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 of Group I and species A and B corresponding to influenza virus and DogCatcher and DogTag, respectively, in the reply filed on August 21, 2026 is acknowledged.
Applicant states that the restriction is not agreed to, but reserves the right to argue distinctness of the Groups and species at a later date.
However, MPEP § 818.01(c) and 37 C.F.R. 1.144 state:
To preserve the right to petition from the requirement for restriction, including an election of species requirement, all errors to be relied upon in the petition must be distinctly and specifically pointed out in a timely filed traverse by the applicant… If applicant does not distinctly and specifically point out supposed errors in the restriction requirement, the election should be treated as an election without traverse and be so indicated to the applicant by use of form paragraph 8.25.02.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-12, 15-19, and 22-24 are pending; claims 7, 10, 11, 19, and 22-24 are withdrawn due to non-elected subject matter; and claims 1-6, 8, 9, 12, and 15-18 are under consideration.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on June 3, 2024 has been considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d), see paragraph [0123], for example. Applicant must append SEQ ID NOs. to all mentions of specific sequences comprising four or more amino acids and ten or more nucleic acids in the specification.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
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 [0110, 0111, 0133, and 0134] of the instant published disclosure (USPgPub 2024/0240203). 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 incorporation of essential material in the specification by reference to an unpublished U.S. application, foreign application or patent, or to a publication (non-patent literature (NPL)) is improper, see paragraphs [0009, 0123, 0124, 0130, and 0134, incorporating foreign applications and NPL references, for example]. Applicant is required to amend the disclosure to include the material incorporated by reference, if the material is relied upon to overcome any objection, rejection, or other requirement imposed by the Office. The amendment must be accompanied by a statement executed by the applicant, or a practitioner representing the applicant, stating that the material being inserted is the material previously incorporated by reference and that the amendment contains no new matter. 37 CFR 1.57(g).
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 Objections
Claim 12 is objected to because of the following informalities: “is a hexon protein” is recited twice in line 2. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 4 and 17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 4 lacks antecedent basis for “the amino acid sequence” of the antigen encoded by the transgene and “the amino acid sequence” of the antigen attached to the second peptide partner. While antigens may inherently possess amino acid residues, specific sequences recited and required are not apparent. The “amino acid sequence” both antigens has not been particularly pointed out and distinctly claimed, as required. Claim 4 requires the sequences to ne at least 40% identical. However, since no sequence of either antigen is provided, 40% identity cannot be determined.
Line 2 of claim 17 recites, “partners are selected from:”, followed by a list. There is a phrase clarifying if the partners recites are each in the alternative, as described in at least paragraph [0027] of the instant published disclosure, USPgPub 2024/0240203. According to MPEP 2173.05(h), the claim 17 recites improper Markush language and are indefinite. It cannot be determined if the claim is intending to recite a single peptide partner or a combination of peptide partners. This rejection could be cured if the claim includes qualifying language preceding the recited alternatives (such as "selected from the group consisting of”). See also MPEP § 2111.03. In the interest of compact prosecution, claim 17 is interpreted as intending to recite peptide pairs in the alternative, gleaned from paragraph [0027]. The interpretation gleaned from the instant disclosure does not preempt the requirement for a clarifying amendment.
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, 8, 9, 12, and 15-18 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.
Claim 1 requires the antigen expressed by a transgene to have at least one T cell epitope and an antigen attached to a second peptide partner to have at least one B cell epitope. Claim 2 requires that the antigens share at least one epitope and claim 4 requires that the antigens are at least 40% identical. Claim 8 identifies the antigen encoded by the transgene and the antigen attached to a second peptide partner are the influenza virus nucleoprotein and the hemagglutinin protein or a fragment thereof, respectively.
However, there are no structural motifs or patterns provided in the instant disclosure that would identify the broad genus of sequences encompassed by the claims as T-cell epitopes and B cell epitopes. Paragraph [0144] of the instant published disclosure (USPgPub 2024/0240203) defines a B cell epitope as “the part of an antigen that is recognised by the immune system specifically by antibodies and B cells”. Paragraph [0145] defines a T cell epitope as “the part of the antigen that is recognised by T cells”. However, a definition by function alone is not sufficient because it is only an indication of what a thing does, rather than what it is. Eli Lily, 119 F.3 at 1568, 43 USPQ2d at 1406.
The only T cell epitope provided in the instant disclosure is disclosed in paragraph [0190], CD8+ T cell epitope EGFP200-208. There are no B cell epitopes taught. There is no specific written description that identifies a range of peptide sequences or structures to permit one of skill in the art to recognize the sequences encompassed by the claims, as asserted. For these reasons, it is concluded that the specification does not reasonably convey possession of the full scope of T-cell epitopes and B cell epitopes claimed.
