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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/10/2025 has been entered. It is noted that a new Examiner, George Lountos, is examining the case.
Claim Status
Claims 1-21 and 27 are pending.
Claims 1-3 are amended by the Applicant.
Claims 22-26 and 28-46 are canceled.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/21/25 was filed after the mailing date of the Non-Final Rejection on 12/20/2024. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 1, 8, and 9 are objected to because of the following informalities:
Claim 1 recites “where a multitude of such substantial portion of the hepatitis virus”. The underlined portion contains a grammatical error. Appropriate correction is required.
Claim 8 recites “of at least highly conserved regions of N and C termini of flagellin variants”. The underlined portion contains a grammatical error. Appropriate correction is required. Claim 9 recites “multitude of such substantial portion of the hepatitis virus”. The underlined portion contains a grammatical error. 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.
(previous rejection, maintained) Claims 1-21, 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. The term "substantial portions" in claim 1 is a relative term which renders the claim indefinite. The term "substantial portions" is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The term "substantial portions" does not set a clear limitation on what may be included in the amino acid sequence of the D0 and D1 flagellin domains. Applicants have argued in the reply filed 04/21/2025, that the disclosure includes a definition of the term "substantial portions", which is as follows: As used herein, the term "substantial portion" refers to part of an entity, short of its entirety, but with sufficient portions thereof such that it can function in a fashion that is equivalent to the full entity as far as this invention is concerned. For example, in the context of flagellin domain(s), a substantial portion of a domain or domains can generate equivalent levels of immunity as the full domain or domains. In certain embodiments, such substantial portion refers to at least 90 or 95 percent of the full amino acid sequence of the full domain or domains. In the context of a VLP- forming polypeptide, a substantial portion thereof refers to a portion of the full- length polypeptide that, once expressed, can still form a VLP in an aqueuous environment. For example, the first 149 aa (amino acids) of the full HBc sequence would qualify as a substantial portion of the HBc sequence in the context of being used as a VLP-forming polypeptide" (specifications filed 04/12/2022, [78]). However, this definition is itself indefinite as it is unclear how immunity would be measured, and how the level of immunity between differing subject receiving such a vaccine may generate different levels of an immune response. Furthermore, providing examples of differing embodiments does not necessarily limit what qualifies as a "substantial portion" for the purposes of claim interpretation. Therefore, the term "substantial portion(s) still renders claims 1-21 indefinite. For these reasons, claims 1-21 are rejected.
Response to Arguments
Applicant's arguments, see pg. 7, filed 11/10/2025 have been fully considered but they are not persuasive. Applicant has argued that claim 1 has been amended by removing “or substantial portions thereof with equivalent levels of immunogenicity” and requests withdrawal of all rejections under 35 U.S.C. § 112(b). However, claims 1, 3-5, and 8-10 recite “substantial portion”.
(previous rejection, withdrawn) Claims 1-21 and 27 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. Independent claims 1 and 27 recite " a flagellin protein or a substantial portion thereof with an equivalent level of immunogenicity..." It is unclear whether this level of immunogenicity is in reference to the substantial portions of the DO and D1 domains, or in reference to the quoted "flagellin domains" in parentheses. Furthermore, the instant specifications do not define how immunogenicity is measured is precisely measured. For example, the instant specifications cite an increase in rectal temperature in mice, and stimulation of more potent dendritic cell maturation as potentially being signs of increased immunogenicity (specifications filed 04/12/2022). One of ordinary skill in the art would generally define immunogenicity as the ability of a substance to trigger an immune response. However, this does not provide a clear enough definition of how immunogenicity can be measured for the purposes of claim interpretation. Additionally, it is unclear if the recitation of "flagellin domains" in parentheses, as recited in claim 1, is intended to be a limitation of the claim. Furthermore, dependent claims 2-21 do not resolve this issue. Accordingly, claims 1-21 and 27 are rejected.
Response to Arguments
Applicant’s arguments, see pg. 7, filed 11/10/25, with respect to the rejection(s) of claims 1-21 and 27 under 112(b) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. Applicant has argued that claim 1 has been amended by removing “or substantial portions thereof with equivalent levels of immunogenicity”. However, upon further consideration, a new ground(s) of rejection is made in view of amendments to claims 1-3.
Claims 1 -21 and 27 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 1 (and claims 2-21 dependent on) recites “an amino acid sequence for at least both the D0 and D1 domains of a flagellin protein”. The term “at least both” makes the boundaries of the domains unclear. It is unclear if at least both means two domains or if it implies two or more elements. It is unclear if it refers to only the D0 or D1 domains or includes other domains as well. Therefore, the scope of the flagellin structure is ambiguous thus rendering the claim indefinite.
