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 .
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3, 8-13, 16-21, and 24-31 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 line 16 recites that the bispecific construct further comprises at least one cysteine clamp to facilitate the linkage between scFc subunits. There is insufficient antecedent basis for the limitation “scFc subunits” in the claim. This wherein clause appears to modify an existing structure, yet there is no mention of scFc subunits prior to line 16. It is unclear to what scFc subunits the clause refers. Additionally, is this scFc different from the scFc-linker-CD3ε in lines 21-22? Are these the same scFc subunits?
Claim 1 line 21 recites “CD3(amino acid 1-6)” and “CD3(amino acid 1-27)”. The use of parentheticals here makes unclear require is required. Is CD3 required? Are amino acids 1-6 or 1-27 alternatives to CD3? Do amino acids 1-6 or 1-27 refer to a subsequence of CD3? If so, can this be from any species?
Claims 8 recites that the bispecific construct comprises a half-life extending moiety. Is this half-life extending moiety in addition to the scFc subunit recited in claim 1 line 16 and 21 or in addition to the albumin subunit recited in claim 1 lines 20-21?
Similarly, claims 9 and 11 recite that the half-life extending moiety is a scFc region. It is unclear is this is the same scFc referenced in claim 1 lines 16 and 21. Claim 10 recites an additional linker. Because it is unclear is the half-life extending moiety is the scFc or albumin recited in claim 1, it is unclear if the additional linker is the linker in claim 1 line 21, is L0 in claim 1, or is another not previously disclosed linker.
For the purpose of compact prosecution, the scFc recited in claim 1 is interpreted as the same as the half-life extending moiety of claim 8. The parentheticals following CD3ε in claim 1 are interpreted as the first 1-6 or 1-27 amino acids of human CD3ε. The link for the half-life extending moiety of claim 10 is interpreted as being neither L0, L1, L2, L3, nor the linker in claim 1 line 21, but rather an additional not previously recited linker.
Claims 3, 8-13, 16-21, and 24-31 are rejected for depending from claim 1 and failing to remedy the indefiniteness. Of note, claim 1 recites the expression of an effector protein that is part of the TCR-CD3 complex on the immune cell, but the claims do not require that one of the binding sites of the bispecific construct bind to these particular proteins. Similarly, claim 24 defines an effector protein, but the claims do not require the bispecific construct binds the effector protein.
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, 3, 8-13, 16-21, and 24-31 are rejected under 35 U.S.C. 103 as being unpatentable over Ghayur et al. (WO 2014/106015 A2; Published: July 3, 2014), as evidenced by the Worthington Biochemical Corporation Overview of Chymotrypsin, in view of Raum et al. (US 2017/0218079 A1; Published: August 3, 2017), Yan et al. (US 2017/0247476 A1; Published: August 31, 2017), Moore et al. (US 2008/0260738 A1; Published: October 23, 2008), Reiter et al. (Clinical Cancer Research. 2: 245-252; Published: February 1996), and Chen et al. (Advanced Drug Delivery Reviews. 65: 1357-1369; Published Online: September 29, 2012).
Regarding the order of domains in claim 1, Ghayur et al. teaches the claimed structure; see Figure 4A and claim 1. Regarding linkers L1 and L3 in claims 1, 3, and 20, Ghayur et al. teaches that L1 is ASTKGPSVFPLAPS and L3 is RTVAAPSVFIFPPS; see Example 17. Both of these sequences contain a phenylalanine (F) which the protease chymotrypsin cleaves at the C-terminal end; see Worthington Biochemical Corporation Overview of Chymotrypsin. Note, there is no limiting definition for protease cleavage site; see instant paragraph 00101. Regarding claim 17 and the length of linker L2, Ghayur et al. teaches that it is 30, 35, 40 or 45 amino acids in length, however, constructs comprising the 30 amino acid long L2 linker were poorly expressed; see Examples 17 and 18. Regarding the linker lengths in claims 1 and 17-21, Ghayur et al. teaches that there is a clear need for linker engineering during the construction and optimization of these DVD-based antibodies and found that antigen binding was improved when the L3 linker was lengthened; see page 99 second paragraph, Example 23, and Figure 10.
