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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on May 23, 2023 has been considered by the examiner.
Specification
The use of the term “NCBI”, recited in paragraph [0010, 0012, 0013, and 0028] of the published application, USPgPub 2024/0000915, 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.
Applicant is reminded that the incorporation of essential material, i.e., Chinese Patent Application No. 202011347629.5, recited in “Cross Reference to Related Applications” in the May 23, 2023 preliminary amendment, CN 101293918 B, recited in paragraphs [0049, 0051-0053, and 0058], CN 101148661 B recited in paragraphs [0052, 0053, and 0060], CN 1976718 A, recited in paragraph [0058], and CN 104418942 A, recited in paragraph [0063], all incorporated by reference in paragraph [0038], and NCBI® database accession numbers: P04012, CBM41728.1, QEE83877.1, CRF31180.1, CRF31054.1, CRF31153.1, CBM41721.1, ACL12350.1, QDH43412.1, AAF25684.1, recited in paragraphs [0010, 0012, 0013, and 0028] and in claim 12 in the instant published specification, by reference to a foreign application or patent, or to a publication, is improper. 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 materials in 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.
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter of “chimeric” virus-like particles, recited twice in claim 26. Paragraph [0018] of the instant published disclosure states: “mucosa-tropic and/or skin-tropic HPV pentamer or virus-like particle”, but no disclosure of a “chimeric” virus-like particle. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). The claimed chimeric virus-like particles of instant claim 26 requires a mucosa-tropic or a skin-tropic HPV type in combination with the instant modified HPV6 L1 claimed. However, no such chimera is set forth in the disclosure. If the “chimeric” virus-like particle, was not set forth in the specification as filed, an amendment introducing these materials into the instant disclosure will be treated as an attempt to introduce new matter (similar to attempts to incorporate essential material by reference to unpublished material).
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 11-14, 16, 17, and 19-26 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.
Instant claim 11 requires a C-terminus modified HPV6 L1 protein, wherein one or more basic amino acids of 31 amino acids at C-terminus are substituted, but it cannot be determined where the 31 amino acid residue positions at the C-terminus are relative to, or where the C-terminus within the HPV6 L1 protein is considered to begin. There is no discussion provided in the disclosure clarifying this issue. Zhou et al. (Virology. 1991; 185: 625-632) depict HPV L1 basic amino acid residue consensus sequences, including HPV6, in Table 3. According to the c-terminal HPV6 sequence of Zhou et al., basic amino acids include upper case lysine and arginine resides:
PNG
media_image1.png
21
396
media_image1.png
Greyscale
This sequence does not include 31 basic residues of lysine and arginine, implied by claim 11. Is claim 11 intended to require substitution of basic amino acid residues within the remaining 31 amino acids at the c-terminus? In the interest of compact prosecution, the claims are interpreted as such since any other interpretation would be repugnant to the basic HPV6 L1 consensus residues established in 1991 by Zhou et al. However, this courtesy does not preempt the requirement for a clarifying amendment. This rejection affects claims 12-14, 16, 17, and 19-26.
Instant claim 12 requires NCBI® accession nos: NP040304.1, AAC80447.1, AAC80442.1, CDK36706.1, AAC80450.1, CDK37192.1, CDK36967.1, CDK36699.1, CDK36544.1, and CCJ09340.1. However, the recited NCBI® designations for the requisite sequences fail to clearly identify the precise HPV6 L1 protein claimed because the accession number is extraneous to the instant disclosure. Since NCBI® sequences are not irrevocably fixed, but are corrected and updated as additional sequence information becomes available, no precise structural information regarding the NCBI® accession numbers can be gleaned. This rejection affects dependent claim 13. In the interest of compact prosecution, claim 12 is interpreted as an HPV6 L1 wild-type protein sequence. This courtesy does not preempt the requirement for a clarifying amendment.
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 11-14, 16, 17, and 19-26 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.
