on its own, while the SIRPa fusion protein in US404 has strong intracellular signaling; (2) the affinity of SIRPy in Piccio to CD47 is 10-fold lower compared to SIRPa. Thus, based on the information disclosed in US404 and Piccio and other art, one of ordinary skill would have had no motivation to modify SIRPy to arrive at the instant invention. On skilled in the art would expect no or quite low intracellular signaling of the SIRPy fusion protein to be produced.
In response to argued structural difference “a”, US404 was relied upon to teach a fusion protein comprising a CD28 Tm, and a CD28 intracellular signaling domain, and a readily substitutable ECD, wherein the fusion protein binding to a target can generate a modulatory signal in a host cell, such as a T cell; whereas Piccio was relied upon to teach a SIRPy ECD for cancer therapy and T cell stimulation/proliferation (see rejections above for details). Further, the Applicant argues wild-type (WT) SIRPy function which one of ordinary skill in the art would understand to be different from that of a SIRPy ECD fusion protein with a CD28 Tm and CD28 intracellular signaling domain. Therefore, the SIRPy fusion protein made obvious over US404 and Piccio would be understood by one of ordinary skill in the art to utilize the CD28 fusion portion for signaling (rather than the WT SIRPy 4aa ICD as argued by Applicant). Applicant argument has been fully considered and is not found persuasive.
In response to argued structural difference “b”, US404 was relied upon to teach a membrane bound fusion protein with a readily substitutable ECD; whereas Piccio was relied upon to teach SIRPy also interacts with CD47 and is known to enhance T cell proliferation upon binding. Therefore the type of fusion protein of the instant invention was taught by US404 (not Piccio). Further, one of ordinary skill in the art would understand the differing fusion proteins of US404, Piccio, and the instant application to constitute overlapping art. Applicant argument has been fully considered and is not found persuasive.
In response to argued structural difference “c”, as discussed above, one of ordinary skill in the art would have been motivated to substitute the SIRPy extracellular domain taught by Piccio for the SIRPa extracellular domain portion of the CAR-P2A-SIRPa fusion protein taught by US404, because Piccio teaches SIRPy promotes T cell proliferation (e.g., beneficial for cancer therapy). Applicant argument has been fully considered and is not found persuasive.
In response to argued functional difference “a”, as discussed in response to arguments above, the instant invention comprises a SIRPy fusion protein wherein the intracellular signaling relies upon a CD28 intracellular signaling domain. Further, as stated above, US404 teaches the ECD of the fusion protein is readily substitutable, and that binding of the ECD to the target causes intracellular signaling and T cell proliferation. Further, despite any differences in CD47 binding affinity, relative to SIRPa, Piccio teaches SIRPy induces T cell proliferation. Additionally, there is no specific CD47 binding affinity requirement of the SIRPy ECD (either alone or in relation to SIRPa binding affinity) in the instant claim language. For the reasons provided above, the argument regarding the inability of WT SIRPy to generate intracellular signaling is moot and does not apply to the scope of the instant claims, or the application of the prior art (see response to arguments and rejections above for details). Applicant arguments have been fully considered and are not found persuasive.
In response to argued functional difference “b”, as discussed above, the claims are not drawn to the use of WT SIRPy, and US404 was relied upon to teach a fusion protein comprising a CD28 intracellular signaling domain that generates a signal inside of the host cell. Therefore, the argument that the WT SIRPy ICD doesn’t perpetuate a signal is considered moot. Applicant arguments have been fully considered and are not found persuasive.
In response to the assertion that one of ordinary skill would have had “no motivation to modify SIRPy” to arrive at the instant invention, US404 taught the base structure of the fusion protein, not Piccio. Therefore, the ECD of the fusion protein of US404 was modified by substituting the ECD thereof with the SIRPy ECD as taught by Piccio for the reasons discussed above. Applicant arguments have been fully considered and are not found persuasive.
In response to the assertion that one of ordinary skill would “expect no or quite low intracellular signaling of the SIRPy fusion protein to be produced”, as discussed in greater detail above, the fusion protein as taught by US404 comprises a CD28 intracellular signaling domain and a readily substitutable ECD and as such one of ordinary skill in the art would expect a strong signal from the US404 fusion protein’s CD28 intracellular domain and as such would know not to base expectations upon SIRPy WT signaling (as both the Tm and signaling domains of the fusion protein differ from that of WT SIRPy). Applicant arguments have been fully considered and are not found persuasive.
None of the combined references provide motivation to combine SIRPy fusion protein with CAR1 to activate T cells for tumor killing. US404 only used SIRPa fusion protein to activate T cells to kill CD47+ tumor cells; Piccio discloses that WT SIRPy does not deliver activating or inhibitory signals on its own. None of the references provide motivation to combine CAR1 and SIRPy fusion protein to kill tumor cells, and thus new claim 39 is non-obvious.
In response, briefly, US404 was relied upon to teach the CAR-P2A-SIRPa fusion protein expressing T cells for cancer therapy, whereas Piccio was relied upon to teach SIRPy ECD as an alternative ECD. One of ordinary skill in the art would have been motivated to substitute the SIRPy extracellular domain taught by Piccio in place of the SIRPa extracellular domain portion of the CAR-P2A-SIRPa fusion protein taught by US404, because Piccio teaches SIRPy promotes T cell proliferation (e.g., beneficial for cancer therapy). Applicant arguments have been fully considered and are not found persuasive.
Unexpected results: (1) Piccio teaches SIRPy/CD47 interaction didn’t alter T cell or NK cell mediated toxicity, but in the instant invention the SIRPy fusion protein promotes T cell cytotoxicity. Thus, Piccio teaches away in this aspect; (2) Fig. 9 shows that CAR1 with SIRPy fusion protein is more effective at tumor killing than the CAR1 alone; (3) figs. 14-16 shows “huge synergistic effect on stimulating screening” of IFNy, IL2, and TNFa indicating that the combination of CAR1 and SIRPy fusion protein can activate T cells so well that the effect is “definitely unexpected to one of ordinary skill in the art”; (4) Figs. 17-18 show that the in vivo tumor inhibition effects of the CAR1-SIRPy fusion protein expressing T cells are much better than CAR1 or the control T group alone; (5) Example 11 and figs. 20-21the CD19 direct CAR1 and SIRPy fusion protein result in significantly higher effect on in vitro tumor cell lysis or IFNy stimulation that SIRPy fusion protein alone and is “definitely unexpected”; (6) figs. 22-23 show in vivo tumor inhibition effects of the CD19 directed CAR1 and SIRPy fusion protein are much better than CAR1 or the control group alone, are synergistic, and unexpected because Piccio teaches SIRPy binds CD47 with lower affinity than SIRPa.
In response to unexpected result “1”, Piccio wasn’t relied upon to teach T cell mediated cytotoxicity and Piccio describing the WT SIRPy effects on cytotoxicity does not teach away because it does not expressly say that a SIRPy ECD with a CD28 Tm and a CD28 intracellular signaling domain is not effective in cancer therapy and/or reduces cytotoxicity. Further, applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., SIRPy fusion protein promoting T cell cytotoxicity) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Applicant arguments have been fully considered and are not found persuasive.
