DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claim listing filed on February 27, 2026 is pending. Claims 2-11, 14-21, 25, 28-31, and 33-36 are canceled. Claims 1 and 12 are amended. Claims 22-24, 26-27, and 32 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected invention or species. Claims 1 and 12-13 are examined upon their merits.
Withdrawn Objections and Rejections
Applicant’s cancelation of Claims 7-9, 11, 17, 21, and 33-34 have rendered all previous objections and rejections directed to these claims moot.
The rejection of Claims 1 and 13 under 35 U.S.C. 112(b) as being indefinite is withdrawn in view of Applicant’s amendments. Specifically, “a targeting moiety comprising a recombinant heavy-chain-only antibody (VHH)” as recited in Claim 1 provides proper structure for the function of binding SIRP1α. Similarly, “an R149A, L153A, or M148A mutation” as recited in Claim 1 is interpreted as the structure that inherently performs the recited functions of conferring reduced affinity for or activity at its receptor wherein the reduced affinity or activity of the mutated human IFNα2 is restorable by the targeting moiety. Because Applicant traverses that threshold values for “reduced” and “restorable” are not necessary for definiteness (remarks filed 02/27/2026, page 5), Examiner interprets these terms with the broadest reasonable interpretation to encompass any level of reduction or restoration in activity (even a non-significant change) quantified by any means understood in the art prior to filing. Ultimately, the recited function is an inherent property of an IFNα2 comprising a R149A, L153A, or M148A mutation (MPEP § 2112.01).
The rejection of Claims 1 and 12-13 under 35 U.S.C. 103 as being unpatentable over Garcin et al. Nat Commun. 2014 and Morrison et al. US 2016/0115242 in view of Pincetic et al. US 11,779,642 is withdrawn in view of Applicant’s amendments. Specifically, the cited references fail to teach wherein the targeting moiety comprises a recombinant VHH that binds to SIRP1α as required by amended Claim 1.
The rejection of Claims 1 and 13 on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-7, and 11 of U.S. Patent No. 11,384,154 is withdrawn due to the terminal disclaimer filed on 02/27/2026.
The rejection of Claims 1 and 13 on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 6-8, and 11-13 of U.S. Patent No. 10,988,538 is withdrawn due to the terminal disclaimer filed on 02/27/2026.
Claim Objections (New, necessitated by amendment)
The numbering of claims is not in accordance with 37 CFR 1.126 which requires the original numbering of the claims to be preserved throughout the prosecution. When claims are canceled, the remaining claims must not be renumbered. When new claims are presented, they must be numbered consecutively beginning with the number next following the highest numbered claims previously presented (whether entered or not).
Claim 21 is missing. The remarks filed 02/27/2026 state that Claim 21 was canceled without prejudice or disclaimer (page 1). Therefore, it is interpreted that Claims 14-21 are canceled, not Claims 14-20 as currently recited. Appropriate correction is required.
Claim Rejections - 35 USC § 112 (Maintained)
The rejection of Claim 12 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 is maintained.
Claim 12 recites wherein the signaling agent comprises both “(a) one or more mutations conferring reduced or ablated affinity for a receptor relative to a wild type signaling agent and (b) one or more mutations conferring reduced affinity or activity for a receptor relative to a wild type signaling agent; and wherein the receptors are different.” These phrases are considered indefinite functional language because the features (the mutations) are defined by what they do (reduce or ablate affinity or activity for a receptor) rather than by what they are (MPEP § 2173.05(g)). The metes about bounds of the mutations cannot be readily determined, and Claim 12 is rejected as being indefinite.
Applicant's arguments filed February 27, 2026 have been fully considered but they are not persuasive. Applicant addresses mutations described by their function on page 2 of remarks and states that the rejection is overcome by the cancelation of Claim 11. However, the indefinite language is recited in Claim 12 as outlined above. The broadest reasonable interpretation of Claim 12 is that the mutations are in addition to the R149A, L153A, or M148A mutations recited in Claim 1. Therefore, there is no structure recited for the mutations of Claim 12, and the rejection is maintained.
