DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed June 2, 2023 is pending.
Claims 2, 4-6, 8, 9, 12, 16, 17, 20, and 32-50 are canceled.
Claims 1, 3, 7, 10, 11, 13-15, 18, 19, and 21-31 are pending.
Claims 1, 3, and 7 are independent claims.
Election/Restriction
Applicant’s election without traverse to the species of (a) a heavy chain variable domain or region comprising the amino acid sequences set forth in SEQ ID NO:25, SEQ ID NO:26, and SEQ ID NO:27; (b) a chimeric antigen receptor comprising (i) a hinge comprising SEQ ID NO:131, (ii) a transmembrane domain comprising SEQ ID NO:534, and (iii) the combination of signaling domains that includes SEQ ID NO:142, SEQ ID NO:141, and SEQ ID NO:140; and (c) a cell engager comprising a linker comprising SEQ ID NO:112 and for (i) claim 24, the second antigen binding domain comprising SEQ ID NO:148 and SEQ ID NO:149, (ii) for claim 27, a CD16a polypeptide as a species for the second antigen binding domain target, and the VH domain comprising SEQ ID NO:165, and (iii) for claim 31, a CD16a polypeptide as a species for the third antigen binding domain target, and the VH domain comprising SEQ ID NO:165 in the reply filed on March 30, 2026 is acknowledged.
Upon further consideration, the species election requirement with respect to a specific antibody/antigen binding fragment/antibody domain comprising a specific heavy chain variable region and corresponding SEQ ID NOs: as recited in claims 1, 3, and 7 in the office action mailed on March 13, 2026 is withdrawn. The SEQ ID NOs recited in heavy chain variable domains or regions (i) – (xii) in claims 1, 3, and 7 are rejoined.
In view of the withdrawal of the restriction requirement regarding a specific antibody/antigen binding fragment/antibody domain comprising a specific heavy chain variable region and corresponding SEQ ID NOs:, Applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the species restriction requirement of a specific antibody/antigen binding fragment/antibody domain comprising a specific heavy chain variable region and corresponding SEQ ID NOs: is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claims 1, 3, 7, 10, 11, 13-15, 18, 19, and 21-31 are currently under consideration.
Claim Objections
Claims 1, 3, 7, 10, 11, 13-15, and 28-31 are objected to because of the following informalities:
Claims 1, 3, and 7 recite “and SEQ ID NO:11 (or SEQ ID NO:1 with one, two, or three amino acid additions, deletions, or substitutions” where they should recite “and SEQ ID NO:11 (or SEQ ID NO:11 with one, two, or three amino acid additions, deletions, or substitutions” in lines 4 and 5 of bullet (ii).
Claim 10 and 15 recite “one or more signaling domains” where it should recite “one or more intracellular signaling domains” in line 2.
Claim 28 recites “wherein said cell engager comprises a third antigen binding domain” where it should recite “wherein said cell engager further comprises a third antigen binding domain” in lines 1 and 2.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Indefinite Language
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 13-15, 21, 24, 27, and 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.
Claims 13-15, 21, 24, 27, and 31 all reference a figure when claiming a particular structure in their respective limitations. For example, claim 13 recites “wherein said hinge comprises a hinge set forth in Figure 16” in line 2.
It is noted that where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted). See MPEP 2173.05(s).
Therefore, the reference to figures in claims 13-15, 21, 24, 27, and 31 renders the claims, and all dependent claims, indefinite because, in the absence of evidence to the contrary, the reference to the figures in the claims was done for the Applicant’s convenience not out of necessity.
Amending claims 13-15, 21, 24, 27, and 31 to delete the reference to the figures and instead recite the actual structure outlined in the recited Figures would obviate this part of the rejection.
Claims 13, 14, and 21 also recite that the claimed CAR structure, i.e. said hinge (claim 13), transmembrane domain (claim 14), linker (claim 21), “comprises a” hinge, transmembrane domain, or linker set forth in Figure 16, 17, and 15 or 16, respectively. It is unclear if the referenced structures are the ones recited in the Figures or if they only comprise the structures recited in the figures. This uncertainty therefore renders the claims are indefinite.
Amending claims 13, 14, and 21 to replace the term “comprises” with the term “is” would obviate this part of the rejection.
Written Description
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, 3, 7, 10, 11, 13-15, 18, 19, and 21-31 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 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 instant claims are drawn to an antibody, antigen binding fragment, and antibody domain comprising a heavy chain variable domain or region comprising the amino acid sequences set forth in SEQ ID NO: X or SEQ ID NO: X with one, two, or three amino acid additions, deletions, or substitutions, SEQ ID NO: Y or SEQ ID NO: Y with one, two, or three amino acid additions, deletions, or substitutions, and SEQ ID NO: Z or SEQ ID NO: Z with one, two, or three amino acid additions, deletions, or substitutions, wherein X, Y, and Z are the SEQ ID NOs recited for species (i) – (xii) in claims 1, 3, and 7.
