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 .
Election/Restrictions
1. The Election filed June 02, 2026 in response to the Office Action of January 12, 2026 is acknowledged and has been entered. Applicant's election without traverse of Group IV, claims 32-37 and the species SEQ ID NO: 3, IgG1 and a virus is acknowledged.
The full length SEQ ID NO: 3 is free of prior art as used in the claimed methods. Thus, the fragments of SEQ ID NO: 3 are rejoined for examination.
2. Claims 32-34, 37, and 46-79 are pending and under consideration.
Priority
3. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications, fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. Examiner has established a priority date of June 13, 2023 for claims 32-34, 37, and 46-79 because the claims as currently constituted recite “a protein, a fragment of a protein or a peptide which is capable of improving the expression and/or stability of the DSG2 fusion polypeptide in vitro or in vivo” and a review of the parent applications does not reveal the claimed limitation. Applicant is invited to submit evidence pointing to the serial number, page and line where support can be found establishing an earlier priority date.
Drawings
4. The drawings are objected to because the sequence GGGGS in Figure 9 should be labeled with SEQ ID NO: 12.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
5. Claims 32-34, 37, and 46-79 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 written description requirement. 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. This is a new matter rejection.
Independent claims 32 and 37 have been amended to include the new limitations of “a protein, a fragment of a protein or a peptide which is capable of improving the expression and/or stability of the DSG2 fusion polypeptide in vitro or in vivo” comprised by the DSG2 fusion protein.
Applicant argues that support for these amendments can be found in original claims 1 and 5, and in paragraphs [0032], [0039], [0053], [0061], and [0074] of the specification. A review of the cited support reveals support for “a whole or a portion of an immunoglobulin protein or an affinity tag” fused to DSG2 in original claim 1. However, “a whole or a portion of an immunoglobulin protein or an affinity tag” does not provide support for “a protein, a fragment of a protein or a peptide which is capable of improving the expression and/or stability of the DSG2 fusion polypeptide in vitro or in vivo” as it does not describe what proteins have the claimed activity. Thus, the newly added limitation is new matter.
It is noted that although claims like 55-57 are drawn to particular immunoglobulin domains, the specification does not teach which, if any, of these domains is capable of improving the expression and/or stability of the DSG2 fusion polypeptide in vitro or in vivo.
6. Claims 32-34, 37, and 46-79 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating post-COVID-19 syndrome or COVID-19 in a subject, the method comprising: contacting the subject a desmoglein 2 (DSG2) fusion polypeptide, the DSG2 fusion polypeptide comprising: a DSG2 polypeptide having 100% sequence identity with SEQ ID NO: 3 or a portion of a DSG2 polypeptide having 100% sequence identity with a portion of SEQ ID NO: 3; and a protein, a fragment of a protein or a peptide used for purification of the DSG2 fusion polypeptide; wherein the method is effective in ameliorating the one or more symptoms associated with post-COVID-19 syndrome or COVID-19, does not reasonably provide enablement for a method of treating post-COVID-19 syndrome or COVID-19 in a subject, the method comprising:(i) contacting the subject a desmoglein 2 (DSG2) fusion polypeptide, the DSG2 fusion polypeptide comprising: a DSG2 polypeptide having at least 85% sequence identity with SEQ ID NO: 3 or a portion of a DSG2 polypeptide having at least 85% sequence identity with a portion of SEQ ID NO: 3; and a protein, a fragment of a protein or a peptide which is capable of improving the expression and/or stability of the DSG2 fusion polypeptide in vitro or in vivo and/or used for purification of the DSG2 fusion polypeptide; wherein the method is effective in ameliorating the one or more symptoms associated with post-COVID-19 syndrome or COVID-19. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or us the invention commensurate in scope with these claims.
The factors to be considered in determining whether undue experimentation is required are summarized in In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The court in Wands states: "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
The claims are broadly drawn to a method of treating post-COVID-19 syndrome or COVID-19 in a subject, the method comprising:(i) contacting the subject a desmoglein 2 (DSG2) fusion polypeptide, the DSG2 fusion polypeptide comprising: a DSG2 polypeptide having at least 85% sequence identity with SEQ ID NO: 3 or a portion of a DSG2 polypeptide having at least 85% sequence identity with a portion of SEQ ID NO: 3; and a protein, a fragment of a protein or a peptide which is capable of improving the expression and/or stability of the DSG2 fusion polypeptide in vitro or in vivo and/or used for purification of the DSG2 fusion polypeptide; wherein the method is effective in ameliorating the one or more symptoms associated with post-COVID-19 syndrome or COVID-19. Thus, the claims encompass using a DSG2 fusion polypeptides comprising large of genus DSG2 polypeptides having at least 85% sequence identity with a portion of SEQ ID NO: 3 or portion and a large genus of a protein, a fragment of a protein or a peptide which is capable of improving the expression and/or stability of the DSG2 fusion polypeptide in vitro or in vivo and/or used for purification of the DSG2 fusion polypeptide.
