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 .
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 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.
Priority
The instant application, filed 06/13/2023, is a 371 filing of PCT/IB2021/000868, filed 12/14/2021, and claims domestic benefit to US provisional application 63/125,267, filed 12/14/2020.
Status of Claims/Application
Applicant’s preliminary amendment of 02/07/2024 is acknowledged. Claims 1-2, 4, 6, 8, 14, 18, 20, 23, 26, 34, 36, 38-39, 48, and 52 are amended and claims 3, 5, 7, 9-13, 15-17, 19, 21-22, 29-33, 35, 37, 40-47, 49-51, and 53-57 are cancelled. Claims 1-2, 4, 6, 8, 14, 18, 20, 23-28, 34, 36, 38-39, 48, and 52 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 09/11/2023 (2) and 02/07/2024 (2) are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claim Objections
Claim 20 is objected to because of the following informalities: line 2 of the claim recites “Matriplase”, which is not an art recognized protease, and appears to be a misspelling of “Matriptase”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 20 is 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 20 recites the limitation that “the protease” is selected from those recited. The claim depends on claim 18, which recites two different proteases, specifically claim 18 recites “the first cleavable linker comprises a cleavage site for a protease… and/or the second cleavable linker comprises a cleavage site for a protease”. As claim 18 recites two instances of proteases, it is unclear which is being limited by the recitation in claim 20. For instance, claim 20 could be interpreted as applying to only one of the proteases, or both. In the case of both, it is also unclear if both proteases have to be the same or if they could independently be any of the recited protease. See MPEP 2173.05(e) which states “ if two different levers are recited earlier in the claim, the recitation of "said lever" in the same or subsequent claim would be unclear where it is uncertain which of the two levers was intended. “
As the metes and bounds of the claim are unclear, the claim is indefinite.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 4, 6, 8, 14, 18, 20, 23-24, 34, 36, 38, 48, and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Correnti, C.E., et al (2018) Simultaneous multiple interaction T-cell engaging (SMITE) bispecific antibodies overcome bispecific T-cell engager (BiTE) resistance via CD28 co-stimulation Leukemia 32(5); 1239-1243 in view of WO 2019/051102 A2 (May, C., et al) 14 Mar 2019.
Correnti teaches that the efficacy of early bispecific antibodies redirecting T cells to eradicate cancer cells was partly limited because of suboptimal effector cell engagement. More efficient T-cell activation has been obtained with single chain variable fragment (scFv) antibodies, notably Bispecific T-cell Engagers (BiTEs). Many Bites, all relying on CD3 signaling without providing co-stimulation, are in clinical testing in several solid tumors and hematologic malignancies (page 1, paragraph 1). Recent data has shown that expression of CD80 or CD86, which signals through CD28, on cancer cells increases BiTE-induced cytotoxicity in vitro, as does co-treatment with a monoclonal CD28 antibody. These data suggest the importance of co-receptor activation for maximal anti-tumor efficacy of BiTEs, a finding reminiscent of data obtained with T cells expressing chimeric antigen receptors, where significant improvements in potency were achieved after inclusion of co-stimulatory signaling moieties in the CAR constructs. Since non-specific, cancer cell-independent boosting of CD28-mediated co-stimulatory can lead to overwhelming cytokine production, an immunotherapeutic approach built on two BiTEs, or “Simultaneous Multiple Interaction T-cell Engaging [SMITE] bispecifics”, were envisioned. Each of the BiTEs binds cancer cells and either CD3 or CD28 to provide T-cell costimulation when employed together in the presence of the target antigen-expressing cancer (paragraph bridging pages 1-2). Correnti shows a schematic of the SMITE bispecifics in Fig. 1a, which is duplicated below for convenience.
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Correnti exemplifies the platform using a series of CD3- and CD28-directed bispecific antibodies targeting the cancer cell-associated antigens CD19 and ROR1 (page 2, paragraph 2).
Correnti teaches that, consistent with data on T-cell activation, CD28 BiTEs were ineffective alone, but significantly augmented the cytotoxic effects of CD3 BiTEs in a dose-dependent fashion, resulting in maximum cell killing at much lower antibody doses in combination than what could be accomplished with CD3 BiTE alone. Significant enhancement of CD3 BiTE-induced cancer cell killing was also found when the 28 BiTE was directed at a second cancer cell-associated antigen (i.e., the right hand scheme depicted in Fig. 1a), as shown in Fig. 1d and supplemental Fig. 3, allowing for the selective targeting of cancers expressing two independent antigens (page 3, paragraph 3).
Correnti teaches that the data presented indicates CD28 BiTEs can potently co-activate T cells stimulated with a CD3 BiTE at concentrations where either active is inactive, or minimally active alone, and the strict requirement for the presence of target antigen(s) suggests the possibility for both high selectivity and potency. Such pairs of bispecific antibodies can conceptually target any cancer cell surface antigen(s) and will thus provide a versatile platform exploitable for a wide variety of cancers. Correnti further teaches that, while the studies focused on CD28, demonstrating that signaling via CD28 is a key modulator of the therapeutic efficacy of BiTE antibodies, future efforts will develop SMITE bispecific pairs targeting other co-receptor signaling pathways (page 4, paragraph 2).
Correnti, however, does not disclose that the SMITE bispecific antibodies are comprised in the instantly claimed, N- to C- terminus protein structure.
