DETAILED ACTION
Non-Final Rejection
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 .
Election/Restrictions
2. Applicant’s election without traverse of Group I claims 11-22 in the reply filed on 01/12/2026 is acknowledged.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement the applicant’s election without traverse is made final.
Status of Claims
3. Claims 11-26 as filed on 01/12/2026 are pending.
4. Claims 23-26 are withdrawn due to election/restriction.
5. Claims 11-22 are under examination in this office action.
Priority
6. This application is the U.S. National Stage of International Application No. PCT/CN2021/120517, filed on September 26, 2021, which claims the priority of Chinese Patent Application No. 202011346631.0, filed on November 26, 2020.
Information Disclosure Statement
7. The information disclosure statement (IDS) submitted on 05/23/2023 was filed in time and 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 to Nucleotide and/or Amino Acid Sequence Disclosures
8. REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
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).
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.
The instant claim 12 and instant specification recites NCBI Accession No. for the protein sequences (e.g. P04012.1) instead of the SEQ ID NO in compliance with the sequence claims and submission guidelines.
Objections to Specification
9. The use of the term “NCBI”, recited in the specification on page 3, and page 5 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 present in the instant specification, if any additional trade names and/or marks are discovered. Applicant' s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
10. The specification is objected to by providing foreign reference citations that are not of record and/or English translated (in part or whole) as relevant to the disclosed teaching. For example, Applicant referenced the Chinese language Patent Application No. 202011346631.0, filed on November 26, 2020, recited in “Cross Reference to Related Applications” in the 05/23/2023 preliminary amendment, CN101293918B, CN 101148661B (on specification pages 8-9, 11), CN104513826A (on specification page 9), CN101293918B, and CN1976718A (on specification page 10). Applicant may provide copies of English translated portions or entire prior art documents or at least machine English translations of the Chinese prior arts (e.g. google machine English translation) for clarity of record.
11. The specification recites the sequence identified by NCBI sequence accession number P04012.1 and CBM41728.1, QEE83877.1, CRF31180.1, CRF31054.1, CRF31153.1, CBM41721.1, ACL12350.1, QDH43412.1, AAF25684.1, etc. in NCBI database (See, page numbers 3, and 5 and may be other pages of specification). NCBI® accession numbers are essential material and are required by the instant claims by reference to a publication. Incorporation of essential material by reference to a publication is improper under 37 CFR § 1.57(d). Applicant is required to amend the disclosure to include the material incorporated by reference. 37 CFR § 1.57. The amendment must be accompanied by an affidavit or declaration executed by the applicant, or a practitioner representing the applicant, stating that the amendatory material consists of the same material incorporated by reference in the referencing application. See In re Hawkins, 486 F.2d 569, 179 USPQ 157 (CCPA 1973).
Furthermore, if the recited NCBI accession No. No. P04012.1, CBM41728.1, QEE83877.1, CRF31180.1, CRF31054.1, CRF31153.1, CBM41721.1, ACL12350.1, QDH43412.1, AAF25684.1.
in instant claim 12, was not set forth in the specification as filed, and was not publicly available at the time the application was filed, the amendment will be treated as an attempt to introduce new matter (similar to attempts to incorporate essential material by reference to unpublished material). In addition, note that that an amendment introducing an additional sequence corresponding to the intended sequence will probably require a replacement Sequence Listing, CRF and a statement indicating that the paper and CRF sequence submissions are the same.
Claim Interpretation
12. The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 11: The instant claim 11 is interpreted to be directed to a C-terminus modified HPV11 L1 protein, wherein one or more basic amino acids of 31 amino acids at C-terminus are substituted with amino acids selected from the group consisting of: polar uncharged amino acids, non-polar amino acids, and acidic amino acids, compared with wild-type HPV11 L1 protein. The claim is interpreted to be directed to comprise multiple species of variant HPV11 L1 that has substitution of one or more basic amino acids (R, K, or H) substituted with non-basic amino acid of different types belonging to polar or non-polar types, or combinations thereof.
Claim 14: The instant claim 14 comprise C-terminus modified HPV11 L1 protein according to claim 11, wherein the basic amino acid is selected from the group consisting of: arginine and lysine; the polar uncharged amino acid is selected from the group consisting of: glycine, serine, and threonine; the non-polar amino acid is selected from the group consisting of: alanine and valine; the acidic amino acid is selected from the group consisting of: aspartate and glutamate; or combinations thereof.