Claim 1 (and claims 2-21 dependent on) recites “both the D0 and D1 domains of a flagellin protein (“flagellin domains”)”. It is unclear if the recitation of “flagellin domains” in parenthesis, as recited in claim 1, is intended to be a limitation of the claim.
Claim 1 (and claims 2-21 dependent on) recites “where a multitude of such substantial portion of the hepatitis virus core protein would, in aggregate, form a virus-like particle. It is unclear what constitutes a multitude ( how many molecules) or what numerical boundary is needed for aggregation. Additionally, the term “would” is indefinite as it makes the terms of aggregation ambiguous (is it inherent or based on certain conditions, do all molecules aggregate or is there only a probability). The term “such substantial portion” is also unclear and it makes the boundaries of the hepatitis core virus protein unclear. Therefore, this renders the claim indefinite.
Claim 2 recites “with other such fusion proteins”. The term “other such” is indefinite as it is unclear to what defines “other such fusion proteins” therefore making the scope of the other assembly partners ambiguous, thus rendering the claim indefinite.
Claim 2 recites “flagellin domains are displayed at high density on the VLP surface”. The specification (see paragraph 0067) discloses some examples, but it is unclear as to which of these examples, if any, are meant as being “high” density. Thus, the claim is rendered indefinite.
Claim 8 recites “comprising the amino acid sequence of at least highly conserved regions of N and C termini”. The term “at least highly conserved regions” is unclear as to what qualifies as highly conserved, or number of regions included thus rendering the claim indefinite, or to what highly conserved is based on.
Claim 8 recites “of flagellin variants (SEQ ID NO. 3). The term variants imply multiple sequences while SEQ ID NO. 3 is a single sequence. It is unclear what the metes and bounds of the claimed invention is and therefore the claim is rendered indefinite.
Claim 17 recites “the OVA protein”. There is lack of antecedent basis of “the OVA protein”. None of claims 12, 11, or 1 recite “OVA protein”. Therefore, the claim is rendered indefinite.
Claim 27 recites “where a multitude of such substantial portion of the hepatitis virus core protein would, in aggregate, form a VLP. The underlined terms render the claim indefinite as it is not clear what constitutes a multitude of such substantial portion (how many molecules) or what the numerical boundary is needed for aggregation to occur. Also, the term such substantial portion makes it unclear to what the boundaries of the hepatitis core virus protein is. The term “would” also renders the claim indefinite as it is ambiguous if all protein molecules would aggregate or if aggregation is inherent or occurs under certain conditions or even how many aggregated protein molecules are required for aggregation to form a VLP. Therefore, the claim is rendered indefinite.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
(previous rejection, withdrawn) Claims 1-21 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.
Claim 1 recites "an amino acid sequence for a polypeptide that would, in aggregate, form a virus-like particle (VLP) (a "VLP-forming polypeptide")". Thus, claim 1 and its dependent claims, are drawn to a composition comprising a genus of "an amino acid sequence for a polypeptide that would, in aggregate, form a virus-like particle (VLP) (a "VLP-forming polypeptide").
The following is a quotation from MPEP section 2163: The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice..., reduction to drawings..., or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. 'A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Therefore, when a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed.
In the present case, the application teaches: An FljB-HBc VLP (specifications filed 04/12/2022, [106]; [111]). An FH VLP (specifications filed 04/12/2022, [117]; [156]). However, the application does not teach a broader variety of VLPs, such as: HPV VLPs
Influenza Virus A VLPs
HIV VLPs
HEV VLPs
Norovirus VLPs
Arenavirus VLPs
Paramyxovirus VLPs
Coronavirus VLPs
Bunyavirus VLPs
The above VLPs are known in the art, and are taught by Nooraei¹ (see form PTO-892) (Nooraie, pg. 14-16). In addition, Nooraei teaches that, prior to the date of filing, 110 viral proteins from 35 viral families have been shown to be capable of assembly into a VLP (Nooraie, pg. 14, [3]). Furthermore, different VLP forming polypeptides require different expression systems, and some require glycoproteins for proper assembly (Nooraei, pg. 16, [2-5]).