Regarding claims 25-28, Examples 17 and 18 teach the generation of the scDVD by cloning the sequences encoding the VH and VL domains and linker into a pYD yeast expression vector and expressing the construct in yeast; see claims 37-40. Additionally, Ghayur et al. teaches isolating the recombinant binding protein from the culture medium; see page 50.
Regarding claim 29, Ghayur et al. teaches treating a disorder, including oncological disorders, comprising administering a therapeutically effective amount of the bispecific construct; see claim 36 and page 57.
Regarding claim 31, Ghayur et al. teaches a pharmaceutical composition comprising the bispecific construct; see claim 35.
Ghayur et al. does not teach that the bispecific construct is T cell engager with binding sites comprising binding sites comprising the sequences of instant claim 13.
Regarding claims 12 and 24, Raum et al. teaches a bispecific construct comprising one target cell binding domain (PSMA) and one anti-CD3ε binding domain which are single chain fragments; see claims 1 and 2. Regarding claim 13, Raum et al. teaches anti-CD3ε variable heavy and light domain sequences 100% identical to instant SEQ ID NOs: 75 and 76; see Raum et al. SEQ ID NO: 33. Regarding claim 13, Raum et al. teaches anti-PSMA variable heavy and light domain sequences 100% identical to instant SEQ ID NOs: 67 and 68; see Raum et al. SEQ ID NO: 429. Additionally, regarding claims 29 and 30, Raum et al. teaches that the bispecific construct can be used in combination with a chemotherapeutic agent administered concurrently; see paragraph 0280.
Neither Ghayur et al. nor Raum et al. teach a construct which further comprises a single-chain Fc region.
Regarding claim 8, Yan et al. teaches that adding an Fc region to a bispecific construct can increase the half-life of the construct; see paragraph 0036. Regarding claim 9, Yan et al. teaches that the Fc region may be derived from human IgG1, IgG2, IgG3, or IgG4; see paragraph 0052. Further, regarding the linker of claim 10, Yan et al. teaches using a linker comprising a protease cleavage site to link the Fc domain to the bispecific construct; see paragraph 0005. Yan et al. states that formats with longer half-lives could imaginably cause prolonged and poorly localized T cell activation, leading to undesirable side effects; see paragraph 0002. Regarding claim 11, Yan et al. teaches several alterations in the Fc region that can extend the half-life of the construct; see paragraph 0053. Additionally, regarding claims 1 and 16, Yan et al. teaches an additional moiety comprising the first 27 amino acids of CD3ε linked to the anti-CD3 binding domain of a bispecific construct by a linker comprising the sequence GQSSRHRRAL, which Yan et al. teaches comprises a protease, furin, cleavage site; see SEQ ID NOs: 5 and 18.
Neither Ghayur et al., Raum et al., nor Yan et al. teach that the Fc domain is a single-chain Fc region (scFc).
Moore et al. teaches adding a single-chain Fc region to a binding construct, including a bispecific binding construct; see claim 23. Moore et al. teaches that the scFc molecules of the present invention are based on the discovery of methods that allow the formation of a functional Fc dimer from a single polypeptide unit, thereby avoiding the existing problem in the art of random association of CH3 subunits; see paragraph 0046. Similar to Yan et al., Moore et al. teaches that the scFc may be derived from IgG1, IgG2, IgG3, or IgG4 Fc regions; see paragraph 0063. Additionally, Moore et al. describes alterations to avoid Fc gamma receptor binding, thereby avoiding degradation and extending the half-life; see paragraph 0135.
Neither Ghayur et al., Raum et al., Yan et al., nor Moore et al. teach cysteine substitutions to facilitate interactions between domains in the context of a single-chain antibody.
