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 .
Election/Restrictions
Applicant’s election of Group I and species wherein the TAA1 is CS1 and VH comprises SEQ ID NO:1391-1393 and VL comprises SEQ ID NO:1394-1396, TAA2 is BCMA and VH comprises SEQ ID NO:1402-1404 and VL comprises SEQ ID NO:1405-1407, the bispecific antibody comprises SEQ ID NO:1400 or 1411 and the bispecific HLE comprise SEQ ID NO:1401 or 1412 in the reply filed on 02/17/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency –
A) Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
AND
B) This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures are located on p. 25, lines 17-21 ([083]).
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Information Disclosure Statement
It is noted that EP 3068507 is stated as corresponding to US 2016/0279529 A1, (#16 and #5, respectively, of IDS filed 1/31/2023) and both are drawn to “Tracks and Drive for a Tower Ride”.
Specification
References to locations in the specification are to the clean substitute specification filed 2/17/2026.
The disclosure is objected to because of the following informalities: On p. 20, lines 3-4 (the end of the first sentence of [74]), “do less target non-cancer cells.” does not make sense. On p. 20, line 28, “singe-“ should be “single-”. On p. 20, line 32, “..the first and the second binding domain of the multitargeting antigen-binding molecule are capable to independently from each other to maintain their bioactivity….” is incorrect. On p. 21, line 10, “..is that interchain mispairings re preferably prevented in comparison to longer linkers.” is incorrect. On p. 22, line 28, there is repetition of the same sequence, “and short multiplicities thereof (e.g. S(G4S)2 (SEQ ID NO: 3764) and S(G4S)2 (SEQ ID NO: 3764) between the two target binding domains…” On p. 24, line 3, “monospecific CS1xBCMA HLE BiTE® antigen-binding molecule,” is bispecific. On p. 25, line 28, “extra cellular” should be one word. On p. 114, lines 8, 11 and 13, it appears the 12C portions are identical, and so should all refer to either “12C0” or “12C” as appropriate. In Table 13 (p. 123), the full title for columns 2, 3 and 5 are cut-off. In Table 14 (p. 123), the full title for columns 2 and 4 are cut-off. Tables 16 and 17 (p. 126) have commas between the numbers which appears should instead be periods.
The specification is replete with grammatical and idiomatic errors too numerous to mention specifically, examples of which are presented above. The specification should be revised carefully.
Appropriate correction is required.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See p. 68, lines 17 and 19.
The use of the term MicroCal (p. 70, line 5) and GraphPad (at least at p. 111, line 1, and p. 113, line 25), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The chemical formula(s), mathematical formula(s), or table(s) in the location(s) referenced below contain shading (color/grayscale) and therefore do not comply with 37 CFR 1.52 and do not come within the exceptions of 37 CFR 1.58(a). Please delete chemical formula(s), mathematical formula(s), or table(s) with shading from the specification or claims, provide them as formal color drawing(s) in accordance with 37 CFR 1.84, including petition, fee, and amendment in accordance with 37 CFR 1.84(a)(2), and amend the specification to provide a brief description of the drawings in accordance with 37 CFR 1.74. Alternative, remove the shading. The Table 4 has shading (p. 107) that limits both its legibility and reproducibility. Table 14 also has shading (p. 123) that limits legibility and reproducibility. The same applies to the three tables in the middle of p. 124.
Further, it is noted there is no SEQ ID NO: provided for CD20-CD22-T-cell engager molecule 1 on p. 111, line 10.
Improper Markush Grouping
Claims 6, 7 and 11-17 are rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of first and second binding domain pairs is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: each binding domain has a distinct sequence (does not share a single structural similarity) and binds a distinct antigen (does not share a common use). The antigens are selected from the group consisting of: CS1, BCMA, FLT3, CD123, CD20, CD22, EpCAM, MSLN, CDH3 and CLL1. For most claims these may be in any combination. Claim 7 recites particular pairs. Claim 11 recites CDR1-3 of the VH region and claim 12 recites CDR1-3 of the VL region for the first and second antigen binding domain for the different antigens. Claims 13 and 14 recite the VH and VL, respectively, of the first and second antigen binding domain for the different antigens. Claim 15 recites 725 scFv sequences of the first and/or second binding domain. Claim 16 recites sequences of a molecule comprising a first and/or second target binding domain with a third effector binding domain (binds CD3). Claim 17 recites nearly 600 sequences of a molecule comprising a first and/or second target binding domain together with a third effect binding domain (binds CD3) and a fourth domain conferring extended half-life.
Even different antibodies binding the same antigen have different VH and VL CDR sequences (see Table 18). For example, compare anti-CD123 CDR sequences for antibody 20-G11, 20-F12, 21-A6, 21-B4, 21-C9, 23-F4, 25-A9, 32-E5, 39-F4, etc., noting this completely ignores framework regions within the variable region, with all claimed sequences comprising variable regions. Antibodies are not structurally or functionally equivalent if their amino acid sequences are not identical, because sequence affects antigen specificity, species specificity, affinity, immunogenicity, solubility, stability, effector function and/or EC50, for example.
