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 .
Preliminary Amendment
The preliminary amendment dated 03/26/2026 has been entered. Claims 1, 3-6, 8-9, 18-22 are pending.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The earliest possible effective filing date for the instant claims is January 04, 2021 based on the filing date of the Chinese application CN202110002620.9.
Election/Restriction
Applicant’s election with traverse of Group I (a protein product) in the reply filed on 03/26/2026 is acknowledged.
Claims 3-5, and 18-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention (a nucleic acid product), there being no allowable generic or linking claim. See response to the traverse below.
Claims 20-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention (a method of use), there being no allowable generic or linking claim. See response to the traverse below.
Claims 2, and 11-17 have been cancelled
Claims 1, 6 and 8-9 are under examination.
Applicant’s species election with traverse is acknowledged. Applicant elected HPV chimeric protein as shown in SEQ ID NO: 28, wherein the polypeptide from the HPV type 73 L2 protein is inserted into the region of amino acids 428 to 431 of the HPV type 31 L1 protein.
2. The traversal filed by the Applicant is on the grounds that the amended claim 1 recite a special technical feature not taught or suggested by the prior art for at least the following reasons:
- (a). The amino acid (aa) sequence of the chimeric protein is as shown in any one of SEQ ID Nos. 26-33.
- (b). The cited prior art does not teach or suggest the specific insertion site at amino acids 428 to 431. Colau discloses HPV chimeric protein constructs generally comprising HPV L1 proteins with an HPV L2 peptide inserted therein, but does not teach or suggest the specific insertion site at amino acids 428 to 431 of the HPV type 31 L1 protein.
- (c). The specific insertion site at amino acids 428 to 431 makes a contribution over the prior art. The specific insertion site at amino acids 428 to 431 of the HPV type 31 L1 protein - located in the H4 surface region- constitutes a special technical feature that makes a meaningful and significant contribution over the prior art. As demonstrated in Example 12 of the present application, antisera isolated from mice immunized with VLPs having the HPV type 73 L2 polypeptide inserted at amino acids 428 to 431 were each capable of neutralizing at least 17 types of pseudoviruses. Moreover, the neutralizing titers of these antisera against HPV types 16, 18, and 45 were all greater than 103, and the neutralizing titer of the 31L1h4428-431/dE-CS1 antiserum against HPV type 73 was also greater than 103.
By contrast, antisera isolated from mice immunized with VLPs having the polypeptide inserted into the DE loop region (132-136) neutralized only 10 and 8 types of pseudoviruses, respectively, and the corresponding neutralizing titers were all less than 103. These results demonstrate that the specific insertion site at amino acids 428 to 431 of the HPV type 31 L1 protein has a significant impact on both the breadth and potency of the neutralizing antibody response induced by the VLPs, and therefore makes a contribution over the prior art that is not taught or suggested by any of the cited references.
Applicant’s arguments have been fully considered but are not found persuasive
In view of the 35 USC 112b and 35 USC 103 rejection provided below, the claimed inventions lack unity since at least the elected invention lacks inventive step.
- Regarding item (a). Please read rejection 112(b) which includes claim 1 interpretation and the 103 rejection (below).
- Regarding item (b). Applicant argues that the insertion site on loop H4 428-431 is not taught by Colau (or by any of the other cited references in the Restriction Requirement dated 01/27/2026). However, Colau teaches the insertion of the L2 peptide into the hyper variable region of the loop found in the aa region 429-445, that is, this region comprises the region 428-431 of the instant application. The difference between aa 428 vs. aa 429 can be easily explained by potential differences in the numbering system, or the potential aa differences between HPV strains, which a person of ordinarily skill in the art can find obvious.
- Regarding item (c). the biological activity discussed in Example 12 by the applicant is not recited as any limitation of the claims.
Therefore, the amended claim 1 makes no contribution over the prior art as the technical feature is taught by Colau.
Last, in the restriction requirement is stated that, as provided in 37 CFR 1.475 (b), a national stage application containing claims to different categories of invention will be considered to have unity of invention if the claims are drawn only to one of the following combinations of categories:
(1) A product and a process specially adapted for the manufacture of said product; or
(2) A product and a process of use of said product; or
(3) A product, a process specially adapted for the manufacture of the said product, and a use of the said product; or
(4) A process and an apparatus or means specifically designed for carrying out the said process; or
(5) A product, a process specially adapted for the manufacture of the said product, and an apparatus or means specifically designed for carrying out the said process.
