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 .
Status of Application/Amendments/Claims
Applicant’s response filed on 6/2/2026 has been considered. Claims 15-21 are newly added. Claims 7 and 8 are amended. Claims 7, 8 and 15-21 are pending and are the subject of the present Official action. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Priority
Applicant’s claim for the benefit of a prior-filed application PRO 63/162,796, 63/166,915 and PCT/US2022/020990 filed on 3/18/2021, 3/26/2021 and 3/18/2022, respectively, under 35 U.S.C 119(e) or under 35 U.S.C 120, 121 or 365(c) is acknowledged.
Accordingly, the effective priority date of the instant application is granted as 3/18/2021.
Withdrawn Rejections
The 35 U.S.C. 103 rejection of claims 7 and 8 has been withdrawn in light of applicants claim amendments which describe using a MuSK Ig2 blocking antibody agent that specifically binds to Ig2 relative to Ig1 and Ig3 domains.
The nonstatutory double patenting rejections of claims 7 and 8 over co-pending Application No: 17/604,279 and co-pending Application No: 17/769,165 have been withdrawn in light of applicants claim amendments which describe using a MuSK Ig2 blocking antibody agent that specifically binds to Ig2 relative to Ig1 and Ig3 domains.
Claim Interpretation
Claims 7 and 8 describe administering a MuSK Ig2 blocking antibody agent. Taking the broadest reasonable interpretation, this reads on any antibody which binds to a MuSK Ig2 target and consequently prevents other antibodies or molecules from binding to it, thereby interfering with its function.
New 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 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.
Claims 7-8 and 15-21 are rejected under 35 U.S.C. 103 as being unpatentable over Fallon et al. WO 2020/214987, published 10/22/2020 (hereinafter Fallon, reference of record) in view of Yilmaz et al. "MuSK is a BMP co-receptor that shapes BMP responses and calcium signaling in muscle cells." Science signaling 9.444 (2016): ra87-ra87 (hereinafter Yilmaz, reference of record) and Takata et al. "Characterization of pathogenic monoclonal autoantibodies derived from muscle-specific kinase myasthenia gravis patients." JCI insight 4.12 (2019): e127167 (hereinafter Takata). This rejection is newly applied to address applicants claim amendments on 6/2/2026. A response to applicant’s traversal follows the rejection below.
Claims 7 and 8: Fallon describes a method of treating a subject afflicted with neurodegeneration or impaired cognition by reducing the activity of a BMP-MuSK polypeptide complex (Fallon, para 8 and claim 1). Fallon describes how MuSK acts as a BMP co-receptor and how inhibiting its activity may serve as a treatment against neurodegeneration (Fallon, para 5-7 and 89). Fallon explores ways to reduce BMP receptor activity by administering pharmaceutical compositions that modulates MuSK Ig3 including antibodies, oligonucleotides and polypeptides (Fallon, para 8). In particular, Fallon states that the MuSK NG agonizing agent may be an antibody that binds to a MuSK polypeptide (e.g. an antibody that blocks MuSK Ig3) so that it fails to effectively participate in interaction(s) with BMP resulting in a decrease in BMP receptor activity (Fallon, para 7, 100 and 106-109). Although Fallon describes specific embodiments targeting the Ig3 domain of MuSK, Fallon does not disclose a MuSK Ig2 targeting antibody that reduces the activity of a BMP receptor complex.
Claim 15: Fallon presents this as a method to increase neurogenesis in a subject (Fallon, para 77, 88 and 89). Fallon states that “the present disclosure contemplates that manipulating the BMP pathway in NSCs is an attractive target for regulating neurogenesis in the adult brain (Fallon, para 88).
Claims 17: Fallon describes BMP receptors including ALK6 and describes MuSK NG agonizing agents thereof (Fallon, para 104).
Claims 18-19: Fallon provides embodiments wherein the MuSK blocking antibody is a monoclonal antibody comprising two heavy chains and two light chains (Fallon, para 110-114 and claims 10-11).
Claims 20-21: Fallon describes treating neurodegenerative diseases including Alzheimer’s disease and Becker muscular dystrophy (Fallon, para 200-201).
Claims 7 and 8: However, Ig2 is a known part of the ectodomain of MuSK. As shown by Yilmaz in Fig 7 (reproduced below), MuSK is a transmembrane tyrosine kinase whose ectodomain comprises three immunoglobulin-like (Ig1, Ig2, Ig3) domains. The disclosure of Yilmaz and Fig 1, 7 shows that both Ig2 and Ig1 play an important role in this interaction given their integral part in the MuSK ectodomain.