Claims 12-13, and 15-22 are directed to the C-terminus modified HPV11 L1 protein encoding codon optimized polynucleotide sequences comprised in baculovirus vector, plasmid vector, bacmid vector and host cells, e.g. E. coli, yeast cell, and insect cell, for expression of the HPV11 L1 constructs to produce the HPV11 L1 protein or VLPs.
The claims 11-22 are directed to C-terminus modified HPV11 L1 amino acid encoding polynucleotide sequences to produce the C-terminus modified HPV11 L1 proteins at substantially higher quantity (e.g. soluble protein, VLPs) than the wild type HPV11 L1 sequences.
Claim Rejections - 35 USC § 103
13. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
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.
14. Claims 11, 14, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou et al 1991 (Virology. 1991 Dec;185(2):625-32) and further in view of Chen et al 2001 (J Mol Biol. 2001 Mar 16;307(1):173-82), Kong et al 2015 (CN104418942A, 03/18/2015, English translated PDF printout), Wu et al 2015 (CN104710515A, published 06/17/2015, English translated PDF printout), and Yang et al 2006 (Genomics Proteomics Bioinformatics. 2006 Feb;4(1): p. 34-41).
Claims 11, 14 and 16: Zhou et al 1991 is in the art and teaches identification of the nuclear localization signal of human papillomavirus using HPV16 L1 protein as a model. Human papillomavirus type 16 (HPV16) L1 and L2 capsid proteins can be detected only in the nucleus of infected cells. For other proteins that accumulate or destined to be transported to the nucleus are called nuclear proteins, and those nuclear proteins have specific sequences of basic amino acids(aa) termed nuclear localization signals (NLS) that direct the protein from the cytoplasm to the nucleus. A series of deletion and substitution mutations in the HPV16 L1 protein, produced by recombinant vaccinia virus (rVV), to identify NLS within HPV16 L1 and showed that HPV16 L1 C-terminal contains two NLS sequences, each containing basic amino acid clusters. One NLS consisted of 6 basic amino acids (KRKKRK from aa 525 to 530) at the carboxy terminal end of L1. The other NLS contained 2 basic amino acid clusters (KRK from aa 510 to 512 and KR at aa 525, 526) separated by 12 amino acids. Mutations in either one of the NLS basic amino acid clusters did not alter nuclear localization of L1 when the other NLS basic amino acid cluster remained intact, but mutations to NLS basic amino acid clusters prevented nuclear localization of L1 protein. The L1 NLS and nuclear localization could be overridden by introduction of a membrane binding sequence MVVLLAALLVV (non-basic amino acid) at the amino terminal end of the protein. A databases search showed that all sequenced papillomaviruses are predicted to have L1 and L2 capsid proteins with sequences of basic amino acids homologous with one or both NLS of HPV16 L1. (See, Zhou et al 1991, abstract, page 626 col 2 last para continued to page 627, Results col 2 on page 627 last 2 para, discussion, entire article). This Zhou et al 1991 teaches insertional mutation of non-polar amino acids, and deletion of a patch of amino acids at the C-terminal of HPV16 L1 protein that results in loss of nuclear localization of the L1 protein.
Zhou et al 1991 teaches substitution of a cluster of basic amino acids (more than one amino acids) in the NLS at C- terminal of HPV16 L1 with nonpolar amino acids, however, does not teach substitution of a single basic amino acid at C-terminus modified HPV11 L1 protein of 31 amino acids at C-terminus that are substituted with amino acids selected from the group consisting of: polar uncharged amino acids, non-polar amino acids, and acidic amino acids.
Zhou et al 1991 teaches the inventive concept of disruption of NLS basic amino acid cluster by deletion or substation of cluster of a basic amino acid to enable to direct the HPV16 L1 protein to the cytoplasm. Zhou et al 1991 in table 3 (page 631, col 1, lower half of table) shows conserved basic amino acid sequences in the NLS at C-terminal for HPV16 L1, HPV11 L1 and for L1 protein of other HPV types. Therefore, one of the ordinary skills would have been apprised of the importance of the basic amino acid clusters or basic amino acids at the C-terminal for 31 amino acids that determine the NLS and fate of the L1 protein to transport from cytoplasm to the cell nucleus to localize in the nucleus among different HPV serotypes irrespective of the HPV serotype. Therefore, following this prior art would motivate one to substitute, for virally related protein strains, the C-terminal basic amino acid sequences for disruption of L1 protein NLS in HPV11 L1 protein to produce substantially large quantity of soluble L1 protein or VLPs by retaining the produced protein with disrupted NLS within the cytoplasm.