The first paragraph of the rejection relies on Harnish (CCPA 1980), in which the common chemical structure was identified as a dye, coumarin, and coumarin derivatives useful as dyes were found to represent a proper Markush group because even though the dyes encompassed different derivatives, they all shared a coumarin group which was sufficient to impart the property of being a dye. However, in the instant case, the different species of antibodies do not all share a particular sequence that provides the particular use. Instead, antibodies represented by a distinct set of VH and VL CDR1-3 are structurally different. As discussed in Ex parte Hozumi, 3 USPQ2d 1059 (BPAI 1984, non-precedential), a Markush grouping is proper when the embodiments share both a common use and a substantial structural feature essential for that use. The common chemical, to which the case law is directed, determined the particular activity; however, the general structure common to native antibodies or even scFvs, e.g., CDRs in the context of framework regions (FR), of which FR are not recited in some of the instant claims, does not determine the particular activity. Instead it is the specific sequence of the CDR1-3, in this case those of the VH and VL, that determines antigen specificity, as well as species specificity, EC50, affinity, among other biophysical properties.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 4 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 4 depends from claim 1, which requires the linker between the first and second antigen-binding domain to have 5 to 24 amino acids. Claim 4 does not further limit claim 1 because claim 4 also recites the linker has a length of 5-24 amino acids. The reference to “preferably” X amino acids renders the claim indefinite (see 35 USC 112(d) below) and does not further limit claim 1 but is merely a preference. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1-5, 7 and 9-14 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1-5, 7, 9, and 15-17 the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Additionally, claim 9 part (b) recites the peptide linker between the first and second TAA-binding domains has the sequence of SEQ ID NO:12; however, this is a 4 amino acid sequence and is excluded from peptide linker lengths (5-24) of claim 1. Therefore, there is insufficient antecedent basis for this limitation in the claim.
Claim 10 is indefinite because it states, “the antigen-binding molecule further comprises in amino to carboxyl order: a linker a monomer of the forth domain,…” What is confusing is where this is in the molecule of claim 1. That is, if it at the amino terminus or after the third binding domain.
Claims 11-14 are indefinite because it is unclear if the first and second CDR-H1-3 (claim 11), VL (claim 12), VH (claim 13) and VL (claim 14) sequences, respectively, are required to be the same or if the first and second can have different sequences.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a multitargeting antigen-binding molecule wherein the linker between the first and second binding domains is between 6-24 amino acids comprising (G4S)n, wherein n=1, 2, 3 or 4 and the remaining amino acids are G and/or S, and wherein the molecule is a single chain molecule and the amino- to carboxyl-terminal orientation of the first and second binding domains which are single chain antibodies is variable heavy-variable light chain regions (VH-VL), does not reasonably provide enablement for linkers other than GS-containing and wherein they do not comprise multiples of (G4S) and for single chain binding domains wherein the orientation is VL-VH. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 1 is drawn to a multitargeting antigen-binding molecule comprising 3 binding domains, the first binding first target cell surface antigen (TAA1), the second binding a second target cell surface antigen (TAA2), wherein the first and second binding domains bind to TAA1 and TAA2 simultaneously and TAA1 and TAA2 are expressed on the same cell, and the third binding domain binds an extracellular epitope of human and/or Macaca CD3ε (CD3e) chain. Claim 2 adds an optional fourth domain comprising two polypeptide monomers fused by a peptide linker and each comprising a hinge, CH2 and CH3 domain. Claim 3 limits the molecule to a single chain molecule.
While based on the prior art and instant specification it appears there may be some breadth of the linker content and/or length that would provide the skilled artisan with a reasonable expectation of success, it is not without limit.
Chichili et al. (Prot. Sci. 22:152-167, 2013) teaches that linker content and length are important for stability and function of fusion proteins. It is discussed that the flexibility of glycine-rich linkers can allow the two components of the fusion protein to behave independently, depending on the proteins and linker (paragraph bridging pp. 154-155, and p. 154, col. 1, second paragraph). For example, an analysis using the Rop protein looking at linkers with 1-10 glycines found that protein stability was inversely correlated with length of linker. Table 1 lists known linked complexes, showing the diversity of linkers, illustrating the unpredictability of which linkers can support the dual biological activity of a linked complex. The claimed molecule has three binding domains. That means, presumably, each binding domain must be able to bind its target antigen. Chichili et al. states (p. 163, col. 2, second paragraph):
The selection of a linker sequence and length is dependent on the construction of functional chimeric proteins, and therefore, the optimal linker length will vary on a case by case basis. De novo linker design will be successful if the site of interaction between the two proteins is approximately known. More often, the existing knowledge of the known homologous complex structures is used to design linkers of an appropriate length that will mimic the natural interaction. The actual distance between the site of the interaction and the nearby N- or C-terminus to which the binding partner can be fused will provide clues for the de novo design of a linker or an appropriate length.
The specification argues that based on computer modeling one skilled in the art would only expect a longer linker of at least about 30 amino acids between the first and second binding domains to allow each domain to bind its target (Examples 1); however, only a linker of 6-16 amino acids having the sequence of SG4S, S(G4S)2 or S(G4S)3 are disclosed as allowing the “dual targeting” T-cell engager to have functional antigen-binding capacity as required (Example 15, the only disclosure of different length linkers shown to function). There is no reasonable expectation from the specification or prior art that a linker even shorter than 6 would provide the necessary flexibility and length to allow simultaneous binding to the TAA1 and TAA2 on the same cell. The disclosed multitargeting molecules having the dual antigen-binding BiTE®, which binds a first and second binding domains binding TAA1 and TAA2, respectively, simultaneously on the same target cell and a third domain binding CD3e chain and (as set forth in claim 2) a fourth domain comprising two monomers that form an Fc region (hinge-CH2-CH3) in the working examples and Sequence Listing have a S(G4S) linker between the first and second binding domains and between the second and third domains and a G4 linker between the third and fourth (Fc) domains. There is no disclosure of a linker of 5 amino acids between the first and second binding domains or of a sequence other than S(G4S) that allows them to simultaneously bind their TAA antigens on the same target cell in the claimed multitargeting antigen-binding molecule. While based on the prior art and instant specification it appears there may be some breadth of the linker content and/or length that would provide the skilled artisan with a reasonable expectation of success, it is not without limit. For example, it reasonably appears that a linker of 5-25 amino acids and composed of serine and glycine with a base of (G4S) repeats would allow for the claimed first and second binding domain within the context of the multitargeting antigen-binding molecule to function, i.e., to bind each of three targets, the unpredictability and complexity of use of larger linker increases significantly with size and amino acid variability. Different amino acids have different amounts of flexibility and sizes in the context of a linker. Chichili et al. warns (p. 163, col. 2, second paragraph):
Not all amino acids make a perfect choice for linkers, since a certain degree of flexibility and hydrophilicity of the linker are important to retain the functions of the individual domains and allow the fused proteins to interact with each other.4 Gly has low preference to form an α-helix; thus, the lack of a sidechain maximizes the freedom of the backbone conformation.96 Furthermore, Ser and Thr are polar residues that prefer to interact with the solvent than with the fused proteins.4 Thus, polypeptides rich in Gly, Ser, and Thr offer special advantages: (i) rotational freedom of the polypeptide backbone, so that the adjacent domains are free to move relative to one another,44 (ii) enhanced solubility,26 and (iii) resistance to proteolysis.97 The backbone dihedral angles of residues in linkers are highly variable; that is, in Ramachandran plots, they occupy a significantly larger area than either the a-helices or b-sheets.