In response to unexpected results “2”, “4”, and “6”, the SIRPy fusion protein comprises a CD28 Tm and intracellular signaling domain, and US404 teaches that the intracellular signaling (upon ECD binding) causes T cell proliferation (see arguments above and rejection for details). One of ordinary skill in the art would understand T cell proliferation is considered generally beneficial for CAR T cells because it leads to more CAR T cells which in turn results in sustained anti-tumor effects (e.g., more effective tumor killing). Further, it would be obvious to one of ordinary skill in the art that a CAR T cell alone (e.g., CAR 1) would not be expected to kill as many cancer cells as a CAR T cell that is also engineered to express a molecule (e.g., fusion protein) that promotes T cell proliferation upon binding (e.g., more CAR T cells should necessarily result in more killing). Further, the recited figures do not have the proper controls to prove synergy. Specifically, the Applicant would need to show that the CAR-SIRPy fusion protein with a different ECD (e.g., SIRPa) does not produce similar results because, as discussed above, the fusion CAR-SIRPy fusion protein is expected to be more effective than the CAR alone. Regarding claims that SIRPy binds CD47 with lower affinity, see response to arguments above. Additionally, the Applicant’s arguments are directed to elements that are not part of the instant invention in that the CAR with SIRPy fusion protein being more effective than the CAR alone is not part of the instant claim set.
In response to unexpected results “3” and “5”, the recited figures do not have the proper controls to prove synergy. Specifically, the Applicant would need to show that the CAR-SIRPy fusion protein with a different ECD (e.g., SIRPa) does not result in similar cytokine levels because, as discussed in the response to “2” above, the fusion protein binding is expected, based on US404, to induce T cell proliferation, and one of ordinary skill in the art would understand T cell proliferation to be associated with increased IL1, IFNy, and TNFa levels. Further, as discussed above, increasing T cell proliferation increases anti-tumor activity, which one of ordinary skill in the art would understand can increase IL1, IFNy, and TNFa levels through direct lytic release and/or by increasing immune system activation. Further, the Applicant’s arguments are directed to elements that are not part of the instant invention in that the instant claim set does not require the recited cytokine levels.
In summary, all of the Applicant arguments have been thoroughly reviewed but are not persuasive. The new 35 USC 103 rejection(s) of claim(s) 39-41, 43, and 49-56 are maintained.
Free From the Prior Art
During the course of examination, (1) the SIRPy extracellular domain (ECD) of SEQ ID NO: 1, (2) the CEA directed CAR scFv of SEQ ID NO: 25, (3) the CEA directed CAR of SEQ ID NO: 26 (which comprises the CEA scFv of SEQ ID NO: 25), (4) the CD19 directed CAR of SEQ ID NO: 27, (5) the PSCA directed CAR of SEQ ID NO: 28 or 29, and (6) the CAR-encoding nucleic acid SEQ ID NOs: 31-35 were found to have no 100% sequence identity matches that qualify as prior art. For clarity of the record, the closest prior art matches for each of the above-listed sequences are provided below.
Closest Prior Art:
Alignment of SIRPy ECD SEQ ID NO: 1 with WO 2020/068752 A1 (Human signal regulatory protein gamma (SIRP gamma) protein, SEQ 114):
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118
707
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Alignment of CEA directed CAR scFv of SEQ ID NO: 25 (also applies for CEA directed CAR of SEQ ID NO: 26 which comprises the scFv of SEQ ID NO: 25) with WO 2021/188599 A1 (SAR construct related polypeptide, SEQ ID 19513):
Signal Peptide; LCDRs; linker; HCDRs
Query Match 93.8%; Score 1306.5; Length 410;
Best Local Similarity 94.4%;
Matches 251; Conservative 4; Mismatches 8; Indels 3; Gaps 2;
Qy 1 MALPVTALLLPLALLLHAARPDIQMTQSPSSLSASVGDRVTITCSTSSSVSYMHWYQQKP 60
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Db 1 MALPVTALLLPLALLLHAARPDIQLTQSPSSLSASVGDRVTITCSTSSSVSYMHWYQQKP 60
Qy 61 GKAPRLLIYSTSNLASGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCHQWSSYPTFGQG 120
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Db 61 GKAPKLLIYSTSNLASGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCHQWSSYPTFGQG 120
Qy 121 TKVEIKGSTSGSGKPGSGEGST--KGQVQLQESGPGLVRPSQTLSLTCTVSGFTISSGYS 178
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Db 121 TKVEIKGG-GGSGGGGSGGGGSGVHSQVQLQESGPGLVRPSQTLSLTCTVSGFTISSGYS 179
Qy 179 WHWVRQPPGRGLEWIGYIQYSGITNYNPSLKSRVTMLVDTSKNQFSLRLSSVTAADTAVY 238
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Db 180 WHWVRQPPGRGLEWIGYIQYSGITNYNPSLKSRVTMLVDTSKNQFSLRLSSVTAADTAVY 239
Qy 239 YCAREDYDYHWYFDVWGQGSTVTVSS 264
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Db 240 YCAREDYDYHWYFDVWGQGTTVTVSS 265
Alignment of CD19 directed CAR of SEQ ID NO: 27 (only scFv portion shown below) with WO 2021/188599 A1 (FMC63 anti-CD19 scFv, SEQ ID NOs: 10744 and 10986):
CLUSTAL 2.1 multiple sequence alignment
LCDRs; HCDRs
790_CD19scFv DIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGKAPRLLIYHTSRLHSGVPS
WO599_10744/10986 DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPS
******:.******:******:******************. : :***************
790_CD19scFv RFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPYTFGGGTRLEIKGSTSGSGKPGSGE
WO599_10744/10986 RFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEIT-------------