Otherwise, unity of invention might not be present. See 37 CFR 1.475 (c), as is the case for Groups I and II, that are drawn to different products and thus, there is no unity of invention.
The requirement is still deemed proper and is therefore made FINAL.
Specification and Claim Objections
3. The specification and the claims are objected to because of the following informalities: “SEQ ID NO.” should be written as “SEQ ID NO:”. 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.
Claim 1, 6, 8, and 9 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
4. Claim 1 recites: “an HPV chimeric protein comprising or consisting of a HPV type 31 L1 protein or a mutant of the HPV type 31 L1 protein, and a polypeptide from a HPV type 73 L2 protein inserted into the region of amino acids 428 to 431 of the HPV type 31 L1 protein or the mutant of the HPV type 31 L1 protein, wherein
the HPV type 31 L1 protein is as shown in SEQ ID No. 1,
the HPV type 73 L2 protein is as shown in SEQ ID No. 2, and
the amino acid sequence of the human papillomavirus chimeric protein is as shown in any one of SEQ ID Nos. 26-33.”.
Claim 1 is indefinite because the claim recites a polypeptide from the HPV-73 L2 protein but the L2 protein as shown in SEQ ID NO: 2 is 475 amino acids (aa) long. The HPV-31 L1 is as shown in SEQ ID NO: 1 about 504 aa long and such a chimeric protein as recited should be about 979 aa long. In addition, the L1 protein shown in SEQ ID NO: 1 is the wild type L1 protein and not a mutant L1 protein also recited in the claim. None of the SEQ ID NO: 26-33 have that aa length and therefore, they are not as shown in SEQ ID NO: 1 or 2. Claims 6, 8, and 9 are rejected because they depend on claim 1 but do not remedy the situation. For purposes of expedited prosecution, claim 1 has been interpreted as an HPV chimeric protein comprising or consisting of a HPV type 31 L1 protein or a mutant of the HPV type 31 L1 protein, and a polypeptide from a HPV type 73 L2 protein inserted into the region of amino acids 428 to 431 of the HPV type 31 L1 protein or the mutant of the HPV type 31 L1 protein, wherein
the HPV type 31 L1 protein is as shown in SEQ ID No. 1,
the HPV type 73 L2 protein is as shown in SEQ ID No. 2. The inserted protein of SEQ ID NO: 2 might be full-length or a fragment thereof.
5. Claim 1 recites: “an HPV chimeric protein comprising or consisting of a HPV type 31 L1 protein or a mutant of the HPV type 31 L1 protein, and a polypeptide from a HPV type 73 L2 protein inserted into the region of amino acids 428 to 431 of the HPV type 31 L1 protein or the mutant of the HPV type 31 L1 protein, wherein
the HPV type 31 L1 protein is as shown in SEQ ID No. 1,
the HPV type 73 L2 protein is as shown in SEQ ID No. 2, and
the amino acid sequence of the human papillomavirus chimeric protein is as shown in any one of SEQ ID Nos. 26-33.”. However, since the claim appears to refer to both full-length type 31 L1 proteins and mutants thereof, it is unclear where in the L1 protein the region of amino acids 428 to 431 is located. It is therefore suggested that claim 1 be amended to recite a specific SEQ ID NO: as a corresponding sequence for these amino acid positions.
6. Claim 6 recites, “A polymer which is a chimeric pentamer or chimeric virus-like particle comprising the human papillomavirus chimeric protein according to claim 1, or formed by the human papillomavirus chimeric protein according to claim 1.” However, the recitation of “comprising the human papillomavirus chimeric protein according to claim 1” and “formed by the human papillomavirus chimeric protein according to claim 1” appear to be claiming the same involvement of the protein of claim 1. Therefore, it is unclear if these identified portions of claim 6 are intended to limit claim 6 differently.
7. Claim 9 is 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 9 recites the limitation " ….chimeric virus-like particle of HPV of the mucosa-tropic group and/or skin- tropic group….”. There is insufficient antecedent basis for the “mucosa-tropic group and/or skin- tropic group” limitation in claims 9 to identify which of the ”mucosa-tropic group and/or skin- tropic group” the claim refers to.
Appropriate corrections are required.
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.
8. Claims 8 and 9 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 the immunization of mice with the chimeric VLPs and the subsequent production of neutralizing antibody titers, does not reasonably provide enablement for the prevention of papillomavirus infection. 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.