Further, Chichili et al. notes (p. 154, col. 1, end of third paragraph) that, “Interestingly, in naturally occurring, flexible linkers found in many proteisn are rich in Gly residues.” Also in favor of Gly-rich linkers is that they do not tend to alter the interaction between the chimeric protein comprising the linker(s) with the partner to which it binds.
Additionally, not just the overall order of the multitargeting construct but also the orientation of each part is important. In [076], it is stated, “It is important to note in the context of the present invention that while the first binding domain, i.e. the N-terminal binding domain, is comparably easy to access as it has only one adjacent binding domain which potentially causes steric hindrance when binding to the target, the second binding domain is connected to the first binding domain in N-direction.” This indicates that if the first, second or third domains are a single domain binding domain, e.g., a VHH antibody, then the N-terminal must be oriented to be closest to the N-terminus of the multitargeting binding molecule. If the binding domains are single chain binding domains, e.g., a scFv, then the VH would be at the N-terminus. There are no working examples of other orientations. Also, the prior art supports unpredictability of different orientations of scFv in multitargeting constructs. For example, Stamova et al. (Antibodies, 1:172-198, 2012, paragraph bridging pages 179-180) state, “Another unexpected effect which we observed during optimization of bispecific abs is shown in Figure 2. When we altered the order of the heavy and light chain of the first scFv in an antibody in the tandem format this had not only an effect on the binding affinity of the first domain to its target antigen: Unexpectedly, it also effected the binding affinity of the second antibody domain although this domain was not modified at all (Figure 2A,B, and black graph versus red graph). The same was true when the linker size if one of the scFv domains was altered which also effected the binding capability of the second unmodified scFv domain (Figure 2A,C, and black graph versus blue graph). Also rearranging the two scFv domains in a different order had dramatic effects on the binding capability (Figure 2C,D, and blue graph versus purple graph)…. In summary, these data indicate the difficulties of improving the functionality of a bispecific ab molecule. At least currently there are no common rules helping predict the best structure of a novel bispecific ab, thus every novel ab requires an individual optimization.” Also, Asano et al. (MABS, 10(6):854-863, 2018) examined orientation and order of domains of single chain bispecific antibodies. Looking only at ta1-ta8, with binding domains for TAA1 as VL-VH or VH-VL, and for TAA2 as VH-VL or VL-VH and wherein the first and second binding domains are also switched for t2, t4, t6 and t7 so TAA2 binding domain is N-terminal (Fig. 1), it can be seen the differences in both the expression level (Figs. 2B and 6) and cancer growth inhibition (Fig. 2C) between constructs is affected by order.
The prior art shows that selection of linker and domain orientation in multitargeting binding molecules is unpredictable and complex. As admitted by Applicant in the specification in comparing simulated binding of antigen-binding domains of a multispecific binding protein to a target on a cell is not necessarily representative of what actually occurs (e.g.., Example 1).
Therefore, as discussed above and including the breadth of the claims as they relate to linker length and content as well as binding domain structure, the unpredictability and complexity of antigen binding, the nature of the invention which requires antigen binding by a synthetic/non-natural complex molecule, the showing in the prior art of the unpredictability and limitations related to linker length and composition of a multispecific binding molecule as well as the orientation of the different parts making up the molecule, the limited working examples, it would require undue experimentation to use the invention commensurate in scope with the claims.
Claims 1-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The linker must be flexible. Otherwise there is no expectation both TAA1 and TAA2 binding domains could simultaneous bind the same target cell. The specification says the linkers are rich in small or hydrophilic amino acids, such as Gly and Ser, because such composition preferably provide flexibility. Which allows for independent interaction of each binding domains with its target (e.g., p. 21, lines 3-5). All linkers used comprised (G4S), optionally with a Ser at the beginning, with the exception of G4 between the CD3-binding domain and scFc. No other linkers where disclosed to be functional.