The Applicant has disclosed 12 antibody clones that comprise one set of the SEQ ID NOs recited for species (i) – (xii) in claims 1, 3, and 7 (e.g. see clones #1 - #12 (or ab1-12) in Figures 2-13). It is noted that all of these clones are anti-mesothelin antibodies and the SEQ ID NOs correspond to the amino acid sequences of the VH CDRs 1-3 for the respective anti-mesothelin antibodies (e.g. see clones #1 - #12 in Figures 2-13; and Table 37 spanning pages 131 and 132 of the specification). It is further noted that the Applicant has not disclosed any amino acid sequences for the VL CDRs of clones #1 - #12.
The Applicant also discloses that their invention is drawn to binders, i.e. antibodies, antigen binding fragments, antibody domains, CARs, cell engagers, and ADCs, that bind to a mesothelin polypeptide (e.g. see page 32, lines 21-27).
The Applicant defines the term “antibody domain” as a domain of an antibody such as a heavy chain variable domain (VH domain) or a light chain variable domain (VL domain) in the absence of one or more other domains of an antibody (e.g. see page 34, lines 7-19). In some cases, an antibody domain can be a single antibody domain (e.g., a VH domain or a VL domain) having the ability to bind to an antigen. In some cases, an antibody domain provided herein can include the CDRs as described herein (e.g., as described in Table 37) and can be engineered as a single VH domain or a single VL domain (e.g. see page 34, lines 7-19).
When given the broadest reasonable interpretation in light of specification, the antibody, antigen binding fragment, and antibody domain of the instant invention are defined broadly to be any antibody, antigen binding fragment, and antibody domain that binds a mesothelin polypeptide and comprises a heavy chain variable domain or region comprising the amino acid sequences set forth in SEQ ID NO: X or SEQ ID NO: X with one, two, or three amino acid additions, deletions, or substitutions, SEQ ID NO: Y or SEQ ID NO: Y with one, two, or three amino acid additions, deletions, or substitutions, and SEQ ID NO: Z or SEQ ID NO: Z with one, two, or three amino acid additions, deletions, or substitutions, wherein X, Y, and Z are the SEQ ID NOs recited for species (i) – (xii) in claims 1, 3, and 7.
It is noted that no claim recites sufficient structure for the genera of antibodies, antigen binding fragments, and antibody domains that comprise a heavy chain variable domain or region comprising the amino acid sequences set forth in SEQ ID NO: X or SEQ ID NO: X with one, two, or three amino acid additions, deletions, or substitutions, SEQ ID NO: Y or SEQ ID NO: Y with one, two, or three amino acid additions, deletions, or substitutions, and SEQ ID NO: Z or SEQ ID NO: Z with one, two, or three amino acid additions, deletions, or substitutions, wherein X, Y, and Z are the SEQ ID NOs recited for species (i) – (xii) in claims 1, 3, and 7.
It is noted that the claims recite that the antibodies, antigen binding fragments, and antibody domains may comprise less than 6 CDRs.
It is further noted that none of the claims recite the antigen specificity for the claimed antibodies, antigen binding fragments, and antibody domains.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3). In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
Artisans are well aware that knowledge of a given antigen (for instance mesothelin) provides no information concerning the sequence/structure of antibodies or antigen binding molecules that bind the given antigen. For example, Edwards et al. (J. Mol. Biol., 2003, 334:103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document).
As such, it does not seem possible to predict the sequence/structure of an antibody or antigen binding molecules that binds a given antigen, as there does not appear to be any common or core structure present within all antigen binding molecules that gives rise to the function of antigen binding. Further, given data, such as that of Edwards et al., indicating the diversity of sequences in a population of antibodies that bind to a given antigen, no number of species appears to reasonably representative of the breadth of the genus of antibodies or antigen binding molecules that bind the given antigen.
It should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antigen binding molecule to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway Jr et al., Immunology, 3rd Edition, 1997 Garland Publishing Inc., pages 3:1-3:11.see entire selection).
Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody or antigen binding molecule which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
This applies to the instant invention which is drawn to genera of antibodies, antigen binding fragments, and antibody domains that comprise less than a full set of 6 CDRs.
As noted above, the Applicant has disclosed 12 antibody clones that comprise one set of the SEQ ID NOs recited for species (i) – (xii) in claims 1, 3, and 7. These antibodies are anti-mesothelin antibodies and the SEQ ID NOs correspond to the amino acid sequences of the VH CDRs 1-3, respectively. Such a disclosure does not serve to provide sufficient written description of the claimed to genera of antibodies, antigen binding fragments, and antibody domains that comprise less than a full set of 6 CDRs.
The disclosure does not identify sufficient structural features or combination of features which give rise to the function of mesothelin binding. Additionally, there does not appear to be any reasonable shared structure present in the genera of recited antibodies, antigen binding fragments, and antibody domains which gives rise to their functional activity. Ultimately, identifying an antibody, antigen binding fragment, and antibody domain on the basis of binding to mesothelin rather than by identifying the sequence/structure, namely a complete set of six CDRs, of the antibodies, antigen binding fragments, and antibody domains in question is generally insufficient to provide written description.
This reasoning further applies to the claims which recites the limitation “SEQ ID NO: X with one, two, or three amino acid additions, deletions, or substitutions” for each of the recited amino acid sequences. Given that the claimed SEQ ID NOs correspond to the amino acid sequences of the VH CDRs 1-3, the claims do not satisfy the written description requirement because the claim language allows for significant variability in the amino acid sequence structure of the CDRs which would be expected to impact the functional binding activity of the claimed antibodies, antigen binding fragments, and antibody domains based on the state of the prior art.
