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 .
Response to Amendment
Applicant’s remarks and amendments to the claims received 03/05/2026 have been acknowledged. Claim 1 has been amended. Claims 6 and 7 have been cancelled. Claims 22-24 are newly added.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2, and 8 are rejected under 35 U.S.C. 102(a)(1) and 35 USC 102 (a)(2) as being anticipated by Zhu et al (WO2018031947A1, of record), hereinafter Zhu.
Zhu discloses epitope-drug conjugates having an epitope recognized by autoimmune B cells or T cells (i.e. an autoantigen) conjugated to a drug via a linker, wherein the epitope is a desmoglein 1 (Dsg1) or desmoglein 3 (Dsg3) epitope and the drug is a cytotoxic drug such as doxorubicin (Para. 0008-0012). In some embodiments, the linker is a cleavable peptide linker allowing separation of the epitope and the drug (Para. 0053). The epitope can further comprise an N-or C-terminal Fc tag (Para. 0067). Further disclosed are compositions comprising the epitope-drug conjugate (Para. 0094).
Thus, Zhu meets the limitations of instant claims 1, 2, and 8.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 23 is rejected under 35 U.S.C. 103 as being unpatentable over Zhu, as applied to claims 1, 2, and 8 above, and further in view of Kumari et al (Kumari, Avnesh, Sudesh Kumar Yadav, and Subhash C. Yadav. "Biodegradable polymeric nanoparticles based drug delivery systems." Colloids and surfaces B: biointerfaces 75.1 (2010): 1-18), hereinafter Kumari.
The teachings of Zhu have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the toxin is embedded in a nanomolecule.
However, Kumari teaches that biodegradable nanoparticles are widely used as are drug delivery vehicles because they improve solubility, bioavailability, and retention time of encapsulated drugs. They also enable targeted delivery and controlled release, protect encapsulated drugs from premature degradation in the biological environment, and enhance tissues adsorption and cellular uptake. As a result, nanomedicines are more effective than traditional medicines (see Introduction).
It would have been obvious to one of ordinary skill in the art to modify the epitope-(cytotoxic) drug conjugate of Zhu such that the cytotoxic drug daunomycin is encapsulated in a nanoparticle. One of ordinary skill in the art would have been motivated to do so since nanoparticles protect encapsulated drugs from premature degradation in the biological environment, improve solubility and bioavailability, and enable targeted delivery and controlled release as taught by Kumari. As such, artisans would have been motivated to embed the toxin in a nanoparticle to gain these advantages. Therefore, one of ordinary skill in the art would expect the epitope-(cytotoxic) drug conjugate of Zhu such that the cytotoxic drug daunomycin is encapsulated in a nanoparticle to effectively treat a disease or disorder in a subject.
Claims 1, 8, 22, 23, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Rennie et al (Rennie, David P, et al. "An immunotoxin of ricin A chain conjugated to thyroglobulin selectively suppresses the anti-thyroglobulin autoantibody response." The Lancet 322.8363 (1983): 1338-1340, on the IDS of 10/31/2024), hereinafter Rennie, in view of Czajkowsky et al (Czajkowsky, Daniel M et al. “Fc-fusion proteins: new developments and future perspectives.” EMBO molecular medicine vol. 4,10 (2012): 1015-28. doi:10.1002/emmm.201201379), hereinafter Czajkowsky, Chen et al (Chen, Xiaoying et al. “Fusion protein linkers: property, design and functionality.” Advanced drug delivery reviews vol. 65,10 (2013): 1357-69. doi:10.1016/j.addr.2012.09.039), hereinafter Chen, and Kumari et al (Kumari, Avnesh, Sudesh Kumar Yadav, and Subhash C. Yadav. "Biodegradable polymeric nanoparticles based drug delivery systems." Colloids and surfaces B: biointerfaces 75.1 (2010): 1-18), hereinafter Kumari.
Rennie teaches a ricin A chain (toxin) conjugated via the heterobifunctional linker SPDP to human thyroglobulin (TG—a full-length protein) to produce a TG-ricin immunotoxin fusion protein. The TG-ricin immunotoxin specifically suppressed thyroglobulin autoantibody response of lymphocytes from patients with Hashimoto's thyroiditis, demonstrating that an autoantigen conjugated to a toxin provide a highly selective means for deleting autoantibody-secreting lymphocyte clones in patients with autoimmune disease (see Summary, Methods: Immunotoxin Preparation, and Discussion).
Rennie does not teach that the TG-ricin A toxin fusion protein comprises an Fc domain nor that the autoantigen TG is linked to the ricin A chain toxin via a peptide linker. Further, it is not specifically taught that the toxin is embedded in a nanomolecule.
However, Czajkowsky teaches that Fc-fusions are homodimers in which an Fc domain of an antibody (or immunoglobulin) is covalently linked to another protein. The presence of the Fc domain markedly increases the plasma half-life of the fused partner due to its interaction with the salvage neonatal Fc-receptor (FcRn), prolonging therapeutic activity of the fused partner. In addition, most Fc-fusions are expressed as homodimers and can be modified to polymerize into well-defined complexes containing twelve fused partners, increasing avidity and thus potency of the fused partner (first paragraph of Introduction).