Example 1 uses computer modeling to determine linker lengths that would not be expected to affect independent antigen binding activity, i.e., that would not induce steric hindrance between the two target cell antigen-binding portions. It is predicted that 6 amino acids is too short and that a better linker would be at least 20 residues (note instant claim 1 and dependent claim 4 recite the linker is between 5-24 amino acids in length). Dependent claim 5 requires the linker to be (G4S)n, where n is 1, 2, 3 or 4, so the linker is 5, 10, 15 or 20 amino acids in length. Only a linker of 6-16 amino acids having the sequence of SG4S, S(G4S)2 or S(G4S)3 between (and within) antigen-binding domains are disclosed as allowing the “dual targeting” T-cell engager to have functional antigen-binding capacity as required (Example 15, the only disclosure of different length linkers shown to function). There is no reasonable expectation from the specification or prior art that a linker even shorter than 6 (i.e., 5) would provide the necessary flexibility and length to allow simultaneous binding to the TAA1 and TAA2 on the same cell. The disclosed multitargeting molecules have the dual antigen-binding BiTE®, which binds a first and second binding domains binding TAA1 and TAA2, respectively, simultaneously on the same target cell and a third domain binding CD3ε chain and (as set forth in claim 2) a fourth domain comprising two monomers that form an Fc region (hinge-CH2-CH3). The working examples and Sequence Listing have a S(G4S) linker between the first and second binding domains and between the second and third domains and a G4 linker between the third and fourth (Fc) domains. There is no disclosure of a linker of 5 amino acids between the first and second binding domains or of a sequence other than S(G4S) that allows them to simultaneously bind their TAA antigens on the same target cell in the claimed multitargeting antigen-binding molecule. While based on the prior art and instant specification it appears there may be some breadth of the linker content and/or length that would provide the skilled artisan with a reasonable expectation of success, it is not without limit. For example, it reasonably appears that a linker of 5-25 amino acids and composed of serine and glycine with a base of (G4S) repeats would allow for the claimed first and second binding domain within the context of the multitargeting antigen-binding molecule to function, i.e., to bind each of three targets, the unpredictability and complexity of use of larger linker increases significantly with size and amino acid variability. Different amino acids have different amounts of flexibility and sizes in the context of a linker. Chichili et al. warns (p. 163, col. 2, second paragraph):
Not all amino acids make a perfect choice for linkers, since a certain degree of flexibility and hydrophilicity of the linker are important to retain the functions of the individual domains and allow the fused proteins to interact with each other.4 Gly has low preference to form an α-helix; thus, the lack of a sidechain maximizes the freedom of the backbone conformation.96 Furthermore, Ser and Thr are polar residues that prefer to interact with the solvent than with the fused proteins.4 Thus, polypeptides rich in Gly, Ser, and Thr offer special advantages: (i) rotational freedom of the polypeptide backbone, so that the adjacent domains are free to move relative to one another,44 (ii) enhanced solubility,26 and (iii) resistance to proteolysis.97 The backbone dihedral angles of residues in linkers are highly variable; that is, in Ramachandran plots, they occupy a significantly larger area than either the a-helices or b-sheets.
Further, Chichili et al. notes (p. 154, col. 1, end of third paragraph) that, “Interestingly, in naturally occurring, flexible linkers found in many proteins are rich in Gly residues.” Also in favor of Gly-rich linkers is that they do not tend to alter the interaction between the chimeric protein comprising the linker(s) with the partner to which it binds (p. 154, col. 2, last paragraph).
Additionally, not just the overall order of the multitargeting construct but also the orientation of each part is important. In [076] of the specification, it is stated, “It is important to note in the context of the present invention that while the first binding domain, i.e. the N-terminal binding domain, is comparably easy to access as it has only one adjacent binding domain which potentially causes steric hindrance when binding to the target, the second binding domain is connected to the first binding domain in N-direction.” This indicates that if the first, second or third domains are a single domain binding domain, e.g., a VHH antibody, then the N-terminal must be oriented to be closest to the N-terminus of the multitargeting binding molecule. If the binding domains are single chain binding domains, e.g., a scFv, then the VH would be at the N-terminus. There are no working examples of other orientations. Also, the prior art supports unpredictability of different orientations of scFv in multitargeting constructs. This is also supported by Stamova et al. (Antibodies, 1:172-198, 2012, paragraph bridging pages 179-180), in which it is stated, “Another unexpected effect which we observed during optimization of bispecific abs is shown in Figure 2. When we altered the order of the heavy and light chain of the first scFv in an antibody in the tandem format this had not only an effect on the binding affinity of the first domain to its target antigen: Unexpectedly, it also effected the binding affinity of the second antibody domain although this domain was not modified at all (Figure 2A,B, and black graph versus red graph). The same was true when the linker size if one of the scFv domains was altered which also effected the binding capability of the second unmodified scFv domain (Figure 2A,C, and black graph versus blue graph). Also rearranging the two scFv domains in a different order had dramatic effects on the binding capability (Figure 2C,D, and blue graph versus purple graph)…. In summary, these data indicate the difficulties of improving the functionality of a bispecific ab molecule. At least currently there are no common rules helping predict the best structure of a novel bispecific ab, thus every novel ab requires an individual optimization.”
A single chain multitargeting antigen-binding molecule comprising a first and second binding domain comprising a paratope which binds simultaneously a target cell surface antigen (TAA1 and TAA2, respectively) on the same cell and each of which is a single domain antibody or scFv in N- to C-terminus orientation and are linked by a S(G4S)n linker wherein in n=1, 2, 3 or 4 (independent claim 1 sets a maximum length of 24 amino acids), and the TAA2 binding domain is linked to a single chain CD3ε-binding domain by a linker S(G4S)2 or S(G4S)3, which is linked by G4 to a scFc.meets the written description provision of 35 USC 112, first paragraph. However, the claims are directed to or encompass multispecific antigen-binding molecules in which the binding domains may have shorter or longer linkers and for some claims linkers of indiscriminate amino acid content and/or wherein the N- to C-terminal orientation of the VH and VL for scFv binding domains is not VH-VL. None of these other multispecific antigen-binding domains meets the written description provision of 35 USC 112(a).