Further, the following prior art references provide additional prior art recognition of the structural and functional equivalency of the L1 protein of the HPV11 and HPV16 strains that would motivation one of ordinary skill in the art to modify the Zhou reference C-terminal basic modifications specifically applied to HPV16 L1 to the suggested HPV11L1 embodiment of the primary Zhou reference.
Yang et al 2006 used bioinformatic analysis to predict the nuclear localization signals (NLS) of 107 types of HPV L1 proteins including HPV11 L (See, abstract, Table 1, table 1 page 37 col 1 HPV 11, entire prior art) and thus Yang et al 2006 teaches that NLS are largely conserved in different HPV types in the 31 amino acids at the C-terminal.
Chen et al 2001 is in the art and teaches that the L1 major capsid proteins of human papillomavirus HPV 11 and HPV 16 were purified and analyzed for structural integrity and in vitro self-assembly. Proteins were expressed in Escherichia coli as glutathione-S-transferase-L1 (GST-L1) fusions and purified to near homogeneity as pentamers (equivalent to viral capsomeres), after thrombin cleavage from the GST moiety and removal of tightly associated GroEL protein. Sequences at the amino and carboxy termini contributing to formation of L1 pentamers and to in vitro capsid assembly were identified by deletion analysis. For both HPV11 and HPV16 L1, up to at least ten residues could be deleted from the amino terminus (Delta N10) and 30 residues from the carboxy terminus (Delta C30) without affecting pentamer formation. The HPV16 pentamers assembled into relatively regular, 72-pentamer shells ("virus-like particles" or VLPs) at low pH, with the exception of HPV16 L1 Delta N10, which assembled into a 12-pentamer, T=1 capsid (small VLP) under all conditions tested. The production of large quantities of assembly-competent L1, using the expression and purification protocol described here, has been useful for crystallographic analysis, and will be valuable for studies of virus-receptor interactions and potentially for vaccine design (See, abstract). For example, the similarity of HPV16 and HPV11 L1 sequences ceases abruptly 30 residues from the carboxy terminus, just C-terminal to helix h5 (See, page 180, col 1 para 4). The C-terminus 26 amino acid residues deleted at encompass deletions of basic amino acids, lysine and arginine residues (upper case) conserved in papillomavirus L1 proteins, according to Table 3 of Zhou et al 1991 page 631 col 1.
Kong et al 2015 (CN104418942A) is in the art and teaches C-terminal 9 amino acids or 21 amino acids truncated L1 proteins and nucleotide sequences encoding these truncated L1 proteins of HPV, and VLPs for HPV11-type, and other additional HPV types, production of the truncated proteins using E coli (prokaryotic vector), eukaryotic cells and eukaryotic vector, baculovirus vector and insect cells, Saccharomyces cerevisiae yeast and yeast vector (See, Kong et al 2015, CN104418942A, English translated PDF print out, abstract, claim 1, page 4).
To the extent that the Zhou et al 1991 reference method discussed above does not expressly teach a “single” mutant L1 basic amino C-terminal substitution, the Wu et al 2015 reference cited below teach that changin “one or more” basic amino acid represent an obvious design choice.
Wu et al 2015 (CN104710515A) is in the art and discloses an approach or method of a non-basic amino acid substitution with another non-basic amino acid (non-polar amino acid) in human papilloma virus L1 protein mutants and a preparation method thereof, and a pharmaceutical composition containing at least one of the mutants, especially a vaccine containing at least one of the mutants (See, abstract). A human papillomavirus L1 protein refers to HPV types 6, 11, 16, 18, 31, 33, 34, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 67, 68, 70, 72, 73 or 82, 85, 97, HPV types and/or a combination of several. A mutant of human papilloma virus L1 protein, (reads on HPV11 L1 protein) which is characterized in that the leucine L* in the C-terminal α-helix 5 FPLGRKFL*LQAG of the human papillomavirus L1 protein is mutated (mutated reads on substituted) into alanine A (non-polar amino acid) or serine S (polar amino acid), preferably mutated to alanine A (non-polar amino acid). The human papillomavirus (HPV) L1 protein refers to HPV11 type L1 (See, CN104710515A, English translated PDF print out, page 4, Contents of Invention, lines 1-7, claims 1-2).