Reiter et al. teaches making cysteine substitutions in the framework of the single-chain antibody fragment to facilitate disulfide bond formation between the variable heavy and light domains; see page 247 left column. Reiter et al. teaches that a major problem with single-chain antibody fragments is stability and the formation of aggregates; see page 246 right column. Reiter et al. teaches that the formation of a disulfide bridge between the variable heavy and light domains increases stability and reduces aggregation; see page 250.
Given that Ghayur et al. teaches that the binding constructs can be used to treat cancer by targeting CD3 to crosslink T cells to a cell surface target (see pages 57-60 and 135 and Example 37), it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success modifying the construct taught by Ghayur et al. to target CD3ε and the tumor antigen PSMA with the antigen binding sites taught by Raum et al. Further, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success using the bispecific construct to treat cancer because both Ghayur et al. and Raum et al. support treating cancer with a bispecific construct comprising those binding sites. One of ordinary skill in the art would be motivated to use the bispecific construct taught by Ghayur et al. over the BITE embodiment taught by Raum et al. because the bispecific constructs taught by Ghayur et al. are less prone to aggregate and, thus, would be expected to have reduced side effects; see Ghayur et al. page 191-192.
Regarding the linker lengths, given that Ghayur et al. teaches that there is a clear need for linker engineering during the construction and optimization of these DVD-based antibodies, it would have been obvious to one ordinary skill in the art to optimize linker length to achieve desired antigen binding and stability goals. Regarding claims 17-21, there are broadly two categories of linker length: the same length or different lengths. Thus, it would have been obvious to one of ordinary skill in the art to optimize linker lengths by assessing some embodiments where the linkers are all the same length or having differing lengths. One of ordinary skill in the art would have arrived at the instantly claimed embodiments through routine experimentation as guided and exemplified by Ghayur et al. Indeed, Chen et al. teaches how linker length can influence the quantity of fusion protein expression, the folding or aggregation of fusion proteins, and the binding affinity of fusion proteins; see whole document. Chen et al. teaches one instance where lengthening the linker resulted in greater binding affinity; see page 1367 left column. One of ordinary skill in the art would have been motivated to optimize the link length to improve recombinant expression, construct folding, and binding affinity.
Regarding the additional moiety, it would have been obvious to one of ordinary skill in the art to add the CD3ε moiety to the bispecific construct taught by Ghayur et al. with the anti-CD3 binding site taught by Raum et al. by a protease, furin, cleavable linker since Yan et al. teaches adding this moiety to a bispecific T cell engager in order to restrict activation to the tumor microenvironment and reduce the undesirable side effects of prolonged T cell activation.
It would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to add an Fc region to the bispecific construct taught by Ghayur et al. in order to improve its half-life. One would have been motivated to use a scFc region as taught by Moore et al. because the bispecific construct is merely a single polypeptide and because this scFc region avoids CH3 aggregation. One would have been motivated to use Fc regions derived from IgG1, IgG3, and IgG4 as those antibodies have longer half-lives and one would be motivated to further increase the half-life of the constructs by adding alterations known to reduce Fc gamma receptor binding and increase FcRn receptor binding. Regarding the use of a protease cleavable linker, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to add the Fc region taught by Moore et al. via a cleavable linker as taught by Yan et al. in order to reduce undesirable side effects from prolonged effect of the bispecific construct.
Given that Reiter et al. teaches that single-chain antibodies are prone to dissociation and aggregation and that disulfide bonds achieved through cysteine mutations can provide stability and reduce aggregation and that Raum et al., which teaches the variable heavy and light domains, also teaches adding cysteine bonds to improve the stability (see paragraph 0153), it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to add cysteine substitutions to the variable heavy and light domains of the construct of the copending claims to improve stability. While Ghayur et al. teaches that the scDVD bispecific construct is stable, it is a single-chain antibody fragment, which are more prone to dissociation and aggregation. Since the construct taught by Ghayur et al. comprises the variable heavy and light domains taught by Raum et al. which teaches stabilizing the single-chain antibody with cysteine bonds, one of ordinary skill in the art would have been motivated to add cysteine substitutions, or cysteine clamps, to further provide stability and reduce the risk of aggregation and resulting potential side effects.