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
With the exception of the multispecific antigen-binding molecule structures referred to above, the skilled artisan cannot envision the detailed chemical structure of the encompassed polynucleotides, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/134134 A1 (WO’134, cited in the IDS filed 1/31/2023), US 2019/0359710 A1 (Fey), Husain et al. (BioDrugs, 32: 441–464, 2018) and Alhallak et al. (Clin. Lymph. Myeloma Leuk. 19:e156, 15 September 2019)
WO 2017/134134 (WO’134) teaches a bispecific single chain Fc antibody construct (Fig. 1a), wherein two single chain Fv antibodies (scFv) in the VH-VL orientation (BiTE®) are linked to a Fc region comprising a hinge-CH2-CH3-linker-hinge-CH2-CH3 region (Fc region of SEQ ID NO:17-24, [0171]-[0172]); termed BiTE®-HLE for half-life extending, and [0281]). The CD3 is preferably human or Macaca CD3ε ([0013]). Inclusion of the HLE scFc in the BMCA-BiTE® significantly decreased systemic clearance rates ([0282] and Table 7). “The binding against FcRn is mediated through the Fc portion within the constructs. Stronger binding against human FcRn as described in the literature is an indicator for longer half-life in vivo due to a higher intracellular rescue of the respective protein and a therefore reduced degradation rate.” ([0298]) Constructs with scFc also contained lower high molecular weight species than with hFc ([0283] and Table 9) and formulations with the scFc construct also had higher protein recovery ([0287]). Compared to a human albumin (hALB) construct, the scFc construct was more heat stable and had less chemical modification in the CDRs ([0293]). The first binding domain targets BCMA and the second CD3 ([0282]), with the linkers between the VH and VL regions being S(G4S)3 and between the BCMA and CD3-binding domains being SG3 and between the last VL and scFv being G4 (SEQ ID NO:55 and 73). However, a preferred linker between the first, second and third domains is (G4S)x, where x is an integer greater than 1, e.g., 2 or 3 ([0179]). As set forth in [0180], “In a preferred embodiment the antibody construct of the invention is characterized to comprise in an amino to carboxyl order:(a) the first domain; (b) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-3; (c) the second domain; (d) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 2, 3, 9, 10, 11 and 12; (e) the first polypeptide monomer of the third domain; (f) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 6, 7 and 8; and (g) the second polypeptide monomer of the third domain.” Here, SEQ ID NO:1-3 are G4S, (G4S)2 and (G4S)3, respectively. It is noted ([0030]) that “The term “bispecific antibody construct” of the invention also encompasses multispecific antibody constructs such as trispecific antibody constructs,…” BCMA is expressed on multiple myeloma (MM) cells and supports their growth and survival ([0006]). WO’134 does not teach a specific trispecific T cell engaging molecule.
Fey teaches (Fig. 3A-B) a trispecific scFv construct with three scFv in tandem linked by a (G4S)4 linker and which is specific for CD123 and CD33, both of which are expressed on acute myeloid leukemia (AML) cells, and CD16 (which binds FcγRIII). The linkers between the VH and VL of the scFv are (G4S)3. In the construct, CD123 and CD33 can simultaneously bind on the same tumor cell, leading to greater avidity with double-positive AML cells, thereby potentially reducing systemic toxicity due to increase in specific binding and functioning even in patients whose cells have become resistant to mono-targeting agents through escape variants (antigen-loss variants) ([0005]-[0006], [0014], [0058]). The triplebody (sctb) bound AML cell lines as well as primary leukemia cells from patients (Examples 8 and 10.1). The sctb also contains a CD16-binding site which provides an advantage of binding an effector cell (NK cells in this case), as shown by the effect of the sctb in the presence of NK cells through redirected lysis (e.g., Example 8 and [0004],[0122]). Alternatively, T cell engaging antibodies typically bind CD3 on T cells to trigger cytolytic death of, for example, CD123-expressing AML cells by RDL (re-directed lysis) or ADCC (antibody dependent cellular cytotoxicity) (e.g., [0008] and [0012]). Additionally, the bispecific antibody may have a scFc region comprising two fused polypeptide monomers with the N- to C-order of hinge-CH2-CH3-linker-hinge-CH2-CH3 (col. 4, lines 29-36).
Husain et al. discuss (p. 455, col. 1, second paragraph) that “Most solid tumor targets are expressed in normal tissue to some extent, and if the differential of expression between tumor and normal tissue is not enough to support a positive therapeutic index, one potential strategy that is being explored is the simultaneous targeting of a second tumor-associated protein (Table 5). An example of this application was published by Gantke et al., where they constructed a trispecific antibody directed against B-cell maturation antigen (BCMA) and CD200, two B-cell targets, and CD16 to recruit NK cells. BCMA is an attractive antigen for multiple myeloma but low expression in keratinocytes has been reported, thus a dual targeting approach could increase selectivity towards double positive plasma cells. Results showed that indeed the trispecific antibody was significantly more potent towards cells expressing both antigens than any antigen alone [207].” Further, Blinatomomab, a bispecific T cell recruiting antibody, has been approved (p. 457, col. 2, first paragraph).
Alhallak et al. teaches a nanoparticle comprising antibodies conjugated to a nanoparticle, wherein the antibodies bind BCMA, CS1, and/or CD38, all antigens of which are expressed on multiple myeloma (MM), as well as binding CD3 (multispecific T cell engagers: nanoMuTEs). The binding of the BCMA/CS1/CD38/CD3 nanoMuTE compared to the nanoBiTEs was significantly higher for all samples. Both were able to activate T cells only in the presence of target cells, with the nanoMuTE showing greater activation of T cells and T cell-redirected MM cell lysis compared to the individual nanoBiTEs. In a MM mouse xenograft model, both forms redirected T cells to the tumor and reduced tumor burden compared to control.