Therefore, based on the prior art teachings recited supra, it would have been obvious to one of the ordinary skills in the art to disrupt the HPV11 L1 NLS by substitution of one or more basic amino acids of the 31 C-terminal amino acids with the claimed non-basic amino acids for substantially higher amount of soluble HPV11 L1 protein as compared to the wild type HPV11 L1 protein.
Claim 16. The combined teachings of Zhou et al 1991, Chen et al 2001, and Wu et al 2015 teaches a C-terminus modified HPV11 L1 protein as recited supra and therefore teaches a DNA vector construct or a polynucleotide sequence encoding the C-terminus modified HPV11 L1 protein according to claim 11 (See, prior arts by Zhou et al 1991, Chen et al 2001, Kong et al 2015, and Wu et al 2015).
It would have been obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to modify the prior art teachings of Zhou et al 1991 with the additional teachings of Chen et al 2001, Kong et al 2015, Wu et al 2015, and Yang et al 2006 to disrupt the nuclear localization signal (NLS) amino acid sequence by substituting basic amino acids with non-basic amino acids to prevent the nuclear transport of expressed L1 protein so that the soluble L1 proteins are retained in the cytoplasm for easier purification protocol or assembly into VLP to arrive at the invention of claims 11, 14, and 16. One of the ordinary skills in the art would have been motivated to disrupt the HPV 11 L1 NLS for producing soluble protein for purification or efficient assemble into VLPs for production of vaccine or diagnostic to arrive at the inventions of claims 11, 14 and 16 and use for commercial success. There would be a reasonable expectation of success given the applied prior art teachings in the art as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 11, 14 and 16. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
15. Claims 12 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Zhou et al 1991 (Virology. 1991 Dec;185(2):625-32), Chen et al 2001 (J Mol Biol. 2001 Mar 16;307(1):173-82), Kong et al 2015 (CN104418942A, 03/18/2015, English translated PDF printout), Wu et al 2015 (CN104710515A, published 06/17/2015, English translated PDF printout), and Yang et al 2006 (Genomics Proteomics Bioinformatics. 2006 Feb;4(1): p. 34-41),
and further in view of Sette et al 2009 (US7572882B2, 11/08/2009).
Claims 12 and 13: The combined teachings of Zhou et al 1991, Chen et al 2001, Wu et al 2015, and Yang et al 2006 teaches claim 11 as recited supra, and the teachings that render obvious claim 11 are incorporated here in entirety. The combined teachings, however, does not teach a claim 13 limitation SEQ ID NO: 1 that disclose wild-type HPV11 L1 amino acid sequence.
Examiner note regarding claim 12: The recited NCBI® designations for the requisite sequences fail to clearly identify the precise HPV11 L1 protein sequences claimed because the accession numbers are extraneous to the instant disclosure. In the interest of compact prosecution, claim 12 is interpreted as HPV11 L1 wild-type protein sequences.
Sette et al 2009 (US7572882B2, 11/08/2009) is in the HPV11 art and teaches HPV11 L1 amino acid sequence SEQ ID NO: 26 (Db) that has 100% sequence identity with SEQ ID NO: 1 (Qy).