Nature of the invention/Breadth of the claims. The claims are drawn to a vaccine for the prevention of HPV infection comprising the HPV chimeric protein of claim 1 or the polymer of claim 6, an adjuvant, as well as an excipient or carrier for vaccines, further comprising at least one VLP or chimeric VLP of HPV of the mucosa-tropic group and/or skin- tropic group.
State of the prior art/Predictability of the art. Applicant should note that the examiner is interpreting the term “preventing” as completely negating or precluding infection of the virus, as the term is generally known by one of ordinary skill in the art. At the outset, prevention of an infection is not possible, since it is understood to mean prevention of a single virion from infecting a single cell. An infection may be inhibited, but not entirely prevented. In fact, the mechanism by which the invention operates depends on an infection occurring post-immunization. The Food and Drug Administration (FDA) of the United States has approved 3 HPV vaccines. One example of such a vaccine is Gardasil 9. In comparison to the claimed composition, Gardasil 9 is a sterile suspension for intramuscular administration comprising 9 HPV VLPs derived from different strains. The package insert for Gardasil 9 (provided herein) teach in Section 1:
GARDASIL 9 is a vaccine indicated in girls and women 9 through 45 years of age for the prevention of the following diseases:
• Cervical, vulvar, vaginal, anal, oropharyngeal and other head and neck cancers caused by Human Papillomavirus (HPV) types 16, 18, 31, 33, 45, 52, and 58. (1.1)
• Genital warts (condyloma acuminata) caused by HPV types 6 and 11. (1.1)
And the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58:
• Cervical intraepithelial neoplasia (CIN) grade 2/3 and cervical adenocarcinoma in situ (AIS). (1.1)
• Cervical intraepithelial neoplasia (CIN) grade 1. (1.1)
• Vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3. (1.1)
• Vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3. (1.1) • Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3. (1.1)
GARDASIL 9 is indicated in boys and men 9 through 45 years of age for the prevention of the following diseases:
• Anal, oropharyngeal and other head and neck cancers caused by HPV types 16, 18, 31, 33, 45, 52, and 58. (1.2)
• Genital warts (condyloma acuminata) caused by HPV types 6 and 11. (1.2)
And the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58:
• Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3. (1.2) The oropharyngeal and head and neck cancer indication is approved under accelerated approval based on effectiveness in preventing HPV- related anogenital disease. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial (1).
Limitations of Use and Effectiveness:
• Vaccination with GARDASIL 9 does not eliminate the necessity for vaccine recipients to undergo screening for cervical, vulvar, vaginal, anal, oropharyngeal and other head and neck cancers as recommended by a health care provider. (1.3, 17)
• GARDASIL 9 has not been demonstrated to provide protection against disease caused by:
• HPV types not covered by the vaccine
• HPV types to which a person has previously been exposed through sexual activity. (1.3)]
In addition, the package insert at Table 6 reveal the success of Gardasil 9 at protecting girls and boys against different cancers, however, not all cancers were prevented. For example, in boys, Gardasil 9 was 90%, 77.5% and 74% effective against development of External genital lesions, AIN 1/2/3, and AIN 2/3, respectively. Therefore, Gardasil 9 did not prevent infection by HPV boys as evidenced by the percentage of those developing lesions or AIN.
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Working examples. The disclosure does not include any working examples of a method for preventing an infection caused by a HPV.
Guidance in the specification. The specification provides guidance toward the construction of expression vectors comprising the chimeric protein by synthesizing the HPV31L1 gene protein and mutants thereof with the inserted HPV37L2. The chimeric proteins were expressed in a baculovirus system and purified. The VLPs were characterized by dynamic light scattering particle size analysis and transmission electron microscopy observation. Further, mice were immunized with the VLPs and the production of neutralizing antibody titers was determined (Examples 1 to 12 and drawings 1-4).
Amount of experimentation necessary. In view of the breadth of the claims (a vaccine for the prevention of HPV infection comprising the HPV chimeric protein of claim 1 or the polymer of claim 6, an adjuvant, as well as an excipient or carrier for vaccines, further comprising at least one VLP or chimeric VLP of HPV of the mucosa-tropic group and/or skin- tropic group), the nature of the invention, the state of the art (prevention of HPV infections with vaccines is not yet established), the limited guidance and working examples in the specification, and the low level of predictability (no evidence of preventing infection), it would require undue experimentation for one skilled in the art to use the claimed methods.
Claim Rejections - 35 USC § 103
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.
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.
