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
Applicant’s election without traverse of the following species:
protein antigen or an epitope of a protein antigen, where the antigen is a cytokine;
Im7;
ColE7; and
inflammatory disease.
in the reply filed on April 10, 2026 is acknowledged.
Claims 1-6, 14-24, and 35-37 are pending; claims 16, 21, 22, and 24 are withdrawn due to non-elected subject matter; and claims 1-6, 14, 15, 17-20, 23, and 35-37 are under consideration.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 5/24/2023; 12/1/2023; and 2/11/2026 have been considered by the examiner.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code in paragraphs [0536 and 0649] of the instant published disclosure, USPgPub 2024/0093159. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the term “TRITON X-100” in paragraph [0457] of the instant published disclosure, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Applicant is required to properly annotate all trade names and/or marks recited in the instant specification.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
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.
Claims 1-6, 18-20, 23, and 35-37 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 written description rejection.
Claims 1-6, 18-20, 23, and 35-37 require conjugation of an HBV VLP surface with a functional molecule through paired attachment to a bacterial toxin inhibitor and a bacterial toxin, respectively, as recited in instant claim 2. Paragraph [0165] of the instant published disclosure, USPgPub 2024/0093159, lists the following bacterial toxin-inhibitor pairs: ColE7 and Im7, ColE8 and Im8, ColE9 and Im9, ColE2 and Im2, or Barnase and Barstar, but the instant working examples only exemplify Im7-ColE7, depicted in instant Figures 3-11 and 13-25 and Barnase and Barstar, depicted in Figures 26-28. The instant disclosure fails to demonstrate possession of all bacterial toxin inhibitors and bacterial toxins encompassed by the instant claims. The skilled artisan would not predict or identify bacterial toxin inhibitors and a bacterial toxins without guidance. Seo et al. (“Type IX class utilizing cell signals for organizing toxin–antitoxin systems”, Trends in Microbiology. 2026 Mar 26) review nine toxin–antitoxin (TA) systems, see “Current toxin–antitoxin classification system” and Figure 2, depicting toxin–antitoxin expressions and mechanisms. The instant disclosure does not adequately describe the genus of toxin-antitoxin inhibitors encompassed by the claims.
The applicable standard for the written description requirement can be found in MPEP 2163; University of California v. Eli Lilly, 43 USPQ2d 1398 at 1407; PTO Written Description Guidelines; Enzo Biochem Inc. v. Gen-Probe Inc., 63 USPQ2d 1609; Vas- Cath Inc. v. Mahurkar, 19 USPQ2d 1111; and University of Rochester v. G.D. Searle & Co., 69 USPQ2d 1886 (CAFC 2004). To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In this case, the only bacterial toxin-antitoxin pairs reduced to practice are: ColE7-Im7 and Barnase-Barstar. There is no disclosure of sufficient characteristics of the claimed genus of bacterial toxin-antitoxin pairs to allow persons of ordinary skill in the art to recognize that applicants were in possession of the claimed genus. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
The court clearly states in Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not clearly allow persons of ordinary skill in the art to recognize that the inventors invented what is claimed. As discussed above, the skilled artisan cannot envision the distinguishing, identifying characteristics of the encompassed genus of bacterial toxin-antitoxin pairs claimed. Given that the specification has only described ColE7-Im7 and Barnase-Barstar, the full breadth of the claims does not meet the written description provision of 35 U.S.C. 112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Claims 36 and 37 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 claim(s) contains 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.
Claim 36 is drawn to a method of treating any subject having any disease or preventing any disease from occurring in any subject predisposed for that disease by administering an HBV VLP comprising at least one pair of binding proteins comprising any bacterial toxin and its inhibitor; and one or more functional molecules, wherein each hepatitis B capsid protein is attached to a first binding protein, wherein each functional molecule is attached to a second binding protein, and wherein the first and second binding proteins are bound to each other. There is no evidence instantly provided that the claimed HBV-toxin inhibitor-toxin-functional molecule complex is a panacea against any disease or can be used as a prophylactic in any subject predisposed for any disease. There is no data or evidence in any peer-reviewed document providing support for any medicinal cure-all elixir of life encompassed by the instant claim.
The elected disease recited in claim 37 is inflammatory. Inflammatory diseases listed in the instant published disclosure (USPgPub 20240093159) in paragraph [0482] include: arthritis, asthma, tuberculosis, periodontis, chronic ulcers, sinusitis, hepatitis, glomerulonephritis, inflammatory bowel syndrome/disease, preperfusion injury, transplant rejection, sickle cell disease, allergies, cardiovascular disease, psoriasis, cytokine-mediated pruritus, COPD, diabetes, bronchitis, Crohn's disease, atherosclerosis, dermatitis, arteritis, lupus. The title of Chavda et al. is: “Inflammation: the cause of all diseases” in (Cells. 2024 Nov 18; 13 (22): 1906), some of which are listed in section 3. In section 4, Chavda et al. opine, “Advancing the understanding of how inflammation drives various pathological conditions could pave the way for innovative therapeutic strategies, preventing the detrimental effects of chronic inflammation and ultimately improving health outcomes and quality of life.” The instant disclosure does not provide a nexus between the lack of knowledge in the current state of the art and the method claimed.
