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 .
Application Status
The amended claims filed January 9, 2026 are acknowledged. Claims 1-10 and 13-36 are pending. Claims 11-12 have been canceled. Claims 1, 3-4, 10, 30, 32, and 34 have been amended. Claim 21 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-10 and 13-36 are pending. Claims 1-10, 13-20, and 22-36 are under examination herein.
Notice Regarding Non-Compliant Claim Amendments
It is noted that claim 10, as amended on January 9, 2026, contains subject matter which was not previously set forth in any previous version of the claim but that has not been properly annotated (via underlining) to reflect this fact. Specifically, the claim was amended to further recite “; and wherein the beta TCR polypeptide comprises an amino acid sequence according to any one of SEQ ID NOs: 9, 74, 77, 78, 81, 82, 83, or 84”, which was previously set forth in claim 12 (now canceled).
It is further noted that claims 13-18, 20-29, 31, and 33, which were annotated as “(Original)” in the amended claims filed August 12, 2025, are annotated as “(Previously Presented)” in the amended claims filed January 9, 2026, despite having no record of being earlier amended during prosecution.
In the interest of compact prosecution, these claims will be examined herein.
Applicant is advised to follow the rules of MPEP § 714 (in particular section (II)(C)) in future amendment submissions.
Objections to the Specification and Drawings Withdrawn
The objections to the specification are withdrawn in view of Applicant's amendments thereto.
The objection to the drawings is withdrawn in view of Applicant's amendments to Figure 50F.
Claim Objections Withdrawn
The previous grounds of objection to claims 3-4, 30, and 33 are withdrawn in view of Applicant's amendments to said claims.
Claim Rejections Withdrawn
All prior rejections of claims 11-12 are rendered moot by the cancelation of the claims.
The rejection of claim 32 under 35 U.S.C. § 112(b) as being indefinite is withdrawn in view of Applicant's amendment to the claim.
The prior grounds of rejection of claims 10 and 34 under 35 U.S.C. § 112(a) for failing to satisfy the written description requirement are withdrawn in view of Applicant's amendments to said claims.
The rejection of claims 1-10, 14, 16-18, 20, 22, 26-28, and 31-36 under 35 U.S.C. § 103 as being unpatentable over Lin (WO 2019/222283 A1) in view of Jakobsen (WO 2013/041865 A1) and Wang (US 2018/0148508 A1), and of claims 1 and 23-31 further in view of Dubridge (US 2019/0031749 A1) and Wesche (Poster presented at AACR Annual Meeting 2018, April 14-18, 2018, Chicago, IL; Cancer Research 78(13 Suppl): Abstract no. 3814; cited in IDS), is withdrawn in view of Applicant's amendments to claim 1.
The rejection of claims 1-2, 8-10, and 13-19 under 35 U.S.C. § 103 as being unpatentable over Lin (WO 2019/222283 A1) in view of Jakobsen (WO 2013/041865 A1) and Wang (US 2018/0148508 A1), further in view of Campbell (WO 2019/113385 A1; cited in IDS), is overcome by Applicant's statement pursuant to 35 U.S.C. § 102(b)(2)(C) that, not later than the effective date of the claimed invention, the cited reference of WO 2019/113385 A1 and the instant application were owned by Janux Therapeutics, Inc.
NEW CLAIM OBJECTIONS NECESSITATED BY AMENDMENT
AND NEW CLAIM REJECTIONS
Claim Objections
Claim 34 is objected to because of the following informalities: As amended, the claim recites “to” in duplicate in the wherein clause (“…wherein the scFv comprises an amino acid sequence according to to SEQ ID NO: 86 or SEQ ID NO: 8”). This is a new objection necessitated by claim amendment. The duplicate should be deleted.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 1-10, 14, 16-18, 20, 22, 26-28, and 31-36 are rejected under 35 U.S.C. 103 as being unpatentable over Lin (WO 2019/222283 A1; cited in PTO-892 mailed October 1, 2025) in view of Jakobsen (WO 2013/041865 A1; cited in IDS), Wang (US 2018/0148508 A1; cited in PTO-892 mailed October 1, 2025), and Moore (US 2017/0204139 A1). This is a new rejection that has been modified from an earlier rejection of record.