***********:****.*: **:***:***************:***.
790_CD19scFv GSTKGQVQLQESGPGLVKPSQTLSLTCTVSGVSLPDYGVSWIRQPPGKALEWLGVIWGSE
WO599_10744/10986 -----EVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSE
:*:********* ***:**:********************* *.***********
790_CD19scFv TTYYNSSLKTRLTISKDNSKNQVVLTMTNMDPVDTATYYCAKHYYYGGSYAMDYWGQGSS
WO599_10744/10986 TTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTS
******:**:**** *****.**.*.*..::. *** *********************:*
790_CD19scFv VTVSS
WO599_10744/10986 VTVSS
*****
Alignment of PSCA directed CAR of SEQ ID NO: 28 with WO 2017/062628 A1 (Anti-PSCA scFv-IgG4(EQ)-CD28tm-CD28gg-CD3zeta fusion construct, SEQ 27):
Query Match 89.0%; Score 3316; Length 671;
Best Local Similarity 91.2%;
Matches 634; Conservative 2; Mismatches 15; Indels 44; Gaps 5;
Qy 2 IQDIQLTQSPSSLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKLASGVP 61
| |||||||||:||||||||||||||||||||||||||||||||||||||||||||||||
Db 21 IPDIQLTQSPSTLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKLASGVP 80
Qy 62 SRFSGSGSGTDFTLTISSLQPEDFATYYCQQWSSSPFTFGQGTKVEIKGSTSGSGKPGSG 121
|||||||||||||||||||||||||||||||| |||||||||||||||||||| | | |
Db 81 SRFSGSGSGTDFTLTISSLQPEDFATYYCQQWGSSPFTFGQGTKVEIKGSTSGGGS-GGG 139
Qy 122 EGSTKGSEVQLVESGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDP 181
| ||||||| ||||||||||||||||||||||||||||||||||||||||||||||
Db 140 SGGGGSSEVQLVEYGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDP 199
Qy 182 ENGDTEFVPKFQGRATISADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGQGTLVTVSSL 241
||||||||||||||||:||||||||||||||||||||||||||||||||||||||||||
Db 200 ENGDTEFVPKFQGRATMSADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGQGTLVTVSS- 258
Qy 242 EESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNW 301
|||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||
Db 259 -ESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNW 317
Qy 302 YVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTIS 361
||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||
Db 318 YVDGVEVHNAKTKPREEQFQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTIS 377
Qy 362 KAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV 421
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 378 KAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV 437
Qy 422 LDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKEFFWVLVVVG 481
|||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||
Db 438 LDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK-MFWVLVVVG 496
Qy 482 GVLACYSLLVTVAFIIFWVRSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS 541
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 497 GVLACYSLLVTVAFIIFWVRSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS 556
Qy 542 VKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQ 601
|| |||||||||||||||||
Db 557 -------------------------------------GGG---RVKFSRSADAPAYQQGQ 576
Qy 602 NQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMK 661
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 577 NQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMK 636
Qy 662 GERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 696
|||||||||||||||||||||||||||||||||||
Db 637 GERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 671
Alignment of PSCA directed CAR of SEQ ID NO: 29 with US 2021/069239 A1 (PSCA-targeting CAR construct, SEQ ID 23):
Query Match 78.4%; Score 2095.5; Length 486;
Best Local Similarity 81.8%;
Matches 418; Conservative 5; Mismatches 31; Indels 57; Gaps 7;
Qy 4 DIQLTQSPSSLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKLASGVPSR 63
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 22 DIQLTQSPSSLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKLASGVPSR 81
Qy 64 FSGSGSGTDFTLTISSLQPEDFATYYCQQWSSSPFTFGQGTKVEIKGSTSGSGKPGSGEG 123
||||||||||||||||||||||||||||||||||||||||||||||||||| | | | |
Db 82 FSGSGSGTDFTLTISSLQPEDFATYYCQQWSSSPFTFGQGTKVEIKGSTSGGGS-GGGSG 140
Qy 124 STKGSEVQLVESGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPEN 183
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 141 GGGSSEVQLVESGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPEN 200
Qy 184 GDTEFVPKFQGRATISADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGQGTLVTVSSLEA 243
||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |
Db 201 GDTEFVPKFQGRATISADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGQGTLVTVSS--A 258
Qy 244 PPRASALPAPPTGSALPDPQTASALPD---PPAASALP----EF---FWVLVVVGGVLAC 293
: | ||| : | | |: | | |: :| |||||||||||||
Db 259 AGTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDFWVLVVVGGVLAC 318
Qy 294 YSLLVTVAFIIFWVRSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSVKRGR 353
|||||||||||||||||||| |||||||||||||||||||||||||||||||||
Db 319 YSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS----- 373
Qy 354 KKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYN 413
||||||||||||||||||||||
Db 374 --------------------------------------RVKFSRSADAPAYQQGQNQLYN 395
Qy 414 ELNLGRREEYDVLDKRRGRDPEMGGKP-RRKNPQEGLYNELQKDKMAEAYSEIGMKGERR 472
||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||
Db 396 ELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERR 455
Qy 473 RGKGHDGLYQGLSTATKDTYDALHMQALPPR 503
|||||||||||||||||||||||||||||||
Db 456 RGKGHDGLYQGLSTATKDTYDALHMQALPPR 486
Alignment of the CAR-encoding nucleic acid of SEQ ID NO: 31 with WO 2020/181983 A1 (anti-CEA scFv CAR construct DNA, SEQ ID NO: 39)
Query Match 51.0%; Score 1416; Length 1677;
Best Local Similarity 100.0%;
Matches 1416; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GACATCCAGATGACCCAGAGCCCAAGCAGCCTGAGCGCCAGCGTGGGTGACAGAGTGACC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 262 GACATCCAGATGACCCAGAGCCCAAGCAGCCTGAGCGCCAGCGTGGGTGACAGAGTGACC 321
Qy 61 ATCACCTGTAGTACCAGTTCGAGTGTAAGTTACATGCACTGGTACCAGCAGAAGCCAGGT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 322 ATCACCTGTAGTACCAGTTCGAGTGTAAGTTACATGCACTGGTACCAGCAGAAGCCAGGT 381