The specification teaches detecting anti-DSG2 antibodies in post- COVID-19 serum samples. The specification teaches recovered COVID-19 patients demonstrated significantly higher and sustained levels of anti-DSG2 autoantibodies as compared to a healthy control population, and comparable to that of a diagnosed Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) group. See Example 2, ¶¶ [0198-0201], Tables 5 and 6 and Fig. 1.
The specification teaches blocking of anti-DSG2 antibodies present in Post-COVID-19 patient sera from binding to the DSG2 extracellular domain by DSG2 fusion polypeptides with different affinity tags. The specification teaches DSG2FP #1 (amino acids 49-608 of SEQ ID NO:30; Linker (IEGRMD (SEQ ID NO: 28)); amino acids 100-330 of IgG1 (SEQ ID NO: 4) had the best blocking activity. The specification teaches at least 70% blocking activity by the DSG250-602)-6xHis fusion polypeptide. The specification teaches a fusion of DSG2 amino acids 491-602 of SEQ ID NO: 1 (EA) to a hexahistidine peptide tag shows some effectiveness in blocking activity. The specification teaches a combination of a fusion of DSG2 amino acids 50-155 of SEQ ID NO: 1 (EC1) to a hexahistidine peptide tag and EC2 (151-268)-6xHis, a fusion of DSG2 amino acids 151-268 of SEQ ID NO: 1 (EC2) to a hexahistidine peptide tag had little to no blocking activity in different serum samples. See Example 3-¶¶ [0202-0203] and Fig. 3.
The specification teaches that the DSG2 fusion polypeptides described above and in Example 3 also had the ability to block anti-DSG2 antibodies present in ARVC patient sera from binding to the DSG2 extracellular domain. See Example 7- -¶¶ [0212-0213] and Fig. 8.
One cannot extrapolate the teachings of the specification to enable the scope of the claims because effect of changes of protein sequence on protein structure and function is unpredictable and the specification has only a exemplified a few DSG2 polypeptide fusions that block anti-DSG2 antibodies from COVID-19 serum or ARVC patient sera and the specification has not specifically described or exemplified a protein, a fragment of a protein or a peptide which is capable of improving the expression and/or stability of the DSG2 fusion polypeptide in vitro or in vivo. The sensitivity of protein binding interactions to alterations of even a single amino acid in a sequence are also exemplified by Coleman et al. (Research in Immunology, 1994; 145(1): 33-36) who teach single amino acid changes in an antigen can effectively abolish antibody antigen binding. Additionally, Abaza et al. (Journal of Protein Chemistry, Vol. 11, No. 5, 1992, pages 433-444, see abstract in particular) teach single amino acid substitutions outside the antigenic site on a protein affects antibody binding. Further, the sensitivity of binding proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. of Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein. Furthermore Pero et al. (US PG Pub 2003/0105000) specifically teach that the SH2 domain of Grb14 is 81% similar to the SH2 domain of Grb7 on the amino acid level, but although Grb7 binds to ErbB2, Grb14 does not bind to ErbB2. Further, although the SH2 domain of Grb2 is only 50% similar to Grb7 on the amino acid level, both Grb2 and Grb7 bind to the same site on ErbB2. See ¶ 0255 of the published application. These references demonstrate that even a single amino acid alteration or what appears to be an inconsequential chemical modification will often dramatically affect the biological activity and characteristics of a binding protein. Thus, given that the claims encompass using a DSG2 fusion polypeptides comprising large of genus DSG2 polypeptides having at least 85% sequence identity with a portion of SEQ ID NO: 3 or portion and a large genus of a protein, a fragment of a protein or a peptide which is capable of improving the expression and/or stability of the DSG2 fusion polypeptide in vitro or in vivo and/or used for purification of the DSG2 fusion polypeptide that need to interact with undefined DSG2 antibodies and given the unpredictability of changes of protein sequence on protein structure and function, undue experimentation would be required to make and use the methods as broadly claimed.
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.
7. Claim(s) 32-34, 37, 46-49, 51-53, 59, 62-66, 68-70, 76 and 79 are rejected under 35 U.S.C. 103 as being unpatentable over Schinner et al. (JCI Insight, 2020;5(9): e130141, pp. 1-16, IDS), “Schinner” in view of Ward et al. (Clinical and Experimental Immunology, April 24, 2023, 213: 243–251), “Ward”.