Lin discloses conditionally active target binding proteins that contain binding moieties comprising non-CDR loops for masking the binding of a binding molecule to its target and CDRs for binding bulk serum proteins (e.g., Abstract). An exemplary embodiment is illustrated in Figure 3 and reproduced below. In embodiments of the invention the second target antigen-binding domain is an anti-CD3 scFv, relevant to claims 1 and 31. See also, e.g., ¶ 0008.
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Lin teaches that the binding moiety can be a half-life extending sdAb capable of binding to albumin, which masks the binding of the target antigen binding domain or a non-immunoglobulin binding molecule to its target via specific intermolecular interactions between the binding moiety and the target antigen binding domain or non-immunoglobulin binding moiety (e.g., ¶ 0005), relevant to claims 1, 14, and 26-28. Lin discloses that when the cleavable linker is cleaved, e.g., by a matriptase, the binding moiety is separated from the (first) target antigen binding domain and said target antigen binding domain binds to its target (e.g., ¶ 0006, 0009), relevant to claim 20.
Regarding the first target antigen binding domain, Lin teaches that in some embodiments the target antigen binding domain binds a tumor antigen, e.g., MAGE (e.g., ¶ 0006, 0086), relevant to claim 8. In some cases, the first antigen-binding domain is a soluble TCR fragment comprising a Vα domain and a Vβ domain (e.g., ¶ 0087), relevant to claims 1-7.
Lin further provides pharmaceutical compositions comprising the binding proteins of the invention (e.g., Abstract) and nucleic acids encoding the same (e.g., ¶ 00108), further relevant to claims 35-36.
However, Lin does not disclose a conditionally active target-binding protein comprising a soluble anti-MAGE-A3 TCR comprising a TCRα polypeptide comprising the amino acid sequence of instant SEQ ID NO: 5 and a TCRβ polypeptide comprising the amino acid sequence of SEQ ID NO: 9, nor a linker comprising a matriptase-cleavage substrate comprising the amino acid sequence of instant SEQ ID NO: 4. Lin also does not disclose that the anti-CD3 scFv comprises an amino acid sequence of instant SEQ ID NO: 86, or that the binding moiety for masking comprises an amino acid sequence that has less than 70% sequence identity to an amino acid sequence of the tumor cell antigen.
Jakobsen discloses T cell receptors (TCRs) comprising a TCRα variable domain and a TCRβ variable domain, which bind to a peptide having the amino acid sequence of “EVDPIGHLY”, corresponding to residues 168-176 of the MAGE-A3 protein (e.g., Abstract; Background, page 1). Jakobsen teaches that MAGE-A3 is implicated in many cancers, including melanoma, lung cancer, esophageal carcinomas, and others (e.g., page 1). Jakobsen teaches that the “EVDPIGHLY” peptide is the best characterized epitope of MAGE-A3 and is recognized by both HLA-A1 and HLA-B35 restricted T cells (e.g., page 1). In an embodiment, Jakobsen discloses an exemplary TCR of the invention, “a24b101”, which comprises a TCRα polypeptide comprising the amino acid sequence of SEQ ID NO: 7 (which shares 100% sequence identity to instant SEQ ID NO: 5) and a TCRβ polypeptide comprising the amino acid sequence of SEQ ID NO: 11 (which shares 100% sequence identity to instant SEQ ID NO: 9) (e.g., Figures 6, 11; page 16; Example 4, page 28), relevant to claims 8-11. Jakobsen teaches that the TCRs of the invention may be αβ heterodimers or may be in a single chain format (e.g., pages 15-16).