Claim Rejections - 35 USC § 112 (New, necessitated by amendment)
Claim 13 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 13 recites the limitation "the one or more mutations" in line 1. There is insufficient antecedent basis for this limitation in the claim. For the purpose of compact prosecution, “the one or more mutations” in Claim 13 is interpreted as “the R149A, L153A, or M148A mutation allows for attenuation of activity” which has proper antecedent basis in Claim 1. Examiner interprets “attenuation” as synonymous with “reduced” and encompasses any level of attenuation (even a non-significant change) quantified by any means understood in the art prior to filing. Ultimately, the recited function (attenuation of activity) is an inherent property of an IFNα2 comprising a R149A, L153A, or M148A mutation (MPEP § 2112.01).
Claim Rejections - 35 USC § 112 (Modified, necessitated by amendment)
The rejection of Claims 1 and 12-13 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 is maintained. 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.
Applicant's arguments filed February 27, 2026 have been fully considered but they are not persuasive. Applicant argues that amended Claim 1 has proper written description because an anti-mouse SIRP1α VHH/human IFN Q124R chimera is taught in the specification wherein the Q124R mutant is representative of an attenuated human IFNα2 mutant that can be assayed in vivo in a murine model as evidenced by Garcin et al. Nat. Comm 2014 (of record). Between the teachings of the instant specification and Garcin, an IFNα2 comprising SEQ ID NOs: 46 or 47 and an R149A, L153A, or M148A mutation has proper written description. However, Claim 1 is directed to an IFNα2 comprising at least 98% identity to SEQ ID NOs: 46 or 47 and an R149A, L153A, or M148A mutation. Because SEQ ID NOs: 46 and 47 comprise 165 amino acid residues, any combination of three amino acids (2% of 165) can be inserted, deleted, or substituted (of record in non-final office action filed 10/02/2025). One of the mutations is required to be R149A, L153A, or M148A. Thus, the modified IFNα2 of Claim 1 can comprise any combination of two amino acids that are inserted, deleted, or substituted in addition to R149A, L153A, or M148A. Neither the instant specification or Garcin evaluate how combining other mutations with R149A, L153A, or M148A affects IFNα2 function, such as the mutations described in Claim 12. Because of the 2% variation in sequence identity, the modified IFNα2 of Claim 1 is still directed to a genus that lacks proper written description.
Further, “a recombinant VHH that recognizes and binds to SIRP1α” as recited in Claim 1 describes a genus of VHH nanobodies by the antigen to which they bind. It is understood in the art that hundreds of different CDR sequences can bind a single antigen with varying degrees of affinity. In Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), the Federal Circuit explained that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself and cannot rely upon the "newly characterized antigen" test. In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional (MPEP § 2163.II). Id. In re Xencor, Inc., No. 24-1870 (Fed. Cir. Mar. 13, 2025), it was decided that a claim directed to a method of treating by administering an anti-C5 antibody lacked sufficient written description because the specification did not provide a representative number of species to sufficiently support the broad genus of anti-C5 antibodies being claimed (page 6). The specification only disclosed one anti-C5 antibody, which was found insufficient given the “various specificities and epitopes” of the genus (page 6). The case law supports the lack of written description for the instantly claimed genus of anti-SIRP1α VHH antibodies.
Claims 1 and 12-13 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 enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The specification is not enabled for the genus of modified IFNα2 comprising at least 98% sequence identity to SEQ ID NOs: 46 or 47 (of record in non-final office action filed 10/02/2025). Amended Claim 1 is now directed to a genus of anti-SIRP1α VHH. It is of record in the non-final office action filed 10/02/2025 that antibodies that bind SIRP1α were known in the art prior to filing; however, VHH (also known as nanobodies) that bind SIRP1α were not sufficiently understood or publicly available prior to filing. Nanobodies differ from antibodies and antibody fragments in that they only possess three heavy chain variable CDRs and no light chain variable CDRs and the heavy chain CDR3 is significantly longer than a conventional antibody. It was understood in the art prior to filing how nanobody CDRs can be grafted onto a humanized VHH template (as evidenced by Vincke et al. J Biol Chem. 2009); however, it was not understood until after the effective filing date how to graft CDRs from conventional antibodies (6 CDRs) onto nanobody frameworks, and even then, the method required optimization using a phage library (Wagner et al. Int. J. Mol. Sci. 2018, 19, 3444; abstract and Fig. 1). Therefore, even though conventional anti-SIRP1α antibodies were sufficiently understood in the art prior to filing, this does not translate to anti-SIRP1α VHH as recited in Claim 1.