Chen teaches that the most basic function of linkers in recombinant fusion proteins is to covalently join the functional domains (e.g. flexible linkers or rigid linkers) or to release them under desired conditions (cleavable linkers) (first paragraph under section 5). Several examples of peptide linkers are disclosed such as 1) GS linkers (flexible) which improve flexibility and solubility (section 3.1); 2) alpha helix forming linkers having the motif (EAAAK)n (rigid) which separate functional domains more efficiently than flexible linkers (section 3.2); and 3) and the disulfide linker (LEAGCKNFFPR↓SFTSCGSLE) (cleavable) which reduce steric hindrance, improve bioactivity, or achieve independent actions/metabolism of individual domains of recombinant fusion proteins after linker cleavage (section 3.3).
Kumari teaches that biodegradable nanoparticles are widely used as are drug delivery vehicles because they improve solubility, bioavailability, and retention time of encapsulated drugs. They also enable targeted delivery and controlled release, protect encapsulated drugs from premature degradation in the biological environment, and enhance tissues adsorption and cellular uptake. As a result, nanomedicines are more effective than traditional medicines (see Introduction).
It would have been obvious to one of ordinary skill in the art to modify the TG-ricin A chain toxin fusion protein such that a) the heterobifunctional SPDP (N-succinimidyl 3-(2-pyridyldithio)-propanoate) linker is replaced with a peptide linker; b) the fusion protein further comprises an Fc domain of an immunoglobulin; and c) the toxin is encapsulated in a nanoparticle (i.e. nanomolecule). One of ordinary skill in the art would have been motivated to do so since a peptide linker (similar to the SDPD linker) can be used is to join the functional domains of a fusion protein as taught by Chen and thus has the same purpose as the SDPD linker. An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Further, the Fc domain of an immunoglobulin can increase plasma half-life and thus prolong therapeutic activity of a fusion partner as taught by Czajkowsky. In addition, it can be modified to polymerize into larger complexes, increasing the avidity and thus potency of the fused partner as further taught by Czajkowsky. Lastly, nanoparticles protect encapsulated drugs from premature degradation in the biological environment, improve solubility and bioavailability, and enable targeted delivery and controlled release as taught by Kumari. As such, artisans would have been motivated to embed the toxin in a nanoparticle to gain these advantages. Therefore, one of ordinary skill in the art would reasonably expect an autoantigen-toxin fusion protein comprising full-length thyroglobulin linked to a nanoparticle embedded with ricin A chain toxin and further comprising an Fc domain to be able to effectively treat thyroiditis in a subject.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Rennie in view of Czajkowsky, as applied to claims 1, 8, 22, 23, and 24 and further in view of Stevens et al (Stevens, Natalie E., Allison J. Cowin, and Zlatko Kopecki. "Skin barrier and autoimmunity—mechanisms and novel therapeutic approaches for autoimmune blistering diseases of the skin." Frontiers in Immunology 10 (2019): 1089), hereinafter Stevens.
Rennie demonstrated that a platform where full-length autoantigens can be linked to toxins to selectively eliminate autoantibody-producing cells, offering an adaptable and targeted approach to treating autoimmune disease. Rennie did not teach that the full-length autoantigen conjugated to a toxin can be desmoglein 3.
However, Stevens teaches that pemphigus disorders are caused by autoantibodies targeting desmoglein proteins Dsg1 and Dsg3 (elected species) (Stevens et al, see 2nd paragraph of Introduction). Therefore, DSG1 or DGS3 can be identified as autoantigens and used in an autoantigen-toxin conjugate to selectively eliminate these harmful autoantibodies, thereby treating pemphigus disorder.
It would have been obvious to one of ordinary skill in the art to modify the autoantigen-toxin conjugate platform taught by Rennie such that the full-length autoantigen used is desmoglein 3 (DSG3) in order to treat pemphigus disorders. One of ordinary skill in the art would have been motivated to do so since autoantibodies targeting desmoglein 3 cause pemphigus disorders as taught by Stevens. As such, desmoglein 3 is a full-length autoantigen that can be used in an autoantigen-toxin conjugate to selectively eliminate these harmful autoantibodies, thereby treating pemphigus disorder. Therefore, one of ordinary skill in the art would have reasonably expected an autoantigen-toxin conjugate comprising a full-length desmoglein 3 protein linked to toxin can effectively eliminate autoantibodies targeting desmoglein 3 and thus treat pemphigus disorder in a subject.
Response to Arguments
Applicant's arguments filed 03/05/2026 have been fully considered but they are not persuasive.
With respect to the rejection under 35 USC 102, Applicant argues that claim 1 as amended, and claims dependent therefrom, recites a fusion protein comprising an Fc domain of an immunoglobulin, an autoantigen, and a peptide linker linking the protein to an ablative molecule or toxin. As such, Applicant asserts that Lu does not disclose the claimed fusion protein and is thus not anticipatory art.
In response to Applicant’s argument, the Examiner notes that Lu teaches epitope drug conjugates having an epitope recognized by autoimmune B cells or T cells (i.e. an autoantigen) conjugated to a drug via a linker, wherein the epitope is a desmoglein 1 (Dsg1) or desmoglein 3 (Dsg3) epitope, the drug is a cytotoxic drug such as doxorubicin (Para. 0008-0012), and the linker is a peptide linker. In some embodiments, the epitope can further comprise an N-or C-terminal Fc tag (Para. 0067). Thus, contrary to Applicant’s assertion, Lu does teach the instantly claimed fusion protein. Therefore, the 35 USC 102 rejection over Lu is maintained.
In agreement with applicant, the Examiner notes that cancellation of claim 7 renders moot the rejection of this claim under 35 USC 103.
Conclusion
No claims are 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 LIA TAYLOR whose telephone number is (571)272-6336. The examiner can normally be reached 8:30 - 5:00 M-F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MISOOK YU can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641