The skilled artisan would not predict that the instantly claimed HBV-toxin inhibitor-toxin-functional molecule complex would be efficacious in treating any subject having any inflammatory disease or preventing any inflammatory disease from occurring in any subject predisposed for that disease upon administration. Oeda et al. (Biomedical Reports. 2016; 11: 63-69) teach human immune responses to HBV induces pruritus (listed as an inflammatory condition in instant paragraph [0482]). Figure 1 of Oeda et al. depicts populations with HBV infection suffer from pruritus. Therefore, the skilled artisan would conclude administration of the instant HBV VLP would induce inflammation, based on the data provided by Oeda et al. Guan et al. (Immunotherapy. 2012; 4 (12): 1799-1807) teach attaching IL-17 to the surface of an HBV VLP particle, which is shown to exacerbate intestinal inflammation in chronic murine colitis, see “Immunization of the vaccine exacerbates, rather than improves, intestinal inflammation in chronic murine colitis”, “Intestinal inflammation is exacerbated in association with enhanced production of IL‑17 & TNF”, and Figures 1, 3, and 4. Ma et al. (American journal of respiratory cell and molecular biology. 2013 May; 48 (5): 540-549) conclude that chronic inflammation and sustained airway hyperresponsiveness were not reversed upon administration with an HBV VLP-IL-13. See “Vaccine” and Figures 5 and 6.
There is no teaching in the instant disclosure ameliorating any disease inflammation or preventing any disease inflammation in the instant disclosure. Example 19 describes IL-33 decorated HBV VLPs administered to mice. Figure 22 depicts antibody responses induced by the mice, but there is no evidence that any inflammatory disease is treated or prevented from occurring, as asserted by the instant claims.
For these reasons, it is determined that an undue quantity of experimentation would be required of the skilled artisan to make and use the instant invention.
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.
Claims 1-6, 14, 15, 17, and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Hartzell et al. (American Chemical Society Publications. 14 Sept. 2020; 14: 12642-12651) and Juraja et al. (Protein Engineering, Design & Selection. 2006; 19 (5): 231–244).
The HBV VLP of Hartzell et al. comprises modified capsid proteins decorated with nanoluciferases, i.e., functional molecules, as required by instant claims 1 and 5. The HBV capsid proteins are bound to SpyCatcher proteins (a first binding protein) and the nanoluciferase reporters are fused to SpyTags (a second binding protein) with a modular antibody binding domain (third antigen binding protein), if used for biosensing, or an epidermal growth factor receptor targeting peptide (third antigen binding protein) and suicide enzyme, if used for drug delivery, see Figure 1. The nanoluciferase-SpyTag components form an isopeptide bond with the HBV capsid-SpyCatcher components. These teachings are pertinent against instant claims 1, 3, and 6. In the paragraphs bridging pages 12643-12644 and 12644-12645, Hartzell et al. teach modifying the HBV VLP-SpyCatcher into a modular platform by fusing a Z-domain to the N-terminus of a 40-repeat elastin-like polypeptide (ELP) biopolymer, as required by instant claim 4. The HBV VLP displaying the epidermal growth factor receptor targeting and suicide enzyme induced breast cancer cell obliteration in Figures 4 and 5, satisfying the immunogenic composition of instant claim 35.
Hartzell et al. do not suggest the first and second binding proteins comprising a bacterial toxin inhibitor, Im7, and the bacterial toxin, ColE7, respectively, as required by instant claims 1, 2, 14, 15, and 17.
Juraja et al. teach display of bacterial toxin inhibitor, Im7, on the surface of a bacteriophage, see “Display of Im7 on the surface of fd-bacteriophage” on page 236. Juraja et al. determine specific binding of Im7 to the DNase domain of colicin E7 (ColE7), see the previous section, “Cloning and expression of the wild-type Im7 protein”, “Im7-H3 chimeras target gp120”, and Figures 2b-2d, 3b, and 7.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have substituted the SpyCatcher on the HBV VLP and SpyTag proteins, taught by Hartzell et al., with the Im7 and ColE7 proteins, respectively, taught by Juraja et al. because Juraja et al. teach the Im7 and DNase complex of ColE7 form one of the highest known affinity protein-protein interactions, measured at 10-14 M, and can readily form chimeric proteins, see Figures 1 and 2 and the full paragraphs in the first column on page 232. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have substituted the SpyCatcher on the HBV VLP and SpyTag-labeled proteins, taught by Hartzell et al., because Juraja et al. show Im7 (scaffold)-H3 chimera (CDR3 loop from the anti-HIV-1 human antibody IgG1b12) specific binding to the DNase complex of ColE7 and HIV gp120, see “Im7-H3 chimeras target gp120”, and Figures 3 and 7.
