DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
2. This Office Action is in response to the amendment filed 30 March 2026, wherein Applicant amended claims 12-13 and 35-36.
Claims 12-13 and 35-43 are under consideration.
Information Disclosure Statement
3. The information disclosure statements (IDS) submitted on 03 December 2025 and 30 March 2026 were filed after the mailing date of the Non-Final Rejection on 02 December 2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Objections Withdrawn
Specification
4. The objections to the drawings and specification for disclosed sequences missing SEQ ID NOs is withdrawn in view of Applicant’s amendments.
5. The objection to the specification for use of trade names or trademarks without proper identifier is withdrawn in view of Applicant’s amendments.
Rejections Withdrawn
Claim Rejections - 35 USC § 112(b)
6. The rejections of claims 12-13 and 35-43 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite are withdrawn in view of Applicant’s amendments.
Claim Rejections - 35 USC § 112(a)
7. The rejection of claim 36 under 35 U.S.C 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, for lacking written description support for a derivative polypeptide that “induces an improved immune response” is withdrawn in view of Applicant’s amendments.
Claim Rejections - 35 USC § 101
8. The rejections of claims 13 and 35 under 35 U.S.C. 101 for being drawn to an abstract idea are withdrawn in view of Applicant’s amendments.
Claim Rejections - 35 USC § 102
9. The rejections of claims 12, 36-38, and 41-43 under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Gough (US 20070264283 A1; 15 November 2007) (See PTO-892 filed 02 December 2025) are withdrawn in view of Applicant’s amendments.
Claim Rejections - 35 USC § 103
10. The rejections of claims 13 and 35 under 35 U.S.C. 103 as being obvious over Gough (supra) in view of Hosseini (Viral Immunol., 1 April 2017, 30(3)) (See PTO-892 filed 02 December 2025) are withdrawn in view of Applicant’s amendments.
Rejections Maintained
Claim Rejections - 35 USC § 112(a)
11. Claims 12-13 and 35-43 remain 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 claims are drawn to “a derivative of a naturally-occurring HPV6 or HPV11 early region polypeptide selected from the group consisting of E1, E2, E4, E6, and E7”, wherein the derivative or mutation has to possess all the limitations required in items a) through d). However, as the specification nor the drawings disclose any specific examples of these mutations of these proteins, one of ordinary skill would not think that a “representative number of species” were possessed at the time of filing.
Applicant’s Arguments: Applicant has amended claim 12 to a narrower claim scope that now requires an early region protein with a rearrangement of amino acids. Applicant argues that the genus of the narrowed scope is supported in the specification and no longer reads on “all possible modifications”. Applicant has cited various paragraphs of the specification and MPEP/case law sections.
Examiner’s Response to Traversal: Applicant's arguments have been fully considered but they are not found persuasive with respect to the issue below.
The claims above still recite a genus of peptides with one or more modifications of rearrangement and specific functions. The addition of the early region polypeptide and limiting the one or more modifications to rearrangement does not alleviate the lack of written description support for a specific set of polypeptides with these characteristics. The claims are not limited to only a species made and tested by Applicant. Applicant cited a series of paragraphs from the specification; however, they only broadly mention the early region polypeptides and contemplate the rearrangements, but do not actually demonstrate possession of any of these specific derivates. Likewise, Designs 1-5 show general rearrangements of the polypeptides themselves, but does not demonstrate all aspects that could read on “rearrangement of amino acids” which could simply be moving a single amino acid residue and inserting it elsewhere in the protein. Indeed, Applicant fails to point out any specific functional species tested. The claims above do not even require specific antigenic fragments Applicant asserts to be taught. Teaching how to rearrange sequences is a matter of enablement, but this is a rejection over written description and the two are severable. This results in an unfathomable number of possibilities for which Applicant does not have support. Furthermore, the derivatives are required to have all the functions as required in a)-d), and determining which derivatives satisfy all the limitations would be highly unpredictable. In addition, the reasons that the cited sections and caselaw apply are not stated and thus are considered not persuasive. As claim 12 and its dependents still read on a large number of modifications that require specific functions, the specification is not in commensurate with the claims and Applicant has not shown possession of the recited genus.
New Objections
Claim Objections
12. Claim 12 is objected to because of the following informalities: “11” should be inserted before “(HPV11)”. Appropriate correction is required.
New Rejections
Claim Rejections - 35 USC § 103
13. 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.
15. 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.
16. Claims 12, 36-37, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Preville (WO 2005089792 A1; Published 29 September 2005), in view of Shin (April 2012, Hum. Vaccines. Immunother., 8(4): 470-478) and Ella (CN 102112152 A; Published 29 June 2011) and Isomura (2004, J. Virol., 78(23): 12788-12799).