WO’102 teaches methods of reducing the toxicity and side effects of bispecific antibodies that bind to important physiological targets, such as CD3 and tumor antigens. Many antigen binding proteins, such as antibodies, can have significant off-target side effects, and thus there is a need to only activate the binding capabilities of a therapeutic molecule in the vicinity of the disease tissue, to avoid off-target interactions. Accordingly, WO’102 discloses multivalent conditionally effective proteins that have a number of functional domains. In general, one of these domains is an antigen binding domain (ABD) that will bind a target tumor antigen (TTA), and another is an ABD that will bind a T-cell antigen, such as CD3, under certain conditions. The MCE also includes one or more protease cleavage sites. That is, the therapeutic molecules are made in a “pro-drug” like format, wherein the CD3 binding domain is inactive until exposed to a tumor environment. The tumor environment contains proteases, such that, upon exposure to the protease, the prodrug is cleaved and becomes active (pages 16-17, [0086]).
WO’102 teaches an embodiment of the pro-drug format comprising a protein comprising, from N- to C- terminal:
A first single domain antigen binding domain (sdABD) that binds to a human tumor target antigen (TTA) (sdABD-TTA);
A first domain linker;
A constrained Fv domain comprising:
A first variable heavy domain comprising a vhCDR1, vhCDR2, and vhCDR3;
A constrained non-cleavable linker (CNCL); and
A first variable light domain comprising vlCDR1, vlCDR2, and VlCDR3;
A second domain linker;
A second sdABD-TTA;
A cleavable linker (CL);
a constrained second pseudo Fv domain comprising:
a second light variable domain;
a non-cleavable linker (NCL); and
a second heavy variable domain;
a third domain linker; and
a third sdABD that binds to human serum albumin;
wherein said first variable heavy domain and said first variable light domain are capable of binding human CD3, but said constrained Fv domain does not bind CD3;
wherein said first variable heavy domain and said first pseudo variable light domain intramolecularly associate to form an inactive Fv; and wherein the first variable light domain and said first pseudo variable heavy domain intramolecularly associated to form an inactive Fv (page 60, claim 1).
WO’102 also teaches that the prodrug protein can have a format in which the second constrained Fv comprises a constrained non-cleavable linker (page 48, [00236] – page 49, [00239]).
WO’102 also demonstrates embodiments in which the cleavable linker is after the first Fv and before a second sdABD (page 51, [00255]), as well as embodiments in which the domain linker before the sdABD that binds HSA is a cleavable linker (Fig. 23A).
WO’102 teaches that Fv domain, as used in the disclosure, is a polypeptide that comprises the VL and VH domains of an antigen binding domain, generally from an antibody. Fv domains usually form an “antigen binding domain” or “ABD”, if they contain active VH and VL domains. In some cases the Fv domain is made up of a VH and VL on a single polypeptide chain, but with a constrained linker such that an intramolecular ABD cannot be formed. In these embodiments, it is after cleavage that two active ABDs are formed (page 22, [00109]; page 7, [0025]).
WO’102 further teaches that the orientation of the scFv domains can be in either orientation from N- to C- terminus, such as VH-linker-VL or VL-linker-VH (page 28, [00136]).
WO’102 teaches that proteases are known to be secreted by some diseased and tissues, for example tumor or cancer cells, creating a microenvironment that is rich in proteases or a protease-rich microenvironment. In some cases, cells surrounding the tumor secrete proteases into the tumor microenvironment (page 39, [00185]). Proteases are proteins that cleave proteins, in some cases, in a sequence specific manner. Proteases include, but are not limited to, cathepsins, granzymeB, matriptase, MMP2, MMP9, meprin, and thrombin (pages 39-40, [00186]; page 62, claim 12). WO’102 also teaches cleavable linkers for enterokinase, KLK7-6, KLK7-13, KLK7-11, KLK7-10, and uPA (Fig. 5G, 12/105).
WO’102 further teaches prodrug composition made by culturing host cells comprising the expression vector(s) as is well known in the art (page 54, [00273]). Formulations of the pro-drug compositions can include single proteins or two proteins with optional pharmaceutically acceptable carriers, excipients, or stabilizers in the form of lyophilized formulations of aqueous solutions (page 54, [00274]).
WO’102 further teaches two protein compositions in which two different molecules are included that, in the absence of cleavage, intramolecularly associate to form pseudo-Fvs. In the presence of the protease, the cleavage sites are cleaved, releasing the variable domains and the protein pair then forms an active antigen binding domain to CD3. What is important in the design of these constructs is that the active variable domain and the sdABD-TTA remain together after cleavage, such that the two cleaved portions are held together by the tumor antigen receptor on the tumor surface and then can form an active anti-CD3 binding domain (page 52, [00262]-[00263]).