Claims 16-17: Yilmaz describes type I BMP receptors including ALK6 which acts in a ligand-independent manner (Yilmaz, abstract and intro para 2). Yilmaz characterizes the MuSK ectodomain (comprising Ig1, Ig2, Ig3, CRD) and its binding to BMP4 (Yilmaz, Fig 1).
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Claims 7 and 8: Furthermore, MuSK Ig2 blocking antibodies that specifically bind to a MuSK Ig2 domain relative to Ig1 and Ig3 domains are known in the art as shown by Takata. Takata explores the binding properties of MuSK specific recombinant mAbs (Takata, pg 4 and Fig 1). In particular, Takata discloses an embodiment to a MuSK Ig2 blocking antibody (Takata, pg 5 and Fig 3B). Takata verifies this by generating a MuSK Ig2 only variant (ΔIg1 and ΔIg3) and observed binding but did not observe binding in the case of a MuSK ΔIg2 variant (Takata, pg 5 and Fig 3B).
It would have been prima facie obvious to one of ordinary skill in the art to administer a MuSK Ig2 blocking antibody as described by Takata that reduces the activity of the BMP receptor complex as a method for treating neurodegeneration or increasing neurogenesis as described by Fallon. It would have been a matter of combining prior art elements according to known methods to yield predictable results given that Fallon describes a similar strategy of administering a MuSK Ig3 blocking antibody agent that reduced the activity of the BMP receptor complex as an effective a method for treating neurodegeneration (Fallon, para 7, 100 and 106-109). One of ordinary skill in the art would be motivated to administer a MuSK Ig2 blocking antibody given the close structural and functional similarity of Ig2 to Ig3 which make up the MuSK ectodomain as shown in the figure above, leading one of ordinary skill to consider them both as effective blocking targets for modulating the BMP-MuSK binding process. Furthermore, Takata expressly describes methods to generate and verify binding of a monoclonal MuSK Ig2 blocking antibody. One would have reasonable expectation of success since there are reliable methods for performing alternative splicing to generate MuSK proteins and blocking antibodies thereof. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the claimed invention to have been prima facie obvious to at the time the invention was made.
Response to Traversal
It is noted that although the rejection is newly applied, some of applicant’s arguments are still relevant and are addressed below.
Applicant traverses the rejection by arguing that Fallon teaches that the Ig3 domain specifically interacts with the BMP receptor and does not disclose the role of the Ig2 domain of MuSK. Applicant points to the specification which describes the binding of BMP receptors to the Ig2 domain of MuSK. Applicant argues that one of skill in the art would not be motivated to target the Ig2 domain of MUSK, which includes a different structure and interacts with a different ligand (ALK) for increasing neurogenesis. Applicant argues that Yilmaz only experiments with the entire MuSK ectodomain and found that the Ig3 was necessary for high affinity BMP4 binding and does not describe the specific functional role of Ig2.
This argument has been fully considered, but is not found persuasive since Yilmaz shows that the ectodomain of MuSK comprises three immunoglobulin-like (Ig1, Ig2, Ig3) domains which are both structurally/functionally similar and integral to the ectodomain. The disclosure of Fallon clearly establishes Ig3 as an effective target for blocking BMP receptor complex signaling. Given that Ig2 and Ig3 are adjacent within the MuSK ectodomain, one of ordinary skill would logically consider targeting Ig2 using the same strategy. Furthermore, the prior art teaches MuSK Ig2 blocking antibodies that specifically bind to a MuSK Ig2 domain relative to Ig1 and Ig3 domains are known in the art as shown by Takata. Thus, it would have been prima facie obvious to one of ordinary skill in the art to administer a MuSK Ig2 blocking antibody that reduces the activity of the BMP receptor complex as a method for treating neurodegeneration or increasing neurogenesis. Although applicant argues that Fallon does not disclose the role of the Ig2 domain of MuSK, Yilmaz clearly shows that this is a known domain and a viable blocking target. One cannot show non-obviousness by attacking references individually where the rejections are based on combinations of references, see MPEP 2145.
Nonstatutory Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the "right to exclude" granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Langi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717 .02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP 706.02(1)(1) - 706.02(1)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 7-8 and 15-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-85, 17-19 and 22-31 of co-pending Application No: 17/769,165 (US Patent Application Publication Number US 2023/0304012) in view of Yilmaz (supra) and Takata (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims would anticipate the instant claims if they were available as prior art. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. This rejection is newly applied to address applicants claim amendments on 6/2/2026. A response to applicant’s traversal follows the rejection below.