Furthermore, this reasoning also further applies to claim 7 which is drawn to an antibody domain which the Applicant has defined as a domain of an antibody, such as a VH domain or a VL domain in the absence of one or more other domains of an antibody. Given that the Applicant defines an antibody domain as a binder and the art teaches that a full set of 6 CDRs is required for antigen binding, the antibody domain of claim 7 which, as defined by the Applicant, does not comprise both a VH and VL domain would not comprise all of the required 6 CDRs for antigen binding and therefore would not be considered a binder.
It is further noted that none of the claims recite the antigen specificity for the claimed antibodies, antigen binding fragments, and antibody domains. Antibodies are glycoproteins that possess the ability to react in vitro and in vivo specifically and selectively with the antigenic determinants or epitopes eliciting their production or with an antigenic determinant closely related to the homologous antigen. Antibodies are immunoglobulins that are formed in response to immunogens or that are screened for specificity an antigen/immunogen.
It has been well established in the art that the antigen binding specificity is critical to how the skilled artisan would employ antibodies in various modalities (e.g., affinity purification, detection or diagnostic assays, bioassays, treatment), including those consistent with the instant disclosure (see specification, including the Summary of the Invention). However, the instant claims do not recite an antigen specificity for the antibodies, antigen binding fragments, and antibody domains.
The specification provides insufficient direction and guidance regarding how antibodies comprising the claimed sequences bind an antigen in the absence of an antigen specificity for mesothelin and yet retain substantially the same binding specificity of the anti- mesothelin antibodies, antigen-binding fragments, and antibody domains which are described consistent with the disclosed utilities of the instant disclosure (see Detailed Description / claims, etc.).
This also applies to the cell engager of claims 18, 19, and 21-30. These claims do not recite any structure for the second and third antigen binding domains of the cell engager which may bind: to any cell (claims 18, 19, 21, and 28), a T cell (claims 22-24), specifically CD3 on a T cell (claim 23), an NK cell (claims 25-27 and 29-31), or specifically CD16a, NKG2A, NKG2D, NKp30, NKp44, or NKp46 on an NK cell (e.g. see claims 26 and 30). Identifying a cell engager on the basis of binding to any cell, a T cell, specifically CD3 on a T cell, an NK cell, or specifically CD16a, NKG2A, NKG2D, NKp30, NKp44, or NKp46 on an NK cell rather than by identifying the sequence/structure, namely a complete set of six CDRs, of the antigen binding domains of the cell engager in question is generally insufficient to provide written description.
The claims are drawn to broad genera of antibodies, antigen binding fragments, and antibody domains that comprise less than a full set of 6 CDRs, which are functionally defined by their ability to bind to mesothelin (according to the specification) and a broad genus of cell engagers, which are functionally defined by their ability to bind a cell, without reciting a corresponding structure expected to correlate with this ability as supported by Applicant’s disclosure.
Thus, there is insufficient written description for the breadth of antibodies, antigen binding fragments, antibody domains, and cell engagers as currently claimed, which are distinct and diverse and do not share a common structure that contributes to a common ability to bind to mesothelin or a cell, respectively.
Therefore, in view of the breadth of the claims and the limited disclosure, artisans would reasonably conclude that applicant was not in possession of the full breadth of antibodies, antigen binding fragments, antibody domains, and cell engagers as encompassed by the claims at the time the instant application was filed.
Deleting claim 7, amending claims 1 and 3 to: (i) delete the phrase “or SEQ ID NO: X with one, two, or three amino acid additions, deletions, or substitutions”; (ii) indicate which VH CDRs the recited amino acids correspond to (i.e. SEQ ID NO: 1 is the amino acid sequence for VH CDR1, etc.); (iii) recite the amino acid sequences for VL CDRs 1-3; and (iv) recite that the antibodies and antigen binding fragments bind mesothelin, and amending claims 18, 19, and 21-30 to recite a full set of six CDRs for the first and second antigen binding domains of the cell engager and its corresponding antigen specificity, would obviate this part of the rejection.
Claim Rejections - 35 USC § 102
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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3, and 7 are rejected under 35 U.S.C. 102(a)(1)/(2) as being anticipated by Buyse and Boutton 2017 (US20170121399A1)/Sato et al. 2022 (US20220135690A1, PGPUB of U.S. Application No. 17/517,528 which has a prior filing date of 11/03/2020, a reference of record), respectively.