9. Claims 1, 6 and 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Colau (US 2012/0087937 A1 publication date Apr. 12, 2012, IDS US patent application citation 1), in view of P17388.1 (GenBank Accession Number: Pl 7388.1, (version 09/18/2019), and ALJ 32593.1 (GenBank Accession Number: ALJ 32593.1, (19.10.2015).
The instant invention recites, an intended use in claims 8 and 9 “for the prevention of papillomavirus infection and/or a papillomavirus infection-induced disease”. MPEP § 2111.02 (II) recites, “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the pre-amble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limita-tions, then the preamble is not considered a limitation and is of no significance to claim construction.” Therefore, this intended use is not interpreted to significantly alter the structure of the claimed invention and is not read into the claim for the purpose of applying prior art.
In view of the 35 USC 112b rejection over claim 1 and the sequence length indefiniteness (see above), the invention of claim 1 is interpreted as an HPV chimeric protein comprising or consisting of a HPV type 31 L1 protein or a mutant of the HPV type 31 L1 protein, and a polypeptide from a HPV type 73 L2 protein inserted into the region of amino acids 428 to 431 of the HPV type 31 L1 protein or the mutant of the HPV type 31 L1 protein, wherein
the HPV type 31 L1 protein is as shown in SEQ ID No. 1,
the HPV type 73 L2 protein is as shown in SEQ ID No. 2. The inserted protein of SEQ ID NO: 2 might be full-length or a fragment thereof.
Colau teaches HPV protein constructs and their use. The constructs are chimeric proteins comprising HPV L1 proteins with an HPV L2 peptide inserted into the L1 protein (instant claim 1). Such chimeric proteins may be formulated into immunogenic (e.g., vaccine compositions, and optionally formulated with HPV L1 VLP based vaccines which reads on instant claim 6, (where a polymer is chimeric VLP comprising the human papillomavirus chimeric protein), and instant claim 8 and 9, (adjuvants, diluents and carriers)), (abstract and paragraphs 0032, 0034, 0050 and 0056). The HPV L1 and L2 polypeptides disclosed by Colau may be from any genotype of HPV including in particular the high risk cancer causing HPV types HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68 or 73 and the genital warts causing HPV types such as HPV 6 or 11 and the skin causing types such as types HPV5 and HPV8 or even types 2 and 3 associated with common warts, and HPV76 associated with benign cutaneous warts [0072], (instant claims 1 and 9). Colau also teaches that the inserted L2 protein can comprise at least one peptide comprising an epitope of an L2 polypeptide inserted within the HPV L1 polypeptide [0010]. For instance, a fragment of L2 comprising a peptide comprising amino acids 56-75 of an HPV L2 polypeptide inserted within the HPV L1 polypeptide [0011]. The insertion of the L2 peptide into the hyper variable region of the loop found in the aa region 429-445 is also taught for HPV-16 L1 (Table 1) and for the HPV-18 L1 (Table 2) the exposed regions. These regions can provide suitable insertion sites for the L2 peptide, specially the hypervariable regions within these regions. Suitably the L2 peptide is inserted into the C terminus invading arm, into the hypervariable region of the loop or C terminus arm (aa 429-445) [0092].
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Therefore, Colau teaches the insertion of the L2 peptide into the hyper variable region of the loop found in the aa region 429-445, that is, this region comprises the region 428-431 of the instant application. The difference between aa 428 vs. aa 429 can be easily explained by potential differences in the numbering system, or the potential aa differences between HPV strains, which a person of ordinarily skill in the art can find obvious. Additionally, it would further be obvious that the exact insertion site is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. It would have been customary for an artisan of ordinary skill to determine the optimal insertion site within the hyper variable regions (which are the most amenable for insertions) in the loop needed to achieve the desired results for any of the HPV strains to be utilized for the construction of an HPV chimeric protein. The principle of law states from MPEP 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages." (Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382); Generally, differences in the amino acids of an insertion site will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such difference is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum site by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 2. Colau teaches in Example 3, methods for testing immunogenicity and cross-reactivity of chimeric L1/L2 antigens in an animal model and the neutralization experiments to characterize the antibodies being generated.
Colau does not teach SEQ ID NO:1 or NO:2 or a portion of SEQ ID NO: 2 being inserted into SEQ ID NO: 1 at the region of amino acids 428 to 431 of the HPV type 31 L1.
P17388.1 teaches a 100% identical to SEQ ID NO: 1. See alignment below.