Claims 7-8 and 15-21: The co-pending claims describes a method of treating a subject afflicted with neurodegeneration or increasing neurogenesis by increasing the level or activity of a MuSK polypeptide lacking a functional Ig3 domain and/or reducing the level or activity of a BMP-MuSK polypeptide complex wherein the MuSK comprises a functional Ig3 domain (Claims 1-3). The co-pending claims describes embodiments wherein a further pharmaceutical composition is administered that increases the altered splicing of MuSK transcripts (Claims 19-27). The co-pending claims describes describe wherein the agent is an antibody or polyclonal antibody (Claims 12-14). The co-pending claims describes alterations wherein one or more exons are skipped (Claims 24-29). Although the co-pending claims describes a MuSK polypeptide lacking a functional Ig3 domain and a BMP-MuSK polypeptide complex wherein the MuSK comprises a functional Ig3 domain, the co-pending claims do not disclose a MuSK polypeptide lacking a functional Ig2 domain, BMP-MuSK polypeptide complex comprising a functional Ig2 domain or agents that act on MuSK Ig2.
However, it would have been prima facie obvious to one of ordinary skill in the art to administer a MuSK Ig2 blocking antibody, targeting the Ig2 domain rather than the Ig3 domain, for reducing the activity of a BMP receptor complex as a method for treating neurodegeneration or increasing neurogenesis. It would have been a matter of combining prior art elements according to known methods to yield predictable results given that the co-pending claims describes a MuSK Ig3 blocking antibody agent which increase the activity of a MuSK polypeptide that lacks a functional Ig3 domain. The prior art teaches that MuSK Ig2 blocking antibodies that specifically bind to a MuSK Ig2 domain relative to Ig1 and Ig3 domains are known in the art as shown by Takata. Takata explores the binding properties of MuSK specific recombinant mAbs (Takata, pg 4 and Fig 1). In particular, Takata discloses an embodiment to a MuSK Ig2 blocking antibody (Takata, pg 5 and Fig 3B). Takata verifies this by generating a MuSK Ig2 only variant (ΔIg1 and ΔIg3) and observed binding but did not observe binding in the case of a MuSK ΔIg2 variant (Takata, pg 5 and Fig 3B). One of ordinary skill in the art would be motivated to administer a MuSK Ig2 blocking antibody rather than a Ig3 blocking antibody given that Fallon expressly considers the interaction of Ig3 relative to the Ig2 and that both immunoglobulins comprise the ectodomain of MuSK and play important roles in the BMP-MuSK binding complex. One would have reasonable expectation of success since there are reliable methods for performing alternative splicing to generate ΔIg2 MuSK proteins and blocking antibodies thereof as described by Yilmaz. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the claimed invention to have been prima facie obvious to at the time the invention was made.
Response to Traversal
It is noted that although the rejection is newly applied, some of applicant’s arguments are still relevant and are addressed below.
Applicant traverses the rejection by arguing that the pending claims are directed towards modulating the Ig3 domain and that Yilmaz does not describe any functional role of the Ig2 domain of MuSK. Applicant argues that it was not until the present specification was filed until the unique interaction and function of the Ig2 domain with ALK that it was contemplated to specifically target the MuSK Ig2 domain to increase neurogenesis.
This argument has been fully considered, but is not found persuasive since Yilmaz shows that the ectodomain of MuSK comprises three immunoglobulin-like (Ig1, Ig2, Ig3) domains which are both structurally/functionally similar and integral to the ectodomain. The disclosure of the pending claims clearly establishes Ig3 as a target for blocking BMP receptor complex signaling. Furthermore, MuSK Ig2 blocking antibodies that specifically bind to a MuSK Ig2 domain relative to Ig1 and Ig3 domains are known in the art as shown by Takata. Given that Ig2 and Ig3 are adjacent within the MuSK ectodomain, one of ordinary skill would logically consider targeting Ig2 using the same strategy. Thus, it would have been prima facie obvious to one of ordinary skill in the art to administer a MuSK Ig2 blocking antibody that reduces the activity of the BMP receptor complex as a method for treating neurodegeneration or increasing neurogenesis.
Conclusion
No claims 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 extension fee 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 Dr. ALEXANDER NICOL whose telephone number is (571)272-6383. The examiner can normally be reached on M-F 8-5 EST.
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Alexander Nicol
Patent Examiner
Art Unit 1633
/ALEXANDER W NICOL/Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
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