Independent claims 1, 3, and 7 are drawn to an antibody, an antigen binding fragment, or an antibody domain, respectively, comprising:
a heavy chain variable domain or region comprising the amino acid sequences set forth in SEQ ID NO:1 or SEQ ID NO:1 with one, two, or three amino acid additions, deletions, or substitutions, SEQ ID NO:2 or SEQ ID NO:2 with one, two, or three amino acid additions, deletions, or substitutions, and SEQ ID NO:3 or SEQ ID NO:3 with one, two, or three amino acid additions, deletions, or substitutions;
a heavy chain variable domain or region comprising the amino acid sequences set forth in SEQ ID NO:9 or SEQ ID NO:9 with one, two, or three amino acid additions, deletions, or substitutions, SEQ ID NO:10 or SEQ ID NO: 10 with one, two, or three amino acid additions, deletions, or substitutions, and SEQ ID NO:11 or SEQ ID NO:11 with one, two, or three amino acid additions, deletions, or substitutions;
a heavy chain variable domain or region comprising the amino acid sequences set forth in SEQ ID NO:17 or SEQ ID NO:17 with one, two, or three amino acid additions, deletions, or substitutions, SEQ ID NO: 18 or SEQ ID NO: 18 with one, two, or three amino acid additions, deletions, or substitutions, and SEQ ID NO: 19 or SEQ ID NO: 19 with one, two, or three amino acid additions, deletions, or substitutions;
a heavy chain variable domain or region comprising the amino acid sequences set forth in SEQ ID NO:25 or SEQ ID NO:25 with one, two, or three amino acid additions, deletions, or substitutions, SEQ ID NO:26 or SEQ ID NO:26 with one, two, or three amino acid additions, deletions, or substitutions, and SEQ ID NO:27 or SEQ ID NO:27 with one, two, or three amino acid additions, deletions, or substitutions;
a heavy chain variable domain or region comprising the amino acid sequences set forth in SEQ ID NO:33 or SEQ ID NO:33 with one, two, or three amino acid additions, deletions, or substitutions, SEQ ID NO:34 or SEQ ID NO:34 with one, two, or three amino acid additions, deletions, or substitutions, and SEQ ID NO:35 or SEQ ID NO:35 with one, two, or three amino acid additions, deletions, or substitutions;
a heavy chain variable domain or region comprising the amino acid sequences set forth in SEQ ID NO:41 or SEQ ID NO:41 with one, two, or three amino acid additions, deletions, or substitutions, SEQ ID NO:42 or SEQ ID NO:42 with one, two, or three amino acid additions, deletions, or substitutions, and SEQ ID NO:43 or SEQ ID NO:43 with one, two, or three amino acid additions, deletions, or substitutions;
a heavy chain variable domain or region comprising the amino acid sequences set forth in SEQ ID NO:49 or SEQ ID NO:49 with one, two, or three amino acid additions, deletions, or substitutions, SEQ ID NO:50 or SEQ ID NO:50 with one, two, or three amino acid additions, deletions, or substitutions, and SEQ ID NO:51 or SEQ ID NO:51 with one, two, or three amino acid additions, deletions, or substitutions;
a heavy chain variable domain or region comprising the amino acid sequences set forth in SEQ ID NO:57 or SEQ ID NO:57 with one, two, or three amino acid additions, deletions, or substitutions, SEQ ID NO:58 or SEQ ID NO:58 with one, two, or three amino acid additions, deletions, or substitutions, and SEQ ID NO:59 or SEQ ID NO:59 with one, two, or three amino acid additions, deletions, or substitutions;
a heavy chain variable domain or region comprising the amino acid sequences set forth in SEQ ID NO:65 or SEQ ID NO:65 with one, two, or three amino acid additions, deletions, or substitutions, SEQ ID NO:66 or SEQ ID NO:66 with one, two, or three amino acid additions, deletions, or substitutions, and SEQ ID NO:67 or SEQ ID NO:67 with one, two, or three amino acid additions, deletions, or substitutions;
a heavy chain variable domain or region comprising the amino acid sequences set forth in SEQ ID NO:73 or SEQ ID NO:73 with one, two, or three amino acid additions, deletions, or substitutions, SEQ ID NO:74 or SEQ ID NO:74 with one, two, or three amino acid additions, deletions, or substitutions, and SEQ ID NO:75 or SEQ ID NO:75 with one, two, or three amino acid additions, deletions, or substitutions;
a heavy chain variable domain or region comprising the amino acid sequences set forth in SEQ ID NO:81 or SEQ ID NO:81 with one, two, or three amino acid additions, deletions, or substitutions, SEQ ID NO:82 or SEQ ID NO:82 with one, two, or three amino acid additions, deletions, or substitutions, and SEQ ID NO:83 or SEQ ID NO:83 with one, two, or three amino acid additions, deletions, or substitutions; or
a heavy chain variable domain or region comprising the amino acid sequences set forth in SEQ ID NO:89 or SEQ ID NO:89 with one, two, or three amino acid additions, deletions, or substitutions, SEQ ID NO:90 or SEQ ID NO:90 with one, two, or three amino acid additions, deletions, or substitutions, and SEQ ID NO:91 or SEQ ID NO:91 with one, two, or three amino acid additions, deletions, or substitutions.
Buyse and Boutton teach an antibody comprising a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO:81 (or SEQ ID NO:81 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:82 (or SEQ ID NO:82 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:83 (or SEQ ID NO:83 with one, two, or three amino acid additions, deletions, or substitutions) (e.g. see SEQ ID NO: 392, 89L+110K in Figure 19). See sequence alignment below. The antibody taught by Buyse and Boutton is specific for RANK-L, a therapeutically relevant target (e.g. see [0083]).