Further relevant to the configurations recited in claims 2-7, Jakobsen discloses that a preferred embodiment of the invention is provided by a TCR of the invention associated (usually by fusion to an N- or C-terminus of the alpha or beta chain) with an anti-CD3 antibody or a functional fragment thereof, e.g., an scFv fragment (e.g., pages 19-20). Relevant to claims 3 and 31-34, Jakobsen teaches an scFv comprising the amino acid sequence of SEQ ID NO: 20 (which shares 100% sequence identity to that of instant SEQ ID NO: 86) fused via a GGGGS linker to the N-terminus of a MAGE-A3 TCRβ chain (e.g., Figure 14; Example 5, page 30). Jakobsen teaches that a fusion protein comprising the a24b101 anti-MAGE-A3 TCR and an anti-CD3 scFv activates T cells in the presence of MAGE-A3 presenting tumor cells (e.g., Figure 15D).
Jakobsen further teaches nucleic acids encoding a TCR of the invention and pharmaceutical compositions comprising a TCR of the invention (e.g., Abstract; pages 17-18; claims 13-16), further relevant to claims 35-36.
Wang describes masked chimeric antigen receptors (mCARs) comprising a masking peptide and one or more antigen-specific targeting domains, which are selectively activated upon cleavage of the masking peptide by proteases commonly active in the tumor microenvironment and have the advantage of minimizing off-target cell killing activity (e.g., Abstract; ¶ 0003-0008). In an embodiment, the structural arrangement of the mCAR, from N-terminus to C-terminus, when the mask is not cleaved, is mask – linker – cleavage site – linker - CAR (e.g., ¶ 0010). Relevant to claims 20 and 22, Wang discloses a cleavage site having the amino acid sequence of “LSGRSDNH” (SEQ ID NO: 2), which shares 100% sequence identity to instant SEQ ID NO: 4 (e.g., ¶ 0014, 0070; Table 1, pages 13-14). As evidenced by the instant specification, the “LSGRSDNH” substrate is recognized and cleaved by several proteases, including matriptase (e.g., page 124).
Relevant to claims 16-18, Wang discloses exemplary masking peptides which comprise, consist, or consist essentially of a sequence of “CISPRGCPDGPYVMY” (SEQ ID NO: 1), “LLGPYELWELSH” (SEQ ID NO: 17), or “RCNPNMEPPRCWAAEGD” (SEQ ID NO: 22), which are at least 10 amino acids in length and no more than 20 amino acids in length. Wang teaches that masking peptides are unique to each antigen-specific targeting domain (ASTD) (specific for a tumor antigen) and may be 5-50 amino acids long (e.g., ¶ 0033-0035, 0066).
Moore describes polypeptides that include a cleavable moiety that is a substrate for at least one protease selected from matriptase and uPA, and molecules comprising said cleavable moiety (e.g., Abstract; ¶ 0006-0216). The activatable molecules described by Moore may have a structural arrangement comprising: masking moiety (MM) – optional linker – cleavable moiety (CM) – optional linker – antibody or antigen-binding fragment thereof, although the molecules may also comprise serum half-life extending moieties such as serum albumin or polypeptides that bind to serum proteins (e.g., ¶ 0006-0009, 0075-0103, 0236-0258). Further relevant to claim 1, Moore teaches that the MM is not a natural binding partner of the antibody and contains no more than 50% or no more than 70% sequence homology to any natural binding partner of the antibody (e.g., ¶ 0236-0256). Moore teaches that the activatable antibodies of the invention “provide for reduced toxicity and/or adverse side effects that could otherwise result from binding of the AB at non-treatment sites if the AB were not masked or otherwise inhibited from binding to the target” (¶ 0251).
Moore also teaches several embodiments in which the CM comprises an amino acid sequence which contains the amino acid sequence of “LSGRSDNH” (e.g., ¶ 0047-0050), further relevant to claims 20 and 22.