Regarding the method of making the construct, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success recovering the antibody because Ghayur et al. teaches transfecting host cells with an expression vector to express the binding protein, then isolating the binding protein from the culture medium.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
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, 8-13, 16-21, and 24-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-13, 16-23, 26, and 27 of copending Application No. 17/616,580 in view of Ghayur et al. (WO 2014/106015 A2; Published: July 3, 2014) as evidenced by the Worthington Biochemical Corporation Overview of Chymotrypsin in view of Raum et al. (US 2017/0218079 A1; Published: August 3, 2017), Yan et al. (US 2017/0247476 A1; Published: August 31, 2017), Reiter et al. (Clinical Cancer Research. 2: 245-252; Published: February 1996), and Chen et al. (Advanced Drug Delivery Reviews. 65: 1357-1369; Published Online: September 29, 2012).
Regarding instant claims 1 and 3, copending claims 1 and 2 recite a similar structure. Copending claim 7 teaches a construct which binds to tumor antigens, DLL3 or MSLN, and CD3. Regarding claims 1 and 24, copending claims 16 and 17 teach that the construct binds a cell which expresses an effector protein that is part of the human TCR-CD3 complex or is CD3ε.
Regarding instant claims 8, 9, and 11, copending claims 3-5 recites the construct comprising a half-life extending moiety which is a scFc region linked by an additional linker and which comprises alterations that extend half-life.
Regarding instant claim 12, copending claim 6 teaches that VH1, VL1, VH2, and VL2 all comprise different sequences.
Regarding instant claims 17-22, copending claims 8-13 teach linker lengths.
Regarding instant claims 23 and 24, copending claims 16 and 17 teach that the immune effector cell comprising the CD3ε protein.
Regarding instant claims 25-28, copending claims 18-21 recite a nucleic acid encoding the construct, a vector comprising the nucleic acid, a host cell comprising the vector, the method of making the construct.
Regarding instant claims 29 and 30, copending claims 22 and 23 teach a method of treating cancer which includes administering an additional agent.
Regarding instant claim 31, copending claim 26 recites a pharmaceutical composition comprising the construct.
The copending claims are silent to the sequence of the linkers or whether the linkers comprise protease cleavage sites.
Ghayur et al. teaches the claimed structure; see Figure 4A and claim 1. Regarding linkers, Ghayur et al. teaches that L1 is ASTKGPSVFPLAPS and L3 is RTVAAPSVFIFPPS; see Example 17. Both of these sequences contain a phenylalanine (F) which the protease chymotrypsin cleaves at the C-terminal end; see Worthington Biochemical Corporation Overview of Chymotrypsin. Note, there is no limiting definition for protease cleavage site; see instant paragraph 00101. Regarding the length of linker L2, Ghayur et al. teaches that it is 30, 35, 40 or 45 amino acids in length, however, constructs comprising the 30 amino acid long L2 linker were poorly expressed; see Examples 17 and 18. Regarding the proximal linker (L1 and L3) lengths, Ghayur et al. teaches that there is a clear need for linker engineering during the construction and optimization of these DVD-based antibodies and found that antigen binding was improved when the L3 linker was lengthened; see Figure 10.
Neither the copending claims nor Ghayur et al. teach that the bispecific construct is T cell engager with binding sites comprising binding sites comprising the sequences of instant claim 13.
Regarding claims 12 and 24, Raum et al. teaches a bispecific construct comprising one target cell binding domain (PSMA) and one anti-CD3ε binding domain which are single chain fragments; see claims 1 and 2. Regarding claim 13, Raum et al. teaches anti-CD3ε variable heavy and light domain sequences 100% identical to instant SEQ ID NOs: 75 and 76; see Raum et al. SEQ ID NO: 33. Regarding claim 13, Raum et al. teaches anti-PSMA variable heavy and light domain sequences 100% identical to instant SEQ ID NOs: 67 and 68; see Raum et al. SEQ ID NO: 429. Additionally, regarding claims 29 and 30, Raum et al. teaches that the bispecific construct can be used in combination with a chemotherapeutic agent administered concurrently; see paragraph 0280.