PNG
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248
626
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Greyscale
Alignment of Buyse and Boutton’s SEQ ID NO: 392 and fused instant SEQ ID NOs: 81-83:
Sato et al. teach an antibody comprising a heavy chain variable domain comprising the amino acid sequences set forth in SEQ ID NO:65 (or SEQ ID NO:65 with one, two, or three amino acid additions, deletions, or substitutions), SEQ ID NO:66 (or SEQ ID NO:66 with one, two, or three amino acid additions, deletions, or substitutions), and SEQ ID NO:67 (or SEQ ID NO:67 with one, two, or three amino acid additions, deletions, or substitutions) (e.g. see page 40, Table 9, SEQ ID NO: 161, variant CXCR5-1-128). See sequence alignment below. The antibody taught by Sato et al. is specific for the chemokine receptor CXCR5.
Alignment of Sato et al.’s SEQ ID NO: 161 and fused instant SEQ ID NOs: 65-67:
Query Match 56.7%; Score 77.1; Length 119;
Best Local Similarity 22.9%;
Matches 19; Conservative 1; Mismatches 4; Indels 59; Gaps 2;
Qy 1 GFTFSSYA-----------------ISYNGDHT--------------------------- 16
|||||||| ||||| :|
Db 26 GFTFSSYAMSWVRQAPGKGLEWVAVISYNGGNTYYPDSVKGRFTISRDNSKNTLYLQMNS 85
Qy 17 ---------------TRNYFFDY 24
|| |||
Db 86 LRAEDTAVYYCARGDDNNYAFDY 108
As such, claims 1, 3, and 7 are anticipated by Buyse and Boutton/Sato et al.
Claim Rejections - 35 USC § 103
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.
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 10, 11, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over as being anticipated by Buyse and Boutton 2017 (US20170121399A1) or Sato et al. 2022 (US20220135690A1, PGPUB of U.S. Application No. 17/517,528 which has a prior filing date of 11/03/2020, a reference of record) in view of Sadelain et al. 2013 (Cancer Discov. 3 (4): 388–398).
Dependent claim 10 is drawn to a chimeric antigen receptor comprising an antigen binding domain, a hinge, a transmembrane domain, and one or more signaling domains, wherein said antigen binding domain comprises an antigen-binding fragment of claim 3.
Dependent claim 11 limits the antigen binding domain to that which comprises a scFv having the ability to bind to a mesothelin polypeptide.
Dependent claim 15 limits the one or more signaling domains to SEQ ID NOs: 140-142.
The teachings of Buyse and Boutton and Sato et al. are outline in the 102 rejection above.
Buyse and Boutton and Sato et al. do not teach a chimeric antigen receptor comprising an antigen binding domain, a hinge, a transmembrane domain, and one or more signaling domains, wherein said antigen binding domain comprises an antigen-binding fragment of claim 3.
Sadelain et al. teach that chimeric antigen receptors (CAR) are recombinant receptors that provide both antigen-binding and T-cell–activating functions (e.g. see Abstract). CARs represent a new class of drugs with exciting potential for cancer immunotherapy (e.g. see Abstract).
Sadelain et al. also teach that CARs are recombinant receptors that typically target native cell surface antigens (e.g. see page 389, left column, second paragraph). The moieties used to bind to antigen fall in 3 general categories: (i) single-chain variable fragment (scFv) derived from antibodies; (ii) Fabs fragment antigen-binding (Fab) selected from libraries; or (iii) nature ligands that engage their cognate receptor (e.g. see page 389, left column, third paragraph). scFvs derived from murine immunoglobulins are commonly used, as they are easily derived from well-characterized monoclonal antibodies (e.g. see page 389, left column, third paragraph).
Sadelain et al. also teach that CARs comprise a hinge (spacer), a transmembrane domain (TM), and one or more signaling domains (e.g. see Figure 1 and its caption, copied below).
Regarding claim 15, Sadelain et al. also teach a CAR comprising CD28, 4-1BB, and CD3ζ intracellular signaling domains (e.g. see page 392, paragraph spanning left and right columns). It is noted that while Sadelain et al. do not explicitly recite the amino acid sequences of the CD28, 4-1BB, and CD3ζ intracellular signaling domains, given that the amino acid sequences as instantly claimed for each of these domains are the wildtype versions, the intracellular signaling domains taught by Sadelain et al. would necessarily have the same amino acid sequences as those instantly claimed, especially in the absence of evidence to the contrary.
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Figure 1 from Sadelain et al. 2013 (Cancer Discov. 3 (4): 388–398)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Buyse and Boutton or Sato et al. to incorporate the teachings of Sadelain et al. to include that antigen-binding fragment of claim 3 is comprised in the antigen binding domain of a CAR also comprising a hinge, a transmembrane domain, and one or more signaling domains. This is because the antigen binding moieties of a CAR are commonly scFvs derived from murine immunoglobulins or antibody fragments.
Given that CARs are a class of drugs with exciting potential for cancer immunotherapy and the antigen binding moieties of a CAR are commonly scFvs derived from murine immunoglobulins because they are easily derived from well-characterized monoclonal antibodies; it would have been obvious to a skilled artisan, with the goal of designing a CAR for the treatment of a cancer by targeting RANK-L (Buyse and Boutton) or CXCR5 (Sato et al.), to use the antibodies taught by Buyse and Boutton and Sato et al. to derive an antigen binding moiety of a CAR from with a reasonable expectation of success.
