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 .
Applicant’s remarks, filed 4/7/2026, are acknowledged and entered into the record. Applicants amended claims 1-10, 12, 14-15, 17, 21-22, 24 and 26; and canceled claims 11, 16, 18-20, 23 and 25, in the remarks of 4/7/2026.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The present application claims benefit under 35 U.S.C. 119(e) to U.S. Provisional applications 63/297951, filed 1/10/2022; 63/337591, filed 5/2/2022; 63/339960, filed 5/9/2022; 63/342041, filed 5/13/2022; 63/345354, filed 5/24/2022; 63/345369, filed 5/24/2022; 63/345388, filed 5/24/2022; and 63/427128, filed 11/22/2022.
Status of Claims
Claims 1-10, 12-15, 17, 21-22, 24 and 26-27 are pending and are being examined on the merits.
Claim Objections-Withdrawn
The objection to claims 6, 18 and 25 is withdrawn. Applicants removed the objectional language from claim 6, and canceled claims 18 and 25.
The objection to claims 6, 11, 18 and 25 is withdrawn. Applicants removed the objectional language from claim 6, and canceled claims 11, 18 and 25.
The objection to claims 12, 16 and 23 is withdrawn. Applicants removed the objectional language from claim 12, and canceled claims 16 and 23. However, applicants did not amend claim 9, which was also objected to (see below).
The objection to claims 6, 11, 18 and 25 is withdrawn. Applicants removed the objectional language from claim 6, and canceled claims 11, 18 and 25.
Claim Objections-New, maintained
Claims 1, 7, 14 are objected to because of the following informalities: Claims 1, 7, 14 and 21 have been amended to include “wherein the signal peptides is optimized…”. If referring to a plurality of “peptides”, then the proper conjugation is “are”; if referring to a singular peptide, then “peptides” should be singular. Appropriate correction is required.
Claims 3, 4 and 9 are objected to because of the following informalities: Claims 3 and 9 recite “a single chain antibody variable domain fragment”. A single chain antibody variable domain is known as an scFv; it is unnecessary to add “fragment” to the description of an scFv, as it is inherently an antibody fragment. Further, the “scFv” acronym is not presented at its first use, in claim 3, but is used repeatedly in claims 4 and 9. If applicants are going to use the “scFv” acronym, it should be defined at its first use and then used exclusively throughout the rest of the claims. Appropriate correction is required.
Claim Interpretation
Claim 9 recites whereby the tumor cell binding domain is selected from a group consisting of (a), (b) and (c), whereby each of (a), (b) and (c) further recite a “group consisting of.” Claim 9 is being interpreted as requiring a single species of binding domain selected from any of the total species listed in (a), (b) and (c). For example, any scFv binding domain meets the limitation of being selected from the group of claim 9(a).
Claim Rejections - 35 USC § 112(b)- Withdrawn
The rejection of claims 6, 11, 18-20 and 25 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, is withdrawn. Specifically, applicants amended claim 6 to remove the indefinite language, and canceled claims 11, 18 and 25.
Claim Rejections - 35 USC § 112(b)- Maintained, Amended
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.
Claims 1-10, 12-15, 17, 21-22, 24 and 26-27 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.
Claims 1, 7, 14 and 21 are amended to recite a “wherein the signal peptide is optimized to increase secretin of the therapeutic protein from a gamma delta T cell by at least about 15% relative to the corresponding non-optimized signal peptide.” However the claims do not provide a description of what is required in order for the signal peptide to be “optimized” for a gamma delta T cell. The specifications describe expression codon optimized (ECO) signal peptides, including two unique optimization sequences for the IL2 signal peptide (pg. 4, para. 0049). However, said optimized IL2 signal peptides are not identified or claimed in claim 1; claim 2 limits the signal peptides to mSA, IL2 or hSCF derived peptides, but also does not limit the signal peptide to either of the “optimized” IL2 signal peptides. It is unclear what is required of the “optimized” signal peptide of claim 1 versus a “corresponding non-optimized” signal peptide. What are the structural requirements for the signal peptide to be considered optimized? Is there a particular shared structural feature of an optimized signal peptide that imparts optimized function of increasing secretion of the protein from gamma/delta T cells? While it is clear that the claim requires a signal peptide that increases secretion by > 15%, it is unclear what structural limitations differentiate an “optimized” signal peptide from a “corresponding non-optimized signal peptide”. Thus, it is unclear to a skilled artisan attempting to use a signal peptide, whether or not they are infringing on the claims. As the metes and bounds of the claims are unclear, claims 1, 7, 14 and 21 are rejected for indefiniteness. Claims 2, 8 15 and 22 explicitly define the signal peptide for use in the associated constructs and therefore remedy the indefiniteness. However, claims 9-10 and 12-13 depend from claim 7; claim 17 depends from claim 14; and claims 24 and 26-27 depend from claim 21, yet fail to rectify the indefiniteness issues. Therefore claims 9-10, 12-13, 17, 24 and 26-27 are also rejected.