It would have been obvious to the artisan of ordinary skill before the effective filing date of the instant invention to have had a trispecific T cell engaging single chain molecule in the format of WO’134 wherein in addition to the BCMA- and CD3-binding domains, there was also a CS1-, CD38- or CD200-binding domain next to the BCMA binding domain to better target the molecule to AML or MM cancer cells so that the CD3-binding portion redirected T cells to those cancer cells for lysis. The use of multiple binding domains targeting a single cancer cell type is supported by Fey, Hussain et al. and Alhallak et al. and has advantages of increasing selectivity and use even when cancer cells fail to express one of the antigens. WO’134 set forth the advantages of single chain multispecific antibody constructs comprising an Fc region to extend serum half-life. As with WO’134 it would have been obvious to have both cancer antigen binding domains next to each other followed by a CD3-binding domain followed by a Fc region which comprised a hinge-CH2-CH3-linker-hinge-CH2-CH3 region as used by WO’134 of SEQ ID NO:17-24, as in the instant application (see claim 2) and taught by Fey. The linkers used in the prior art are less than 24 amino acids, and according to WO’134 preferably 5-15 amino acids {(G4S)x, where x=1,2 or 3}. It would have been obvious wherein the linker between the first and second monomers of the scFc were SEQ ID NO:5, 6, 7 or 8 as taught by WO’134. The prior art constructs were shown to allow the bi- and multispecific binding proteins to function and induce cytolysis of the target cells, thereby providing a reasonable expectation of success when used in similar contexts.
Claims 1-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/134134 A1 (WO’134, cited in the IDS filed 1/31/2023), US 2019/0359710 A1 (Fey), Husain et al. (BioDrugs, 32: 441–464, 2018) and Alhallak et al. (Clin. Lymph. Myeloma Leuk. 19:e156, 15 September 2019) as applied to claims 1-10 above, and further in view of US Patent 11,918,650 (Abel).
The applied Abel reference has a common applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
WO 2017/134134 (WO’134) teaches a bispecific single chain Fc antibody construct (Fig. 1a), wherein two single chain Fv antibodies (scFv) in the VH-VL orientation (BiTE®) are linked to an Fc region comprising a hinge-CH2-CH3-linker-hinge-CH2-CH3 region (Fc region of SEQ ID NO:17-24, [0171]-[0172]); termed BiTE®-HLE for half-life extending, and [0281]). The CD3 is preferably human or Macaca CD3ε ([0013]). Inclusion of the HLE scFc in the BMCA-BiTE® significantly decreased systemic clearance rates ([0282] and Table 7). “The binding against FcRn is mediated through the Fc portion within the constructs. Stronger binding against human FcRn as described in the literature is an indicator for longer half-life in vivo due to a higher intracellular rescue of the respective protein and a therefore reduced degradation rate.” ([0298]) Constructs with scFc also contained lower high molecular weight species than with hFc ([0283] and Table 9) and formulations with the scFc construct also had higher protein recovery ([0287]). Compared to a human albumin (hALB) construct, the scFc construct was more heat stable and had less chemical modification in the CDRs ([0293]). The first binding domain targets BCMA and the second CD3 ([0282]), with the linkers between the VH and VL regions being S(G4S)3 and between the BCMA and CD3-binding domains being SG3 and between the last VL and scFv being G4 (SEQ ID NO:55 and 73). However, a preferred linker between the first, second and third domains is (G4S)x, where x is an integer greater than 1, e.g., 2 or 3 ([0179]). As set forth in [0180], “In a preferred embodiment the antibody construct of the invention is characterized to comprise in an amino to carboxyl order:(a) the first domain; (b) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-3; (c) the second domain; (d) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 2, 3, 9, 10, 11 and 12; (e) the first polypeptide monomer of the third domain; (f) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 6, 7 and 8; and (g) the second polypeptide monomer of the third domain.” Here, SEQ ID NO:1-3 are G4S, (G4S)2 and (G4S)3, respectively. It is noted ([0030]) that “The term “bispecific antibody construct” of the invention also encompasses multispecific antibody constructs such as trispecific antibody constructs,…” BCMA is expressed on multiple myeloma (MM) cells and supports their growth and survival ([0006]). WO’134 does not teach a specific trispecific T cell engaging molecule.
Fey teaches (Fig. 3A-B) a trispecific scFv construct with three scFv in tandem linked by a (G4S)4 linker and which is specific for CD123 and CD33, both of which are expressed on acute myeloid leukemia (AML) cells, and CD16 (which binds FcγRIII). The linkers between the VH and VL of the scFv are (G4S)3. In the construct, CD123 and CD33 can simultaneously bind on the same tumor cell, leading to greater avidity with double-positive AML cells, thereby potentially reducing systemic toxicity due to increase in specific binding and functioning even in patients whose cells have become resistant to mono-targeting agents through escape variants (antigen-loss variants) ([0005]-[0006], [0014], [0058]). The triplebody (sctb) bound AML cell lines as well as primary leukemia cells from patients (Examples 8 and 10.1). The sctb also contains a CD16-binding site which provides an advantage of binding an effector cell (NK cells in this case), as shown by the effect of the sctb in the presence of NK cells through redirected lysis (e.g., Example 8 and [0004],[0122]). Alternatively, T cell engaging antibodies typically bind CD3 on T cells to trigger cytolytic death of, for example, CD123-expressing AML cells by RDL (re-directed lysis) or ADCC (antibody dependent cellular cytotoxicity) (e.g., [0008] and [0012]). Additionally, the bispecific antibody may have a scFc region comprising two fused polypeptide monomers with the N- to C-order of hinge-CH2-CH3-linker-hinge-CH2-CH3 (col. 4, lines 29-36).