Regarding the limitation “wherein said antigen binding domain comprises a scFv having the ability to bind to a mesothelin polypeptide” in lines 1 and 2 of claim 11, Buyse and Boutton, Sato et al., and Sadelain et al. are silent on these properties. However, silence about a particular property does not necessarily constitute its absence. The office does not have the facilities and resources to provide the factual evidence needed in order to establish that there is a difference between the materials, i.e., that the claims are directed to new materials and that such a difference would have been considered unexpected by one of ordinary skill in the art, that is, the claimed subject matter, if new, is unobvious. In the absence of evidence to the contrary, the burden is on the Applicant to prove that the claimed materials are different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Although Buyse and Boutton, Sato et al., and Sadelain et al. are silent with regard to the CAR having the ability to bind to a mesothelin polypeptide, it is noted that a compound and all of its properties are inseparable; they are one and the same thing (see In re Papesch, CCPA 137 USPQ 43; In re Swinehart and Sfiligoj, 169) USPQ 226 (CCPA 1971)). Therefore, in the absence of evidence to the contrary, the CAR taught by Buyse and Boutton or Sato et al. in view of Sadelain et al. would have the claimed property recited in claim 11.
When a claim recites using an old composition or structure and the use is directed to a result or property of that composition or structure then the claim is anticipated. See MPEP 2112.02. Also, see Bristol-Myers Squibb Co. v. Ben Venue Laboratories, Inc. 58 USPQ2d 1508 (CA FC 2001); Ex parte Novitski 26 USPQ 1389 (BPAI 1993); Mehl/Biophile International Corp. V. Milgraum, 52 USPQ2d 1303 (Fed. Cir. 1999); Atlas Powder Co. V. IRECO, 51 USPQ2d 1943 (Fed. Cir. 1999).
The property recited in claim 11 flows naturally from the teachings of the prior art. (citing Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985 (“The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.”), and Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347 (Fed. Cir. 1999) (“[T]he discovery of... a scientific explanation for the prior art's functioning, does not render the old composition patentably new to the discoverer.”)).
An obvious formulation cannot become nonobvious simply by measuring and claiming an activity of the formulation in a particular context, “because ‘[t]o hold otherwise would allow any formulation—no matter how obvious—to become patentable merely by testing and claiming an inherent property.’” Persion Pharm., slip op. at 13 (Fed. Cir. Dec. 27, 2019) (citing Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012)); see also Gen. Elec. Co. v. Jewel Incandescent Lamp Co., 326 U.S. 242, 249 (1945) (“It is not invention to perceive that the product which others had discovered had qualities they failed to detect.”).
The Courts have held that there is no requirement that those of ordinary skill in the art know of the inherent property. See MPEP 2131.01(d) and MPEP 2112 - 2113.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 13 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over as being anticipated by Buyse and Boutton 2017 (US20170121399A1) or Sato et al. 2022 (US20220135690A1, PGPUB of U.S. Application No. 17/517,528 which has a prior filing date of 11/03/2020, a reference of record) in view of Sadelain et al. 2013 (Cancer Discov. 3 (4): 388–398), as applied to claim 10, and further in view of Davey et al. 2020 (Cancers. 13(1), 38).
Dependent claim 13 limits the hinge to that which comprises SEQ ID NO:131.
Dependent claim 14 limits the transmembrane domain to that which comprises SEQ ID NO:534.
The combined teachings of Buyse and Boutton or Sato et al. in view of Sadelain et al. pertaining to claim 10, and the rationale for combining them are outlined in the 103 rejection above.
The combined reference teachings do not teach that the hinge comprises SEQ ID NO:131 or that the transmembrane domain comprises SEQ ID NO:534.
Davey et al. teach that CARS comprising a CD28 hinge-TM with induce a higher incidence of CRS and neurotoxicity than the corresponding sequences from CD8, regardless of whether the CD28 or the 4-1BB costimulatory domain is used (e.g. see Abstract and Conclusions).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combined teachings of Buyse and Boutton or Sato et al. in view of Sadelain et al. as applied to claim 10, and incorporate the teachings of Davey et al. to include that the hinge comprises SEQ ID NO:131 and the transmembrane domain comprises SEQ ID NO:534.
Given that CARs comprising a CD8 hinge-TM are associated with lower risk of CRS and neurotoxicity; it would have been obvious to a skilled artisan to modify the CAR taught by Buyse and Boutton or Sato et al. in view of Sadelain et al. to specifically include a CD8 hinge-TM with a reasonable expectation of success. It is noted that while Davey et al. do not explicitly recite the amino acid sequences of the CD8 hinge-TM, given that the amino acid sequences as instantly claimed for each of these domains are the wildtype versions, the intracellular signaling domains taught by Sadelain et al. would necessarily have the same amino acid sequences as those instantly claimed, especially in the absence of evidence to the contrary.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 18, 19, 22, 23, 25, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over as being anticipated by Buyse and Boutton 2017 (US20170121399A1) or Sato et al. 2022 (US20220135690A1, PGPUB of U.S. Application No. 17/517,528 which has a prior filing date of 11/03/2020, a reference of record) in view of Stein et al. 2012 (Antibodies. 1(1), 88-123).