In view of the fact that the examples provided in the instant disclosure do not demonstrate possession of the above examples of VLPs being formed with flagellin domains D0 and D1, and that the application has not identified the above examples of VLPs forming with flagellin domains, there is insufficient written description for the indicated genus of a VLP forming polypeptide, as in claim 1. While the application identifies an FljB-HBc VLP, and an FH VLP, it does not identify a representative sample of "an amino acid sequence for a polypeptide that would, in aggregate, form a virus-like particle (VLP) (a "VLP-forming polypeptide"). Thus, the application does not identify species clearly within the claimed genus. For the reasons above, and in view of the uncertainty as to which an amino acid sequence would be expressed and assembled into a VLP with the D0 and D1 flagellin domains, the application has not provided sufficient written description support for "an amino acid sequence for a polypeptide that would, in aggregate, form a virus-like particle".
Furthermore, applicant argues (reply filed 04/21/2025) that claim 1 has been amended to include the limitation of an amino acid sequence for a polypeptide that is at least a substantial portion of a hepatitis virus core protein.
However, this amendment does not overcome this rejection because claim 1 is still open ended by reciting "A fusion protein comprising an amino acid sequence for a polypeptide that is at least a substantial portion of a hepatitis virus core protein where multitude of such polypeptides would, in aggregate, form a virus-like particle " Given the broadest reasonable interpretation, claim 1 and claims dependent therefrom may still further comprise amino acids beyond what is contained in the hepatitis virus core protein. The instant disclosure does not present a sufficient number of species for differing substantial portions of the hepatitis core protein, or the open ended aspect of claim 1 which may go beyond what is contained on the full hepatitis core protein, that would, in aggregate, for a VLP.
Therefore, claim 1 is rejected. Additionally, claims 2-21 are also rejected because they are dependent on claim 1 and do not resolve the above issues.
Response to Arguments
Applicant’s arguments, see p. 5, filed 11/10/2025, with respect to the rejection(s) of claim(s) 1-21 under 112(a) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of amendments to claims 1-3. Applicants have amended claim 1 to clarify that element (b) of the fusion protein “consists of” either full length of a hepatitis virus core protein or a substantial portion thereof, where the claimed substantial portion of the hepatitis virus core protein is further characterized as “would, in aggregate, form a virus like particle. Applicants argue that the close-ended operator “consists of” clarifies that for the VLP-forming polypeptide portion of the claimed fusion protein, the sequence derives only from the hepatitis virus core protein and not from any other VLP-forming viral sequences (see pg. 5, filed 11/10/2025). However, the written description does not present a sufficient number of species for a for a multitude of such substantial portions of the hepatitis core protein, and therefore, does not resolve the written description issue.
Claims 1-21 and 27 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.
Claim 1 ( and claims 2-21 dependent on) recites “an amino acid sequence for a VLP-forming peptide that consists of either a full-length or a substantial portion of a hepatitis virus core protein where a multitude of such substantial portion of the hepatitis virus core protein, would, in aggregate for a virus-like particle (VLP)…” The instant application disclosure does not present a sufficient number of species for a multitude of such substantial portions of the hepatitis core protein. Therefore, claim 1 and claim 2-21 dependent on, are rejected.
Claim 27 recites “hepatitis virus core protein or a substantial portion thereof where a multitude of such substantial portion of the hepatitis virus core protein…”. The instant application disclosure does not present a sufficient number of species for a multitude of such substantial portion of the hepatitis virus core protein and therefore the claim is rejected.
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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 1-7, 9, 11-15, 18-21, and 27 are rejected under 35 U.S.C 103 as being unpatentable over Compans, (US 20140255441 A1; published 2014) in view of Li et al. (Biochemical Engineering Journal, Vol. 140, pg. 157-167, published 2018) and further in view of Zhang et al. (Scand. J. Immunol., Vol. 65, pg. 320, published 2007).
Regarding claim 1, Compans teaches recombinant formation of a fusion protein comprising both D0 and D1 domains of a flagellin protein, and an amino acid sequence or a polypeptide, that in aggregate form a VLP (Compans, [23]; [49]; [86]).
Regarding claim 21, Compans teaches use of the above fusion protein as a vaccine, or vaccine adjuvant (Compans, [6-10]).
Regarding claims 6-7, Compans teaches that the flagellin protein is native to Salmonella and is a FliC variant (Compans, [6-7]; [38]).
Regarding claim 9, Compans teaches that the fusion protein comprises an amino acid sequence for the D2 domain of the flagellin (Compans, Fig. 1; [23]).
Regarding claims 11-15, Compans teaches that the fusion protein includes an immunogenic sequence comprising multiple copies of a full length M2e, which also comprises the extracellular domain of M2e (Compans, Fig. 1; [23]; [38]).
Regarding claims 18-19, Compans teaches that the immunogenic sequence, M2e, is recombinantly inserted into the amino acid sequence of the D3 domain, thereby replacing part or all of the D3 domain (Compans, Fig. 1; [23]).