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ALJ 32593.1 teaches a sequence that is 100% identical to SEQ ID NO: 2. See alignments below
Sequence alignment SEQ ID NO: 2 and ALJ 32593.1 (Late protein L2 (HPV73))
Title: US-18-260-309-2
Perfect score: 2447
Sequence: 1 MRRKRDTHIRKKRASATQLY..........YLLKRKRKRLSYSFTDVATY 475
Database : AASEQ2_01082026_155940.pep:*
ALIGNMENTS
Query Match 100.0%; Score 2447; DB 1; Length 475;
Best Local Similarity 100.0%;
Matches 475; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MRRKRDTHIRKKRASATQLYKTCKQAGTCPPDVIPKVEGSTIADNILKYGSIGVFFGGLG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MRRKRDTHIRKKRASATQLYKTCKQAGTCPPDVIPKVEGSTIADNILKYGSIGVFFGGLG 60
Qy 61 IGSGSGSGGRTGYVPLSTGTPSKPVEMPLQPIRPSVVTSVGPSDSSIVSLVEESSFIESG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 IGSGSGSGGRTGYVPLSTGTPSKPVEMPLQPIRPSVVTSVGPSDSSIVSLVEESSFIESG 120
Qy 121 IPGPTSIVPSTSGFDITTSVNSTPAIIDVSAISDTTQISVTTFKNPTFTDPSVLQPPPPL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 IPGPTSIVPSTSGFDITTSVNSTPAIIDVSAISDTTQISVTTFKNPTFTDPSVLQPPPPL 180
Qy 181 EASGRLLFSNDTVTTHSYENIPLDTFVVTTDHNSIVSSTPIPGRQPAARLGLYGRAIQQV 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 EASGRLLFSNDTVTTHSYENIPLDTFVVTTDHNSIVSSTPIPGRQPAARLGLYGRAIQQV 240
Qy 241 KVVDPAFLTTPTRLVTYDNPAFEGLQDTTLEFQHSDLHNAPDSDFLDIVKLHRPALTSRK 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 KVVDPAFLTTPTRLVTYDNPAFEGLQDTTLEFQHSDLHNAPDSDFLDIVKLHRPALTSRK 300
Qy 301 TGIRVSRLGQRATLSTRSGKRIGAKVHFYHDISPIPTNDIEMQPLVTPQTPSIVTGSSIN 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 TGIRVSRLGQRATLSTRSGKRIGAKVHFYHDISPIPTNDIEMQPLVTPQTPSIVTGSSIN 360
Qy 361 DGLYDVFLENDVEDTVVQQTYTPTSIHSNSLVSSDVSTATANTTIPFSTGLDTHPGPDIA 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 DGLYDVFLENDVEDTVVQQTYTPTSIHSNSLVSSDVSTATANTTIPFSTGLDTHPGPDIA 420
Qy 421 LPLPSTETIFTPIVPLQPAGPIYIYGSGFILHPSYYLLKRKRKRLSYSFTDVATY 475
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 LPLPSTETIFTPIVPLQPAGPIYIYGSGFILHPSYYLLKRKRKRLSYSFTDVATY 475
It would have been obvious to one of ordinary skill in the art to combine the teachings of Colau with P17388.1 to generate a chimeric protein comprising HPV-31 L1, or a mutated HPV-31 L1, with either a fragment of the L2 protein or a full-length L2 inserted in the Hyper Variable Loop defined by amino acids 428 to 445. This chimeric protein, or VLPs derived thereof, can be used as a vaccine as discussed above. It would have further been obvious to use as the insert a L2 polypeptide of ALJ 32593.1 (either the full length or a fragment thereof). The combination is obvious because: (1) the HPV chimeric proteins disclosed by Colau comprise HPV L2 protein, or fragments thereof, inserted into HPV L1 protein as required by claim 1, and (2) P17388.1 and ALJ 32593.1 teach the sequences of the L1 (SEQ ID NO: 1) and L2 (SEQ ID NO: 2) claimed by the instant application. One of ordinary skill would have been motivated to do so because Colau teaches HPV chimeric proteins as vaccines with the L1 protein or mutants thereof comprising an insertion (L2 protein), and ALJ 32593.1 teaches the L2 protein sequence. It would further have been obvious that identifying, the mutated L1 protein, the L2 fragment sequence to be inserted and the optimal insertion site within the hyper variable regions (which are the most amenable for insertions) in the loop needed to achieve the desired results for any of the HPV strains to be utilized for the construction of an HPV chimeric protein would have been customary for an artisan of ordinary skill to optimized. The principle of law states from MPEP 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages." (Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382); Generally, differences in the amino acids of an insertion site will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such difference is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum site by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 2.