The specification teaches the functional properties of a VHH directed against murine SIRP1α in Example 1 but does not provide amino acid structures for the anti-murine SIRP1α VHH, how the anti-murine SIRP1α VHH was produced, or where the anti-murine SIRP1α VHH was commercially purchased. The specification teaches general methodologies for how anti-SIRP1α VHH can be manufactured (pages 70-72), but performing these methodologies to obtain a representative number of the anti-SIRP1α VHH would constitute undue experimentation. For example, screening a library of VHH to determine which structures bind SIRP1α and verifying the hits in binding assays (page 71) is a substantial inventive contribution that one of ordinary skill would have to perform in order to make and use the instantly claimed chimeric proteins with a reasonable expectation of success.
Applicant's arguments filed February 27, 2026 have been fully considered but they are not persuasive. Applicant argues that amended Claim 1 is enabled because it recites a recombinant VHH that binds SIRP1α and an IFNα2 comprising at least 98% to SEQ ID NOs: 46 or 47 and an R149A, L153A, or M148A mutation. While being enabling for an IFNα2 comprising SEQ ID NOs: 46 or 47 and an R149A, L153A, or M148A mutation (based on the specification and the teachings of Garcin et al.; of record), the specification is not enabled for the genus of modified IFNα2 comprising 2% variation in SEQ ID NOs: 46 or 47 and the genus of anti-SIRP1α VHH. The rejection is maintained.
Double Patenting (Maintained)
1. The provisional rejection of Claims 1 and 13 on the ground of nonstatutory double patenting as being unpatentable over claims 198, 200, 210-211, and 213 of copending U.S. App. No. 17/042,512 is maintained.
Applicant's arguments filed February 27, 2026 have been fully considered but they are not persuasive. Applicant argues that there is nothing in copending U.S. App. No. 17/042,512 that would allow a person skilled in the art to envision the particular recited chimeric protein of the present claims. Examiner maintains that the copending claims teach a chimeric protein comprising a modified IFNα2 that has at least 95% identity to SEQ ID NOs: 1 or 2 and an R149A mutation (Copending Claims 198 and 200) wherein copending SEQ ID NOs: 1 and 2 are 100% identical to instant SEQ ID NOs: 46 and 47, respectively. The chimeric protein comprises a targeting moiety that is a VHH (copending Claim 210) and binds to SIRP1α (copending Claim 213). Therefore, the chimeric protein of instant Claim 1 is either anticipated and/or rendered obvious by the copending claims, and the rejection is maintained.
2. The provisional rejection of Claims 1 and 13 on the ground of nonstatutory double patenting as being unpatentable over claims 88-89, 93, 95, and 97-98 of copending U.S. App. No. 18/625,774 is maintained.
Applicant's arguments filed February 27, 2026 have been fully considered but they are not persuasive. Applicant argues that there is nothing in the disclosure of the present application that would allow a person skilled in the art to envision the particular sequence-defined subject matter of the claims of copending U.S. App. No. 18/625,774. The sequences listed in copending Claim 88 are for a SIRP1α targeting “single-domain antibody” which is defined to be synonymous with a “VHH” as defined on page 2 of the copending specification. By reciting specific sequences, the copending claims are directed to chimeric protein species of the instantly claimed chimeric protein genus. A species anticipates a claimed genus (MPEP § 2131.02), and the rejection is maintained.
3. The rejection of Claims 1 and 13 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-2, 5-6, 8, and 12 of U.S. Patent No 12,084,497 in view of Garcin et al. Nat Commun. 2014 (of record) and Morrison et al. US 2016/0115242 (of record) is maintained.
Applicant's arguments filed February 27, 2026 have been fully considered but they are not persuasive. Applicant argues that there is nothing in the disclosure of the present application that would allow a person skilled in the art to envision the particular sequence-defined subject matter of the patented claims of U.S. 12,084,497. The sequences listed in patented Claim 1 are for a SIRP1α targeting “single-domain antibody” which is defined to be synonymous with a “VHH” as defined in col. 2 lines 20-22 of the patented specification. By reciting specific sequences, the patented claims are directed to anti-SIRP1α VHH species of the instantly claimed anti-SIRP1α VHH genus. A species anticipates a claimed genus (MPEP § 2131.02), and the rejection is maintained.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH COOPER PATTERSON whose telephone number is (703)756-1991. The examiner can normally be reached Monday - Friday 8:00am - 5:00pm EST.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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