WO’102 further teaches dimerization constructs, such as those shown in Fig. 2, which comprise a sdABD-TTA. WO’102 teaches that, upon cleavage, the prodrug construct splits into two components, a half-life extension domain, such as a sdABD that binds to HSA, linked to a Fv and an active moiety. In the presence of a second active moiety from a different cleaved molecule, the protein self assembles into a dimeric active moiety that contains two anti-TTA domains (page 7, [0025], page 8, [0027]). As WO’102 is teaching two proteins that dimerize, the teachings of WO’102 meet the limitation of a homodimer protein.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the simultaneous multiple interaction T-cell engaging bispecific antibodies of Correnti to be in a pro-drug format using the formats disclosed by WO’102. In these formats, it would have been obvious to have the first or second sdABD bind to the same or different target tumor antigens and have the first and second scFv bind CD3 and CD28, in either order. It would have also been obvious to have the cleavable linker, when present, be between the first scFv and the second sdABD in order to form the two bispecific antibodies taught by Correnti upon cleavage, arriving at the instantly claimed invention. An ordinarily skilled artisan would have been motivated to use the pro-drug formats disclosed by WO’102 in order to reduce potential toxicity and side effects of bispecific antibodies that bind to important physiological targets such as CD3 and tumor antigens by using a pro-drug like format in which the CD3 binding domain is inactive until exposed to the tumor environment. An ordinarily skilled artisan would have had a reasonable expectation of success as both Correnti and WO’102 are teaching bispecific antibodies that target a target tumor antigen and an antigen present on immune cells.
Regarding claims 14 and 23-24, WO’102 further teaches that the polypeptide constructs bind to at least one antigen binding domain, wherein the antigen binding domain binds to at least one target antigen. In some embodiments, the target antigen binding domains specifically bind to a tumor antigen. In some embodiments, the target antigen binding domains specifically and independently bind to a tumor target antigen (“TTA”) selected from at least one of EpCAM, EGFR, HER-2, HER-3, cMET, LyPD3, B7H3, CEA, and FOLR1 (page 36, [00169]). Additionally, like Correnti, WO’102 teaches that the sdABDs can be homo-targeting, in which both target the same TTA, or hetero-targeting, in which one sdABD binds to a first TTA and the other to a different TTA (page 13, [0059]).
WO’102 further teaches targeting sdABDs for EGFR (Fig. 5A, figure 6/105) that are identical to instant SEQ ID NOs: 4, 5, and 9-10, as shown in the alignments below:
Instant SEQ ID NO: 4 and WO’102, SEQ ID NO: 1
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Instant SEQ ID NO: 5 and WO’102 SEQ ID NO: 9
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Instant SEQ ID NO: 9 and WO’102 SEQ ID NO: 5
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Instant SEQ ID NO: 10 and WO’102 SEQ ID NO: 13
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It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have either both or one of the sdABDs in the protein taught by the combination of Correnti and WO’102 target EGFR, using one of the sdABD sequences disclosed by WO’102, based on the teachings of the combined references. It would have been obvious to have one or both sdABD target EGFR as WO’102 teaches EGFR as a viable TTA for targeting with sdABD that also target a T cell antigen, such as CD3. Additionally, both Correnti and WO’102 teach that the TTAs targeted can be the same or different. It would have bene obvious to use the sdABD sequences of WO’102 as WO’102 teaches them as sdABD sequences that can be used in the disclosed constructs. An ordinarily skilled artisan would have had a reasonable expectation of success because both Correnti and WO’102 are teaching bispecific antibodies that bind a TTA as well as a T cell.
Regarding claims 34 and 36, WO’102 further teaches anti-CD3 scFv domains for use in the disclosed proteins (Fig. 5D, 9/105). WO’102, SEQ ID NOs: 61and 49 are identical to instant SEQ ID NOs: 205 and 206, respectively, as shown in the alignments below:
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It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to use the CD3 VH and VL disclosed by WO’102 in the protein taught by the combination of Correnti and WO’102. It would also be obvious to have the CD3 VH/VL be either the first or second VH/VL. It would have been obvious to use the CD3 VH/VL of WO’102 as WO’102 teaches the VH and VL as viable sequences for use in the bispecific antibodies. It would have been obvious to use the CD3 VH/VL as either the first or second VH/VL as WO’102 teaches its use in both positions and Correnti teaches that, as long as the other scFv targets a co-stimulatory signaling pathway, such as CD28, co-stimulated SMITE bispecific antibodies will be produced. An ordinarily skilled artisan would have had a reasonable expectation of success as both Correnti and WO’102 teach bispecific antibodies that bind a target tumor antigen and CD3.
Regarding claim 38, WO’102 further teaches that the proteins include half-life extension domains. Such domains are contemplated to include HSA binding domains. HSA is the most abundant protein in plasma, present at about 50 mg/ml, and has a half-life of around 20 days in humans. HSA serves to maintain plasma pH, contributes to colloidal blood pressure, functions as a carrier of many metabolites and fatty acids, and serves as a major drug transport protein in plasma (page 37, [00175]-[00176]). The half-life extension domain provides for altered pharmacodynamics and pharmacokinetics of the antigen binding protein itself. As above, the half-life extension domain extends the elimination half-life. The half-life extension domain also alters pharmacodynamic properties including alteration of tissue distribution, penetration, and diffusion of the antigen-binding protein. In some embodiments, the half-life extension domain provides for improved tissue, including tumor, targeting, tissue penetration, tissue distribution, diffusion within the tissue, and enhanced efficacy, as compared with a protein without a half-life extension binding domain. In one embodiment, therapeutic methods effectively and efficiently utilize a reduced amount of the antigen-binding protein, result in reduced side effects, such as reduced non-tumor cell toxicity (page 38, [00180]). WO’102 teaches that a preferred sdABD-HSA is that of SEQ ID NO: 45 (page 52, [00261]), which is identical to instant SEQ ID NO: 220, as shown in the ABSS alignment below:
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It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to use the sdABD-HSA sequence disclosed by WO’102 as the third sdABD that binds to human serum albumin in the protein disclosed by the combination of Correnti and WO’102. It would have been obvious to use the sequence disclosed by WO’102 for the sdABD-HSA as WO’102 teaches that it is a viable, even preferred, sequence for the half-life extension domain. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Claims 34, 36, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Correnti, C.E., et al (2018) Simultaneous multiple interaction T-cell engaging (SMITE) bispecific antibodies overcome bispecific T-cell engager (BiTE) resistance via CD28 co-stimulation Leukemia 32(5); 1239-1243 in view of WO 2019/051102 A2 (May, C., et al) 14 Mar 2019 as applied to claim 1 above, and in further view of US 2020/0199234 A1 (Georges, G., et al) 25 Jun 2020.