Regarding claim 12, Preville teaches making a recombinant protein using two different HPV16 E7 peptides: the first of which is a fragment of the E7 protein from amino acids 49-57 and the second of which is a fragment of the E7 protein from amino acids 43-77 (Page 13, ¶ 6), therefore resulting in a recombinant protein that has residue overlap between the two epitopes. Preville does not teach using HPV6 or HPV11 epitopes. However, Shin teaches HPV11 E6 dominant epitope 6 (FCKNALTTAEIYSYA) and subdominant epitope 7 (TAEIYAYAYKNLKVV) (Page 473, ¶ 1), which are next to each other, seen in Figure 4B below:
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Furthermore, a sequence alignment shows that there is an overlap between the two epitopes:
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Epitope 6 and 7 are both found on the E6 protein (Page 473, ¶ 1). Furthermore, Ella teaches “An object of the present invention is to enhance immunogenicity by using chimeric fusion with viral and bacterial proteins to provide multiple copies of epitopes, thereby increasing the immunogenicity of candidate vaccines.” (Page 4, ¶ 3). Therefore, it would have been obvious to one of ordinary skill before the time of filing to take the method of Preville and further use the HPV11 epitopes of Shin that have the residue overlap in order to enhance immunogenicity, as suggested by Ella. It is equally obvious to use the same peptide sequence multiple times as discussed above. Whether you fuse the two different epitopes together into one polypeptide, or use multiple copies of epitope 6, for example, a rearrangement occurs with residues that used to be only C-terminal to a fixed residue now being N-terminal to the same and/or vice versa. Making such fusions is standardly done by recombinant DNA technology and so a polynucleotide encoding all obvious fusions above is equally obvious.
A rationale to support a conclusion that a claim would have been obvious is that there is some teaching, suggestion, or motivation in the prior art or in the knowledge generally available to one of ordinary skill in the art to modify the reference or combine reference teachings, and the modification or combination would have a reasonable expectation of success. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 (2007) (see MPEP §§ 2143, G. and 2143.02).
Regarding claim 36, Shin teaches using the NIH BIMAS HLA-binding prediction software to determine the immune dominant peptides within the E6/E7 consensus antigens. (Page 472, ¶ 1).
Regarding claims 37 and 41, Shin teaches cloning the HPV fusion-expression polynucleotide into a pVAX expression vector under the control of the cytomegalovirus intermediate-early promoter (Page 475, ¶ 3). Expression of the proteins was verified using indirect immunofluorescence assays (Page 475,
¶ 5). This vector was later injected into mice as a vaccine (Page 475, ¶ 2 and 3). Shin does not teach using a CMV promoter with the enhancer region.
However, Isomura teaches “The human CMV MIE enhancer-containing promoter regulates the level of MIE gene expression. […] The enhancer is divided into a distal component and a proximal component (40). The distal enhancer between positions −550 and −300 is not required at high MOI, but it is required for efficient IE gene expression and viral replication at low MOI (40).” (Page 12788, ¶2). Therefore, it would have been obvious to one of ordinary skill to include the CMV enhancer region for better gene expression. A rationale to support a conclusion that a claim would have been obvious is that there is some teaching, suggestion, or motivation in the prior art or in the knowledge generally available to one of ordinary skill in the art to modify the reference or combine reference teachings, and the modification or combination would have a reasonable expectation of success. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 (2007) (see MPEP §§ 2143, G. and 2143.02).
17. Claims 13 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Preville (Supra) Shin (Supra), Ella (Supra), and Isomura (Supra), as applied to claims 12, 36-37, and 41 above, and further in view of Hosseini (Viral Immunol., 1 April 2017, 30(3)) (See PTO-892 mailed 02 December 2025).
Regarding claims 13 and 35, Preville, Shin, and Ella teach the limitations of claim 12, all discussions thereon above incorporated here. Shin does teach one in silico method to predict antigenicity, as discussed above, but does not teach any other analytical techniques. However, Hosseini teaches:
In silico prediction of in vivo antigen epitope recognition: “By the use of BCPred method in BCPREDS server of epitope regions in L1 and L2, protein sequences were determined. A total of 71 epitopes for L1 and 70 epitopes for L2 HPV serotypes were predicted. In the next step, epitopes with high score were used as candidates for application in vaccine construct (Table 2).” (Results, ¶ 1). As suggested above, the epitope prediction model allows the user to predict the best vaccine candidates without having to test every epitope in vivo.
Amino acid sequence physiochemical property analysis: “The sequences of primary construct were analyzed in Expasy's ProtParam tool and results are presented in Table 6.” (Results, ¶ 5). These results include the molecular weight of the protein, number of amino acids, theorical pI, positively and negatively-charged residues, instability index, and AI, GRAVY. Hosseini further teaches “This plot showed that major parts of the new protein construct have hydrophilic property and thus harbor antigenic potency” (Page 220, ¶ 1).