Claim 7-10 and 12-13 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 7 recites “an engineered gamma delta T cell capable of secreting at least one therapeutic protein that has been expression cassette optimized,”. It is unclear what “expression cassette optimized” is referring to. First, is the expression cassette optimizing the therapeutic protein or the engineered gamma delta T cell? Second, does the expression cassette also comprise an optimization? Third, what structural manipulations are required to meet the limitation of an “optimized” expression cassette? It is unclear what structural limitations are required to meet the claim limitation of “expression cassette optimized”. As the metes and bounds of the claim are unclear, claim 7 is rendered indefinite. Claims 8-10 and 12-13 depend from claim 7 but fail to rectify the issue of indefiniteness, therefore claims 8-10 and 12-13 are also rejected.
Response to Arguments
Applicant's arguments filed 4/7/2026 have been fully considered but they are not persuasive. Applicants amended the claims to recite “optimized to increase secretion of the therapeutic protein from a gamma delta T cell by at least 15% relative to the corresponding non-optimized signal peptide.” Applicants contend that the claims have been amended to provide objective structural and functional boundaries for the term “optimized”, (remarks, pg. 9, para. 2).
In response the examiner contends that the claims do not provide objective structural boundaries for the term “optimized”. When reciting an “optimized” signal peptide, it suggests the signal peptide is structurally manipulated, such as through amino acid substitutions, to impart the desired functionality. Here the applicants claim, for example, a mSA signal peptide of SEQ ID NO: 3 (claim 2). However, the mSA signal peptide of SEQ ID NO: 3 is known in the art, as taught by Attallah et al. (see below). Thus, no further “optimization” is occurring to the signal peptide itself. Rather, it is interpreted that the proper signal peptide is selected, which optimizes the therapeutic protein to have increased secretion from a gamma delta T cell. In that case, the signal peptide, itself, is not being optimized, it is being selected for use in the therapeutic protein, whereby it is an optimal peptide for such use, as it increases secretion by > 15%. Thus, applicants could claim a signal peptide which increases secretion of the therapeutic protein by > 15% compared to a (reference) signal peptide, or no signal peptide at all.” The distinction is that the claims are not drawn to “methods for optimizing signal peptides”, rather they are drawn to selection of appropriate signal peptides for use in the therapeutic protein. Similarly, an expression cassette is not “optimized” by inclusion of the appropriate sequence encoding the signal peptide. Claims drawn to “optimizing” either a signal peptide or an expression cassette need to then define the structural manipulations that constitute the boundaries of “optimizing”. Here, it is interpreted that neither the signal peptides nor the expression cassettes are, themselves, being optimized; rather that selection of the appropriate signal peptide imparts optimal features to the therapeutic protein. It is suggested that applicants remove the “optimized” terminology from the claims if the claims only require specific, appropriate signal peptides for inclusion, signal peptides that are known in the art and are not being further “optimized” in any way. Further, claims to any signal peptide that increases secretion of the therapeutic protein in a gamma delta T cell by >15% may suffer from a lack of descriptive support for a claimed genus of signal peptides, without identifying the shared structural features, which would be common to all species of the claimed genus, which impart the functionality of increasing secretion by a gamma delta T cell by >15%. Such identification of structural similarity would be required for the skilled artisan to know, a priori, which species of signal peptides available in the art would work in the claimed invention. Thus, if applicants are not intending to claim novel signal peptides by structure or methods of optimizing signal peptides for use in gamma delta T cells, and instead are claiming a select number of signal peptide species for use in the therapeutic protein which are inherently beneficial for secretion from gamma delta T cells, then the claims should be limited to the select grouping of appropriate species of signal peptides for use in the therapeutic protein.