Taken together, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the constitutively active target-binding protein taught by Lin to:
substitute a soluble α/β TCR that binds to, e.g., MAGE-A3 (such as described by Jakobsen), as the tumor-targeting domain, linked to the specific anti-CD3 scFv comprising the amino acid sequence of instant SEQ ID NO: 86 (taught by Jakobsen), and
incorporate a masking peptide (between 10-20 amino acid residues in length) that impairs binding of said soluble TCR to the tumor cell antigen (such as described by Wang, Lin, and Moore) outside of the tumor microenvironment, connected to an N-terminus of the soluble TCR by a linker comprising a substrate (e.g., the amino acid sequence of instant SEQ ID NO: 4) for a tumor-specific protease (e.g., matriptase), such as described by Wang and Moore,
wherein the construct further comprises an albumin-binding single-domain antibody that extends the half-life of the construct and is linked N-terminally to the masking peptide (e.g., as illustrated by Lin). The further incorporation of an albumin-binding single-domain antibody, as noted by Lin, would extend the half-life of the therapeutic construct. Relevant to (1), the skilled artisan would have been motivated to substitute anti-MAGE-A3 TCR/anti-CD3 scFv fusion taught by Jakobsen in place of the target binding domain/scFv portion described by Lin, because Jakobsen teaches that MAGE-A3 is a tumor-specific antigen that is expressed in many cancers, and because the MAGE-A3 TCR/CD3 scFv fusion taught by Jakobsen activates T cells in the presence of MAGE-A3-presenting cells. There would have been a reasonable expectation of success because one of ordinary skill in the art would recognize that the soluble anti-MAGE-A3 TCR/anti-CD3 scFv fusion protein taught by Jakobsen has an analogous structure and function to the target-binding domain/T cell binding moiety in the conditionally active target-binding protein of Lin and could be incorporated into the protein to achieve the intended purpose of simultaneously targeting a tumor-specific antigen (MAGE-A3) and a T cell (CD3).
Relevant to (2), the skilled artisan would have been further motivated to incorporate a masking peptide that impairs binding of the soluble TCR, connected to the tumor antigen-binding protein via a linking moiety comprising a matriptase-cleavable substrate, because Wang, Lin, and Moore teach that such a modification would render the construct conditionally active only in a tumor microenvironment (which is characterized by high expression of proteases), which Wang and Moore note has the advantage of minimizing off-target cell killing by and reducing toxicity of the therapeutic construct. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that a masking moiety serves as a suitable means for achieving the purpose of minimizing on-target off-tumor effects and lowering the toxicity of a therapeutic protein. Furthermore, Moore provides a proof-of-concept that a masking moiety with less than 70% sequence homology to the target binding partner of the antigen-binding moiety may be used to effectively mask binding of the molecule to the target antigen outside of the tumor microenvironment. As set forth in MPEP § 2143, known work in one field of endeavor (e.g., with therapeutic antibodies) may prompt variations of it for use in the same field or a different one (e.g., with therapeutic TCR constructs) based on design incentives if the variations are predictable to those of ordinary skill in the art.
Furthermore, relevant to the alternative configurations recited in claims 2-7, one of ordinary skill in the art would recognize that there are a finite number of configurations in which a fusion protein comprising an albumin-binding moiety, a masking peptide, an α/β TCR, and an anti-CD3 scFv antibody (e.g., VH-linker-VL or VL-linker-VH) may be arranged, based on their respective structures. The skilled artisan, through routine and conventional activities known to those in the art, could generate a fusion protein having any of the instantly claimed configurations as suggested by the prior art and measure their activity using known methods in the art to determine the most effective configuration(s) through the process of routine optimization. In effect, making such configurations with the structures disclosed in the prior art would be seen as simple substitution of one known element for another to obtain predictable results and combining prior art elements according to known methods to yield predictable results.
Claims 1 and 23-31 are rejected under 35 U.S.C. 103 as being unpatentable over Lin (WO 2019/222283 A1; supra) in view of Jakobsen (WO 2013/041865 A1; supra), Wang (US 2018/0148508 A1; supra), and Moore (US 2017/0204139 A1; supra) as applied to claims 1-10, 14, 16-18, 20, 22, 26-28, and 31-36 above, and further in view of Dubridge (US 2019/0031749 A1; cited in PTO-892 mailed October 1, 2025) and Wesche (Poster presented at AACR Annual Meeting 2018, April 14-18, 2018, Chicago, IL; Cancer Research 78(13 Suppl): Abstract no. 3814; cited in IDS). This is a new rejection that has been modified from an earlier rejection of record.