Instant claim 11 requires a C-terminus modified HPV6 L1 protein, wherein one or more basic amino acids of 31 amino acids at C-terminus are substituted, but it cannot be determined where the 31 amino acid residue positions at the C-terminus are relative to or where the C-terminus within the HPV6 L1 protein is considered to begin. Instant claim 12 recites NCBI® accession numbers designating wild-type HPV6 L1 protein sequences. However, these accession numbers fail to clearly identify the precise location of the 31 amino acid residue positions at the C-terminus required because the accession numbers are extraneous to the application. Instant claim 13 requires SEQ ID NO: 1 as the wild-type HPV6 L1. However, the last 31 c-terminal residues of the sequence are not arginine or lysine basic residues, defined in instant claim 14, but also comprise glycine, serine and threonine polar uncharged amino acids and non-polar alanine and valine residues, see the alignment of instant SEQ ID NO: 1 with Geneseq database accession no: AAB98397 in WO200141799 by Sette et al. 2007, sharing 100% identity. Zhou et al. (Virology. 1991; 185: 625-632) depict HPV L1 basic amino acid residue consensus sequences, including HPV6, in Table 3. According to the c-terminal HPV6 sequence of Zhou et al., basic amino acids include upper case lysine and arginine resides:
PNG
media_image1.png
21
396
media_image1.png
Greyscale
This sequence does not include 31 basic residues of lysine and arginine, implied by claim 11.
According to the consensus sequence of HPV6 L1 of Zhou et al., also depicted in Geneseq database accession no: AAB98397 sequence of Sette et al., there are 10 basic amino acids, lysine and arginine. Instant claim 11 requires that these residues are substituted with polar uncharged amino acids, non-polar amino acids and acidic amino acids, when compared with wild-type HPV6 L1 protein. Instant claim 14 lists the substituted amino acids: the polar uncharged amino acid selected from glycine, serine, or threonine; the non-polar amino acid selected from alanine or valine; and the acidic amino acids selected from aspartate or glutamate, i.e., a total of 7 variables. However, there is no written support provided for substituting one or more of the 10 basic amino acids within the c-terminus of HPV6 L1 with one or more of seven possible amino acid residues, i.e., 710 or 282,475,249 possible combinations.
Paragraph [0012] of the instant published disclosure (USPgPub 2024/0000909), lists six C-terminally modified HPV6 L1 proteins that are constructed: 6L1CS1, 6L1CS2, 6L1CS3, 6L1CS4, 6L1CS5, 6L1CS6, 6L1CS7 and 6L1CS8, corresponding to: SEQ ID No. 2, SEQ ID No. 3, SEQ ID No. 4, SEQ ID No. 5, SEQ ID No. 6, SEQ ID No. 7, SEQ ID No. 8 and SEQ ID No. 9, respectively. However, only three constructs produced robust quantities of HPV L1 proteins: 6L1CS2, 6L1CS4, and 6L1CS6, shown in Table 1. The skilled artisan would be unable to recognize or identify which of the millions of c-terminally modified HPV6 L1 proteins claimed produce adequate quantities of expression, required in instant claims 16-22. Only two constructs, 6L1CS4 and 6L1CS6 are shown to possess particle size consistent with good uniformity, presented in Table 2 and Figures 3A and 3B. Therefore, there is no written support provided for the genus of constructs of claim 11, comprising 710 members, forming the multimer required in instant claims 23-26. Figure 4 and Example 8 show only 6L1CS4 induces neutralizing antibody titers similar to wild-type HPV6 L1 VLP. Therefore, there is no adequate written description for any one of the millions of c-terminally modified HPV6 L1 proteins claimed capable of inducing sufficient neutralizing antibody titers to prevent papillomavirus infection or related disease, asserted by instant claims 24-26.
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 factor present in the specification are SEQ ID NOs: 2-9. There is no disclosure of sufficient characteristics of the claimed genus of c-terminally modified HPV6 L1 proteins, substituted at one or more basic amino acids, to allow persons of ordinary skill in the art to recognize that applicants were in possession of the claimed genus. Paragraph [0064] of the instant disclosure states:
[0064] In summary, the inventor found that the expression levels of mutants obtained by C-terminus amino acid substitution modification of HPV6L1 vary from each other, and are irregular. There is also a certain difference in the immune activities among the VLPs assembled thereby. Therefore, it cannot be expected that HPV6L1 mutants with high expression level, effective assembly and good immune activity can be obtained by the method of C-terminus substitution modification.
Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus. 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 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 c-terminally modified HPV6 L1 proteins claimed. Given that the specification has only described SEQ ID NOs: 2-9, 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 12 and 13 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.