Three-dimensional (3D) structure analysis: “After selection of epitopes, these epitopes were refined by the degree of solvent accessibility. Each residue at the surface of a protein can potentially be touched by water, and the area of an atom on the surface that can be touched by water is called the accessibly molecular surface or solvent-exposed area. So it is advisable to elect epitopes with higher degree of solvent accessibility. For fulfillment it, the structure of the L1 and L2 proteins was needs. The crystal structures of L1 and L2 protein had not been determined before. For obtaining a 3D structure model of L1 proteins, the crystal structure of these proteins was used as PDB template in Swiss Model Alignment interface protein modeling server (10).” (Materials and Methods, ¶ 3).
Predicting immunogenicity: “To our knowledge, reports of B cell epitope prediction for L1 and L2 of HPVs is limited; so we predicted the most probable immunogenic regions of L1 and L2…” (Page 211, right column, ¶ 3).
Hosseini also teaches: “These epitope sequences fused together in a tandem… Check of antigenicity also revealed that major parts of new protein construct have hydrophilic property and thus harbor antigenic potency.” (Discussion).
To design the final vaccine construct, “Then, by other bioinformatics analyses, 20 epitopes were selected and fused in tandem repeats, reverse translated, and codon optimized to relevant sequence. […] After all, sequence of final construct reverse translated to DNA and this codon-optimized sequence showed Codon Adaptation Index (CAI) of >0.8 for expression in Escherichia coli. Finally, this sequence ligated into pET28a bacterial expression vector.” (Abstract).
Therefore, it would have been obvious to a person of ordinary skill before the effective filing date of the claimed invention to find the fusion proteins as made obvious by Preville, Shin, and Ella, and further apply the techniques of Hosseini to analyze the proteins. The fusion of multiple epitopes will cause a change in the 3D structure, immunogenicity, and physiological properties from the wild-type epitopes. Once the fusion proteins are analyzed and the best vaccine candidates identified, it would further be obvious to design a polynucleotide that encodes for the best fusion protein candidates. This polynucleotide would then be produced/synthesized by recombination DNA technology as discussed supra. This allows one of ordinary skill to screen for the best possible epitopes without having to test them all in vivo, allowing for faster vaccine development. Applying a known technique to a known device (method or product) ready for improvement to yield predictable results is likely to be obvious. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, D.). Other advantages would be for selecting antigenicity desired, solubility desired, and isoelectric point desired for later pharmacological and purification (ion exchange chromatography) purposes, which are standard practice in this art for peptide drugs/immunogens.
18. Claims 38-40, and 42-43 are rejected under 35 U.S.C. 103 as being unpatentable over Preville (Supra), Shin (Supra), Ella (Supra), Isomura (Supra), and Hosseini (Supra) as applied to claims 13 and 35 above, and further in view of Burny (US 20200123571 A1; Provisional filed 29 September 2016) (See PTO-892 filed 02 December 2025).
Regarding claims 38-40 and 42-43, Preville, Shin, and Ella teach the limitations of claims 12 and 37, all discussions thereon above incorporated here. Shin teaches using the vector pVAX1 but does not teach an adenoviral vector. However, Burny teaches an HPV vaccine comprising a pharmaceutically acceptable carrier and one or more vectors (¶ [0006]) wherein, “Accordingly, in one embodiment, a transgene comprising nucleic acid sequences encoding HPV E1, E2, E6 and/or E7 antigenic peptides, from multiple hrHPV types, is incorporated into a viral vector, such as an adenoviral vector […] Adenoviral vectors may also be derived from adenoviruses isolated from gorillas…” (¶ [0473]). Burny further teaches replication-defective adenoviruses (¶ [0396]) and making a formulation by suspending or dissolving the vector in a pharmaceutically acceptable carrier (¶ [0531]). It is standard in the art to use replication-defective vectors for safety purposes, as they are no longer capable of replication and infection.
Therefore, it would have been obvious to a person of ordinary skill before the effective filing date of the claimed invention to use the methods of Shin and use a replication-deficient gorilla adenoviral vector suggested in Burny instead of pVAX1 to make a formulation with a pharmaceutically acceptable carrier, as both references use their respective vectors for encoding HPV fusion proteins. The simple substitution of one known element for another is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, B.). Gorilla adenoviral vectors are taught as a functional virus option above and making them replication deficient is standard practice in this art for the advantage of producing a vaccine which will not lead to generation of a second virus, though intended as therapy, in the patient, but instead, remaining only therapeutic. This provides the additional advantage for tight control of dose given to the patient. Replication of the therapeutic virion would change the dose of therapeutic virion in the patient over time, complicating dosing.
Conclusion
19. No claim is 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 KRISTINA E LY whose telephone number is (571)272-5169. The examiner can normally be reached Monday - Thursday, 8:00 am - 5:00 pm EST.
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/KRISTINA E. LY/Examiner, Art Unit 1671 /Michael Allen/Supervisory Patent Examiner, Art Unit 1671
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