The teachings of Lin are recited in the 35 U.S.C. § 103 rejection above.
However, Lin does not disclose that the albumin-binding moiety of the conditionally active target-binding protein comprises an amino acid sequence of instant SEQ ID NO: 72. Lin also does not disclose that the albumin-binding moiety of the conditionally active target-binding protein is connected by a linker sequence comprising one of the amino acid sequences recited in claims 24-25.
The teachings of Jakobsen, Wang, and Moore are provided above.
Dubridge discloses single domain serum albumins binding proteins with improved thermal stability, binding affinities, and robust aggregation profiles, as well as multispecific proteins comprising a single domain serum albumin binding protein (e.g., Abstract). Dubridge teaches that albumin has an extraordinarily long circulatory half-life and can be used in a variety of ways to increase the circulatory half-life of therapeutic molecules (e.g., ¶ 0004). Relevant to claims 26-30, Dubridge discloses an exemplary single domain serum albumin binding protein having an amino acid sequence of SEQ ID NO: 9 (e.g., ¶ 0005), which shares 100% sequence identity to that of instant SEQ ID NO: 72. Relevant to claims 23-24, Dubridge discloses that multispecific binding proteins of the invention are constructed by combining genes encoding the three binding domains (including a single domain albumin binding domain) separated by peptide linkers into a single genetic construct (e.g., ¶ 0064-0069). Exemplary linkers, including (GS)n, (GGGS)n, and (GGGGS)n, are recited on pages 14-15.
Wesche discloses various configurations of “TriTAC” (Tri-specific T cell Activating Construct) molecules, which are T-cell engaging therapeutic proteins optimized for the treatment of solid tumors and long serum half-life. Wesche discloses, “TriTAC constructs are made of a single polypeptide designed to bind to a cancer surface antigen, the CD3 epsilon subunit of the TCR, and to human serum albumin. CD3 is bound by a single-chain variable fragment (scFv) while both tumor-targeting and albumin-binding is achieved by single domain antibodies. The latter allow TriTACs to be very small, stable, and easily produced and purified. Non-covalent binding to serum albumin has been validated as an effective way to extend the serum half-life of other proteins up to several weeks” (Abstract).
Wesche teaches that the TriTAC protein may be configured with an albumin-binding domain “A” linked to a target binding domain “T”, further linked to a T-cell binding domain “C”, in the order of “C:T:A” and “A:T:C”, connected with G4SG3S linkers (said linker sharing 100% sequence identity to instant SEQ ID NO: 71) (“Platform Engineering”), relevant to claims 1, 23, 25-28, and 31. The G4SG3S linker described by Wesche has a formula of (GGGGS)1 and a formula of (GGGS)1, further reading on claim 24. Wesche discloses that the TriTACs are “very potent and efficacious in vitro and in vivo”, and “combine the advantages of IgG based approaches (long half-life, manufacturability and stability) with the hallmarks of the pioneering BiTE molecules (small size, good tissue penetration and high degree of flexibility” (Summary).
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to substitute into the conditionally active target-binding protein collectively taught by Lin, Jakobsen, Wang, and Moore, the albumin-binding single-domain antibody construct disclosed by Dubridge (a single domain serum albumin binding protein having an amino acid sequence of instant SEQ ID NO: 72), and to connect said albumin-binding sdAb via a linker comprising, e.g., the amino acid sequence of instant SEQ ID NO: 71 or of (GGGGS)n (instant SEQ ID NO: 49). The skilled artisan would have been motivated to do so because Dubridge teaches that the sdAb has improved thermal stability and binding affinity as well as increased serum half-life, and can be incorporated into multispecific binding proteins. One of ordinary skill in the art would further have been able to incorporate, through routine and conventional activities in the art, any of the various Gly/Ser linker proteins to connect said half-life extending moiety to the masking peptide through the process of routine optimization. There would have been a reasonable expectation of success because those of ordinary skill in the art would recognize that the albumin-binding sdAbs and the Gly/Ser linkers used to connect said sdAb to the masking peptide, as described by Wesche and Dubridge, are functional equivalents known for the same purpose. In effect, making such complexes with the structures disclosed in the prior art would be seen as simple substitution of one known element for another to obtain predictable results and combining prior art elements according to known methods to yield predictable results.