Instant claims 12 and 13 require NCBI® accession nos: NP040304.1, AAC80447.1, AAC80442.1, CDK36706.1, AAC80450.1, CDK37192.1, CDK36967.1, CDK36699.1, CDK36544.1, and CCJ09340.1. However, the NCBI® designations for the requisite sequences fail to clearly identify the precise HPV6 L1 proteins claimed because the accession numbers are extraneous to the instant disclosure. Since NCBI® sequences are not irrevocably fixed, but are corrected and updated as additional sequence information becomes available, no precise structural information regarding the NCBI® accession numbers can be gleaned. The structures corresponding to the NCBI® accession numbers may refer to sequences which change or even become deleted after the application filing date and are not guaranteed as a consistent source of information for requisite material. The skilled artisan cannot access the structure submitted to the database or determine what or how the structure has changed since the original submission date. For these reasons, the structures representing the NCBI® database accession number submissions, are indeterminable to adequately identify the HPV6 L1 proteins claimed. The instant disclosure does not support an adequate written description of the sequence corresponding to NCBI® accession nos: NP040304.1, AAC80447.1, AAC80442.1, CDK36706.1, AAC80450.1, CDK37192.1, CDK36967.1, CDK36699.1, CDK36544.1, and CCJ09340.1.
Claim 26 is 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 26 recites, “mucosa-tropic HPV virus-like particle or chimeric virus-like particle; skin-tropic HPV virus-like particle or chimeric virus-like particle; or combinations thereof.”.
Paragraph [0018] of the instant published disclosure (USPgPub 2024/0000909 states: “the vaccine can also comprise at least one selected from other mucosa-tropic and/or skin-tropic HPV pentamer or virus-like particle…”. Therefore, while there is sufficient disclosure for administering a mucosa-tropic and/or skin-tropic HPV pentamer or virus-like particle in combination with the instant modified HPV6 L1, there is no written description for a chimeric VLP comprising the instant modified HPV6 L1 and a mucosa-tropic or a skin-tropic HPV type. The claimed subject matter requiring a “chimeric” virus-like particle comprising the instant modified HPV6 L1 and a mucosa-tropic or a skin-tropic HPV type was not set forth in the specification as filed.
Claims 23-26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a c-terminally HPV6 L1 comprising SEQ ID NO: 5 (6L1CS4) to form a multimer, does not reasonably provide enablement for any c-terminally-modified HPV6 L1, where one or more basic amino acids within the remaining 31 amino acids at the c-terminus are substituted with any one or more polar uncharged amino acids, non-polar amino acids and acidic amino acids, when compared with wild-type HPV6 L1 protein, to form a multimer effective to prevent papillomavirus infection or related disease thereof. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
Instant claim 23 requires a pentamer or VLP comprising a C-terminus modified HPV6 L1 protein, wherein one or more basic amino acids of the remaining 31 amino acids at C-terminus are substituted. According to the consensus sequence of HPV6 L1 of Zhou et al. (Virology. 1991; 185: 625-632), also depicted in Geneseq database accession no: AAB98397 sequence of Sette et al., which shares 100% identity with instant SEQ ID NO: 1 in the alignment provided, there are 10 basic amino acids, lysine and arginine in the remaining 31 residues of the c-terminus. In claim 11, from which claim 23 depends, these residues are substituted with polar uncharged amino acids, non-polar amino acids and acidic amino acids, when compared with wild-type HPV6 L1 protein. However, there is no written support provided for substituting one or more of the 10 basic amino acids within the c-terminus of HPV6 L1 with one or more of seven possible amino acid residues, i.e., 710 or 282,475,249 possible combinations. There is no evidence provided in the instant disclosure that the broad genus of c-terminally modified HPV6 L1 proteins form the multimer of instant claim 23. Of the millions of possible combinations of c-terminally modified HPV6 L1 proteins asserted to form the multimer of instant claim 23, only two constructs, 6L1CS4 and 6L1CS6, are shown to possess particle size consistent with good uniformity, presented in Table 2 and Figures 3A and 3B. The skilled artisan would not predict substituting any basic amino acid residues at the c-terminus of any HPV6 L1 would form a pentamer or VLP, as asserted and required by the claim.