Husain et al. discuss (p. 455, col. 1, second paragraph) that “Most solid tumor targets are expressed in normal tissue to some extent, and if the differential of expression between tumor and normal tissue is not enough to support a positive therapeutic index, one potential strategy that is being explored is the simultaneous targeting of a second tumor-associated protein (Table 5). An example of this application was published by Gantke et al., where they constructed a trispecific antibody directed against B-cell maturation antigen (BCMA) and CD200, two B-cell targets, and CD16 to recruit NK cells. BCMA is an attractive antigen for multiple myeloma but low expression in keratinocytes has been reported, thus a dual targeting approach could increase selectivity towards double positive plasma cells. Results showed that indeed the trispecific antibody was significantly more potent towards cells expressing both antigens than any antigen alone [207].” Further, Blinatomomab, a bispecific T cell recruiting antibody, has been approved (p. 457, col. 2, first paragraph).
Alhallak et al. teaches a nanoparticle comprising antibodies conjugated to a nanoparticle, wherein the antibodies bind BCMA, CS1, and/or CD38, all antigens of which are expressed on multiple myeloma (MM), as well as binding CD3 (multispecific T cell engagers: nanoMuTEs). The binding of the BCMA/CS1/CD38/CD3 nanoMuTE compared to the nanoBiTEs was significantly higher for all samples. Both were able to activate T cells only in the presence of target cells, with the nanoMuTE showing greater activation of T cells and T cell-redirected MM cell lysis compared to the individual nanoBiTEs. In a MM mouse xenograft model, both forms redirected T cells to the tumor and reduced tumor burden compared to control.
Abel teaches bispecific single chain scFc molecules, including wherein the binding domains bind BCMA and CD3 (e.g., Fig. 9 and col. 5, lines24-31) and have half-life extensions (HLE, col. 2, lines 57-67). The Fc provides increased half-life which “is generally useful in in vivo applications of immunoglobulins especially antibodies and most especially antibody fragments of small size.” (col. 2, lines 57-59) The construct comprises a single chain bispecific antibody construct comprises a binding domain to a target cell surface antigen and CD3-binding domain and third binding domain an scFc in amino-carboxyl order hinge-CH2-CH3-linker-hinge-CH2-CH3 (col. 4, lines 5-40). The BCMA-binding scFv may have the sequence of SEQ ID NO:26, which is identical to instant SEQ ID NO:1410. It discloses a scFv BCMAxCD3-scFc of SEQ ID NO:136, which is identical to amino acids 263-1248 of instant SEQ ID NO:1412, i.e., to the scFv CD3-scFc region. The linker between the first two binding domains is 12 amino acids or fewer, with a preferred linking being (G4S) or polymers of 2 or 3 thereof, and the linker between the CD3 and scFc domains being Gly4 (col. 33, lines 35-57), this corresponds in SEQ ID NO:136 to G4S (amino acids 245-249).
It would have been obvious to the artisan of ordinary skill before the effective filing date of the instant invention wherein the BCMA-binding domain had the sequence of SEQ ID NO:26 of Abel, identical to instant SEQ ID NO:1410, substituted for the BCMA-binding portion of the alternative BCMA-binding domain that is part of SEQ ID NO:136 of Abel, which already comprises an scFv CD3-binding domain linked to an scFc domain identical to corresponding portion of instant SEQ ID NO:1412 (see Sequence Comparison below). It further would have been obvious to have had a trispecific T cell engaging single chain molecule in the format of WO’134 wherein in addition to the BCMA- and CD3-binding domains, there was also a CS1-, CD38- or CD200-binding domain next to the BCMA binding domain to better target the molecule to AML or MM cancer cells so that the CD3-binding portion redirected T cells to those cancer cells for lysis. The use of multiple binding domains targeting a single cancer cell type is supported by Fey, Hussain et al. and Alhallak et al. and has advantages of increasing selectivity and use even when cancer cells fail to express one of the antigens. WO’134 set forth the advantages of single chain multispecific antibody constructs comprising a Fc region to extend serum half-life. As with WO’134 it would have been obvious to have both cancer antigen binding domains next to each other followed by a CD3-binding domain followed by a Fc region which comprised a hinge-CH2-CH3-linker-hinge-CH2-CH3 region as used by WO’134 of SEQ ID NO:17-24, as in the instant application (see claim 2) and taught by Fey. The linkers used in the prior art are less than 24 amino acids, and according to WO’134 preferably 5-15 amino acids {(G4S)x, where x=1, 2 or 3}. It would have been obvious wherein the linker between the first and second monomers of the scFc were SEQ ID NO:5, 6, 7 or 8 as taught by WO’134. The prior art constructs were shown to allow the bi- and multispecific binding proteins to function and induce cytolysis of the target cells, thereby providing a reasonable expectation of success when used in similar contexts.
Sequence Comparison
Comparison of instant SEQ ID NO:1412 to SEQ ID NO: 136 of US 11,918,650 (Abel; BCMA A7 27-C4-G7 CC x CD3 12C0-scFc bsAb HLE, linkers underlined)
Sequence 136, US/15972489
Patent No. 11918650
GENERAL INFORMATION
APPLICANT: Amgen Inc.