The combination of Correnti and WO’102 teach the protein of claim 1 as discussed in detail above.
As discussed above, the combination of Correnti and WO’102 suggests a protein with a construct of EGFR sdABD – domain linker – constrained CD3 scFv – cleavable linker – EGFR sdABD – domain linker – constrained CD28 scFv – cleavable linker – SdABD HSA
The combination of Correnti and WO’102, however, do not teach that the sequence of the protein is one of those recited in instant SEQ ID NOs: 234-249.
WO’102 teaches an anti-EGFR sdABD for use in the constructs comprising SEQ ID NO: 1, which is identical to amino acids: 1-124 and 390-513 of instant SEQ ID NO: 234.
WO’102 also teaches the linker (GGGS)2 as a non-cleavable and constrained linker and demonstrates the use of the linker as the domain linker and the CNCL in constructs (page 41, [00192]; Fig. 62F, SEQ ID NO: 154, 90/105). The linker is identical to the domain and CNCL linkers in instant SEQ ID NO: 234, amino acids: 125-132, 258-265, 514-521, and 642-649.
WO’102 also teaches cleavable linkers including MMP2/9, and teaches the linker SGGPGPAGMKGLPGS (SEQ ID NO: 76) (Fig. 5F, 11/105), which is identical to instant SEQ ID NO: 234, amino acids: 375-389 and 758-772 and also exemplifies the use of the linker in constructs (Fig. 62F, 90/105).
WO’102 also teaches aCD3 VH and VL for scFv domains including SEQ ID NOs: 61 and 49 (page Fig. 5D, 9/105), which are identical to instant SEQ ID NO: 234, amino acids: 133-257 and 266-374, respectively.
WO’102 also teaches an aHSA half-life extension domain of SEQ ID NO: 142 (Fig. 5C; 8/105), which is identical to instant SEQ ID NO: 234, amino acids 773-893.
Using the constructs disclosed by WO’102 to form the pro-drug protein taught by the combination of Correnti and WO’102 results in a sequence that is the same as instantly claimed SEQ ID NO: 234, with the exception of the anti-CD28 VH and VL domains of instant SEQ ID NO: 234, amino acids 522-641 and 650-757.
US’234 teaches tumor targeted bispecific agonistic antigen binding molecules characterized by monovalent binding to CD28 (abstract). US’234 discloses an anti-CD28 heavy chain variable domain of SEQ ID NO: 42 (page 66), which is identical to instant SEQ ID NO: 234, amino acids 522-641.
US’234 also teaches an anti-CD28 light chain of SEQ ID NO: 62 (page 68) that comprises a variable domain that is identical to instant SEQ ID NO: 234, amino acids 650-757.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to construct the pro-drug protein taught by the combination of Correnti and WO’102 using the sequences disclosed by WO’102 and to further substitute the VH and VL region of the anti-CD28 scFv with the VH and VL of the anti-CD28 antibody disclosed US’234. It would have been obvious to construct the pro-drug using the sequences disclosed by WO’102 as WO’102 teaches the sequences as being viable for use in the construction of pro-drug proteins that are bispecific and bind to a TTA and T cell antigen. It would have been obvious to substitute the VH and VL region of the anti-CD28 scFv with the VH and VL of the anti-CD28 antibody disclosed US’234 as US’234 teaches antibody regions that bind to CD28, which is a T cell target taught by the combination of Correnti and WO’102. By using the sequences disclosed by Correnti, WO’102, and US’234, an ordinarily skilled artisan would arrive at a sequence that is identical to instant SEQ ID NO: 234.
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.
US 11,406,710
Claims 1-2, 4, 6, 8, 14, 18, 20, 23-24, 34, 36, 38-39, 48, and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. US 11,406,710 in view of Correnti, WO’102, and US’234.
US’710 claims a polypeptide comprising, from N- to C- terminus: a sdABD that binds a TTA (sdABD-TTA); a first domain linker; a constrained Fv domain with a first VH – CNCL – VL; a second domain linker; a second sdABD-TTA; a cleavable linker; a pseudo Fv domain comprising a first pseudo VL domain-NCL-pseudo VH domain; a third domain linker; and a third sdABD that binds human serum albumin; wherein the CNCL is positioned between the first VH and VL and prevents the domains from interacting to form an active Fv capable of biding to CD3; and the first VH and VL is capable of binding CD3 but said constrained Fv does not bind CD3 when the CL is intact. US’710 claims that the TTA is the same or different, and are selected from EGFR, EpCAM, FOLR1, and B7H3. US’710 claims that the cleavable linker is cleaved by a human protease selected from the group consisting of MMP2, MMP9, Meprin A, Meprin B, Cathepsin S, Cathepsin K, Cathepsin L, granzymeB, uPA, Kallekriein7, matriptase, and thrombin. US’710 claims that the NCL of the pseudo domain is a constrained non-cleavable linker (CNCL).