Claims 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Hartzell et al. and Juraja et al. as applied to claims 1-6, 14, 15, 17, and 35 above, and further in view of Pumpens et al. (Intervirology 2001; 44: 98–114).
See the teachings of Hartzell et al. and Juraja et al. above. Neither reference teaches the first binding protein inserted into the major dominant region of the HBV VLP between residues 76-80 and has deletions at E77 and D78.
Pumpens et al. teach the major B-cell HBc epitopes are localized within residues 76-81 located at the spike tips of the major immunodominant region (MIR), see “Fine Structure of the HBc Particle” and Figure 1. Figure 2 depicts blue arrows pointing to E77 and D78 insertion sites and boundaries for ‘permitted’ deletions/ substitutions.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have inserted the first binding protein, Im7 of Hartzell et al. and Juraja et al., into the HBV VLP MIR with deleted E77 and D78, taught by Pumpens et al., with a reasonable expectation of success because Pumpens et al. teach the MIR spike tips with E77 and D78 deletions allow for high capacity of insertions, see “Internal Insertions”.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Hartzell et al. and Juraja et al. as applied to claims 1-6, 14, 15, 17, and 35 above, and further in view of Chen et al. (Human Vaccines & Immunotherapeutics. Sept. 2012; 9: (1): 26-49).
See the teachings of Hartzell et al. and Juraja et al. above. None of the references teach chemical modification comprising DEAE, as recited.
Chen et al. teach purifying VLPs through a series of DEAE chromatography, see the first two paragraphs on page 41.
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to have purified the HBV VLPs of Hartzell et al. and Juraja et al. using DEAE chromatography, taught by Chen et al., because Chen et al. teach DEAE is applicable to large scale VLP purification, resulting in high purity >95%, see the first two paragraphs on page 41. One of ordinary skill in the art prior to the instant effective filing would have had a reasonable expectation of success to have purified the HBV VLPs of Hartzell et al. and Juraja et al. using DEAE chromatography, taught by Chen et al., because Chen et al. teach plant-expression systems can robustly produce large quantities of potent immunogenic HBV VLPs in a short time period that are used as carriers for heterologous surface presentation, see the paragraph bridging the column on page 31.
Claims 23 is rejected under 35 U.S.C. 103 as being unpatentable over Hartzell et al. and Juraja et al. as applied to claims 1-6, 14, 15, 17, and 35 above, and further in view of Guan et al. (Immunotherapy. 2012; 4 (12): 1799–1807).
See the teachings of Hartzell et al. and Juraja et al. above. Neither reference mentions the protein antigen is a cytokine, recited in claim 23.
Guan et al. teach HBV VLPs displaying IL-17, see the paragraph above the “Materials & methods” and “Preparation & identification of vaccines & carrier HBcAg”.
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to have expressed IL-17, taught by Guan et al., on the HBV VLP surface of Hartzell et al. and Juraja et al. to provide “potential immunotherapy for treatment of diseases associated with insufficient IL‑17 production, such as hyper-IgE syndrome”, quoted in the last line of the abstract of Guan et al. One of ordinary skill in the art to have expressed IL-17, taught by Guan et al., on the HBV VLP surface of Hartzell et al. and Juraja et al. because Guan et al. teach surface expression of IL-17 on an HBV VLP surface.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Young et al. (USPgPub 2008/0299148) claim nodavirus VLPs decorated with bacterial anti-toxins that are administered to bind bacterial toxins in a subject, see paragraphs [0067, 0068] and claims 20 and 36.
Ji et al. (Applied Materials Today. June 2020; 19: 100575) teach HBV VLP- SpyCatcher conjugated with SpyTag-pTau422 ameliorates cognition deficits and neuropathology progression in Tau.P301S transgenic mice. See Figures 1, 4, 7, and 8.
Wu et al. (Biomaterials. 2014; 35: 8416e8426) teach Murine Leukemia Virus virus-like-particles (VLPs) displaying bacterial toxin MazF, see section 2.3, that protect cells continuously expressing bacterial antitoxin MazE, see Figure 5.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHANON A FOLEY whose telephone number is (571)272-0898. The examiner can normally be reached M-F, generally 5:30 AM-5 PM, flexible.
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/Shanon A. Foley/Primary Examiner, Art Unit 1671
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