Schinner teaches arrhythmogenic cardiomyopathy (AC) is a genetic disease causing arrhythmia and sudden cardiac death with only symptomatic therapy available at present. Mutations of desmosomal proteins, including desmoglein-2 (Dsg2) and plakoglobin (Pg), are the major cause of AC and have been shown to lead to impaired gap junction function. See abstract.
Schinner teaches we provide evidence that stabilization of Dsg2 binding by a linking peptide (Dsg2-LP) is efficient to rescue arrhythmia in an AC mouse model immediately upon perfusion. Dsg2-LP, designed to cross-link Dsg2 molecules in proximity to the known binding pocket, stabilized Dsg2-mediated interactions on the surface of living cardiomyocytes as revealed by atomic force microscopy and induced Dsg2 oligomerization. See abstract and Figures 1-6.
Schinner teaches Dsg2-LP was derived from the Dsg2 EC1 domain CFDARGNFC linked together to comprise to Ac-CFDARGNFC-aminohexan-CFDARGNFC-NH2. Either DSG2 domains could be used for purification of the DSG2 fusion polypeptide.
The CFDARGNFC peptide comprises an amino acid sequence with 100% identity to SEQ ID NO: 3. See Appendix.
Schinner teaches these results demonstrate that stabilization of Dsg2 binding by Dsg2-LP can serve as a novel approach to treat arrhythmia in patients with AC. See abstract.
Schinner teaches as set froth above, but does not teach treating COVID-19 or a post-COVID19 syndrome in a subject.
Ward teaches that increased levels of DSG2 protein in sera from acute COVID-19 patients. Ward teaches that that DSG2 autoantibody levels are increased significantly in convalescent sera following severe COVID-19 but not in hospitalized patients recovering from influenza infection or healthy controls. Levels of autoantibody in sera from patients with severe COVID-19 were comparable to levels in patients with non-COVID-19-associated cardiac disease, potentially identifying DSG2 autoantibodies as a novel biomarker for cardiac damage. See abstract, Table 2 and Figures 1 and 2.
Ward teaches DSG2 protein was within the intercalated discs of cardiac tissue and disruption of the intercalated disc between cardiomyocytes in patients who died from COVID-19. Ward teaches our results reveal the potential for DSG2 protein and autoimmunity to DSG2 to contribute to unexpected pathologies associated with COVID-19 infection. See abstract and Fig. 3.
Ward teaches autoantibodies against DSG2 are associated with arrhythmogenic right ventricular cardiomyopathy (ARVC). See p. 244-left column, 3rd paragraph.
Ward teaches clinical studies have reported post-COVID-19 complications such as thromboembolism, ischaemia, arrhythmias, conduction defections, and myocarditis as symptoms of post-COVID-19 long-COVID. See p. 250-left column, 1st paragraph.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Schinner and Ward and use the Dsg2-LP of Schinner treat COVID-19 or a post-COVID19 syndrome in a subject to treat cardiac symptoms like arrhythmias because Schinner teaches Dsg2-LP is efficient to rescue arrhythmia in an AC mouse model and that stabilization of Dsg2 binding by Dsg2-LP can serve as a novel approach to treat arrhythmia in patients and Ward teaches that that DSG2 autoantibody levels are increased significantly in convalescent sera following severe COVID-19, Ward teaches autoantibodies against DSG2 are associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) and Ward teaches clinical studies have reported post-COVID-19 complications including arrhythmias. Thus one of skill in the art would have been motivated to treat COVID-19 or a post-COVID19 syndrome in a subject to treat cardiac symptoms like arrhythmias with Dsg2-LP given that Schinner teaches Dsg2-LP is efficient to rescue arrhythmia and arrhythmias are a symptom of COVID-19 or a post-COVID19 syndrome.
Additionally, It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to evaluate patients having COVID-19 for common symptoms of a viral infection like fever, chills, headache, congestion, runny nose and the like to help diagnose their condition.
Conclusion
8. No claims allowed.
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER J REDDIG whose telephone number is (571)272-9031. The examiner can normally be reached M-F 8:30-5:30 Eastern Time.
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/PETER J REDDIG/Primary Examiner, Art Unit 1646
APPENDIX.
Alignment of SEQ ID NO: 3 with CFDARGNFC
RESULT 1
AASEQ2_06252026_094323
Query Match 0.9%; Score 27; DB 1; Length 9;
Best Local Similarity 100.0%;
Matches 5; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 84 DARGN 88
|||||
Db 3 DARGN 7
Prosecution Insights