US’710 differs from the instantly claimed invention in that both the first and second scFv of the instantly claimed invention bind to antigens on immune cells (such as CD3) do not bind to the same antigen. The format of the instantly claimed protein also differs in the position of the cleavable linker. The instantly claimed invention also claims compositions comprising the protein as well as homodimers comprising the first and second protein.
The teachings of Correnti, WO’102, and WO’843 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the polypeptide in the claims of US’710 by substituting the pseudo Fv domain with an Fv domain that binds CD28 and to have the cleavable linker be before the second sdABD-TTA based on the teachings of WO’102 and motivated by Correnti. It would have also been obvious to have the polypeptides in alternative compositions, such as protein pairs and homodimers, as taught by WO’102. An ordinarily skilled artisan would have been motivated to make these modifications as Correnti teaches that the addition of CD28 targeting bispecific T cell engagers can potently co-activate T cell stimulated with a CD3 BiTE at concentrations where either agent is inactive or minimally active alone and allows for high selectivity and potency. An ordinarily skilled artisan would have had a reasonable expectation of success as both Correnti and the claims of US’710 are drawn to polypeptides that comprise a binding domain for a TTA and for an immune cell antigen, such as CD3. It would have been obvious to use alternative formats and compositions, such as those taught by WO’102 as both US’710 and WO’102 are directed towards pro-drug polypeptide compositions that provide bispecific antibodies that function as BiTEs.
It would also have been prima facie obvious to one of ordinary skill in the art to construct the polypeptide using the sequences disclosed by WO’102 and to further substitute the VH and VL region of the anti-CD28 scFv with the VH and VL of the anti-CD28 antibody disclosed US’234. It would have been obvious to construct the pro-drug using the sequences disclosed by WO’102 as WO’102 teaches the sequences as being viable for use in the construction of pro-drug proteins that are bispecific and bind to a TTA and T cell antigen. It would have been obvious to substitute the VH and VL region of the anti-CD28 scFv with the VH and VL of the anti-CD28 antibody disclosed US’234 as US’234 teaches antibody regions that bind to CD28, which is a T cell target taught by the combination of Correnti and WO’102. By using the sequences disclosed by Correnti, WO’102, and US’234, an ordinarily skilled artisan would arrive at a sequence that is identical to instant SEQ ID NO: 234.
US 12,128,102
Claims 1-2, 4, 6, 8, 14, 18, 20, 23-24, 34, 36, 38-39, 48, and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. US 12,128,102 in view of Correnti, WO’102, and US’234.
US’102 claims a pair of polypeptides comprising: a first polypeptide comprising a first target antigen binding domain linked to a first domain linker to a first single chain Fv (scFv) domain directed to CD3 antigen, where the first polypeptide further comprises a half-life extension domain, and a second polypeptide comprising a second target antigen binding domain linked using a second domain linker to a second single chain Fv (scFv) domain directed to a CD3 antigen, wherein the second polypeptide further comprises a half-life extension domain; wherein the first and second scFv domain comprises an inactive Vh domain and an active VL domain joined through cleavable linkers. US’102 further claims that the half-life extension domains comprise a sdABD that binds HSA, that the target antigens are EpCAM, EGFR, or FOLR1, and that the cleavable linkers are cleaved by a human protease, including MMP2, MMP9, meprin, matriptase, thrombin, uPA, or cathepsin. US’102 further claims that each pair of polypeptides further comprises an additional target antigen binding domain and that the antigen binding domains are the same or different. US’102 claims an expression vector comprising nucleic acids that encode the polypeptides, host cells comprising the expression vector, and pharmaceutical compositions comprising the pair of polypeptides. US’102 also claims methods of treating cancer comprising administering the pair of polypeptides.
The claims of US’102 differ from the instantly claimed invention in that US’102 does not claim that one of the scFv bind an immune cell that is different than the first. Additionally, claims 1 and 52 of the instantly claimed invention differ in the structure of the pro-drug protein.
The teachings of Correnti, WO’102, and WO’843 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the polypeptide in the claims of US’710 by substituting the one of the scFvs with an scFv that binds CD28 based on the teachings of Correnti. It would have also been obvious to have the polypeptides in alternative compositions, such as a protein or composition of homodimers, as taught by WO’102. An ordinarily skilled artisan would have been motivated to substitute one of the scFvs with one that targets CD28 as Correnti teaches that the addition of CD28 targeting bispecific T cell engagers can potently co-activate T cell stimulated with a CD3 BiTE at concentrations where either agent is inactive or minimally active alone and allows for high selectivity and potency. An ordinarily skilled artisan would have had a reasonable expectation of success as both Correnti and the claims of US’102 are drawn to polypeptides that comprise a binding domain for a TTA and for an immune cell antigen, such as CD3. It would have been obvious to use alternative formats and compositions, such as those taught by WO’102 as both US’102 and WO’102 are directed towards pro-drug polypeptide compositions that provide bispecific antibodies that function as BiTEs.