Neither the copending claims, Ghayur et al., nor Raum et al. teach a construct which further comprises a single-chain Fc region linked by cleavable linker.
Regarding claim 8, Yan et al. teaches that adding an Fc region to a bispecific construct can increase the half-life of the construct; see paragraph 0036. Regarding claim 9, Yan et al. teaches that the Fc region may be derived from human IgG1, IgG2, IgG3, or IgG4; see paragraph 0052. Further, regarding the linker of claim 10, Yan et al. teaches using a linker comprising a protease cleavage site to link the Fc domain to the bispecific construct; see paragraph 0005. Yan et al. states that formats with longer half-lives could imaginably cause prolonged and poorly localized T cell activation, leading to undesirable side effects; see paragraph 0002. Regarding claim 11, Yan et al. teaches several alterations in the Fc region that can extend the half-life of the construct; see paragraph 0053. Additionally, regarding claims 1 and 16, Yan et al. teaches an additional moiety comprising the first 27 amino acids of CD3ε linked to the anti-CD3 binding domain of a bispecific construct by a linker comprising the sequence GQSSRHRRAL, which Yan et al. teaches comprises a protease, furin, cleavage site; see SEQ ID NOs: 5 and 18.
Neither the copending claims, Ghayur et al., Raum et al., nor Yan et al. teach cysteine substitutions to facilitate interactions between domains in the context of a single-chain antibody.
Reiter et al. teaches making cysteine substitutions in the framework of the single-chain antibody fragment to facilitate disulfide bond formation between the variable heavy and light domains; see page 247 left column. Reiter et al. teaches that a major problem with single-chain antibody fragments is stability and the formation of aggregates; see page 246 right column. Reiter et al. teaches that the formation of a disulfide bridge between the variable heavy and light domains increases stability and reduces aggregation; see page 250.
Given that the copending claims do not disclose linker sequences, Ghayur et al. discloses the same structure with linker sequences that comprise a protease cleavage site, and both Ghayur et al. and the copending claims teach a method for treating cancer comprising administering the bispecific construct, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success using linkers with protease cleavage sites as taught by Ghayur et al. for in the identical structure of the copending claims.
Regarding the linker lengths, given that Ghayur et al. teaches that there is a clear need for linker engineering during the construction and optimization of these DVD-based antibodies, it would have been obvious to one ordinary skill in the art to optimize linker length to achieve desired antigen binding and stability goals. Regarding claims 17-21, there are broadly two categories of linker length: the same length or different lengths. Thus, it would have been obvious to one of ordinary skill in the art to optimize linker lengths by assessing some embodiments where the linkers are all the same length or having differing lengths. One of ordinary skill in the art would have arrived at the instantly claimed embodiments through routine experimentation as guided and exemplified by the copending claims and Ghayur et al. Indeed, Chen et al. teaches how linker length can influence the quantity of fusion protein expression, the folding or aggregation of fusion proteins, and the binding affinity of fusion proteins; see whole document. Chen et al. teaches one instance where lengthening the linker resulted in greater binding affinity; see page 1367 left column. One of ordinary skill in the art would have been motivated to optimize the link length to improve recombinant expression, construct folding, and binding affinity.
Regarding the additional moiety, it would have been obvious to one of ordinary skill in the art to add the CD3ε moiety to the bispecific construct taught by the copending claims and Ghayur et al. with the anti-CD3 binding site by a protease, furin, cleavable linker since Yan et al. teaches adding this moiety to a bispecific T cell engager in order to restrict activation to the tumor microenvironment and reduce the undesirable side effects of prolonged T cell activation.
It would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to add an Fc region to the bispecific construct taught by copending claims and Ghayur et al. in order to improve its half-life. One would have been motivated to use a scFc region as taught by the copending claims because the bispecific construct is merely a single polypeptide and because this scFc region avoids CH3 aggregation. One would have been motivated to use Fc regions derived from IgG1, IgG3, and IgG4 as those antibodies have longer half-lives and one would be motivated to further increase the half-life of the constructs by adding alterations known to reduce Fc gamma receptor binding and increase FcRn receptor binding. Regarding the use of a protease cleavable linker, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to add the Fc region taught by copending via a cleavable linker as taught by Yan et al. in order to reduce undesirable side effects from prolonged effect of the bispecific construct.