Dependent claim 18 is drawn to a cell engager comprising a first antigen binding domain, a linker, and a second antigen binding domain, wherein said first antigen binding domain comprises an antigen-binding fragment of claim 3.
Dependent claim 19 limits the antigen binding domain to that which comprises a scFv having the ability to bind to a mesothelin polypeptide.
Dependent claim 22 limits the second antigen binding domain to that which binds a polypeptide expressed on the surface of T cell.
Dependent claim 23 limits the polypeptide expressed on the surface of the T cell to a CD3 polypeptide.
Dependent claim 25 limits the second antigen binding domain to that which binds a polypeptide expressed on the surface of NK cells.
Dependent claim 26 limits the polypeptide expressed on the surface of the NK cells to a CD16a polypeptide.
The teachings of Buyse and Boutton and Sato et al. are outline in the 102 rejection above.
Buyse and Boutton and Sato et al. do not teach a cell engager comprising a first antigen binding domain, a linker, and a second antigen binding domain, wherein said first antigen binding domain comprises an antigen-binding fragment of claim 3.
Stein et al. teach cell engagers comprising a first antigen binding domain, a linker, and a second antigen binding domain (e.g. see Figure 1). These cell engagers are designed to recruit the body’s own cells as effectors for the elimination of cancer cells (e.g. see page 89, first paragraph). This approach offers several unique advantages, including a reduced immunogenicity and a greater ease of manufacture (e.g. see page 89, first paragraph).
Regarding claim 19, Stein et al. also teach that the cell engager antigen binding domains comprise scFvs (e.g. see figure caption of Figure 1).
Regarding claims 22, 23, 25, and 26, Stein et al. also teach cell engagers that specifically bind to NK cells through CD16a or T cells through CD3 (e.g. see Figure 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Buyse and Boutton or Sato et al. to incorporate the teachings of Stein et al. to include that antigen-binding fragment of claim 3 is comprised in the first antigen binding domain of a cell engager. This is because the antigen binding moieties of a cell engager are commonly scFvs or antibody fragments.
Given that cell engagers are designed to recruit the body’s own cells as effectors for the elimination of cancer cells, cell engagers offer several unique advantages, including a reduced immunogenicity and a greater ease of manufacture, and the antigen binding moieties of a cell engager are commonly scFvs or antibody fragments; it would have been obvious to a skilled artisan, with the goal of designing a cell engager for the treatment of a cancer by targeting RANK-L (Buyse and Boutton) or CXCR5 (Sato et al.), to use the antibodies taught by Buyse and Boutton and Sato et al. to derive an antigen binding moiety of a cell engager from with a reasonable expectation of success.
Regarding the limitation “wherein said antigen binding domain comprises a scFv having the ability to bind to a mesothelin polypeptide” in lines 1 and 2 of claim 19, Buyse and Boutton, Sato et al., and Stein et al. are silent on these properties. However, silence about a particular property does not necessarily constitute its absence. The office does not have the facilities and resources to provide the factual evidence needed in order to establish that there is a difference between the materials, i.e., that the claims are directed to new materials and that such a difference would have been considered unexpected by one of ordinary skill in the art, that is, the claimed subject matter, if new, is unobvious. In the absence of evidence to the contrary, the burden is on the Applicant to prove that the claimed materials are different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Although Buyse and Boutton, Sato et al., and Stein et al. are silent with regard to the cell engager having the ability to bind to a mesothelin polypeptide, it is noted that a compound and all of its properties are inseparable; they are one and the same thing (see In re Papesch, CCPA 137 USPQ 43; In re Swinehart and Sfiligoj, 169) USPQ 226 (CCPA 1971)). Therefore, in the absence of evidence to the contrary, the cell engager taught by Buyse and Boutton or Sato et al. in view of Stein et al. would have the claimed property recited in claim 19.
When a claim recites using an old composition or structure and the use is directed to a result or property of that composition or structure then the claim is anticipated. See MPEP 2112.02. Also, see Bristol-Myers Squibb Co. v. Ben Venue Laboratories, Inc. 58 USPQ2d 1508 (CA FC 2001); Ex parte Novitski 26 USPQ 1389 (BPAI 1993); Mehl/Biophile International Corp. V. Milgraum, 52 USPQ2d 1303 (Fed. Cir. 1999); Atlas Powder Co. V. IRECO, 51 USPQ2d 1943 (Fed. Cir. 1999).
The property recited in claim 19 flows naturally from the teachings of the prior art. (citing Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985 (“The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.”), and Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347 (Fed. Cir. 1999) (“[T]he discovery of... a scientific explanation for the prior art's functioning, does not render the old composition patentably new to the discoverer.”)).
An obvious formulation cannot become nonobvious simply by measuring and claiming an activity of the formulation in a particular context, “because ‘[t]o hold otherwise would allow any formulation—no matter how obvious—to become patentable merely by testing and claiming an inherent property.’” Persion Pharm., slip op. at 13 (Fed. Cir. Dec. 27, 2019) (citing Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012)); see also Gen. Elec. Co. v. Jewel Incandescent Lamp Co., 326 U.S. 242, 249 (1945) (“It is not invention to perceive that the product which others had discovered had qualities they failed to detect.”).