Claim Rejections - 35 USC § 103- Maintained, Amended
The following rejections have been amended to account for amended and canceled claims submitted in the applicant’s remarks of 4/7/2026.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over Alvarez Vallina et al., (WO 2021/165248; published 8/26/2021) and Attallah et al. (Protein Expression and Purification, 2017 (132)).
WO ‘248 teaches a secretable bispecific antibody comprising an anti-CD19 scFv and an anti-CD3 scFv, and engineered T cells secreting the bispecific antibody (abstract). WO ‘248 teaches that the tandem scFvs are also known as bispecific T cell engagers (BiTE), and consist of two scFvs connected by a flexible linker on a single polypeptidic chain (pg. 1, lines 22-24). WO ‘248 teaches that the secretable BiTE comprises the anti-CD19 A3B1 scFv and the anti-CD3 OKT3 scFv, and wherein the OKT3 anti-CD3 scFv binds the CD3ε subunit (pg. 6, lines 24-25 and 28-29). WO ‘248 teaches that suitable linkers for linking the two scFvs include (G4S)n (pg. 8, lines 14-16). WO ‘248 teaches the construct also comprises a signal peptide, which may be a human kappa light chain signal peptide or an IL-2 signal peptide (pg. 8, lines 5-11). Thus, WO ‘248 teaches a bispecific construct comprising from N-terminus to C-terminus, a signal peptide which is cleaved off prior to secretion (IL-2 peptide), a tumor cell-binding protein domain (anti-CD19 scFv), a linker (G4S), and a T cell binding domain (anti-CD3 scFv).
Regarding the “gamma delta T cell optimized” signal peptide, the instant specifications describe “exemplary” signal peptides of the invention include IL-2 signal peptides (which are not specifically defined), and modified serum albumin (mSA) peptides of instant SEQ ID NO: 3 (specifications, pg. 21, para. 0147). In the event that the IL-2 signal peptide of WO ‘248 does not qualify as a gamma delta T cell optimized signal peptide, reference is made to Attallah et al., (Protein Expression and Purification).
Attallah et al. teaches a highly efficient modified human serum albumin signal peptide to secrete proteins in cells derived from different mammalian species (title). Attallah teaches the mSA peptide has the amino acid sequence MKWVTFISLLFLFSSSSRA (pg. 28, Table 1), which is 100% identical in amino acid sequence to the mSA peptide of instant SEQ ID NO: 3. Attallah teaches the expression of a scFv-Fc fusion protein in multiple cell lines, wherein alternative signal peptides were used for comparison, including a human kappa chain peptide and the mSA peptide (abstract). Attallah teaches the mSA signal peptide was successful in directing the secretion of the active proteins in different types of mammalian cells (abstract), including being 6-7 times more effective than the human kappa chain signal peptides (pg. 30, Fig. 2B).
It would have been obvious to one of skill in the art to modify the secretable anti-CD19/anti-CD3 bispecific construct, comprising a kappa light chain signal peptide, of WO ‘248 to instead comprise the mSA signal peptide of Attallah et al. One would have been motivated to do so given that the mSA signal peptide of Attallah increased secretion pathway expression of the protein by 6-7 fold over a kappa light chain signal peptide, as taught by Attallah et al. There would have been a reasonable expectation for success given that the mSA signal peptide and the kappa light chain signal peptide are substitutable alternatives for the same use as taught by Attallah et al. Thus, the invention was prima facie obvious to one of skill in the art at the time the invention was made.
Regarding claims 1-5, the combination protein of WO ‘248 and Attallah, comprising a mSA signal peptide, an anti-CD19 scFv, a G4S linker, and an anti-CD3 scFv, makes obvious the protein of instant claims 1-5.
Response to Arguments
Applicant's arguments filed 4/7/2026 have been fully considered but they are not persuasive. Applicants contend that neither Alvarez Vallina nor Attallah teach or suggest a signal peptide optimized to increase secretion of the therapeutic protein from gamma delta T cell by at least 15% relative to the corresponding non-optimized signal peptide; neither reference speaks to gamma delta T cells specifically (remarks, pg. 10, para. 2). Applicants contend that Alvarez Vallina (WO ‘248) fails to screen signal peptides for secretion in any cells, therefore lacking a comparative analysis, selection criteria or quantitative framework for improving secretion. Likewise, Attallah does not disclose gamma delta T cells, thus does not provide motivation for optimizing signal peptides to achieve improved secretion in gamma delta T cells (remarks, pg. 10, paras. 3-5). Applicant contends that gamma delta T cells are fundamentally different cellular environments, thus the reference provide no direction that would lead a skill artisan to adapt or implement the disclosed concepts in gamma delta T cells, nor do they provide any basis to expect the improved secretion rates when applied to gamma delta T cells.
