DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 4 June, 2025 has been entered.
Election/Restrictions
Applicants elected group I (noncovalently bound compounds) and the species anti-EGFR antibody and SLAMF7 polypeptide without traverse in the reply filed on 7 March, 2022 and the phone call with Patrick Finn, applicant’s representative, on 24 March, 2022. In the response of 1 Feb, 2023, applicants amended the claims so that they no longer read on this elected species.
Claims Status
Claims 1-3 and 31 are pending.
Claim 1 has been amended.
Claim 31 is new.
Maintained/Modified Rejections
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Stamova et al (Antibodies (2012) 1 p172-198) in view of Gajria et al (Expert Rev. Anticancer Ther. (2011) 11(2) p263-275), Jokiranta et al (J. Immunol. (1993) 151(4) p2124-2131), Sano et al (Biotechnology (1991) 9 p1378-1381, previously cited), and Chen et al (Nature (2017) 544, p493-510, previously cited).
Applicants are claiming a construct comprising a moiety that binds to an antigen presenting cell non-covalently bound to a moiety that binds to a cancer cell to increase the level of phagocytosis of the cancer cell. Dependent claims discuss the binding (biotin/streptavidin).
Stamova et al discuss bispecific antibody constructs for retargeting immune effector cells (title). By binding to both a tumor cell and an immune effector cell, the effector cell can be activated and the tumor cell eradicated (p175, 4th paragraph). Note that effector cells include T-cells, and other effector cells, such as NK cells, macrophages, and neutrophils (i.e. antigen presenting cells)(p175, 4th paragraph). This is to a human population, note p173, 2nd paragraph. Antibodies to cancer cell polypeptides, such as Her2, are given as the binder to cancer cells (p175, 4th paragraph). The way the bispecific antibody is constructed is not particularly limiting, and can include two antibodies fused together, or fragments of antibodies fused together (fig 1, p176). By using the dimerization and docking region of human cAMP dependent protein kinase A and the anchoring domain from A-kinase anchor protein, dimers and trimers of Fab fragments binding to different binding sites can be made (p177, 1st paragraph). This later forms a covalent complex due to the formation of a disulfide bond (p177, 1st paragraph).
The difference between this reference and the instant claims is that this reference doesn’t explicitly discuss non-covalent binding of the two fragments of the bispecific antibody, or specify SEQ ID 5 or trastuzumab.
Gajria et al discuss Her2 breast cancer and trastuzumab (title). Trastuzumab is a monoclonal antibody to Her2 (abstract). This reference links the anti-Her2 antibody of Stamova et al to trastuzumab.
Jokiranta et al discuss biotinylation of monoclonal antibodies (title); a standard procedure to exploit the specific interaction between biotin and avidin (abstract). Sano et al discusses a protein A-streptavidin construct to create a compound that will bind antibodies to biotin molecules (abstract). Note that both of these references are about 30 years old; the use of biotin and streptavidin to bind antibodies to various components has been known for a long time. These references discuss using avidin/streptavidin and biotin conjugates of antibodies to create non-covalent conjugates.
Chen et al discuss the role of SLAMF7 in the phagocytosis of hematopoietic tumor cells (title). A cell line that was not phagocytosed as wild type was phagocytosed by macrophages when transfected to express SLAMF7 (p494, 1st column, 2nd paragraph, continues to 2nd column). Immunoprecipitation experiments show that the polypeptide binds to MAC-1 on macrophages (p495, 2nd column, 3d paragraph). The reference explicitly states that SLAMF7 positive malignancies will be engulfed by phagocytes in response to a specific therapy (p497, 1st column, 2nd paragraph). This reference states that macrophages bind to SLAMF7 and phagocytose cells expressing the ligand.
Therefore, it would be obvious to use the streptavidin/biotin conjugation of Jokiranta et al and Sano et al to attach the two parts of the bispecific antibodies of Stamova et al, as a simple substitution of one known element (the binding of Stamova et al) for another (the binding of Jokiranta et al and Sano et al) yielding expected results (attachment of the two portions of the bispecific antibody). As Jokiranta et al teach that this is a standard procedure, and Stamova et al discuss a great deal of diversity in the bispecific antibodies, an artisan in this field would attempt this modification with a reasonable expectation of success.
Furthermore, it would be obvious to use the SLAMF7 of Chen et al for the effector cell binding agent of Stamova et al as a simple substitution of one known element (the effector cell binding agent of Stamova et al) for another (the macrophage binding agent of Chen et al) yielding expected results (binding of the construct to both tumor cells and macrophages to increase phagocytosis). As the SLAMF7 polypeptide of Chen et al does the same thing as the effector cell binding agent of Stamova et al, an artisan in this field would make this substitution with a reasonable expectation of success.
Stamova et al mention non-covalent binding of the antigen presenting cell binding moiety and a cancer binding moiety, such as an antibody that binds to Her2, which Gajria et al states trastuzumab is an example. Chen et al teaches SLAMF7 (identical to SEQ ID 5 of the instant claims) as a binder to antigen presenting cells. Thus, the combination of references render obvious claim 1.
Jokiranta et al and Sano et al render obvious using streptavidin/biotin to connect antibodies to other structures, rendering obvious claims 2 and 3.