As taught in Greenspan et al (Nature Biotechnology. 17; 10:936-937 (1999), defining epitopes is not as easy as it seems (page 937). Epitopes have been defined in terms of the spacial organization of residues that make contact with a ligand and the structural characterization of the molecular interface for the binding of the molecules to define the epitope boundaries (page 937 middle of page). The epitope defined in this manner will likely include residues that contact the ligand but are energetically neutral or even destabilizing to binding. "In addition, a priori it will not include any residue that makes no contact with a ligand but whose substitution may profoundly affect ligand recognition through influence on the stability of the free form of the macromolecule, or participation in long-range allosteric effects". "Even when the residues making contacts with ligands are known with certainty, say from the crystal structure of the complex, the question remains with regard to the energetic involvement of each residue (page 936 right column, first paragraph). Therefore, "amino acids should be recognized to have multiple ways of contributing to a noncovalent interaction" (page 937, middle of page). The specification teaches epitope mapping of the F5 and C1 using competition assay (page 69, lines 25-26 and figure 2), however, the results are not clear that the antibodies do in fact bind the same epitope. As evidenced by Greenspan et al a number of factors not primarily related to the contours of the contacts of the molecules contribute to the free energy change, sometimes profoundly.
There is no teaching provided in the instant specification for an antigen encoded by a transgene and another antigen attached to a second peptide partner that have at least 40% identity to each other as required by instant claim 4. The elected antigens of claim 8, identifying the influenza virus nucleoprotein and the hemagglutinin protein or a fragment thereof, as the transgene and second antigen, respectively. In the full paragraph on page 2 and the paragraph bridging pages 2-3, Hu et al. (Current topics in medicinal chemistry. 2017 Aug 1;17 (20): 2271-2285) describe the hemagglutinin (HA) protein as one of the three surface proteins and docks with the host receptor while the nucleoprotein (NP) facilitates vRNA transcription and replication and organizes RNA packaging and nuclear trafficking. In the first full paragraph on page 4, Hu et al. teach NP is highly conserved among influenza A virus strains from different species. With such divergent functions and location within and on the virion, HA and NP, there is no evidence in the art or in the instant disclosure that HA and NP would have sequences that share at least one epitope (claim 2) and are at least 40% identical (claim 4). Claims 2 and 4 require characteristics and features that HA and NP do not share. Therefore, the instant disclosure does not provide a representative of the genus of antigens claimed.
Claim 18 requires that the antigen attached to the second peptide partner is over 15 kDa. However, this limitation does not identify the claimed antigen since there are a number of antigens, including Garlic Virus C and Cactus virus X, that are over at least 15 kDa according to the UniProt database:
PNG
media_image1.png
715
357
media_image1.png
Greyscale
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.
Vas-Cath Inc. V. Mahurkar, 19USPQ2d 1111, clearly states "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 [he or she] invented what is claimed." (See Vas-Cath at page 1116). Conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers V. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
There is no disclosure of sufficient characteristics of the claimed antigens comprising T cell and B cell epitopes, respectively, to allow persons of ordinary skill in the art to recognize that applicants were in possession of the exponential quantity of T-cell epitope and B-cell epitope antigens encompassed by the claims. The specification does not clearly allow persons of ordinary skill in the art to recognize that the inventors invented what is claimed. The claims do not meet the written description provision of 35 U.S.C. 112, first paragraph.
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, 12, and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Howarth et al. (WO 2018/197854, of record), Vujadinovic et al. (Biomedicines. 2018; 6 (81): doi: 10.3390, of record), and Matthews (Molecular pharmaceutics. 2011 Feb 7;8 (1) : 3-11).
Howarth et al. disclose SpyTag and SpyCatcher peptides spontaneously forming an isopeptide bond, as required by instant claims 16 and 17, used to conjugate antigens to VLPs and viruses, including adenoviruses, as required by instant claims 1. See page 13, line 28 to page 14, line 10; page 22, line 28 to page 23, lines 2 and 28-35; page 28, lines 28-30; the page 38, line 30 to page 39, line 6; and Figures 9-16.
Howarth et al. do not teach the adenovius vectors (AdV) expressing a transgene encoding an antigen that has at least one T cell epitope or expressing the SpyTag/Spycatcher attached to a second antigen from the same viral pathogen that has at least one B cell epitope from a modified capsid protein of the adenovirus, as required by instant claims 1, 3, 5, and 15. Howarth et al. also do not teach expressing an antigen from an adenovirus capsid protein-modified hexon, fiber, and/or protein XI, as required in instant claim 12.