Query Match 100.0%; Score 2698; Length 501;
Best Local Similarity 100.0%;
Matches 501; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MWRPSDSTVYVPPPNPVSKVVATDAYVKRTNIFYHASSSRLLAVGHPYYSIKKVNKTVVP 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MWRPSDSTVYVPPPNPVSKVVATDAYVKRTNIFYHASSSRLLAVGHPYYSIKKVNKTVVP 60
Qy 61 KVSGYQYRVFKVVLPDPNKFALPDSSLFDPTTQRLVWACTGLEVGRGQPLGVGVSGHPLL 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 KVSGYQYRVFKVVLPDPNKFALPDSSLFDPTTQRLVWACTGLEVGRGQPLGVGVSGHPLL 120
Qy 121 NKYDDVENSGGYGGNPGQDNRVNVGMDYKQTQLCMVGCAPPLGEHWGKGTQCSNTSVQNG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 NKYDDVENSGGYGGNPGQDNRVNVGMDYKQTQLCMVGCAPPLGEHWGKGTQCSNTSVQNG 180
Qy 181 DCPPLELITSVIQDGDMVDTGFGAMNFADLQTNKSDVPLDICGTVCKYPDYLQMAADPYG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 DCPPLELITSVIQDGDMVDTGFGAMNFADLQTNKSDVPLDICGTVCKYPDYLQMAADPYG 240
Qy 241 DRLFFYLRKEQMFARHFFNRAGTVGEPVPDDLLVKGGNNRSSVASSIYVHTPSGSLVSSE 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 DRLFFYLRKEQMFARHFFNRAGTVGEPVPDDLLVKGGNNRSSVASSIYVHTPSGSLVSSE 300
Qy 301 AQLFNKPYWLQKAQGHNNGICWGNHLFVTVVDTTRSTNMTLCASVSKSATYTNSDYKEYM 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 AQLFNKPYWLQKAQGHNNGICWGNHLFVTVVDTTRSTNMTLCASVSKSATYTNSDYKEYM 360
Qy 361 RHVEEFDLQFIFQLCSITLSAEVMAYIHTMNPSVLEDWNFGLSPPPNGTLEDTYRYVQSQ 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 RHVEEFDLQFIFQLCSITLSAEVMAYIHTMNPSVLEDWNFGLSPPPNGTLEDTYRYVQSQ 420
Qy 421 AITCQKPTPEKEKQDPYKDMSFWEVNLKEKFSSELDQFPLGRKFLLQSGYRGRTSARTGI 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 AITCQKPTPEKEKQDPYKDMSFWEVNLKEKFSSELDQFPLGRKFLLQSGYRGRTSARTGI 480
Qy 481 KRPAVSKPSTAPKRKRTKTKK 501
|||||||||||||||||||||
Db 481 KRPAVSKPSTAPKRKRTKTKK 501
It would have been obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to modify the combined prior art teachings of Zhou et al 1991, Chen et al 2001, Wu et al 2015, and Yang et al 2006 with additional teachings of Sette et al 2009 that disclosed HPV11 L amino acid sequence to arrive at the invention of claims 12-13. One of the ordinary skills in the art would have been motivated to develop the HPV11 L1 expression construct for mutagenesis of C-terminal 31 amino acids to disrupt the HPV11 L1 NLS for producing soluble protein for purification and commercial success. There would be a reasonable expectation of success given the applied prior art teachings in the art as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 12-13. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
16. Claims 17, 19, and 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Zhou et al 1991 (Virology. 1991 Dec;185(2):625-32), Chen et al 2001 (J Mol Biol. 2001 Mar 16;307(1):173-82), Kong et al 2015 (CN104418942A, 03/18/2015, English translated PDF printout), Wu et al 2015 (CN104710515A, published 06/17/2015, English translated PDF printout), and Yang et al 2006 (Genomics Proteomics Bioinformatics. 2006 Feb;4(1): p. 34-41), and further in view of Rose et al 1994 (J Gen Virol. 1994 Sep;75 (Pt 9):2445-9), and Sun et al 2016 (Appl Microbiol Biotechnol (2016) 100:1231–1240).
The combined prior art teachings Zhou et al 1991, Chen et al 2001, Kong et al 2015, Wu et al 2015, Yang et al 2006 as recited supra teaches instant claim 16 directed to a polynucleotide encoding the C-terminus modified HPV11 L1 protein. However, does not teach added limitations of claims 17, and 19-22.
Claims 17, and 19-22: Rose et al 1994 teaches (partially) the instant claim 17 limitation polynucleotide sequence of HPV11 L1 for expression using the recombinant baculovirus-infected Spodoptera frugiperda (Sf9) cells and cell-free culture supernatants and production of HPV11 L1 VLPs. The instant claim 19 limitation, the construction of recombinant baculovirus comprising HPV11 L1 is also disclosed (that reads on a vector comprising the polynucleotide) (See, abstract, page 2445 col 2 para 2, page 2446 Fig. 1-2).
Rose et al 1994 does not teach codon optimization the polynucleotide sequence of HPV11 L1 to express in insect cells Sf9.