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.
(1)
Claims 1-10, 13-20, 22, and 31-36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 107-108 of co-pending Application No. 17/263,7351 in view of Lin (WO 2019/222283 A1; supra), Jakobsen (WO 2013/041865 A1; supra), Wang (US 2018/0148508 A1; supra), and Moore (US 2017/0204139 A1; supra). This is a new rejection.
Co-pending claims 107-108 recite a method of inhibiting an interaction of a TCR with a peptide-major histocompatibility complex (pMHC), which comprises administering an inhibitory peptide that binds to the TCR without the aid of a MHC, wherein the TCR is an anti-MAGE-A3 TCR comprising a TCRα domain comprising the amino acid sequence of SEQ ID NO: 3 (which shares 100% sequence identity to instant SEQ ID NO: 5) and a TCRβ domain comprising the amino acid sequence of SEQ ID NO: 4 (which shares 100% sequence identity to instant SEQ ID NO: 9), and the inhibitory peptide comprises the amino acid sequence of SEQ ID NO: 15 (which shares 100% sequence identity to the peptide comprising instant SEQ ID NO: 3 2), relevant to claims 1, 8-10, and 13-19. (As set forth in MPEP § 2112.01, products of identical composition cannot have mutually exclusive properties. A chemical composition and its properties are inseparable.)
However, the co-pending reference application does not expressly recite a polypeptide complex comprising a soluble anti-MAGE-A3 TCR comprising said combination of TCRα and TCRβ domains, which is linked to the peptide comprising instant SEQ ID NO: 3 that impairs binding of MAGE-A3 to said soluble TCR and linked to a half-life extending molecule, and further linked to a scFv that binds to an effector cell antigen.
The teachings of Lin, Jakobsen, Wang, and Moore are set forth in the 35 U.S.C. § 103 rejection above.
Based on the further teachings as set forth above, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to incorporate the inhibitory peptide (as a masking peptide) and the anti-MAGE-A3 TCR construct (as a soluble TCR against a tumor-associated antigen) of the co-pending claims into a constitutively active target-binding protein complex, wherein said target-binding protein complex further comprises a matriptase-cleavable linker (e.g., the matriptase-cleavable linker taught by Wang and Moore), a half-life extending moiety (e.g., an albumin-binding single-domain antibody), and an scFv that binds to an effector cell antigen (e.g., the specific anti-CD3 scFv comprising the amino acid sequence of instant SEQ ID NO: 86 as taught by Jakobsen). The further incorporation of an albumin-binding single-domain antibody, as noted by Lin, would extend the half-life of the therapeutic construct. The skilled artisan would have been motivated to construct the complex with an anti-MAGE-A3 TCR/anti-CD3 scFv fusion like that taught by Jakobsen because Jakobsen teaches that MAGE-A3 is a tumor-specific antigen that is expressed in many cancers, and because the MAGE-A3 TCR/CD3 scFv fusion taught by Jakobsen activates T cells in the presence of MAGE-A3-presenting cells. There would have been a reasonable expectation of success because the anti-MAGE-A3 TCR constructs recited by each of the co-pending reference application and by Jakobsen comprise structurally identical TCRα and TCRβ domains.