Qy 121 AAGGCTCCAAGGCTGCTGATCTACAGCACATCCAACCTGGCTTCTGGTGTGCCAAGCAGA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 382 AAGGCTCCAAGGCTGCTGATCTACAGCACATCCAACCTGGCTTCTGGTGTGCCAAGCAGA 441
Qy 181 TTCAGCGGTAGCGGTAGCGGTACCGACTTCACCTTCACCATCAGCAGCCTCCAGCCAGAG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 442 TTCAGCGGTAGCGGTAGCGGTACCGACTTCACCTTCACCATCAGCAGCCTCCAGCCAGAG 501
Qy 241 GACATCGCCACCTACTACTGCCATCAGTGGAGTAGTTATCCCACGTTCGGCCAAGGGACC 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 502 GACATCGCCACCTACTACTGCCATCAGTGGAGTAGTTATCCCACGTTCGGCCAAGGGACC 561
Qy 301 AAGGTGGAAATCAAAGGATCCACTTCCGGTTCAGGAAAGCCCGGGAGTGGTGAAGGTAGC 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 562 AAGGTGGAAATCAAAGGATCCACTTCCGGTTCAGGAAAGCCCGGGAGTGGTGAAGGTAGC 621
Qy 361 ACTAAAGGCCAGGTCCAGCTGCAGGAGAGCGGTCCAGGTCTTGTGAGACCTAGCCAGACC 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 622 ACTAAAGGCCAGGTCCAGCTGCAGGAGAGCGGTCCAGGTCTTGTGAGACCTAGCCAGACC 681
Qy 421 CTGAGCCTGACCTGCACCGTGTCTGGCTTCACCATCAGCAGTGGTTATAGCTGGCACTGG 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 682 CTGAGCCTGACCTGCACCGTGTCTGGCTTCACCATCAGCAGTGGTTATAGCTGGCACTGG 741
Qy 481 GTGAGACAGCCACCTGGACGAGGTCTTGAGTGGATTGGATACATACAGTACAGTGGTATC 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 742 GTGAGACAGCCACCTGGACGAGGTCTTGAGTGGATTGGATACATACAGTACAGTGGTATC 801
Qy 541 ACTAACTACAACCCCTCTCTCAAAAGTAGAGTGACAATGCTGGTAGACACCAGCAAGAAC 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 802 ACTAACTACAACCCCTCTCTCAAAAGTAGAGTGACAATGCTGGTAGACACCAGCAAGAAC 861
Qy 601 CAGTTCAGCCTGAGACTCAGCAGCGTGACAGCCGCCGACACCGCGGTCTATTATTGTGCA 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 862 CAGTTCAGCCTGAGACTCAGCAGCGTGACAGCCGCCGACACCGCGGTCTATTATTGTGCA 921
Qy 661 AGAGAAGACTATGATTACCACTGGTACTTCGATGTCTGGGGTCAAGGCAGCACGGTCACC 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 922 AGAGAAGACTATGATTACCACTGGTACTTCGATGTCTGGGGTCAAGGCAGCACGGTCACC 981
Qy 721 GTCTCCTCAGGTGCGGCCGCCCTCGAGACCACGACGCCAGCGCCGCGACCACCAACACCG 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 982 GTCTCCTCAGGTGCGGCCGCCCTCGAGACCACGACGCCAGCGCCGCGACCACCAACACCG 1041
Qy 781 GCGCCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCG 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1042 GCGCCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCG 1101
Qy 841 GGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCTGTGATATCTACATCTGGGCGCCC 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1102 GGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCTGTGATATCTACATCTGGGCGCCC 1161
Qy 901 TTGGCCGGGACTTGTGGGGTCCTTCTCCTGTCACTGGTTATCACCCTTTACTGCAAACGG 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1162 TTGGCCGGGACTTGTGGGGTCCTTCTCCTGTCACTGGTTATCACCCTTTACTGCAAACGG 1221
Qy 961 GGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACT 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1222 GGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACT 1281
Qy 1021 CAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTG 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1282 CAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTG 1341
Qy 1081 AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACAAGCAGGGCCAGAACCAGCTC 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1342 AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACAAGCAGGGCCAGAACCAGCTC 1401
Qy 1141 TATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGC 1200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1402 TATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGC 1461
Qy 1201 CGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAAT 1260
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1462 CGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAAT 1521
Qy 1261 GAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGC 1320
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1522 GAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGC 1581
Qy 1321 CGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACC 1380
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1582 CGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACC 1641
Qy 1381 TACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGC 1416
||||||||||||||||||||||||||||||||||||
Db 1642 TACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGC 1677
Alignment of the CAR-encoding nucleic acid of SEQ ID NO: 32 with CN113493520-A (Dual CAR structure 2 DNA, SEQ ID NO: 2):
Query Match 84.4%; Score 1242.6; Length 3045;
Best Local Similarity 90.2%;
Matches 1329; Conservative 0; Mismatches 144; Indels 0; Gaps 0;
Qy 1 ATGGCTCTGCCAGTGACAGCTCTGCTGCTGCCTCTGGCTCTGCTGCTGCACGCAGCTAGA 60
||||| ||||||||||| || ||||||||||||||||| ||||||||||||||||| |
Db 1 ATGGCACTGCCAGTGACCGCCCTGCTGCTGCCTCTGGCCCTGCTGCTGCACGCAGCACGC 60
Qy 61 CCCGACATCCAGATGACCCAGAGCCCTTCTTCTCTGAGCGCCAGCGTGGGAGACAGAGTG 120
|| |||||||||||||| ||| ||| || ||| ||||||||||| ||| | |||
Db 61 CCAGACATCCAGATGACACAGTCCCCCAGCTCCCTGTCTGCCAGCGTGGGCGACCGGGTG 120
Qy 121 ACCATCACTTGCAGGGCCAGCCAGGACATCAGCAAGTACCTGAATTGGTACCAGCAGAAG 180
|||||||| ||||| ||| ||||| ||||||||||| ||||| |||||||||||||||
Db 121 ACCATCACATGCAGAGCCTCTCAGGATATCAGCAAGTATCTGAACTGGTACCAGCAGAAG 180
Qy 181 CCAGGCAAGGCCCCTAGACTGCTGATCTACCACACAAGCAGACTGCACAGCGGAGTGCCT 240
|||||||||||||| || ||||||||||| ||||| | | |||||| ||||||||
Db 181 CCAGGCAAGGCCCCCAGGCTGCTGATCTATCACACCTCCCGCCTGCACTCTGGAGTGCCA 240
Qy 241 AGCAGATTCAGCGGCAGCGGAAGCGGAACCGACTACACCCTGACCATCAGCAGCCTGCAG 300
||| | ||| ||| |||||||||||||||||||||||||| ||| |||||||||
Db 241 AGCCGGTTCTCCGGATCTGGAAGCGGAACCGACTACACCCTGACAATCTCTAGCCTGCAG 300
Qy 301 CCAGAGGACTTCGCCACCTACTACTGCCAGCAGGGCAACACACTGCCTTACACCTTCGGC 360
|| ||||| |||||||| ||||| |||||||||||||| || ||||| || || || |||
Db 301 CCTGAGGATTTCGCCACATACTATTGCCAGCAGGGCAATACCCTGCCATATACATTTGGC 360
Qy 361 GGAGGCACAAGACTGGAGATCAAGGGCAGCACAAGCGGAAGCGGCAAACCAGGAAGCGGA 420
||||| || || |||||||||||||| |||| ||||||||||| |||||| ||||
Db 361 GGAGGAACCAGGCTGGAGATCAAGGGATCCACATCTGGAAGCGGCAAGCCAGGATCCGGA 420