It would also have been prima facie obvious to one of ordinary skill in the art to construct the polypeptide using the sequences disclosed by WO’102 and to further substitute the VH and VL region of the anti-CD28 scFv with the VH and VL of the anti-CD28 antibody disclosed US’234. It would have been obvious to construct the pro-drug using the sequences disclosed by WO’102 as WO’102 teaches the sequences as being viable for use in the construction of pro-drug proteins that are bispecific and bind to a TTA and T cell antigen. It would have been obvious to substitute the VH and VL region of the anti-CD28 scFv with the VH and VL of the anti-CD28 antibody disclosed US’234 as US’234 teaches antibody regions that bind to CD28, which is a T cell target taught by the combination of Correnti and WO’102. By using the sequences disclosed by Correnti, WO’102, and US’234, an ordinarily skilled artisan would arrive at a sequence that is identical to instant SEQ ID NO: 234.
18/021,730
Claims 1-2, 4, 6, 8, 14, 18, 20, 23-28, 34, 36, 38-39, 48, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 53-72 of copending Application No. 18/021,730 in view of Correnti, WO’102, and US’234.
App’730 is claims sdABDs that bind human HER2 (sdABD-HER2) comprising the sequences recited in claims 53-54. The sequences recited include sdABD-HER2 structures that are the same as those recited in instant claims 25-26 and 28. For instance, the alignment of instant SEQ ID NO: 45 and App’730, SEQ ID NO: 141 is shown below.
Instant SEQ ID NO: 45, App’730, SEQ ID NO: 141
PNG
media_image9.png
232
620
media_image9.png
Greyscale
App’730 further claims a fusion protein comprising, from N- to C- terminal, a first sdABD that binds HER2 (sdABD-HER2); a first domain linker, a constrained FV that comprises a VH, CNCL, and VL; a second domain linker; a second sdABD-HER2; a cleavable linker; a constrained pseudo Fv domain comprising a VL; NCL; and VH; a third domain linker and a third sdABD that binds HSA; wherein the first VH and VL are capable of binding human CD3, but the pseudo domain is not; the first VH and the pseudo VH intramolecularly associate to form an inactive Fv; and the first VH and pseudo VH intramolecularly associate to form an inactive Fv; wherein the first and second sdABD-HER2 have the structures of claim 53. App’730 claims that the sdABD-HER2s are the same or different, and that the order of the variable domains are VH-VL or VL-VH. App’730 further claims that cleavable linker comprises a cleavage linker domain of the recited sequences that is cleaved by a human protease including MMP2, MMP9, meprin A, meprin B, cathepsin, granzyme B, uPA, kallerkriein7, matriptase, and thrombin. App’730 claims fusion protein sequences, nucleic acids encoding the sdABDs, expression vectors, and host cells as well as pharmaceutical compositions.
App’730 differs from the instantly claimed invention in that both the first and second scFvs bind to antigens on immune cells but not the same antigen. The format of the instantly claimed protein also differs in the position of the cleavable linker. The instantly claimed invention also claims compositions comprising the protein as well as homodimers comprising the first and second protein.
The teachings of Correnti, WO’102, and WO’843 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the polypeptide in the claims of App’730 by substituting the pseudo Fv domain with an Fv domain that binds CD28 and to have the cleavable linker be before the second sdABD-TTA based on the teachings of WO’102 and motivated by Correnti. It would have also been obvious to have the polypeptides in alternative compositions, such as protein pairs and homodimers, as taught by WO’102. An ordinarily skilled artisan would have been motivated to make these modifications as Correnti teaches that the addition of CD28 targeting bispecific T cell engagers can potently co-activate T cell stimulated with a CD3 BiTE at concentrations where either agent is inactive or minimally active alone and allows for high selectivity and potency. An ordinarily skilled artisan would have had a reasonable expectation of success as both Correnti and the claims of App’730 are drawn to polypeptides that comprise a binding domain for a TTA and for an immune cell antigen, such as CD3. It would have been obvious to use alternative formats and compositions, such as those taught by WO’102 as both App’730 and WO’102 are directed towards pro-drug polypeptide compositions that provide bispecific antibodies that function as BiTEs.
It would also have been prima facie obvious to one of ordinary skill in the art to construct the polypeptide using the sequences disclosed by WO’102 and to further substitute the VH and VL region of the anti-CD28 scFv with the VH and VL of the anti-CD28 antibody disclosed US’234. It would have been obvious to construct the pro-drug using the sequences disclosed by WO’102 as WO’102 teaches the sequences as being viable for use in the construction of pro-drug proteins that are bispecific and bind to a TTA and T cell antigen. It would have been obvious to substitute the VH and VL region of the anti-CD28 scFv with the VH and VL of the anti-CD28 antibody disclosed US’234 as US’234 teaches antibody regions that bind to CD28, which is a T cell target taught by the combination of Correnti and WO’102. By using the sequences disclosed by Correnti, WO’102, and US’234, an ordinarily skilled artisan would arrive at a sequence that is identical to instant SEQ ID NO: 234.
This is a provisional nonstatutory double patenting rejection.
18/024,597
Claims 1-2, 4, 6, 8, 14, 18, 20, 23-28, 34, 36, 38-39, 48, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 47-66 of copending Application No. 18/024,597 in view of Correnti, WO’102, and US’234.