Claim 31 describes intended targets, but does not give any structural limitations to the construct of Stamova et al, Chen et al, Jokiranta et al, and Sano et al, so the combination renders obvious this claim.
response to applicant’s arguments
Applicants argue that there is no suggestion or motivation in Stamova et al to select any given binding element, that multiple independent selections and modifications are needed, with no direction or expectation of success, that Stamova et al does not single out any antibody or secondary target, that Stamova et al does not suggest non-antibody protein, that antibodies bind to antigen recognition sites while SLAMF7 binds to a receptor, that the constructs of Stamova et al binds via CD3, which leads to cytotoxic granules, which is different than the phagocytosis of SLAMF7, that this is a teaching away from the combination, that Chen et al discusses SLAMF7 in the context of blood cancers, which is a teaching away from solid tumors, that Chen et al states that SLAMF7 is required on both the macrophage and the tumor cell, that Chen et al does not discuss using SLAMF7 outside of its natural production, that the rejection is based on hindsight, that applicants have shown that Chen et al’s experiment using blocking antibodies was incorrect, that an antibody with an anti-MAC1 region would inhibit phagocytosis, and that there is no reasonable expectation of success.
Applicant's arguments filed 4 June, 2025 have been fully considered but they are not persuasive.
Applicants argue that there is no suggestion or motivation to select any particular binding motif in Stamova et al, that the reference does not specify any particular target. In essence, applicants are arguing that, because Stamova et al lists a large number of possibilities, they are not obvious. This makes no logical sense. Assume a researcher discovers that a specific target will work, and publishes that information. Applicant’s argument makes no sense, because there are not multiple possibilities. Now assume that the researcher does more work and finds more targets that work. The system is now better understood, but by applicant’s argument, none of the disclosed embodiments are obvious, even though the system is better understood than one that is clearly obvious.
Applicants argue that Stamova et al is limited to antibodies, so no one would select an alternative binding unit. Stamova et al discusses antibodies, fragments of antibodies, including just the binding segment, and various combinations of different fragments (fig 1, p176, middle of page). There is no real difference between an antibody binding segment and a binding peptide – both are a polypeptide sequence that binds to something. Nor is it considered a great extrapolation from antibody to a binding polypeptide – a person of skill in the art is also a person of ordinary creativity, not an automaton (MPEP 2141(II)(C)). Stamova et al makes clear what is needed is targeting both a tumor cell and an activating receptor on the effector cell (p175, 4th paragraph); while the reference uses antibodies, it is clear that the teachings are not limited to that.
Applicants argue that antibodies bind to antigens while SLAMF7 binds to a receptor, MAC-1. This is a meaningless distinction. If an antibody was generated that bound to MAC-1, with a sequence that just happen to coincide with that of SLAMF7, the binding would be identical, but it would be considered an antigen binder rather than a receptor binder. Likewise, if the variable region of an antibody that bound to MAC-1 was excised from the antibody, it would bind to a receptor, rather than an antigen. In other words, this is merely a difference in terminology between different branches of biology.
Applicants argue that the antibodies of Stamova et al bind to CD3, which has a different effect than the SLAMF7 of Chen et al. Applicants are picking specific embodiments of Stamova et al and ignoring more general teachings. As noted above, Stamova et al teaches what is necessary is binding to both the target cell and an activating receptor on an effector cell (p175, 4th paragraph), not any specific receptor on a specific cell having a specific effect. The teachings of a reference are relevant for all they contain, not just specific examples (MPEP 2123(I)). Nor have applicants explained why a discussion of embodiments that use a different mechanism would lead a person to ignore the broader teachings of the reference.
Applicants argue that Chen et al teaches SLAMF7 in the context of blood cancers, and that this teaches away from solid tumors. There are a few issues with this argument. Chen et al explicitly state that SLAMF7 activates an effector cell; this is what Stamova et al teach is required for the constructs they describe. Second, the polypeptide is expressed by the blood cancers; why would a person make a construct for something already there? Third, this is an intended use; which does not have patentable weight except as how it changes the structure. Finally, applicants have not stated why a receptor binding polypeptide that meets all the requirements of Stamova et al would not be used to make a similar construct because it is expressed on blood cancers, the requirement for a teaching away.
Applicants argue that SLAMF7 is required on both the cancer and the macrophage to cause phagocytosis. Applicants have not explained why this makes the rejection invalid. There is no evidence on record showing that a sufferer of these cancers will generally lack such macrophages.
Applicants argue that Chen et al does not suggest using SLAMF7 outside of its endogenous production. While true, that limitation is made up by Stamova et al. Applicants argue that this is evidence of hindsight, but have not demonstrated why ordinary creativity would preclude a person of skill in the art from realizing that a polypeptide that met all the requirements listed in the prior art would be effective for its intended purpose.
Applicants argue that some of the experiments of Chen et al gave different results in their hands. There are a few issues with this argument. First, applicants have not explained how these differences would lead a person to not use the sequence of Chen et al. Second, obviousness is determined by what a person of skill in the art would know as of applicant’s priority date (text of 35 USC 103). Such a person would not have applicant’s data as of that date.
Applicants argue that, if the construct was administered with an anti-MAC1 antibody, it will not be effective. Chen et al expressly state that SLAMF7 works via Mac-1 (title), so blocking MAC1 would be expected to cause it to be ineffective. However, applicants have not explained how this overcomes the rejection.
Finally, applicants argue that the rejection has not stated why there is a reasonable expectation of success. Applicants have not described why the reason given in the rejection, that Stamova et al teaches that the bispecific binders work over a wide range of antigens and binders, is improper or incorrect.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658