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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 09/01/2026 has been entered.
Response to Amendment
Applicant’s remarks and amendments to the claims filed 09/01/2026 have been acknowledged. Claims 1, 2, 8, and 23 have been canceled. Claims 22 and 24 have been amended. Claim 25 is newly added. The claim amendments overcome the rejection under 35 USC 102(a)(1)/(a)(2) previously set forth in the Final Rejection of 04/01/2026.
Priority
The instant application filed on 09/20/2024 is a 371 of PCT/US2023/016055 filed on 03/23/2023. The PCT has provisional applications 63/322,699 filed 03/23/2022 and 63/322,702 filed on 03/23/2022. While the instant application filed 09/20/2024 discloses nanomolecules embedded with an ablative molecule or toxin, the PCT and provisional applications do not. To comply with the written description requirement of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, or to be entitled to an earlier priority date or filing date under 35 U.S.C. 119, 120, 365, or 386, each claim limitation must be expressly, implicitly, or inherently supported in the originally filed disclosure. Therefore, claims 22 and 24 (currently under examination) which recite the limitation “a nanomolecule embedded with daunomycin” receive the date of 09/20/2024.
Claim Interpretation
Claims 22 and 24 recite a Markush grouping of alternative ablative molecules or toxins selected from a nanomolecule embedded with daunomycin, pseudomonas exotoxin, diphtheria toxin, a ribosome-inactivating protein, and a bleomycin. Thus, “a nanomolecule embedded with daunomycin” is an element of the Markush group; and, for the purposes of examination, other ablative molecules/toxins recited in the Markush group will not be considered embedded in a nanomolecule.
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 22 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Rennie et al (Rennie, David P, et al. The Lancet 322.8363 (1983): 1338-1340, on the IDS of 10/31/2024), hereinafter Rennie, in view of Stevens et al (Stevens, Natalie E. et al. Frontiers in Immunology 10 (2019): 1089, of record), hereinafter Stevens, Czajkowsky et al (Czajkowsky, Daniel M et al. “EMBO molecular medicine vol. 4,10 (2012): 1015-28. doi:10.1002/emmm.201201379, of record), hereinafter Czajkowsky, and Chen et al (Chen, Xiaoying et al. Advanced drug delivery reviews vol. 65,10 (2013): 1357-69. doi:10.1016/j.addr.2012.09.039, of record), hereinafter Chen.
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). Thus, Rennie demonstrates a platform in which full-length autoantigens are linked to toxins to selectively eliminate autoantibody-producing cells, offering an adaptable and targeted approach to treating autoimmune disease.
Rennie does not teach that a) the full-length autoantigen conjugated to a toxin can be desmoglein 3; b) the fusion protein comprises an Fc domain; c) the toxin is linked to the autoantigen via a peptide linker; or d) the toxin is embedded in a nanomolecule.
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.
Czajkowsky further 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 further 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).
It would have been obvious to one of ordinary skill in the art to use an autoantigen-toxin conjugate platform established by Rennie such that a) the full-length autoantigen used is desmoglein 3 (DSG3); b) the linker is a peptide linker; and c) the fusion protein further comprises an Fc domain of an immunoglobulin. 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. Further, a peptide linker can be used 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). Additionally, the Fc domain of an immunoglobulin can increase plasma half-life and thus prolong therapeutic activity of a fusion partner as taught by Czajkowsky. The Fc domain can also be modified to polymerize into larger complexes, increasing the avidity and thus potency of the fused partner as further taught by Czajkowsky. Therefore, one of ordinary skill in the art would reasonably expect an autoantigen-toxin conjugate comprising a full-length desmoglein 3 protein linked to ricin A chain toxin via a peptide linker and further comprising an Fc domain to be able to effectively treat pemphigus disorder in a subject.
Claims 22 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Rashidian et al (WO2023114847A2), hereinafter Rashidian, in view of Vincent et al (US20060013809A1), hereinafter Vincent, and Chen et al (Chen, Xiaoying et al. Advanced drug delivery reviews vol. 65,10 (2013): 1357-69. doi:10.1016/j.addr.2012.09.039, of record), hereinafter Chen, as evidenced by Madhumathi et al (Madhumathi, J., and Rama S. Verma. Current opinion in microbiology 15.3 (2012): 300-309), hereinafter Madhumathi. [NOTE: WO2023114847A2 claims priority to U.S. Provisional Application No. 63/289,595 filed 12/14/2021.].