App’597 claims a fusion protein comprising, from N- to C- terminus: a sdABD that binds a TTA (sdABD-TTA); a first domain linker; a constrained Fv domain with a first VH – CNCL – VL; a second domain linker; a second sdABD-TTA; a cleavable linker; a constrained pseudo Fv domain comprising a first pseudo VL domain-NCL-pseudo VH domain; a third domain linker; and a third sdABD that binds human serum albumin; wherein the first VH and VL are capable of binding human CD3, but the pseudo domain is not; the first VH and the pseudo VH intramolecularly associate to form an inactive Fv; and the first VH and pseudo VH intramolecularly associate to form an inactive Fv.
App’597 claims that the variable domains are in VH-VL or VL-VH order, that the first and second TTA is the same or different, and are selected from B7H3, CA9, EGFR, FOLR1, HER2, LyPD3, Trop2, and any combination thereof. App’597 further claims that the first and second sdABD-TTAs are selected from the group of recited sequences. The recited sequences overlap with those of the instantly claimed invention. For instance, App’597, SEQ ID NO: 272 is identical to Instant SEQ ID NO: 45, which is a sdABD-HER2. App’597 claims nucleic acids, expression vectors, host cells, and methods of making the fusion protein and treating cancer.
App’597 differs from the instantly claimed invention in that both the first and second scFv of the instantly claimed invention bind to antigens on immune cells (such as CD3) do not bind to the same antigen. The format of the instantly claimed protein also differs in the position of the cleavable linker. The instantly claimed invention also claims compositions comprising the protein as well as homodimers comprising the first and second protein.
The teachings of Correnti, WO’102, and WO’843 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the polypeptide in the claims of App’597 by substituting the pseudo Fv domain with an Fv domain that binds CD28 and to have the cleavable linker be before the second sdABD-TTA based on the teachings of WO’102 and motivated by Correnti. It would have also been obvious to have the polypeptides in alternative compositions, such as protein pairs and homodimers, as taught by WO’102. An ordinarily skilled artisan would have been motivated to make these modifications as Correnti teaches that the addition of CD28 targeting bispecific T cell engagers can potently co-activate T cell stimulated with a CD3 BiTE at concentrations where either agent is inactive or minimally active alone and allows for high selectivity and potency. An ordinarily skilled artisan would have had a reasonable expectation of success as both Correnti and the claims of App’597 are drawn to polypeptides that comprise a binding domain for a TTA and for an immune cell antigen, such as CD3. It would have been obvious to use alternative formats and compositions, such as those taught by WO’102 as both App’597 and WO’102 are directed towards pro-drug polypeptide compositions that provide bispecific antibodies that function as BiTEs.
It would also have been prima facie obvious to one of ordinary skill in the art to construct the polypeptide using the sequences disclosed by WO’102 and to further substitute the VH and VL region of the anti-CD28 scFv with the VH and VL of the anti-CD28 antibody disclosed US’234. It would have been obvious to construct the pro-drug using the sequences disclosed by WO’102 as WO’102 teaches the sequences as being viable for use in the construction of pro-drug proteins that are bispecific and bind to a TTA and T cell antigen. It would have been obvious to substitute the VH and VL region of the anti-CD28 scFv with the VH and VL of the anti-CD28 antibody disclosed US’234 as US’234 teaches antibody regions that bind to CD28, which is a T cell target taught by the combination of Correnti and WO’102. By using the sequences disclosed by Correnti, WO’102, and US’234, an ordinarily skilled artisan would arrive at a sequence that is identical to instant SEQ ID NO: 234.
This is a provisional nonstatutory double patenting rejection.
18/172,433
Claims 1-2, 4, 6, 8, 14, 18, 20, 23-28, 34, 36, 38-39, 48, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-9, 13-20, 45, and 53-55 of copending Application No. 18/172,433 in view of Correnti, WO’102, and US’234.
App’433 claims a fusion protein comprising, from N- to C- terminus: a sdABD that binds HER2 (sdABD-TTA); a first domain linker; a constrained Fv domain with a first VH – CNCL – VL; a second domain linker; a second sdABD that binds HER2; a cleavable linker; a constrained pseudo Fv domain comprising a first pseudo VL domain-NCL-pseudo VH domain; a third domain linker; and a third sdABD that binds human serum albumin; wherein the first VH and VL are capable of binding human CD3, but the pseudo domain is not; the first VH and the pseudo VH intramolecularly associate to form an inactive Fv; and the first VH and pseudo VH intramolecularly associate to form an inactive Fv.
App’433 further claims structures for the first and/or second sdABD-HER2, which includes the HER2 sdABD structures of the instant claims. For instance, App’433, SEQ ID NO: 141 is identical to instant SEQ ID NO: 45.
App’433 claims that the sdABD-HER2s are the same or different, and claims that the scFvs can be in either VH-VL or VL-VH order. App’433 further claims fusion proteins where the sdABDs bind HER2, LyPD3, B7H3, CA9, EGFR, EpCAM, sdABD-FOLR1, or Trop2.
App’433 differs from the instantly claimed invention in that both the first and second scFv of the instantly claimed invention bind to antigens on immune cells (such as CD3) do not bind to the same antigen. The format of the instantly claimed protein also differs in the position of the cleavable linker. The instantly claimed invention also claims compositions comprising the protein as well as homodimers comprising the first and second protein.