The skilled artisan would have been further motivated to incorporate the inhibitory peptide comprising SEQ ID NO: 15 as a masking peptide that impairs binding of the soluble TCR, connected to the MAGE-A3 binding protein via a linking moiety comprising a matriptase-cleavable substrate, because Wang, Lin, and Moore teach that such a modification would render the construct conditionally active only in a tumor microenvironment (which is characterized by high expression of proteases), which Wang and Moore note has the advantage of minimizing off-target cell killing by and reducing toxicity of the therapeutic construct. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that a masking moiety serves as a suitable means for achieving the purpose of minimizing on-target off-tumor effects and lowering the toxicity of a therapeutic protein. Furthermore, Moore sets forth a proof-of-concept that a masking moiety with less than 70% sequence homology to the target-binding partner of the antigen-binding moiety may be used to effectively mask binding of the molecule to the target antigen outside of the tumor microenvironment, and the inhibitory peptide of SEQ ID NO: 15 (as recited in the co-pending claims) satisfies this condition.
Furthermore, relevant to the alternative configurations recited in claims 2-7, one of ordinary skill in the art would recognize that there are a finite number of configurations in which a fusion protein comprising an albumin-binding moiety, a masking peptide, an α/β TCR, and an anti-CD3 scFv antibody (e.g., VH-linker-VL or VL-linker-VH) may be arranged, based on their respective structures. The skilled artisan, through routine and conventional activities known to those in the art, could generate a fusion protein having any of the instantly claimed configurations as suggested by the prior art and measure their activity using known methods in the art to determine the most effective configuration(s) through the process of routine optimization. In effect, making such configurations with the structures disclosed in the prior art would be seen as simple substitution of one known element for another to obtain predictable results and combining prior art elements according to known methods to yield predictable results.
This is a provisional nonstatutory double patenting rejection.
(2)
Claims 1 and 23-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 107-108 of co-pending Application No. 17/263,735 in view of Lin (WO 2019/222283 A1; supra), Jakobsen (WO 2013/041865 A1; supra), Wang (US 2018/0148508 A1; supra), and Moore (US 2017/0204139 A1; supra) as applied to claims 1-10, 13-20, 22, and 31-36 above, further in view of Dubridge (US 2019/0031749 A1; supra) and Wesche (Cancer Research 78(13 Suppl): Abstract no. 3814; supra). This is a new rejection.
The teachings of the co-pending reference application are recited in the provisional non-statutory double patenting rejection above.
However, the co-pending reference application does not expressly recite a polypeptide complex comprising an albumin-binding moiety comprising an amino acid sequence of SEQ ID NO: 72 or that said albumin-binding moiety is connected via a linker comprising one of the amino acid sequences set forth in claims 24-25.
The teachings of Lin, Jakobsen, Wang, Moore, Dubridge, and Wesche are provided above.
Based on the further teachings of Dubridge of Wesche, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to substitute into the conditionally active target-binding protein complex collectively taught by the co-pending claims, Lin, Jakobsen, Wang, and Moore, the albumin-binding single-domain antibody construct disclosed by Dubridge (a single domain serum albumin binding protein having an amino acid sequence of instant SEQ ID NO: 72), and to connect said albumin-binding sdAb via a linker comprising, e.g., the amino acid sequence of instant SEQ ID NO: 71 or of (GGGGS)n (instant SEQ ID NO: 49). The skilled artisan would have been motivated to do so because Dubridge teaches that the sdAb has improved thermal stability and binding affinity as well as increased serum half-life, and can be incorporated into multispecific binding proteins. One of ordinary skill in the art would further have been able to incorporate, through routine and conventional activities in the art, any of the various Gly/Ser linker proteins to connect said half-life extending moiety to the masking peptide through the process of routine optimization. There would have been a reasonable expectation of success because those of ordinary skill in the art would recognize that the albumin-binding sdAbs and the Gly/Ser linkers used to connect said sdAb to the masking peptide, as described by Wesche and Dubridge, are functional equivalents known for the same purpose. In effect, making such complexes with the structures disclosed in the prior art would be seen as simple substitution of one known element for another to obtain predictable results and combining prior art elements according to known methods to yield predictable results.
Conclusion
No claims are allowed.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643
1 A Notice of Allowance has been mailed for the co-pending reference application, but a patent has not yet been issued as of this writing.
2 As evidenced by Applicant's disclosure (e.g., page 130), the peptide mask corresponding to Peptide-5 (instant SEQ ID NO: 3) is a cyclic peptide.
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