Rashidian discloses fusion proteins comprising an autoreactive antigen and an immunoglobulin Fc region for the treatment of autoimmune diseases, wherein the autoreactive antigen is desmoglein 3 (Dsg3) or Dsg1 and the effector-cell binding domain is (Abstract; Summary of Invention: Para. 0007 and Para. 0009; and Para. 0096). In some embodiments, the fusion protein further comprises a therapeutic moiety such as a toxin (Para. 0009). The autoimmune disease to be treated by the fusion protein includes skin blistering disorders such as pemphigus vulgaris (Para. 0089 and 0093).
Rashidian does not teach that the toxin is pseudomonas exotoxin, diphtheria toxin, a ribosome-inactivating protein, or a bleomycin nor that the toxin is conjugated to the autoantigen via a peptide linker.
However, Vincent teaches that immunotoxins (i.e. fusion proteins) comprising a targeting domain and a toxin domain can be used to treat autoimmune disorders (Para. 0040), wherein the toxin can be, for example, ricin, pseudomonas exotoxin, bryodin, gelonin, α-sarcin, aspergillin, angiogenin, saporin, abrin, pokeweed antiviral protein, diphtheria toxin, or chemotherapeutic agents such as bleomycin (Para. 0040 and Para. 0058). As evidenced by Madhumathi, ricin bryodin, gelonin, angiogenin, saporin, abrin, and pokeweed antiviral protein are ribosome-inactivating proteins (see Introduction).
Chen further 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).
It would have been obvious to one of ordinary skill in the art to modify the fusion protein disclosed by Rashidian such that a) the toxin is selected from pseudomonas exotoxin, a ribosome-inactivating protein (e.g. ricin bryodin, gelonin, angiogenin, saporin, abrin, pokeweed antiviral protein), diphtheria toxin, or bleomycin and b) the toxin in conjugated to the autoreactive antigen via a peptide linker. One of ordinary skill in the art would have been motivated to do so since fusion proteins comprising a targeting domain and a toxin such as ribosome-inactivating proteins, pseudomonas exotoxins, diphtheria toxin, or bleomycin can be used to treat autoimmune disorders as taught by Vincent. Further, a peptide linker can be to join the functional domains of a fusion protein as taught by Chen and can thus be used to conjugate the autoreactive antigen to a toxin in the fusion proteins of Rashidian. Therefore, one of ordinary skill in the art would reasonably expect an autoantigen-Fc fusion protein of Rashidian comprising Dsg3 further conjugated to pseudomonas exotoxin, a ribosome-inactivating protein (e.g. ricin bryodin, gelonin, angiogenin, saporin, abrin, pokeweed antiviral protein), diphtheria toxin, or bleomycin via a peptide linker to be able to effectively treat pemphigus disorder in a subject.
Claims 22 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Rashidian et al (WO2023114847A2), hereinafter Rashidian, in view of Diener et al (Diener, E et al Science (New York, N.Y.) vol. 231,4734 (1986): 148-50. doi:10.1126/science.3484557, on the IDS of 10/31/2024), hereinafter Diener, and Chen et al (Chen, Xiaoying et al. Advanced drug delivery reviews vol. 65,10 (2013): 1357-69. doi:10.1016/j.addr.2012.09.039, of record), hereinafter Chen, and Kumari et al (Kumari, Avnesh, et al. Colloids and surfaces B: Biointerfaces 75.1 (2010): 1-18, of record), hereinafter Kumari. [NOTE: WO2023114847A2 claims priority to U.S. Provisional Application No. 63/289,595 filed 12/14/2021.].
Rashidian discloses fusion proteins comprising an autoreactive antigen and an immunoglobulin Fc region for the treatment of autoimmune diseases, wherein the autoreactive antigen is desmoglein 3 (Dsg3) or Dsg1 and the effector-cell binding domain is (Abstract; Summary of Invention: Para. 0007 and Para. 0009; and Para. 0096). In some embodiments, the fusion protein further comprises a therapeutic moiety such as a toxin (Para. 0009). The autoimmune disease to be treated by the fusion protein includes skin blistering disorders such as pemphigus vulgaris (Para. 0089 and 0093).
Rashidan does not teach that the toxin is a nanomolecule embedded with daunomycin.
However, Diener teaches that daunomycin coupled to the hapten conjugate of ovalbumin via a linker led to hapten-specific impairment of immunocompetence in murine B lymphocytes, indicating selective binding of the drug-antigen conjugate to target B lymphocytes bearing surface receptors for the hapten (Abstract and 2nd paragraph of the third column on page 148). It is further stated that these type of target-specific irmunosuppressive compounds that contain small molecular weight cytocidal drugs can be used clinically in the treatment of autoimmune disease (Page 150, last paragraph of left column). Thus, daunomycin can be used as the toxin in an antigen-toxin conjugate to effectively eliminate autoreactive B lymphocytes in the treatment of an autoimmune disease.