In response to applicant's argument that neither of the references teach optimizing signal peptides for protein secretion in gamma delta T cells, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Attallah does a comparative analysis of several different signal peptides in driving secretion of scFv protein constructs from several different cell lines. Attallah highlights that the mSA signal peptide (of instant SEQ ID NO: 3) robustly increased recombinant protein secretion across all cell lines tested, by 4x to 1713x, as compared to the alternative signal peptides (see Fig. 2B). Thus, Attallah demonstrates far more than 15% increases in protein secretion, Attallah demonstrates that mSA led to > 400% increases. WO ‘248 teaches secretable CD19/CD3 BiTEs, which include a signal peptide that is cleaved off after translation. WO ‘248 is relied upon for teaching that the components of the therapeutic proteins of claims 1-5 were known in the art at the time of the instant invention. A skilled artisan, looking to improve the secretion of the constructs of WO ‘248, when expressed in gamma delta T cells, would naturally consider substituting the signal peptides of Attallah in place of those of WO ‘248, with a reasonable expectation for success, given the robust effects the mSA signal peptide had at increasing secretion across several different cell lines. Attallah teaches the mSA signal peptide of instant SEQ ID NO: 3 with 100% sequence identity. Thus, neither reference need teach “optimizing” the signal peptide because the claims don’t require optimizing the signal peptide. The claims recite selecting an appropriate signal peptide for enhancing secretion of the protein in gamma delta T cells, and Attallah provides an example of such a signal peptide that works to increase secretion across numerous cell types, including promoting the mSA signal peptide over the kappa light chain signal peptides. WO ‘248 suggests kappa light chain signal peptides as a species of signal peptide for use in the invention. Thus, it would have been obvious to a skilled artisan to use the signal peptide of Attallah in the BiTE construct of WO ‘248, in gamma delta T cells, with a reasonable expectation for success at increased secretion. If applicants are claiming an unexpected result resulting from incorporating the mSA signal peptide of Attallah in gamma delta T cells, applicants should provide a comparison to the closest alternative embodiment, which demonstrates the specific advantage discovered. As the examiner contends there is a reasonable expectation for success for the mSA signal peptide to also increase protein secretion in T cells, regardless of their subtype, and the art does not teach away from using mSA signal peptides in T cells generally, the applicants should demonstrate, for example, that the mSA signal peptide is particularly advantageous, and thus inventive, for use in driving secretion selectively from gamma delta T cells versus, for example, alpha beta T cells. Otherwise, the substitution of the mSA signal peptide to increase protein secretion from any type of cells engineered to secrete a fusion protein, will be considered a reasonable expectation of using the mSA signal peptide, as it was taught in the art, by Attallah et al.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, neither WO ‘248 nor Attallah, nor the art, teach away from using the mSA signal peptide to increase secretion of proteins in gamma delta T cells; instead Attallah suggests its ability to enhance protein secretion translates across cell types. Specifically, Attallah cites the translocation of secretory protein into the lumen of the ER constitutes the limiting step within the classical secretory pathway (pg. 27, col. 2), and that mSA signal peptide directs protein secretion with very high efficiency in cells derived from different mammals (pg. 32, col. 1, para. 6). Thus, Attallah speaks to the generality of use of the mSA signal peptide across various cell types, with reasonable expectation for enhanced protein secretion. Applicant’s argument that the cellular landscape of gamma delta T cells is vastly different is unpersuasive. This seems to suggest that the mSA signal peptide would not be expected to function to traffic secretory proteins into the lumen of the ER of immune cells generally, yet surprisingly works advantageously in gamma delta T cells specifically. T cells are a common cell type for genetic engineering, whether it be for protein expression on the cell surface (i.e., CAR or TCR), or secretable fusion proteins, and signal peptides are commonly used. Indeed WO ‘248 teaches inclusion of signal peptides for expressing and secreting the fusion proteins of the invention. Attallah provides sufficient evidence to believe that the mSA signal peptide would enhance recombinant protein secretion, to some degree, across any genetically engineered cell type for immunological therapy. The instant claims also recite hSCF and IL-2 signal peptides as exemplary embodiments in claim 2; and, similarly, WO ‘248 cites IL-2 signal peptides may be used in the invention of encoding secretable BiTE constructs from immune cells. Thus, in lieu of any evidence of a particular advantage of using the signal peptides for secretion of proteins from gamma delta T cells, verses any other alternative mammalian cells, or other immune cells generally, the art supports that the signal peptides of the instant claims would function similarly as they were previously described in the art. Thus, it is obvious to substitute them into gamma delta T cell population for the same purposes for which they were taught in the art. Applicant’s arguments are not found persuasive and the rejections are maintained.