Instant claims 24-26 are drawn to a vaccine for preventing any papillomavirus infection or related disease thereof by administering the multimer of claim 23. Figure 4 and Example 8 show only 6L1CS4 induces neutralizing antibody titers similar to wild-type HPV6 L1 VLP. There is no guidance provided in the instant specification or working examples demonstrating that any one of the millions of c-terminally modified HPV6 L1 proteins claimed are capable of inducing sufficient neutralizing antibody titers to prevent any type of papillomavirus infection or related disease, asserted by instant claims 24-26.
The skilled artisan would not predict that any c-terminally modified HPV6 L1 proteins claimed would prevent any papillomavirus infection or related diseases thereof. Farmer et al. (Recent Results Cancer Res. 2021 ; 217: 157–195) review the prior art regarding control and treatment of HPV infection and associated cancer. In the full paragraph on page 3, Fuller et al. teach current prophylactic HPV vaccines comprise L1 and/or L2 capsid antigens, self-assembled into VLPs. The VLPs generate neutralizing antibodies, which can prevent HPV infection in healthy individuals. However, the VLPs are incapable of controlling or killing existing HPV-infected and/or transformed cells. In section 2, “Current Preventative HPV Vaccines”, Farmer et al. review: Cervarix™, containing HPV16 and HPV18 VLPs produced in insect cells, only protects against HPV16 and HPV18 infections; Gardasil®, a quadrivalent HPV 6, 11, 16, and 18 VLP vaccine, provides corresponding protection against HPV 6, 11, 16, and 18; and Gardasil®9, comprising L1 VLPs derived from HPV6, 11, 16, 18, 31, 33, 45, 52, and 58, protecting against the corresponding HPV types contained in the vaccine. Therefore, HPV vaccine protection against infection is HPV-type-specific. A vaccine comprising L1 protein-VLPs of HPV6 would not be capable of preventing infection by any other type of HPV.
Regarding prevention of “papillomavirus-related disease” recited in claim 24, in the full paragraph on page 5, Fuller et al. teach Gardasil®9 demonstrates clinical efficacy against HPV31, 33, 45, 52, and 58-associated CIN2/3, AIS, VIN2/3, and VaIN2/3. There is no evidence in the prior art that HPV6-associated warts (found in the paragraph bridging pages 4-5 of Farmer et al.) is preventable in existing HPV6-infected and/or transformed cells. There is no evidence in the instant disclosure or the state of the art indicating that an HPV6 L1 composition is cross reactive with other HPV serotypes or provides prophylaxis against genital warts, CIN2/3, AIS, VIN2/3, and/or VaIN2/3.
Paragraph [0064] of the instant disclosure concludes:
[0064] In summary, the inventor found that the expression levels of mutants obtained by C-terminus amino acid substitution modification of HPV6L1 vary from each other, and are irregular. There is also a certain difference in the immune activities among the VLPs assembled thereby. Therefore, it cannot be expected that HPV6L1 mutants with high expression level, effective assembly and good immune activity can be obtained by the method of C-terminus substitution modification.
For these reasons, it is determined that an undue quantity of experimentation would be required of the skilled artisan to make and use the invention in its full scope.
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 11, 14, 16, 17, and 19-23 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (Journal of Molecular Biology. 2001; 307: 173-182), Zhou et al. (Virology. 1991; 185: 625-632), Tori et al. (Journal of Bacteriology. 2011; 193 (8): 2035-2041), and Sun et al. (Appl. Microbiol. Biotechnol. 2016; 100: 1231–1240, cited in the IDS).
Chen et al. depict a c-terminally truncated HPV11 L1 fusion protein in Figure 3A:
∆C26 (26 residues deleted), fused to intein:
PNG
media_image2.png
49
249
media_image2.png
Greyscale
The 26 residues deleted at the c-terminus 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.:
PNG
media_image3.png
28
381
media_image3.png
Greyscale
While Chen et al. do not mention substituting the deleted basic amino acids with polar uncharged amino acids selected from: glycine, serine and threonine or non-polar amino acids, selected from alanine and valine, or a combination thereof, as required by instant claims 11 and 14, conserved motifs within intein sequences, replacing the c-terminus of HPV11 L1 of Chen et al., comprise glycine, serine, threonine, alanine, and valine amino acids, see Table 1 of Tori et al. Therefore, the 26-residue, c-terminally-deleted HPV11 L1-intein fusion protein of Chen et al. comprises the requisite substitutions instantly required.