Qy 421 GAAGGAAGCACCAAGGGACAGGTGCAGCTGCAGGAAAGCGGACCAGGACTGGTGAAGCCT 480
|| ||| |||||||||||||||||||||||||| |||||| ||||||||||||||
Db 421 GAGGGATCTACCAAGGGACAGGTGCAGCTGCAGGAGTCCGGACCTGGACTGGTGAAGCCA 480
Qy 481 TCTCAGACCCTGAGCCTGACTTGCACCGTGTCAGGAGTGTCCCTGCCAGATTACGGCGTG 540
||||| ||| |||||| || || ||| || ||||||||||| ||||||||||||
Db 481 AGCCAGACACTGTCCCTGACCTGTACAGTGAGCGGCGTGTCCCTGCCTGATTACGGCGTG 540
Qy 541 TCTTGGATCAGACAGCCCCCAGGAAAGGCCCTGGAGTGGCTGGGAGTGATTTGGGGAAGC 600
|| |||||||||||||| || || |||||||||||||||||||| ||||| |||||
Db 541 TCCTGGATCAGACAGCCACCTGGCAAGGCCCTGGAGTGGCTGGGCGTGATCTGGGGCTCT 600
Qy 601 GAGACCACCTACTACAACAGCAGCCTGAAGACCCGGCTGACCATCAGCAAGGACAACAGC 660
|||||||| ||||| || | ||||||||| ||||||| ||| ||||||||||||
Db 601 GAGACCACATACTATTCCACCTCTCTGAAGACCAGGCTGACAATCTCTAAGGACAACAGC 660
Qy 661 AAGAACCAGGTGGTGCTGACCATGACCAACATGGACCCCGTGGACACCGCCACCTACTAT 720
||||| |||||||||||||||||||| ||||||||||| ||||| |||||||| ||||||
Db 661 AAGAATCAGGTGGTGCTGACCATGACAAACATGGACCCTGTGGATACCGCCACATACTAT 720
Qy 721 TGCGCCAAGCACTACTACTACGGCGGAAGCTACGCCATGGACTATTGGGGCCAGGGAAGC 780
|| |||||||||||||| |||||||| ||||| |||||||| || ||||||||||| |
Db 721 TGTGCCAAGCACTACTATTACGGCGGCAGCTATGCCATGGATTACTGGGGCCAGGGCTCC 780
Qy 781 AGCGTGACCGTGTCTAGCCTCGAGACCACGACGCCAGCGCCGCGACCACCAACACCGGCG 840
||||||||| |||||||||||||||||||||||||||||||||||||||||||
Db 781 TCTGTGACCGTGAGCTCCCTCGAGACCACGACGCCAGCGCCGCGACCACCAACACCGGCG 840
Qy 841 CCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGGG 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 841 CCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGGG 900
Qy 901 GGCGCAGTGCACACGAGGGGGCTGGACTTCGCCTGTGATATCTACATCTGGGCGCCCTTG 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 901 GGCGCAGTGCACACGAGGGGGCTGGACTTCGCCTGTGATATCTACATCTGGGCGCCCTTG 960
Qy 961 GCCGGGACTTGTGGGGTCCTTCTCCTGTCACTGGTTATCACCCTTTACTGCAAACGGGGC 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 961 GCCGGGACTTGTGGGGTCCTTCTCCTGTCACTGGTTATCACCCTTTACTGCAAACGGGGC 1020
Qy 1021 AGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAA 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1021 AGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAA 1080
Qy 1081 GAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGAGA 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1081 GAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGAGA 1140
Qy 1141 GTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACAAGCAGGGCCAGAACCAGCTCTAT 1200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1141 GTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACAAGCAGGGCCAGAACCAGCTCTAT 1200
Qy 1201 AACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGG 1260
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1201 AACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGG 1260
Qy 1261 GACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAA 1320
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1261 GACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAA 1320
Qy 1321 CTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGG 1380
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1321 CTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGG 1380
Qy 1381 AGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTAC 1440
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1381 AGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTAC 1440
Qy 1441 GACGCCCTTCACATGCAGGCCCTGCCCCCTCGC 1473
|||||||||||||||||||||||||||||||||
Db 1441 GACGCCCTTCACATGCAGGCCCTGCCCCCTCGC 1473
Alignment of the CAR-encoding nucleic acid of SEQ ID NO: 33 with WO 2020/181983 A1 (anti-CEA scFv CAR construct DNA, SEQ ID NO: 43):
Query Match 71.2%; Score 1249.8; Length 1724;
Best Local Similarity 84.9%;
Matches 1466; Conservative 0; Mismatches 237; Indels 24; Gaps 5;
Qy 45 CCACAGTGCATACGTGGGCTCCAACAGGTCCTCTTGTCGAGCCACAGTGCATACGTGGGC 104
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 7 CCACAGTGCATACGTGGGCTCCAACAGGTCCTCTTGTCGAGCCACAGTGCATACGTGGGC 66
Qy 105 TCCAACAGGTCCTCTTGTCGAGCCACAGTGCATACGTGGGCTCCAACAGGTCCTCTTGTC 164
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 67 TCCAACAGGTCCTCTTGTCGAGCCACAGTGCATACGTGGGCTCCAACAGGTCCTCTTGTC 126
Qy 165 GAGCCACAGTGCATACGTGGGCTCCAACAGGTCCTCTTGTCGAGATCTGGTAGGCGTGTA 224
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 127 GAGCCACAGTGCATACGTGGGCTCCAACAGGTCCTCTTGTCGAGATCTGGTAGGCGTGTA 186
Qy 225 CGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCACTAGGCTAGCA 284
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 187 CGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCACTAGGCTAGCA 246
Qy 285 TGGCTCTGCCAGTGACAGCTCTGCTGCTGCCTCTGGCTCTGCTGCTGCACGCAGCTAGAC 344
|||| | |||||||| || |||| ||||| ||||| ||||||| ||||| || || |
Db 247 TGGCCTTACCAGTGACCGCCTTGCTCCTGCCGCTGGCCTTGCTGCTCCACGCCGCCAGGC 306
Qy 345 CCGACATCCAGATGACCCAGAGCCCTTCTTCTCTGAGCGCCAGCGTGGGAGACAGAGTGA 404
| ||||||||||||||||||||||| ||||||||||||||||| ||||||||||
Db 307 CGGACATCCAGATGACCCAGAGCCCAAGCAGCCTGAGCGCCAGCGTGGGTGACAGAGTGA 366
Qy 405 CCATCACTTGCAGGGCCAGCCAGGACATCAGCAAGTACCTGAATTGGTACCAGCAGAAGC 464
||||||| || || |||| | | || ||| || | ||||||||||||||||
Db 367 CCATCACCTGTAGTACCAGTTCGAGTGTAAG---TTACATGCACTGGTACCAGCAGAAGC 423
Qy 465 CAGGCAAGGCCCCTAGACTGCTGATCTACCACACAAGCAGACTGCACAGCGGAGTGCCTA 524
|||| ||||| || || |||||||||||| |||| || ||| || ||||| |
Db 424 CAGGTAAGGCTCCAAGGCTGCTGATCTACAGCACATCCAACCTGGCTTCTGGTGTGCCAA 483
Qy 525 GCAGATTCAGCGGCAGCGGAAGCGGAACCGACTACACCCTGACCATCAGCAGCCTGCAGC 584
||||||||||||| ||||| ||||| ||||||| |||| | |||||||||||||| ||||
Db 484 GCAGATTCAGCGGTAGCGGTAGCGGTACCGACTTCACCTTCACCATCAGCAGCCTCCAGC 543
Qy 585 CAGAGGACTTCGCCACCTACTACTGCCAGCAGGGCAACACACTGCCTTACACCTTCGGCG 644
|||||||| ||||||||||||||||||| ||| | | | || ||| ||||||
Db 544 CAGAGGACATCGCCACCTACTACTGCCATCAGTGGAGTAGTTATCC---CACGTTCGGCC 600
Qy 645 GAGGCACAAGACTGGAGATCAAGGGCAGCACAAGCGGAAGCGGCAAACCAGGAAGCGGAG 704
||| || | |||| ||||| || ||| ||| || || || || || || |
Db 601 AAGGGACCAAGGTGGAAATCAAAGGATCCACTTCCGGTTCAGGAAAGCCCGGGAGTGGTG 660