Claim Rejections – New, necessitated by amendment
Applicants amended at least claims 7, 14 and 21 to be limited to a T cell binding domain comprising SEQ ID NO: 94. As such a new search was required to determine if the art teaches the new limitations of the claims as amended.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3 and 5-6 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-4, 7-9 and 12-13 of copending Application No. 19/145,404 in view of Attallah et al. (Protein Expression and Purification, 2017 (132)).
Application ‘404 claims a therapeutic agent comprising a scFv that binds to SSTR2 (claim 1), further comprising a signal peptide a linker and a T cell binding protein (claim 2), wherein the linker is GGGS of SEQ ID NO: 155 (claim 3), wherein the T cel binding protein is SEQ ID NO: 94 (claim 4); as well as an engineered gamma delta T cell capable of secreting the therapeutic agent (claim 7), wherein the linker is SEQ ID NO: 155 (claim 8), and the T cell binding protein is SEQ ID NO: 94 (claim 9); as well as a recombinant viral vector encoding the therapeutic protein (claim 12), wherein the linker is SEQ ID NO: 155 and the T cell binding protein is SEQ ID NO: 94 (claim 13).
The T cell binding domain of app ‘404 SEQ ID NO: 94 is 100% identical to that of instant SEQ ID NO: 94.
Attallah et al. teaches the mSA signal peptide of SEQ ID NO: 3 with 100% sequence identity, and that the signal peptide significantly enhances secretion of fusion proteins from various mammalian cells, as described above.
It would have been obvious to one of skill in the art to utilize the signaling peptide of Attallah as the signaling peptide of the therapeutic protein of app ‘404. One would have been motivated to do so with a reasonable expectation for success given the mSA signaling peptide enhances secretion of fusion proteins from engineered mammalian cells, such a T cells and/or gamma delta T cells.
The combination of application ‘404 and Attallah, therapeutic protein of claims 1-4, engineered gamma delta T cells of claims 7-9, and recombinant vectors of claims 12-13, make obvious the therapeutic protein of instant claims 1-3 and 5-6.
This is a provisional nonstatutory double patenting rejection.
Claims 1-10, 12-15, 17, 21-22 and 24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 7-9 and 12-13 of copending Application No. 19/145,404 in view of Attallah et al. (Protein Expression and Purification, 2017 (132)) and Abate-Gada et al., (WO 2021/247474; published 12/9/2021; henceforth WO '474).
The reasons why claims 1-3 and 5-6 are made obvious over a combination of app ‘404 and Attallah is described above. Specifically, app ‘404 and Attallah make obvious a therapeutic protein comprising a signal peptide of SEQ ID NO: 3, an anti-SSTR2 tumor cell binding protein domain, a GGGS linker, and a T cell binding domain of SEQ ID NO: 94.
However, the combination of app ‘404 and Attallah do not describe wherein the anti-SSTR2 tumor cell binding domain scFv is that of instant SEQ ID NO: 52.
WO ‘474 teaches engineered T cells which express a chimeric antigen receptor (CAR), which targets the cells to SSTR-expressing cancers (abstract). WO ‘474 teaches neuroendocrine tumors overexpress SSTR2, and that the CAR constructs comprise an ectodomain which is an SSTR2 binding agent (pg. 1, lines 27-30). WO ‘474 teaches one embodiment of the anti-SSTR2 scFv binding domain is SEQ ID NO: 21 (pg. 4, lines 11-16), which is 100% identical in amino acid sequence to the anti-SSTR2 scFv binding domain of instant SEQ ID NO: 52.
It would have been obvious to one of skill in the art to utilize the anti-SSTR2 scFv binding domain of WO ‘474 SEQ ID NO: 21 as the tumor cell binding domain of the therapeutic proteins of app ‘404. One would have been motivated to do so in order to target the therapeutic proteins of app ‘404 to SSTR2 expressing tumors. There would have been a reasonable expectation for success given the anti-SSTR2 scFv of WO ‘474 SEQ ID NO: 21 is an alternative species of the anti-SSTR2 scFv of app ‘404 SEQ ID NO: 181, and is 94% similar in sequence, and is being substituted for the same purpose for which it is taught in the art, by WO ‘474.