The teachings of Correnti, WO’102, and WO’843 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the polypeptide in the claims of App’433 by substituting the pseudo Fv domain with an Fv domain that binds CD28 and to have the cleavable linker be before the second sdABD-TTA based on the teachings of WO’102 and motivated by Correnti. It would have also been obvious to have the polypeptides in alternative compositions, such as protein pairs and homodimers, as taught by WO’102. An ordinarily skilled artisan would have been motivated to make these modifications as Correnti teaches that the addition of CD28 targeting bispecific T cell engagers can potently co-activate T cell stimulated with a CD3 BiTE at concentrations where either agent is inactive or minimally active alone and allows for high selectivity and potency. An ordinarily skilled artisan would have had a reasonable expectation of success as both Correnti and the claims of App’433 are drawn to polypeptides that comprise a binding domain for a TTA and for an immune cell antigen, such as CD3. It would have been obvious to use alternative formats and compositions, such as those taught by WO’102 as both App’433 and WO’102 are directed towards pro-drug polypeptide compositions that provide bispecific antibodies that function as BiTEs.
It would also have been prima facie obvious to one of ordinary skill in the art to construct the polypeptide using the sequences disclosed by WO’102 and to further substitute the VH and VL region of the anti-CD28 scFv with the VH and VL of the anti-CD28 antibody disclosed US’234. It would have been obvious to construct the pro-drug using the sequences disclosed by WO’102 as WO’102 teaches the sequences as being viable for use in the construction of pro-drug proteins that are bispecific and bind to a TTA and T cell antigen. It would have been obvious to substitute the VH and VL region of the anti-CD28 scFv with the VH and VL of the anti-CD28 antibody disclosed US’234 as US’234 teaches antibody regions that bind to CD28, which is a T cell target taught by the combination of Correnti and WO’102. By using the sequences disclosed by Correnti, WO’102, and US’234, an ordinarily skilled artisan would arrive at a sequence that is identical to instant SEQ ID NO: 234.
This is a provisional nonstatutory double patenting rejection.
18/285,714
Claims 1-2, 4, 6, 8, 14, 18, 20, 23-28, 34, 36, 38-39, 48, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6, 7, 10-11, 14, 18, 27, 32, 36, 38-43, 49-50, 58-59, and 71-72 of copending Application No. 18/285,714 in view of Correnti, WO’102, and US’234.
App’714 claims a method of treating cancer comprising administering to the patient an effective amount of a polypeptide comprising, from N- to C- terminus: a sdABD that binds a tumor target antigen (sdABD-TTA); a first domain linker; a constrained Fv domain with a first VH – CNCL – VL; a second domain linker; a second sdABD that binds a tumor target antigen; a cleavable linker; a constrained pseudo Fv domain comprising a first pseudo VL domain-NCL-pseudo VH domain; a third domain linker; and a third sdABD that binds human serum albumin; wherein the first VH and VL are capable of binding human CD3, but said constrained Fv does not bind CD3 when the CL is intact. App’714 also claims an embodiment where the pseudo scFv is the first scFv and the CD3 Fv is the second scFv. App’714 further claims that the first and second TTA are the same or different and are selected from EGFR and B7H3. App’714 further claims that the cleavable linker is cleaved by a human protease selected from the group consisting of MMP2, MMP9, Meprin A or B, cathepsin S, K, or L, granzymeB, uPA, kallekriein7, matriptase, and thrombin.
App’714 differs from the instantly claimed invention in that both the first and second scFv of the instantly claimed invention bind to antigens on immune cells (such as CD3) do not bind to the same antigen. The format of the instantly claimed protein also differs in the position of the cleavable linker. The instantly claimed invention also claims compositions comprising the protein as well as homodimers comprising the first and second protein.
The teachings of Correnti, WO’102, and WO’843 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the polypeptide in the claims of App’714 by substituting the pseudo Fv domain with an Fv domain that binds CD28 and to have the cleavable linker be before the second sdABD-TTA based on the teachings of WO’102 and motivated by Correnti. It would have also been obvious to have the polypeptides in alternative compositions, such as protein pairs and homodimers, as taught by WO’102. An ordinarily skilled artisan would have been motivated to make these modifications as Correnti teaches that the addition of CD28 targeting bispecific T cell engagers can potently co-activate T cell stimulated with a CD3 BiTE at concentrations where either agent is inactive or minimally active alone and allows for high selectivity and potency. An ordinarily skilled artisan would have had a reasonable expectation of success as both Correnti and the claims of App’714 are drawn to polypeptides that comprise a binding domain for a TTA and for an immune cell antigen, such as CD3. It would have been obvious to use alternative formats and compositions, such as those taught by WO’102 as both App’714 and WO’102 are directed towards pro-drug polypeptide compositions that provide bispecific antibodies that function as BiTEs.
It would also have been prima facie obvious to one of ordinary skill in the art to construct the polypeptide using the sequences disclosed by WO’102 and to further substitute the VH and VL region of the anti-CD28 scFv with the VH and VL of the anti-CD28 antibody disclosed US’234. It would have been obvious to construct the pro-drug using the sequences disclosed by WO’102 as WO’102 teaches the sequences as being viable for use in the construction of pro-drug proteins that are bispecific and bind to a TTA and T cell antigen. It would have been obvious to substitute the VH and VL region of the anti-CD28 scFv with the VH and VL of the anti-CD28 antibody disclosed US’234 as US’234 teaches antibody regions that bind to CD28, which is a T cell target taught by the combination of Correnti and WO’102. By using the sequences disclosed by Correnti, WO’102, and US’234, an ordinarily skilled artisan would arrive at a sequence that is identical to instant SEQ ID NO: 234.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693