Qy 705 AAGGAAGCACCAAGGGACAGGTGCAGCTGCAGGAAAGCGGACCAGGACTGGTGAAGCCTT 764
|||| ||||| || || ||||| ||||||||||| ||||| ||||| || |||| |||
Db 661 AAGGTAGCACTAAAGGCCAGGTCCAGCTGCAGGAGAGCGGTCCAGGTCTTGTGAGACCTA 720
Qy 765 CTCAGACCCTGAGCCTGACTTGCACCGTGTCAGGAGTGTCCCT---GCCAGATTACGGCG 821
||||||||||||||||| ||||||||||| || | || | | ||| ||
Db 721 GCCAGACCCTGAGCCTGACCTGCACCGTGTCTGGCTTCACCATCAGCAGTGGTTATAGCT 780
Qy 822 TGTCTTGGATCAGACAGCCCCCAGGAAAGGCCCTGGAGTGGCTGGGAGTGATTTGGGGAA 881
| ||| | |||||||| || ||| | || |||||| | ||| || | |
Db 781 GGCACTGGGTGAGACAGCCACCTGGACGAGGTCTTGAGTGGATTGGATACATACAGTACA 840
Qy 882 GCGAGACCACCTACTACAACAGCAGCCTGAAGACCCGGCTGACCATCAGCAAGGACAACA 941
| | | ||| |||||||| | || || | | |||| || |||| ||
Db 841 GTGGTATCACTAACTACAACCCCTCTCTCAAAAGTAGAGTGACAATGCTGGTAGACACCA 900
Qy 942 GCAAGAACCAGGTGGTGCTGACCATGACCAACATGGACCCCGTGGACACCGCCACCTACT 1001
||||||||||| | |||| | | || | || ||| |||||||| ||| |
Db 901 GCAAGAACCAGTTCAGCCTGAGACTCAGCAGCGTGACAGCCGCCGACACCGCGGTCTATT 960
Qy 1002 ATTGCGCCAAGCACTACTACTACGGCGGAAGCTACGCCATGGACTATTGGGGCCAGGGAA 1061
|||| || | | |||| | | | ||| | | | ||||| || || |
Db 961 ATTGTGCAAGAGAAGACTATGATTACCACTGGTACTTCGATGTC---TGGGGTCAAGGCA 1017
Qy 1062 GCAGCGTGACCGTGTCTAG------------CCTCGAGACCACGACGCCAGCGCCGCGAC 1109
||| || ||||| || |||||||||||||||||||||||||||||
Db 1018 GCACGGTCACCGTCTCCTCAGGTGCGGCCGCCCTCGAGACCACGACGCCAGCGCCGCGAC 1077
Qy 1110 CACCAACACCGGCGCCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCC 1169
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1078 CACCAACACCGGCGCCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCC 1137
Qy 1170 GGCCAGCGGCGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCTGTGATATCTACA 1229
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1138 GGCCAGCGGCGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCTGTGATATCTACA 1197
Qy 1230 TCTGGGCGCCCTTGGCCGGGACTTGTGGGGTCCTTCTCCTGTCACTGGTTATCACCCTTT 1289
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1198 TCTGGGCGCCCTTGGCCGGGACTTGTGGGGTCCTTCTCCTGTCACTGGTTATCACCCTTT 1257
Qy 1290 ACTGCAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAG 1349
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1258 ACTGCAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAG 1317
Qy 1350 TACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAG 1409
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1318 TACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAG 1377
Qy 1410 GATGTGAACTGAGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACAAGCAGGGCC 1469
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1378 GATGTGAACTGAGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACAAGCAGGGCC 1437
Qy 1470 AGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACA 1529
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1438 AGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACA 1497
Qy 1530 AGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAG 1589
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1498 AGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAG 1557
Qy 1590 GCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGA 1649
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1558 GCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGA 1617
Qy 1650 AAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCA 1709
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1618 AAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCA 1677
Qy 1710 CCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGC 1756
|||||||||||||||||||||||||||||||||||||||||||||||
Db 1678 CCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGC 1724
Alignment of the CAR-encoding nucleic acid of SEQ ID NO: 34 with CN108239144-A (Anti-PSCA CAR construct (PSCA-CAR-7H) encoding DNA, SEQ ID NO: 17):
Query Match 60.4%; Score 912; Length 1488;
Best Local Similarity 76.5%;
Matches 1148; Conservative 0; Mismatches 340; Indels 12; Gaps 2;
Qy 10 GATATCCAGCTGACACAGTCCCCTAGCTCCCTGAGCGCCTCCGTGGGCGACAGGGTGACC 69
||||| |||||||| ||| ||| ||| ||||||||| ||||||||| | ||||||
Db 1 GATATTCAGCTGACCCAGAGCCCGAGCAGCCTGAGCGCGAGCGTGGGCGATCGCGTGACC 60
Qy 70 ATCACATGCAGCGCCTCTAGCTCCGTGAGATTCATCCACTGGTACCAGCAGAAGCCCGGC 129
|| || |||||||| ||| |||| | || || || ||||| |||||||| || |||
Db 61 ATTACCTGCAGCGCGAGCAGCAGCGTGCGCTTTATTCATTGGTATCAGCAGAAACCGGGC 120
Qy 130 AAGGCCCCTAAGAGGCTGATCTATGATACCTCTAAGCTGGCCAGCGGAGTGCCCTCCCGC 189
|| || || || | ||||| ||||||||| || ||||| ||||| ||||| ||||
Db 121 AAAGCGCCGAAACGCCTGATTTATGATACCAGCAAACTGGCGAGCGGCGTGCCGAGCCGC 180
Qy 190 TTCTCTGGCAGCGGCTCCGGCACCGACTTTACCCTGACAATCTCTAGCCTGCAGCCAGAG 249
|| ||||||||| ||||||||| ||||||||||| || ||||||||||| ||
Db 181 TTTAGCGGCAGCGGCAGCGGCACCGATTTTACCCTGACCATTAGCAGCCTGCAGCCGGAA 240
Qy 250 GATTTTGCCACATACTATTGCCAGCAGTGGTCCTCTAGCCCCTTCACCTTTGGCCAGGGC 309
|||||||| || || ||||||||||||||| | ||||| || |||||||||||||||
Db 241 GATTTTGCGACCTATTATTGCCAGCAGTGGAGCAGCAGCCCGTTTACCTTTGGCCAGGGC 300
Qy 310 ACAAAGGTGGAGATCAAGGGATCTACCAGCGGATCCGGCAAGCCTGGATCTGGAGAGGGC 369
|| || ||||| || || || |||||||| |||||| || || || || |||
Db 301 ACCAAAGTGGAAATTAAAGGCAGCACCAGCGGCAGCGGCAAACCGGGCAGCGGCGAAGGC 360
Qy 370 AGCACAAAGGGCTCCGAGGTGCAGCTGGTGGAGTCCGGAGGAGGACTGGTGCAGCCAGGA 429
||||| || ||| ||| |||||||||||||| ||| || || ||||||||||| ||
Db 361 AGCACCAAAGGCAGCGAAGTGCAGCTGGTGGAAAGCGGCGGCGGCCTGGTGCAGCCGGGC 420
Qy 430 GGATCTCTGAGGCTGAGCTGTGCAGCCTCCGGCTTCAACATCAAGGACTACTATATCCAC 489
|| ||| | |||||||| || || |||||| ||||| || || || ||||| ||
Db 421 GGCAGCCTGCGCCTGAGCTGCGCGGCGAGCGGCTTTAACATTAAAGATTATTATATTCAT 480
Qy 490 TGGGTGAGACAGGCACCTGGCAAGGGACTGGAGTGGGTGGCATGGATCGACCCTGAGAAT 549
|||||| | ||||| || ||||| || ||||| |||||||| ||||| || || || ||
Db 481 TGGGTGCGCCAGGCGCCGGGCAAAGGCCTGGAATGGGTGGCGTGGATTGATCCGGAAAAC 540
Qy 550 GGCGATACCGAGTTCGTGCCAAAGTTTCAGGGCAGGGCCACAATCTCTGCCGACACCAGC 609
||||||||||| || ||||| || ||||||||| | || || || || || ||||||
Db 541 GGCGATACCGAATTTGTGCCGAAATTTCAGGGCCGCGCGACCATTAGCGCGGATACCAGC 600
Qy 610 AAGAACACAGCCTACCTGCAGATGAATAGCCTGCGCGCCGAGGATACCGCCGTGTACTAT 669