The combination therapeutic proteins of app ‘404 claims 1-4, engineered gamma delta T cells of claims 6-9, and recombinant viral vectors of claims 12-13, comprising the signal peptide of Attallah and the anti-SSTR2 scFv of WO ‘474, make obvious that of instant claims 1-10, 12-15, 17, 21-22 and 24, whereby the Hum2 scFv of instant SEQ ID NO: 94 is a humanized version of an anti-CD3 scFv.
This is a provisional nonstatutory double patenting rejection.
Claims 1-10, 12-15, 17, 21-22, 24 and 26-27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-4, 7-9 and 12-13 of copending Application No. 19/145,404 in view of Attallah et al. (Protein Expression and Purification, 2017 (132)) and Abate-Gada et al., (WO 2021/247474; published 12/9/2021; henceforth WO '474) and Bedoya et al., (US 2017/0137783; published 5/18/2017).
The reasons why claims 1-10, 12-15, 17, 21-22 and 24 are made obvious over a combination of app ‘404, Attallah and WO ‘474 is described above. Specifically, app ‘404, Attallah and WO ‘474 make obvious a therapeutic protein comprising a signal peptide of SEQ ID NO: 3, an anti-SSTR2 tumor cell binding protein domain of SEQ ID NO: 52, a GGGS linker, and a T cell binding domain of SEQ ID NO: 94.
However, the combination of app ‘404, Attallah and WO ‘474 do not teach a recombinant viral vector comprising an EF1α promoter or a shRNA targeting B2M, of claims 26-27.
Bedoya et al. teaches methods of making immune effector cells that can be engineered to express a chimeric antigen receptor (CAR) and methods of treatment using the same (abstract). Bedoya teaches the exemplary effector cells of the invention include T cells and gamma/delta T cells (pg. 2, para. 0013). Bedoya teaches nucleic acids encoding the CAR, which are DNA vectors or RNA vectors, including lentivirus vectors (pg. 2, para. 0020); and also includes (in vitro transcription) IVT RNA, which encompasses synthetic mRNA (pg. 3, para. 0031). Bedoya teaches an example of a promoter that is capable of expressing the CAR encoding nucleic acid molecule in a mammalian T cell is the Ef1α promoter (pg. 71, para. 0581), among other alternative promoters (paras. 0582-0583). Bedoya teaches the vector may also include a signal sequence to facilitate secretion (pg. 72, para. 0586). Bedoya also teaches that the T cell can be engineered such that it does not express a functional HLA on its surface, whereby downregulation of HLA may be accomplished by reducing or eliminating expression of beta-2-microglobulin (B2M; pg. 35, para. 0383); and that shRNA may be used to knock out or knock down the subunit (pg. 35, para. 0384). Bedoya teaches that methods of shRNA-mediated HLA knock out, and expression systems for shRNAs, are known in the art (pg. 35, paras. 0387-0388); and that applying such methods are a means of making the T cells allogenic (pg. 35, para. 0371; pg. 23, para. 0272).
It would have been obvious to one of skill in the art to modify the recombinant viral vectors of app ‘404, Attallah and WO ‘474 to encode an Ef1α promoter and/or to encode an shRNA targeting B2M. One would have been motivated to do so in the process of routine optimization based on the desired features of the engineered protein expressed in a gamma/delta T cell; including increased expression of the protein and/or knock out of an HLA in order to make the engineered T cells which express the protein allogeneic for a patient population, as taught by Bedoya et al. There would have been a reasonable expectation for success given that use of these elements is common practice in the art of genetically engineering T cells to express a recombinant protein. Thus, the invention as a whole was prima facie obvious to one of skill in the art at the time the invention was made.
Regarding claims 26-27; the combination of app ‘404, Attallah, WO ‘474 and Bedoya make obvious using a Ef1α promoter and/or incorporating a domain encoding an shRNA targeting B2M for knock out in gamma/delta T cells. Said modifications may be made in the design of the suitable vector encoding the construct, or in a synthetic mRNA molecule. Thus, the combination of app ‘404, Attallah, WO ‘474 and Bedoya make obvious instant claims 26-27.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are 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.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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