TITLE OF INVENTION: PHARMACEUTICAL COMPOSITION COMPRISING BISPECIFIC ANTIBODY CONSTRUCTS FOR IMPROVED STORAGE AND ADMINISTRATION
FILE REFERENCE: 32243/51930A
CURRENT APPLICATION NUMBER: US/15/972,489
CURRENT FILING DATE: 2018-05-07
PRIOR APPLICATION NUMBER: US 62/502,578
PRIOR FILING DATE: 2017-05-05
SEQ ID NO 136
LENGTH: 986
TYPE: PRT
OTHER INFORMATION: BCMA A7 27-C4-G7 CC (44/100) x CD3 I2C0-scFc bispecific molecule HLE
Query Match 79.5%; Score 5356; Length 986;
Best Local Similarity 100.0%;
Matches 986; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy(NO:1412)263 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNHIIHWVRQAPGQCLEWMGYINPYPGYHAY 322
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db (NO;136) 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNHIIHWVRQAPGQCLEWMGYINPYPGYHAY 60
Qy 323 NEKFQGRATMTSDTSTSTVYMELSSLRSEDTAVYYCARDGYYRDTDVLDYWGQGTLVTVS 382
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NEKFQGRATMTSDTSTSTVYMELSSLRSEDTAVYYCARDGYYRDTDVLDYWGQGTLVTVS 120
Qy 383 SGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAP 442
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAP 180
Qy 443 KLLIYYTSRLHTGVPSRFSGSGSGTDFTFTISSLEPEDIATYYCQQGNTLPWTFGCGTKV 502
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 KLLIYYTSRLHTGVPSRFSGSGSGTDFTFTISSLEPEDIATYYCQQGNTLPWTFGCGTKV 240
Qy 503 EIKSGGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARI 562
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 EIKSGGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARI 300
Qy 563 RSKYNNYATYYADSVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISY 622
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 RSKYNNYATYYADSVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISY 360
Qy 623 WAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTS 682
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 WAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTS 420
Qy 683 GNYPNWVQQKPGQAPRGLIGGTKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCV 742
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 GNYPNWVQQKPGQAPRGLIGGTKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCV 480
Qy 743 LWYSNRWVFGGGTKLTVLGGGGDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPE 802
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 LWYSNRWVFGGGTKLTVLGGGGDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPE 540
Qy 803 VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKE 862
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKE 600
Qy 863 YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA 922
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA 660
Qy 923 VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 982
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 720
Qy 983 KSLSLSPGKGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSDKTHTCPPCPAPELLGGPSVF 1042
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 KSLSLSPGKGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSDKTHTCPPCPAPELLGGPSVF 780
Qy 1043 LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYR 1102
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 781 LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYR 840
Qy 1103 CVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN 1162
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 841 CVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN 900
Qy 1163 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN 1222
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 901 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN 960
Qy 1223 VFSCSVMHEALHNHYTQKSLSLSPGK 1248
||||||||||||||||||||||||||
Db 961 VFSCSVMHEALHNHYTQKSLSLSPGK 986
Prior Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
Over two decades prior to the instant invention, Mack et al. (Proc Natl Acad Sci USA 92:7021–7025, 1995, cited in the IDS file 1/31/2023) taught the single chain bispecific antibody (scBsc-Ab) that binds epithelial 17-1A antigen on colorectal cancer cells and CD3 on human T cells, triggering cytotoxic T cell cytotoxicity of the cancer cells by crosslinking of CD3. In general, bispecific antibodies are more effective in lysing tumor cells compared to antibody-dependent cytotoxicity (ADCC) or complement activity of monospecific antibodies (p. 7021, col. 1, second paragraph). Traditional bispecific antibodies suffer low yields, by-products and involved purification (p. 7021, end of col. 1). Mack et al. overcame these by producing a small bispecific antibody comprising two single chain Fv (scFv) fragments linked by one or three Gly4Ser units (G4S) and VH and VL by (G4S)2, which were cytotoxic at the nanomolar level against tumor cells (p. 7021, col. 2, first paragraph, p. 7021, col. 2, third paragraph, see also Fig. 1-Right). No difference in target cell lysis was seen using the 5 and 15 amino acid linker between the two Fv’s (p. 7024, col. 1, third paragraph). Purification of the scBsc-Ab has the advantage of not needing to be produced in E. coli, yielding a higher expression level, no need to separate active from inactive or partially active molecules, and no renaturation necessary (p. 7024, col. 2, second paragraph). “Multispecific antibodies directed to three or more different antigens may now also be produced by the single-chain approach, so that the advantages of eukaryotic expression will become even more evident.” (p. 7024, col. 2, third paragraph) This references is cited to show that well before the instant invention the advantage of single chain bispecific antibodies targeting a cancer antigen and CD3 (BiTE®) were made and the advantages thereof disclosed.
Kugler et al. (Br J Haematol. 2010; 150: 574-586, cited in the IDS filed 1/31/23) disclosed a trispecific scFv construct with three scFv in tandem linked by a (G4S)4 linker (Abstract, Fig. 1A) and which is specific for CD123 and CD33, both of which are expressed on acute myeloid leukemia (AML) cells, and CD16 (which binds FcγRIII). In the construct, CD123 and CD33 can be simultaneously bound on the same tumor cell, leading to greater avidity with double-positive AML cells (p. 575, col. 2, second paragraph). The triplebody (sctb) bound both AML cell lines as well as primary leukemia cells from patients (Abstract). It is stated (p 575, col. 2, first paragraph), “The incorporation of a second scFv-binding site for tumour-antigens in these extended formats has led to increased avidity for the tumour cell, increased anti-tumour activity in antibody-dependent cellular cytotoxicity (ADCC) reactions, and improved plasma retention in vivo (Kellner et al, 2008).” The sctb also contains a CD16-binding site which provides an advantage of binding an effector cell (NK cells in this case). This reference is cumulative with US 2019/0359710 (Fey) relied upon above.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Claire Kaufman, whose telephone number is (571) 272-0873. Examiner Kaufman can generally be reached Monday through Friday 7am-3:30pm, Eastern Time.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa Ford, can be reached at (571) 272-0857.
Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600.
Official papers filed by fax should be directed to (571) 273-8300. NOTE: If applicant does submit a paper by fax, the original signed copy should be retained by the applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice .
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
May 21, 2026
Prosecution Insights