Vujadinovic et al. teach displaying antigens comprising B- and T-cell epitopes on adenovirus capsid protein-modified hexon, fiber, and/or protein XI, see the abstract, Figure 2, and Table 1. Table 1 of Vujadinovic et al. list various recombinant AdV vectors encoding a transgene expressing a virus antigen in E1 and a second antigen derived from the same viral pathogen, as required by instant claim 3. The B- and T-cell epitope antigens derived from the same viral protein(s) expressed from the adenovirus comprising a modified capsid in Table 1 of Vujadinovic et al. are presumed to share at least one epitope, as required in instant claim 2, and be at least 40% identical, recited in claim 4, as the instantly claimed antigens. Some of the virus antigens in Table 1 of Vujadinovic et al. expressed from E1 and the modified capsid comprise a receptor binding domain of the antigen, as required in instant claim 6.
It would have been prima facie obvious to one of ordinary skill in the art to have expressed the adenovirus surface-displayed antigens of Vujadinovic et al. using the SpyTag and SpyCatcher peptides of Howarth et al. because SpyTag/SpyCatcher- antigen conjugation spontaneously forms a stable isopeptide bond with high affinity between the SpyTag and SpyCatcher peptides and the antigen, see page 2, lines 1-20 of Howarth et al. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have expressed the antigens of Vujadinovic et al. in the modified adenovirus capsid using the SpyTag and SpyCatcher peptides of Howarth et al. because Matthews teaches the “antigen capsid-incorporation” strategy avoids the suboptimal results associated with conventional transgene expression of antigens by Ad vectors and induces a robust humoral immune response, see “Adenovirus Vectors as Vaccine Agents”, Figure 1, and “Incorporation of Antigens into Viral Capsid Structures for a Vaccine Approach”.
Claims 8, 9, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Howarth et al., Vujadinovic et al., and Matthews as applied to claims 1-6, 12, and 15-17 above, and further in view of Kim et al. (PLoS One. 2013 Sep 25; 8 (9): e75460, hereinafter “Kim ‘2013”), Kim et al. (Viruses. 2017 Aug 21;9 (8): 234), Weaver et al. (PloS one. 2011 Mar 28;6(3):e18314), as evidenced by Ratnayake et al. (Protein expression and purification. 2016 Jan 1; 117: 6-16).
See the teachings of Howarth et al., Vujadinovic et al., and Matthews above. None of the references teach the expression of the influenza nucleoprotein (NP) as the transgene expressed from the adenovirus vector and an influenza hemagglutinin or fragment thereof as the second partner comprising an RBD, as required by instant claims 8 and 9, or that the second peptide partner is over 15 kDa, recited in claim 18.
Kim ‘2013 teaches a recombinant adenovirus encoding an NP, see “Generation and characterization of recombinant adenovirus expressing NP of influenza virus”.
Kim ‘2017 teaches a recombinant adenovirus expressing a hemagglutinin stalk (HA2). Ratnayake et al. teach influenza HA2 is 26.7 kDa in Figure 2.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have expressed the NP and HA2 of Kim ‘2013 and Kim ‘2017, respectively, from the adenovirus surface-displayed antigens of Vujadinovic et al. using the SpyTag and SpyCatcher peptides of Howarth et al. because Kim’2013 teaches potent protection against influenza virus infection and Kim ‘2017 teaches durable cross-protective hemagglutinin stalk antibody responses.
Neither influenza NP or HA2 in either Kim reference possesses an RBD, but the HA1 expressed by the adenovirus of Weaver et al. does, see “Viruses and Vaccines”.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have expressed the HA1 of Weaver et al. from the adenovirus surface-displayed antigens of Vujadinovic et al. using the SpyTag and SpyCatcher peptides of Howarth et al. because Weaver et al. teaches protection against infection.
One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have expressed the antigens of Kim ‘2013 and Kim ‘2017 or Weaver et al. in the modified adenovirus capsid using the SpyTag and SpyCatcher peptides of Howarth et al. because Matthews teaches the “antigen capsid-incorporation” strategy avoids the suboptimal results associated with conventional transgene expression of antigens by Ad vectors and induces a robust humoral immune response, see “Adenovirus Vectors as Vaccine Agents”, Figure 1, and “Incorporation of Antigens into Viral Capsid Structures for a Vaccine Approach”.
Allowable Subject Matter
An adenovirus vector comprising a DogCatcher/DogTag is free of the art.
Keeble et al. (Cell chemical biology. 2022 Feb 17; 29 (2): 339-50) teach developing these peptide binding partners.
Conclusion
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.
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, Michael Allen can be reached at 571-270-3497. 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.
/Shanon A. Foley/ Primary Examiner, Art Unit 1671
Prosecution Insights