|| ||||| || || ||||||||||| ||||||||||| || |||||||| ||||| |||
Db 601 AAAAACACCGCGTATCTGCAGATGAACAGCCTGCGCGCGGAAGATACCGCGGTGTATTAT 660
Qy 670 TGTAAGACAGGAGGATTTTGGGGACAGGGCACCCTGGTGACAGTGTCCTCTCTCGAGGCA 729
|| || || || || |||||||| ||||||||||||||||| ||| | ||
Db 661 TGCAAAACCGGCGGCTTTTGGGGCCAGGGCACCCTGGTGACCGTG------AGCAGCGCG 714
Qy 730 CCACCTCGGGCCAGCGCCCTGCCTGCACCACCCACCGGCTCCGCCCTGCCAGACCCTCAG 789
|| || || || ||||| ||||| || || || |||||| ||| ||||| || || |||
Db 715 CCGCCGCGCGCGAGCGCGCTGCCGGCGCCGCCGACCGGCAGCGCGCTGCCGGATCCGCAG 774
Qy 790 ACAGCATCTGCCCTGCCAGATCCTCCAGCAGCAAGCGCCCTGCCCGAATTCTTCTGGGTG 849
|| || || ||||| ||||| || || || ||||| ||||| || ||||||
Db 775 ACCGCGAGCGCGCTGCCGGATCCGCCGGCGGCGAGCGCGCTGCCG------TTTTGGGTG 828
Qy 850 CTGGTCGTGGTGGGTGGCGTGCTGGCCTGCTACAGCCTGCTGGTGACAGTGGCCTTCATC 909
||||| |||||||| ||||||||||| ||||| |||||||||||||| ||||| || ||
Db 829 CTGGTGGTGGTGGGCGGCGTGCTGGCGTGCTATAGCCTGCTGGTGACCGTGGCGTTTATT 888
Qy 910 ATCTTTTGGGTGAGGAGCAAGCGGAGCAGAGGCGGCCACAGCGACTACATGAACATGACT 969
|| ||||||||| | ||||| || ||| | || ||||| || |||||||||||
Db 889 ATTTTTTGGGTGCGCAGCAAACGCAGCCGCCTGCTGCATAGCGATTATATGAACATGACC 948
Qy 970 CCCCGCCGCCCCGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTC 1029
|| |||||||| || || |||||||| ||||| ||||| ||||| || || ||||| ||
Db 949 CCGCGCCGCCCGGGCCCGACCCGCAAACATTATCAGCCGTATGCGCCGCCGCGCGATTTT 1008
Qy 1030 GCAGCCTATCGCTCCGTTAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCA 1089
|| || |||||| ||| ||||| ||| | || ||||| |||||||| || ||||| ||
Db 1009 GCGGCGTATCGCAGCGTGAAACGCGGCCGCAAAAAACTGCTGTATATTTTTAAACAGCCG 1068
Qy 1090 TTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAA 1149
|||||| | || || || || || || || ||||||||||| |||||||| ||||| |||
Db 1069 TTTATGCGCCCGGTGCAGACCACCCAGGAAGAAGATGGCTGCAGCTGCCGCTTTCCGGAA 1128
Qy 1150 GAAGAAGAAGGAGGATGTGAACTGAGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCG 1209
||||||||||| || || |||||| | ||||| || ||| | ||||| || || || |||
Db 1129 GAAGAAGAAGGCGGCTGCGAACTGCGCGTGAAATTTAGCCGCAGCGCGGATGCGCCGGCG 1188
Qy 1210 TACCAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTAC 1269
|| |||||||||||||||||||| |||||||| || || || || || | || || ||
Db 1189 TATCAGCAGGGCCAGAACCAGCTGTATAACGAACTGAACCTGGGCCGCCGCGAAGAATAT 1248
Qy 1270 GATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAG 1329
||||| |||| || | || ||||| || || || ||||| || || ||| | | ||
Db 1249 GATGTGCTGGATAAACGCCGCGGCCGCGATCCGGAAATGGGCGGCAAACCGCGCCGCAAA 1308
Qy 1330 AACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGT 1389
||||| |||||||||||||| || ||||||||||||||||| |||||||| || || ||
Db 1309 AACCCGCAGGAAGGCCTGTATAACGAACTGCAGAAAGATAAAATGGCGGAAGCGTATAGC 1368
Qy 1390 GAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGT 1449
|| ||||| ||||||||||| ||||| | ||||| || || |||||||| || |||||
Db 1369 GAAATTGGCATGAAAGGCGAACGCCGCCGCGGCAAAGGCCATGATGGCCTGTATCAGGGC 1428
Qy 1450 CTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGC 1509
|| || || || ||||| || ||||| || || || || |||||||| ||||| || |||
Db 1429 CTGAGCACCGCGACCAAAGATACCTATGATGCGCTGCATATGCAGGCGCTGCCGCCGCGC 1488
Alignment of the CAR-encoding nucleic acid of SEQ ID NO: 35 with WO 2020/181983 A1 (Anti-PSCA scFv CAR construct DNA, SEQ ID NO: 37):
Query Match 82.2%; Score 1716; Length 2220;
Best Local Similarity 90.7%;
Matches 1894; Conservative 0; Mismatches 65; Indels 129; Gaps 1;
Qy 1 GACATCCAGGATATCCAGCTGACACAGTCCCCTAGCTCCCTGAGCGCCTCCGTGGGCGAC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 262 GACATCCAGGATATCCAGCTGACACAGTCCCCTAGCTCCCTGAGCGCCTCCGTGGGCGAC 321
Qy 61 AGGGTGACCATCACATGCAGCGCCTCTAGCTCCGTGAGATTCATCCACTGGTACCAGCAG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 322 AGGGTGACCATCACATGCAGCGCCTCTAGCTCCGTGAGATTCATCCACTGGTACCAGCAG 381
Qy 121 AAGCCCGGCAAGGCCCCTAAGAGGCTGATCTATGATACCTCTAAGCTGGCCAGCGGAGTG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 382 AAGCCCGGCAAGGCCCCTAAGAGGCTGATCTATGATACCTCTAAGCTGGCCAGCGGAGTG 441
Qy 181 CCCTCCCGCTTCTCTGGCAGCGGCTCCGGCACCGACTTTACCCTGACAATCTCTAGCCTG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 442 CCCTCCCGCTTCTCTGGCAGCGGCTCCGGCACCGACTTTACCCTGACAATCTCTAGCCTG 501
Qy 241 CAGCCAGAGGATTTTGCCACATACTATTGCCAGCAGTGGTCCTCTAGCCCCTTCACCTTT 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 502 CAGCCAGAGGATTTTGCCACATACTATTGCCAGCAGTGGTCCTCTAGCCCCTTCACCTTT 561
Qy 301 GGCCAGGGCACAAAGGTGGAGATCAAGGGATCTACCAGCGGATCCGGCAAGCCTGGATCT 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 562 GGCCAGGGCACAAAGGTGGAGATCAAGGGATCTACCAGCGGATCCGGCAAGCCTGGATCT 621
Qy 361 GGAGAGGGCAGCACAAAGGGCTCCGAGGTGCAGCTGGTGGAGTCCGGAGGAGGACTGGTG 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 622 GGAGAGGGCAGCACAAAGGGCTCCGAGGTGCAGCTGGTGGAGTCCGGAGGAGGACTGGTG 681
Qy 421 CAGCCAGGAGGATCTCTGAGGCTGAGCTGTGCAGCCTCCGGCTTCAACATCAAGGACTAC 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 682 CAGCCAGGAGGATCTCTGAGGCTGAGCTGTGCAGCCTCCGGCTTCAACATCAAGGACTAC 741
Qy 481 TATATCCACTGGGTGAGACAGGCACCTGGCAAGGGACTGGAGTGGGTGGCATGGATCGAC 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 742 TATATCCACTGGGTGAGACAGGCACCTGGCAAGGGACTGGAGTGGGTGGCATGGATCGAC 801
Qy 541 CCTGAGAATGGCGATACCGAGTTCGTGCCAAAGTTTCAGGGCAGGGCCACAATCTCTGCC 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 802 CCTGAGAATGGCGATACCGAGTTCGTGCCAAAGTTTCAGGGCAGGGCCACAATCTCTGCC 861
Qy 601 GACACCAGCAAGAACACAGCCTACCTGCAGATGAATAGCCTGCGCGCCGAGGATACCGCC 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 862 GACACCAGCAAGAACACAGCCTACCTGCAGATGAATAGCCTGCGCGCCGAGGATACCGCC 921
Qy 661 GTGTACTATTGTAAGACAGGAGGATTTTGGGGACAGGGCACCCTGGTGACAGTGTCCTCT 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 922 GTGTACTATTGTAAGACAGGAGGATTTTGGGGACAGGGCACCCTGGTGACAGTGTCCTCT 981
Qy 721 CTCGAGGAGAGCAAGTACGGCCCTCCCTGCCCCCCTTGCCCTGCCCCCGAGTTCCTGGGC 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 982 CTCGAGGAGAGCAAGTACGGCCCTCCCTGCCCCCCTTGCCCTGCCCCCGAGTTCCTGGGC 1041
Qy 781 GGACCCAGCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCCGGACC 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1042 GGACCCAGCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCCGGACC 1101