There would be a reasonable expectation of success because chimeric proteins have been investigated for over a decade (Colau’s teachings date from 2012), and, in the case of HPV chimeric proteins, they are known to successfully elicit neutralizing antibodies as taught by Colau.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
10. Claims 1, 6 and 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Colau, in view of P17388.1, ALJ 32593.1 and Xie (US2022/0281925A1 Priority date 7/19/2019).
The instant invention recites, an intended use in claims 8 and 9 “for the prevention of papillomavirus infection and/or a papillomavirus infection-induced disease”. MPEP § 2111.02 (II) recites, “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the pre-amble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limita-tions, then the preamble is not considered a limitation and is of no significance to claim construction.” Therefore, this intended use is not interpreted to significantly alter the structure of the claimed invention and is not read into the claim for the purpose of applying prior art.
The invention of claim 1 is interpreted as an HPV chimeric protein comprising or consisting of a HPV type 31 L1 protein or a mutant of the HPV type 31 L1 protein, and a polypeptide from a HPV type 73 L2 protein inserted into the region of amino acids 428 to 431 of the HPV type 31 L1 protein or the mutant of the HPV type 31 L1 protein, wherein
the HPV type 31 L1 protein is as shown in SEQ ID No. 1,
the HPV type 73 L2 protein is as shown in SEQ ID No. 2. The inserted protein of SEQ ID NO: 2 might be full-length or a fragment thereof. The amino acid sequence of the human papillomavirus chimeric protein is SEQ ID NO: 28.
Colau, P17388.1 and ALJ 32593.1 teachings have been discussed above and incorporated herein. However, they do not render obvious the human papillomavirus chimeric protein of SEQ ID NO: 28.
Xie teaches the chimeric HPV sequence SEQ ID NO: 53 which comprises the sequences of instant SEQ ID NO: 1 (see alignment below) as required by instant claim 1 (HPV type 31 L1 protein or a mutant of the HPV type 31 L1 protein). The chimeric HPV L1 can be selected from HPV type 31 (instant claim 1). Xie teaches also HPV VLPs, the preparation methods thereof and use as a vaccine (instant claim 8 and 9), and the VLP is a particle comprising 72 pentamers of said chimeric HPV L1 protein (instant claim 6), (abstract), In addition, VLPs can be composed of intracellularly-expressed HPV L1 and L2 [0124].
Xie does not teach the L2 protein amino acid sequence to be inserted into the L1 protein.
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The ALJ 32593.1 sequence is 100% identical to SEQ ID NO: 2 and comprises the portion (amino acids 14-38) of L2 inserted in to SEQ ID NO: 1 that results in SEQ ID 28 of the instant invention.
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It would have been obvious to one of ordinary skill in the art to combine the teachings of Colau with P17388.1 and ALJ 32593.1 to generate a chimeric protein with a portion of L2 inserted into the claimed amino acid region of L1. It would have further been obvious to use fragments derived from ALJ 32593.1 as the fragment of HPV type 73 L2 to be inserted into the HPV VLP described by Colau and Xie. The combination is obvious because the VLP disclosed by Colau comprises a full length or a fragment of HPV L2 protein inserted into HPV L1 protein as required by claim 1. P17388.1 and Xie teach the sequence of the L1 (SEQ ID NO: 1) and ALJ 32593.1 teaches the sequence of L2 (SEQ ID NO: 2) as claimed by the instant application. One of ordinary skill would have been motivated to do so because Colau and Xie both teach HPV chimeric proteins as vaccines with the L1 protein or mutants thereof comprising an insertion, including L2 (Colau) and ALJ 32593.1 teaches the L2 sequence (full length or fragments thereof). It would further have been obvious that identifying, the mutated L1 protein, the L2 fragment sequence to be inserted and the optimal insertion site within the hyper variable regions to be utilized for the construction of an HPV chimeric protein would have been customary for an artisan of ordinary skill to optimized. The principle of law states from MPEP 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages." (Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382); Generally, differences in the amino acids of an insertion site will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such difference is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum site by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 2.
There would be a reasonable expectation of success because HPV chimeric proteins are known to successfully elicit neutralizing antibodies as taught by Colau.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
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/IMMA BARRERA/
Examiner, Art Unit 1671
/BENJAMIN P BLUMEL/Primary Examiner, Art Unit 1671
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