Chen further 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 further 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 fusion protein disclosed by Rashidian such that a) the toxin is daunomycin conjugated to the autoreactive antigen via a peptide linker and b) the toxin is embedded in a nanoparticle (i.e. nanomolecule). One of ordinary skill in the art would have been motivated to do so since daunomycin can be used as the toxin in an antigen-toxin conjugate to effectively eliminate autoreactive B lymphocytes as taught by Diener. Further, a peptide linker can be to join the functional domains of a fusion protein as taught by Chen and can thus be used to conjugate the autoreactive antigen to a toxin in the fusion proteins of Rashidian. 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-Fc fusion protein of Rashidian comprising Dsg3 further conjugated via a peptide linker to a nanomoleucle embedded with daunomycin to be able to effectively 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 35 USC 103 rejections, Applicant argues the following:
Kumari does not disclose the claim-recited toxins, as amended herein.
Kumari was published in 2010 and Zhu has an earliest priority date of August 12, 2016. Zhu has extensive disclosure; yet Zhu never sees fit to combine the known nanoparticles of Kumari to Zhu's disclosure. This is real-world evidence that a person of ordinary skill in the art would not be motivated to combine these disclosures. Moreover, as Zhu does not disclose the claim-recited toxins, even though Zhu discloses laundry lists of toxins, the combined disclosure does not disclose the claimed invention of claim 22.
The combined disclosures [of the cited prior art] do not disclose the claimed invention of claims 22 and 24. Ricin A chain is not a claim-recited toxin; the auto-antigen is Dsg3 or Dsgl and not thyroblobulin. Moreover, this rejection clearly uses applicant's claim as a road map and randomly identifying elements in a large number of references, without a true motivation to combine the disclosures to arrive at the claimed invention with a reasonable expectation of success.
At least for the foregoing reasons, claims 22 and 24 are patentable over the cited references.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). As stated previously, Rennie demonstrated that a platform where full-length autoantigens (e.g. thryoglobulin) can be linked to toxins (e.g. Ricin A chain) to selectively eliminate autoantibody-producing cells, offering an adaptable and targeted approach to treating autoimmune disease:
“The demonstration that an autoantigen coupled to a toxin can induce specific immunological unresponsiveness suggests that such immunotoxins could provide a novel and highly selective means for deleting autoantibody secreting lymphocyte clones in patients with autoimmune disease.” (Rennie, Summary).
Thus, Rennie contemplates the use of a general platform comprising an autoantigen linked to a toxin for the treatment of other autoimmune disorders in patients; its teachings are not merely limited to the TG/ricin-A conjugate for treatment of autoimmune thyroid disease. Indeed, conjugating an autoantigen or fragment thereof to a toxin for the purpose of treating autoimmune disease was not novel concept. In addition to Rennie et al, Diener et al (on IDS of 10/31/2024) teaches daunomycin coupled to the hapten conjugate of ovalbumin via an acid-sensitive spacer led to hapten-specific impairment of immunocompetence in murine B lymphocytes. Diener even states that “[t] clinical potential of immunotoxins includes the immunotherapy of cancer and the alleviation of various immunoregulatory disorders and autograft rejection. For example, clones of B lymphocytes may be selectively eliminated by the specific binding of the antigen-toxin conjugate to cell surface immunoglobulin receptors. Such studies have involved the specific deletion of B lymphocytes by ricin that had been conjugated to antigens, including self-antigens such as acetylcholine receptors and thyroglobulin” (Abstract and Introduction). Thus, Diener also acknowledges the use of a fusion protein comprising an autoantigen conjugated to a toxin for the treatment of autoimmune disease.
Stevens teaches that pemphigus disorders are caused by autoantibodies targeting desmoglein proteins Dsg1 and Dsg3. As such, 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; and 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. Thus, contrary to Applicant’s assertion, the prior art already provides a “roadmap” to the embodiments of the claimed invention. It is further noted that Applicant has not demonstrated that claimed fusion protein yields results contrary to what would have been reasonably expected from the combined teachings of the prior art.
Lastly, Kumari et al is not relied upon for the type of toxin, but rather the use of nanoparticles. Indeed, Rennie et al already discloses a toxin recited in the instant claims -ricin A chain, which is a type of ribosome inactivating protein as evidenced by Madhumathi et al.
In view of the foregoing, the 35 USC 103 rejections are maintained.
Conclusion
No claims are allowed.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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