Qy 841 CCCGAGGTGACCTGTGTGGTGGTGGACGTGTCCCAGGAGGACCCCGAGGTCCAGTTCAAC 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1102 CCCGAGGTGACCTGTGTGGTGGTGGACGTGTCCCAGGAGGACCCCGAGGTCCAGTTCAAC 1161
Qy 901 TGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCCGGGAGGAGCAGTTC 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1162 TGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCCGGGAGGAGCAGTTC 1221
Qy 961 AATAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGC 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1222 AATAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGC 1281
Qy 1021 AAGGAATACAAGTGTAAGGTGTCCAACAAGGGCCTGCCCAGCAGCATCGAGAAAACCATC 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1282 AAGGAATACAAGTGTAAGGTGTCCAACAAGGGCCTGCCCAGCAGCATCGAGAAAACCATC 1341
Qy 1081 AGCAAGGCCAAGGGCCAGCCTCGGGAGCCCCAGGTGTACACCCTGCCCCCTAGCCAAGAG 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1342 AGCAAGGCCAAGGGCCAGCCTCGGGAGCCCCAGGTGTACACCCTGCCCCCTAGCCAAGAG 1401
Qy 1141 GAGATGACCAAGAATCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGAC 1200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1402 GAGATGACCAAGAATCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGAC 1461
Qy 1201 ATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCT 1260
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1462 ATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCT 1521
Qy 1261 GTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAGGCTGACCGTGGACAAGAGCCGG 1320
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1522 GTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAGGCTGACCGTGGACAAGAGCCGG 1581
Qy 1321 TGGCAGGAGGGCAACGTCTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTAC 1380
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1582 TGGCAGGAGGGCAACGTCTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTAC 1641
Qy 1381 ACCCAGAAGAGCCTGTCCCTGAGCCTGGGCAAGGAATTCTTCTGGGTGCTGGTCGTGGTG 1440
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1642 ACCCAGAAGAGCCTGTCCCTGAGCCTGGGCAAGGAATTCTTCTGGGTGCTGGTCGTGGTG 1701
Qy 1441 GGTGGCGTGCTGGCCTGCTACAGCCTGCTGGTGACAGTGGCCTTCATCATCTTTTGGGTG 1500
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1702 GGTGGCGTGCTGGCCTGCTACAGCCTGCTGGTGACAGTGGCCTTCATCATCTTTTGGGTG 1761
Qy 1501 AGGAGCAAGCGGAGCAGAGGCGGCCACAGCGACTACATGAACATGACTCCCCGCCGCCCC 1560
||||||||||||||||||||||||||||||||||||||||||||||| ||||| | ||
Db 1762 AGGAGCAAGCGGAGCAGAGGCGGCCACAGCGACTACATGAACATGACCCCCCGGAGGCCT 1821
Qy 1561 GGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGC 1620
|| |||||||| ||||| ||||||||||| ||||| || | |||||||| ||||| ||
Db 1822 GGCCCCACCCGGAAGCACTACCAGCCCTACGCCCCTCCCAGGGACTTCGCCGCCTACCGG 1881
Qy 1621 TCCGTTAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCA 1680
|
Db 1882 AGCC-------------------------------------------------------- 1885
Qy 1681 GTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGA 1740
Db 1886 ------------------------------------------------------------ 1885
Qy 1741 GGATGTGAACTGAGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGC 1800
| |||||||||||| ||||||| |||||||| || ||||||||||||
Db 1886 -------------GGGTGAAGTTCAGCCGGAGCGCCGACGCCCCTGCCTACCAGCAGGGC 1932
Qy 1801 CAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGAC 1860
|||| |||||| || |||||||| || || || || || ||||||||||| || |||||
Db 1933 CAGAGCCAGCTGTACAACGAGCTGAACCTGGGCCGGAGGGAGGAGTACGACGTGCTGGAC 1992
Qy 1861 AAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAA 1920
||| | | |||||||||||||||||||| || ||||| | || ||||||||||||||
Db 1993 AAGCGGAGAGGCCGGGACCCTGAGATGGGCGGCAAGCCCCGGAGAAAGAACCCTCAGGAG 2052
Qy 1921 GGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATG 1980
|||||||| || |||||||||||||| |||||||| ||||||||||| ||||| || |||
Db 2053 GGCCTGTATAACGAACTGCAGAAAGACAAGATGGCCGAGGCCTACAGCGAGATCGGCATG 2112
Qy 1981 AAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCC 2040
|| |||||||| |||||||||||||| ||||| ||||| |||||||| || || || |||
Db 2113 AAGGGCGAGCGGCGGAGGGGCAAGGGCCACGACGGCCTGTACCAGGGCCTGAGCACCGCC 2172
Qy 2041 ACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGC 2088
|||||||| |||||||||||||| ||||||||||||||||||||||||
Db 2173 ACCAAGGATACCTACGACGCCCTGCACATGCAGGCCCTGCCCCCTCGC 2220
Summary:
The prior art results above show no 100% sequence identity matches with the instant claimed SIRPy ECD of SEQ ID NO: 1, and there was no rationale found in the prior art to add the two additional residues “LE” to the known SIRPy ECD to arrive at the instant invention of SEQ ID NO: 1. There therefore the SIRPy ECD sequence is not considered obvious in view of the prior art.
Further, the prior art results above show no 100% sequence identity matches to the instant claimed anti-CEA scFv of SEQ ID NO: 25 (which applies for the CEA directed CAR of SEQ ID NO: 26 which comprises the scFv of SEQ ID NO: 25), CD19 directed CAR of SEQ ID NO: 27, or the PSCA directed CAR of SEQ ID NO: 28 or 29. Additionally, no rationale was found in the prior art to make the substitution(s) required to arrive at the instant invention of any of SEQ ID NOs: 25-29. Therefore, SEQ ID NOs: 25-29 are not considered obvious in view of the prior art.
Additionally, as the prior art results above show no 100% sequence identity matches with the instant claimed CAR-encoding nucleic acid sequences selected from SEQ ID NOs: 31-35, and the fact that different nucleic acid sequences correspond with different protein sequences and/or translation efficiency in a host cell, the CAR encoding nucleic acids of SEQ ID NOs: 31-35 are considered non-obvious in view of the prior art.
Conclusion
No claims are currently allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY M CHATTIN whose telephone number is (571)270-0646. The examiner can normally be reached T-F 0600-1600 PST.
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/AMY M. CHATTIN/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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