Sun et al 2016 teaches a 21 amino acid NLS lacking C-terminally truncated HPV6 L1 polynucleotide sequence gene that is optimized for insect cell codons expression (codon optimized for insect cells) and production of the VLPs (See, abstract, page 1238 col 1 last para, page 1232 col 2 para 1, Fig. 6 a, b).
Sun et al 2016 further teaches added limitation of instant claim 20, wherein the vector a recombinant baculovirus (See, abstract, page 1232 col 1 para 2, col 2 para 1).
Sun et al 2016 further teaches added limitation of instant claim 21 a host cell comprising the vector according to claim 19 (See, abstract, page 1238 col 1 last para, page 1232 col 1 para 2, col 2 para 1).
Sun et al 2016 further teaches added limitation of instant claim 22 the host cell according to claim 21, wherein the host cell is insect cell Sf9 (See, abstract, page 1232 col 1 para 2, col 2 para 1).
It would have been obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to modify the combined prior art teachings of Zhou et al 1991, Chen et al 2001, Kong et al 2015, Wu et al 2015, Yang et al 2006 with additional teachings of Rose et al 1994, and Sun et al 2016 to replace the HPV16 L1 polynucleotide sequence of Sun et al and incorporate the teachings on codon optimization and baculovirus expression for the HPV11 L1 polynucleotide sequence taught by the prior arts Zhou et al 1991, Chen et al 2001, and Rose et al 1994 to arrive at the inventions of claims 17, and 19-22. One of the ordinary skills in the art would have been motivated to develop a codon optimized baculovirus expression vector for expression of the claimed HPV11 L1 in the insect cells (e.g. Sf9) for producing soluble protein for purification, HPV11 L1 VLPs for production of immunogens, vaccines and diagnostic antigens for commercial success. There would be a reasonable expectation of success given the applied prior art teachings in the art as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 17, and 19-22. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
HPV11 L1 Sequences (SEQ ID NO) Free of Prior Art
17. Claims 15 and 18:
Claim 15: The SEQ ID No. 2, SEQ ID No. 3, SEQ ID No. 4, SEQ ID No. 5, SEQ ID No. 6 and SEQ ID No. 7 are free of prior art. The prior art identified by ABSS sequence search shows maximum identity between 97.9 to 98.3% identity to the claimed amino acid sequences.
Claim 18: The SEQ ID No. 9, SEQ ID No. 10, SEQ ID No. 11, SEQ ID No. 12, SEQ ID No. 13 and SEQ ID No. 14 are free of prior art. The prior art identified by ABSS sequence search shows maximum identity between 98.2% to 98.7% identity to the claimed amino acid sequences.
The instant claims 15 and 18 are objected to as being dependent upon a rejected base claim but would be allowable over the prior art of record if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
18. Relevant Prior Arts:
Joyce et al 1999. The L1 major capsid protein of human papillomavirus type 11 recombinant virus-like particles interact with heparin and cell-surface glycosaminoglycans on human keratinocytes. J Biol Chem. 1999 Feb 26;274(9):5810-22.
Buck et al 2013. The papillomavirus major capsid protein L1. Virology. 2013 Oct;445(1-2):169-74.
Li et al 1997. Expression of the human papillomavirus type 11 L1 capsid protein in Escherichia coli: characterization of protein domains involved in DNA binding and capsid assembly. J Virol. 1997 Apr;71(4):2988-95.
Bang et al 2016. High-Level Production of Human Papillomavirus (HPV) Type 16 L1 in Escherichia coli. J. Microbiol. Biotechnol. (2016), 26(2), 356–363.
Rao et al 2011. Expression of codon optimized major capsid protein (L1) of human papillomavirus type 16 and 18 in Pichia pastoris; purification and characterization of the virus-like particles. Vaccine. 2011 Oct 6;29(43):7326-34.
Mossadegh et al 2004. Codon optimization of the human papillomavirus 11 (HPV 11) L1 gene leads to increased gene expression and formation of virus-like particles in mammalian epithelial cells. Virology 326 (2004) 57– 66.
Conclusion
19. No claim allowed.
20. Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMADHAN J JADHAO whose telephone number is (703)756-1223. The examiner can normally be reached M-F 8:00-5:00.
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/SAMADHAN JAISING JADHAO/ Examiner, Art Unit 1672
/BENNETT M CELSA/ Primary Examiner, Art Unit 1600