One of ordinary skill in the art prior to the instant effective filing date prior to the instant effective filing date would have been motivated to have deleted the basic amino acids at the c-terminal end of HPV L1 to facilitate purification of intact HPV VLPs during production without affecting pentamer architecture, see the abstract, the last paragraph of the first column above “Results”, “Carboxy-terminal sequences required for L1 pentamer formation”, and Figure 3A of Chen et al.
None of the references teach HPV6 L1, recited in instant claims 11, 14, and 16-22 or expression of L1 from an insect cell codon whole gene-optimized polynucleotide, recited in claims 16 and 17, comprised within a baculovirus vector, recited in claims 19 and 20, in an insect cell, recited in instant claims 21 and 22.
Sun et al. teach a truncated HPV6 L1 with 21 amino acids deleted from the c-terminus, see “Cells and viruses” and the paragraph bridging the columns on page 1238. The HPV6 L1 protein is expressed from a polynucleotide, codon-optimized for insect cells. Recombinant baculoviruses, comprising the codon-optimized polynucleotide, express the truncated L1 protein from infected Sf9 cells, from which HPV6 L1 VLPs are extracted. See “Cells and viruses” and “Cell culture harvest and recombinant protein extraction”.
One of ordinary skill in the art prior tom the instant effective filing date would have been motivated to have replaced the HPV6 L1 c-terminal basic amino acid residues, deleted by Sun et al., with intein, as taught by Chen et al., to facilitate purification of intact HPV VLPs during production without affecting pentamer architecture, see the abstract, the last paragraph of the first column above “Results”, “Carboxy-terminal sequences required for L1 pentamer formation”, and Figure 3A of Chen et al. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success for substituting the HPV6 L1 c-terminal basic amino acid residues, deleted by Sun et al., with intein, as taught by Chen et al. because Sun et al., Chen et al., and Zhou et al. teach HPV L1 c-terminally-deleted amino acids do not affect pentamer assembly, see the paragraph bridging the columns on page 1238 of Sun et al., the abstract, “Carboxy-terminal sequences required for L1 pentamer formation”, and Figure 3A of Chen et al., and the first full paragraph of the second column on page 631 of Zhou et al.
Claims 12 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al., Zhou et al., Tori et al., and Sun et al. as applied to claims 11, 14, 16, 17, and 19-23 above, and further in view of the alignment of instant SEQ ID NO: 1 with Geneseq database accession no: AAB98397 in WO200141799 by Sette et al. 2007.
Examiner note regarding claim 12: The recited NCBI® designations for the requisite sequences fail to clearly identify the precise HPV6 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 HPV6 L1 wild-type protein sequences.
See the teachings of Chen et al., Zhou et al., Tori et al., and Sun et al. above. None of the references teach HPV6 L1 wild-type protein sequences including SEQ ID NO: 1, as required by instant claims 12 and 13.
Geneseq database accession no: AAB98397 in WO200141799 by Sette et al. shares 100% identity with SEQ ID NO: 1.
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to have used Geneseq database accession no: AAB98397 as the HPV6 L1 sequence in the composition of Chen et al., Zhou et al., Tori et al., and Sun et al. to stimulate an immune response against HPV6, see the description above the alignment provided. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have used one Geneseq database accession no: AAB98397 as the HPV6 L1 sequence in the composition of Chen et al., Zhou et al., Tori et al., and Sun et al. because Geneseq database accession no: AAB98397 possesses basic amino acids at the c-terminus, deleted by Sun et al., that do not affect pentamer assembly, see the paragraph bridging the columns on page 1238 of Sun et al., the abstract, “Carboxy-terminal sequences required for L1 pentamer formation”, and Figure 3A of Chen et al., and the first full paragraph of the second column on page 631 of Zhou et al.
Allowable Subject Matter
Claims 15 and 18 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. The prior art does not teach or suggest the sequences recited.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Garcea et al. (“Papillomavirus Structure and Assembly”. In: Garcea, R.L., DiMaio, D. (eds) The Papillomaviruses. 2007; Springer, Boston, MA) teach deletions of up to 30 residues, comprising basic amino acids, in the c-terminus of HPV L1 and subsequent fusion of additional sequences to the c-terminus, permit pentamer formation, see the paragraph bridging pages 72-73.
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