Given that Reiter et al. teaches that single-chain antibodies are prone to dissociation and aggregation and that disulfide bonds achieved through cysteine mutations can provide stability and reduce aggregation and that Raum et al., which teaches the variable heavy and light domains, also teaches adding cysteine bonds to improve the stability (see paragraph 0153), it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to add cysteine substitutions to the variable heavy and light domains of the construct of the copending claims to improve stability. While Ghayur et al. teaches that the scDVD bispecific construct is stable, it is a single-chain antibody fragment, which are more prone to dissociation and aggregation. Since the construct taught by Ghayur et al. comprises the variable heavy and light domains taught by Raum et al. which teaches stabilizing the single-chain antibody with cysteine bonds, one of ordinary skill in the art would have been motivated to add cysteine substitutions, or cysteine clamps, to further provide stability and reduce the risk of aggregation and resulting potential side effects.
Regarding the method of making the construct, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success recovering the antibody because the copending claims and Ghayur et al. teach transfecting host cells with an expression vector to express the binding protein, then isolating the binding protein from the culture medium.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant’s amendments filed November 17, 2025 are acknowledged. Any rejection not repeated above is resolved by amendment.
Applicant's arguments filed November 17, 2025 have been fully considered but they are not persuasive.
Regarding the rejection under 35 U.S.C. 103, Applicant argues that Ghayur et al. does not teach that that L3 is 15 to 30 amino acids long. Ghayur et al. does not teach this length of linker, but does teach the importance of optimizing linker length. Chen et al. has been added to the rejection above to further support the optimization of linker length.
Applicant argues that Ghayur et al. doesn’t teach linkers comprising a protease cleavage site. This is incorrect; see the rejection.
Applicant refers to constructs V1E, B1U, and Z9P and states that the L3 length was varied. These constructs are discussed in paragraph 00242 of the instant disclosure. L3 in V1E (G4S)3, B1U (G4S)6, and Z9P (G4S)12 is not the same as instant L3. In the previous sentence, the Specification teaches that the constructs had the formula “N-terminal CD3e (a.a. 1-6 or a.a. 1-27) peptide-L0-Anti CD3 VH-L1-HLE domain1-L2-Anti MSLN VH-L3-Anti CD3 VL-L4-HLE domain2-L5-Anti MSLN VL, in which the anti-CD3 and anti-MSLN variable domains contain an engineered disulfide bridge building a covalent bond between the specific VH and VL domains. In this format L0, L1, L2, L4 and L5 contain a MMP2/9 restriction site.” L3 of V1E (G4S)3, B1U (G4S)6, and Z9P (G4S)12 is between VH2 and VL1 and does not comprise a protease cleavage site.
Applicant argues that Ghayur et al. does not teach the HHLL format, that can be significantly activated, has increase in vitro expression, and maintain the correct confirmation in the presence of a protease. Ghayur et al. does teach constructs having the VH1 – L1 – VH2 – L2 – VL1 – L3 – VL2; see the rejection above. The claims do not recite these features: that can be significantly activated, has increase in vitro expression, and maintain the correct confirmation in the presence of a protease.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Ebert et al. (WO 2008/119567 A2; Published: October 9, 2008) teaches the anti-PSMA sequences of claim 13 wherein instant SEQ ID NOs: 65 and 66 are 100% identical to SEQ ID NOs: 33 and 161, respectively. Benatuil et al. (WO 2014/106004 A2; Published: July 3, 2014), as evidenced by the Worthington Biochemical Corporation Overview of Chymotrypsin, teaches the structure in claim 1.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE ANN HOLTZMAN whose telephone number is (571)270-0252. The examiner can normally be reached Monday - Friday 8:30am - 5:00pm MT.
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682