The Courts have held that there is no requirement that those of ordinary skill in the art know of the inherent property. See MPEP 2131.01(d) and MPEP 2112 - 2113.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 21 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over as being anticipated by Buyse and Boutton 2017 (US20170121399A1) or Sato et al. 2022 (US20220135690A1, PGPUB of U.S. Application No. 17/517,528 which has a prior filing date of 11/03/2020, a reference of record) in view of Stein et al. 2012 (Antibodies. 1(1), 88-123), as applied to claims 18 and 22, and further in view of Qin and Kwak 2020 (US20200199232A1).
Dependent clam 21 limits the linker to that which comprises SEQ ID NO:112.
Dependent claim 24 limits the second antigen binding domain to that which comprises SEQ ID NO:148 and SEQ ID NO:149.
The combined teachings of Buyse and Boutton or Sato et al. in view of Stein et al. pertaining to claims 18 and 22, and the rationale for combining them are outlined in the 103 rejection above.
The combined reference teachings do not teach that the linker comprises SEQ ID NO:112 or that the second antigen binding domain comprises SEQ ID NO:148 and SEQ ID NO:149.
Qin and Kwak teach an anti-CD3 scFv comprising instant SEQ ID NOs: 112, 148, and 149 (e.g. see SEQ ID NO: 87 on page 22, see sequence alignment below).
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Sequence alignment of Qin and Kwak’s SEQ ID NO: 87 and instant SEQ ID NOs: 112, 148, and 149:
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combined teachings of Buyse and Boutton or Sato et al. in view of Stein et al. as applied to claim 18 and 22, and incorporate the teachings of Qin and Kwak to include that the linker comprises SEQ ID NO:112 and that the second antigen binding domain comprises SEQ ID NO:148 and SEQ ID NO:149.
Given that Qin and Kwak teach an anti-CD3 scFv comprising instant SEQ ID NOs: 112, 148, and 149; it would have been obvious to a skilled artisan to modify the cell engager taught by Buyse and Boutton or Sato et al. in view of Stein et al. to specifically include instant SEQ ID NOs: 112, 148, and 149 with a reasonable expectation of success.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 27-31 are rejected under 35 U.S.C. 103 as being unpatentable over as being anticipated by Buyse and Boutton 2017 (US20170121399A1) or Sato et al. 2022 (US20220135690A1, PGPUB of U.S. Application No. 17/517,528 which has a prior filing date of 11/03/2020, a reference of record) in view of Stein et al. 2012 (Antibodies. 1(1), 88-123), as applied to claims 18 and 25, and further in view of Dimitrov et al. 2017 (WO2018039626, an IDS reference filed 05/23/2024).
Dependent claim 27 limits the second antigen binding domain to that which comprises SEQ ID NO:165.
Dependent claim 28 limits the cell engager to that wherein the cell engager comprises a third antigen binding domain.
Dependent claim 29 limits the third antigen binding domain to that which binds a polypeptide expressed on the surface of NK cells.
Dependent claim 30 limits the polypeptide expressed on the surface of the NK cells to a CD16a polypeptide.
Dependent claim 31 limits the third antigen binding domain to that which comprises SEQ ID NO:165.
The combined teachings of Buyse and Boutton or Sato et al. in view of Stein et al. pertaining to claims 18 and 25, and the rationale for combining them are outlined in the 103 rejection above.
The combined reference teachings do not teach that the cell engager comprises a third antigen binding domain or that the second and/or third antigen binding domain comprises SEQ ID NO:165.
Dimitrov et al. teach anti-CD16a bispecific killer cell engagers (BiKEs) that comprises instant SEQ ID NO: 165 (e.g. see SEQ ID NOs: 31 and 32, mbk6Fc and mbk6CH2D6, respectively, and sequence alignment below). Dimitrov et al. also teach that the activity of mbk6 was higher than that of mbkl 1 and mD1.22-Fc indicating a correlation of binding affinity of BiKEs to CD16A (mD1.22-Fc < mbkl 1 < mbk6) with their functional activity (e.g. see [0100]).
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Sequence alignments of Dimitrov et al.’s SEQ ID NOs: 31 or 32 and instant SEQ ID NO: 165:
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combined teachings of Buyse and Boutton or Sato et al. in view of Stein et al. as applied to claim 18 and 25, and incorporate the teachings of Dimitrov et al. to include that the cell engager comprises a third antigen binding domain or that the second and/or third antigen binding domain comprises SEQ ID NO:165.
Given that Dimitrov et al. teach a very potent anti-CD16a bispecific killer cell engagers (BiKEs) that comprises instant SEQ ID NO: 165; it would have been obvious to a skilled artisan to modify the cell engager taught by Buyse and Boutton or Sato et al. in view of Stein et al. to specifically include instant SEQ ID NOs: 165 with a reasonable expectation of success.
Regarding the claims that are drawn to the cell engager comprising a third antigen binding domain, a skilled artisan would have reasonably expected that by adding a third antigen binding domain to the T cell engager, the cell engager would have greater specificity for its target antigen and in turn greater efficacy. Therefore, it would have been obvious to a skilled artisan to add a third antigen binding domain to the cell engager taught by Buyse and Boutton or Sato et al. in view of Stein et al. with a reasonable expectation of success.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
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/GRACE H LUNDE/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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