Regarding claim 20, Compans teaches that the fusion protein comprises a linker sequence between amino acid sequence of the D0 and D1 domains (part (a) of claim 1) and the VLP forming amino acid sequence (part (b) of claim 1) (Compans, Fig. 1; [23].
Regarding claim 27, Compans teaches that the fusion protein comprises an amino acid sequence for (a) an antigen, (b) a substantial portion of flagellin protein, (c) a VLP forming polypeptide, wherein (a)(b) and (c) are recombinantly linked (Compans, fig. 1; [23]; [38]).
Regarding claim 1, Compans does not teach that the fusion protein comprises an amino acid sequence for a polypeptide that is at least a substantial portion of a hepatitis virus core protein for a polypeptide, that in aggregate form a VLP (Compans, [23]; [49]; [86])
Regarding claim 21, Compans teaches use of the above fusion protein as a vaccine, or vaccine adjuvant (Compans, [6-10]).
Regarding claims 6-7, Compans teaches that the flagellin protein is native to Salmonella and is a FliC variant (Compans, [6-7]; [38]).
Regarding claim 9, Compans teaches that the fusion protein comprises an amino acid sequence for the D2 domain of the flagellin (Compans, Fig. 1; [23]).
Regarding claims 11-15, Compans teaches that the fusion protein includes an immunogenic sequence comprising multiple copies of a full length M2e, which also comprises the extracellular domain of M2e (Compans, Fig. 1; [23]; [38]).
Regarding claims 18-19, Compans teaches that the immunogenic sequence, M2e, is recombinantly inserted into the amino acid sequence of the D3 domain, thereby replacing part or all of the D3 domain (Compans, Fig. 1; [23]).
Regarding claim 20, Compans teaches that the fusion protein comprises a linker sequence between amino acid sequence of the D0 and D1 domains (part (a) of claim 1) and the VLP forming amino acid sequence (part (b) of claim 1) (Compans, Fig. 1; [23]).
Regarding claim 27, Compans teaches that the fusion protein comprises an amino acid sequence for (a) an antigen, (b) a substantial portion of flagellin protein, (c) a VLP forming polypeptide, wherein (a)(b) and (c) are recombinantly linked (Compans, fig. 1; [23]; [38]).
Regarding claim 1, Compans does not teach that the fusion protein comprises an amino acid sequence for a VLP-forming polypeptide that consists of either a full length or substantial portion of a hepatitis virus core protein.
Regarding claim 3, Compans does not teach the fusion protein of claim 1, wherein the VLP-forming polypeptide consists of a hepatitis B core (HBc) protein or a substantial portion thereof.
Regarding claim 4, Compans does not teach that the flagellin D0 and D1 domains are recombinantly inserted into the c/e1 loop of the HBc protein.
Regarding claim 5, Compans does not teach that the flagellin D0 and D1 domains are recombinantly inserted to replace part or all of the c/e1 loop of the HBc protein or the substantial portion thereof.
Li teaches a recombinant VLP comprising a fusion protein consisting of HBc and an OVA epitope inserted into the c/e1 loop of the HBc protein (Li, Fig. 5; pg. 2, section 2.2).
Zhang teaches a recombinant VLP comprising a fusion protein consisting of HBc and epitopes, wherein the epitopes are inserted to replace part of the c/e1 loop of the HBc protein (Zheng, pg. 8, [4]).
It would have been obvious to one of ordinary skill in the art to modify the fusion protein and VLP taught by Compans, by replacing the M1 influenza virus forming protein, with the hepatitis B core - OVA fusion protein taught by Li. One of ordinary skill in the art would have been motivated to combine these teachings because of the advantages offered by utilizing a hepatitis B core protein. For example, Li teaches that the HBc protein has high immunogenicity and allows for the insertion of up to 300 amino acids at the c/e1 loop without affecting its ability to self-assemble (Li, pg. 1, [1]). Furthermore, one of ordinary skill in the art would have a reasonable expectation of success in substituting the M1 influenza protein from Compans, with the HBc protein of Li. Li teaches that the use of HBc protein as an epitope displaying VLP vaccine candidate has been widely studied (Li, pg. 1, [1]). As shown above, Compans also teaches a VLP as an epitope displaying vaccine platform (Compans, Fig. 1, [23]; [38]). Therefore, it would have been obvious to one of ordinary skill in the art the combine the teachings of Compans, Li, and Zheng to arrive at the invention of claims 1-7, 9, 11-15, 18-21, and 27. Accordingly, claims 1-7, 9, 11-15, 18-21, and 27 are rejected.
Response to Arguments
Applicant's arguments filed on 11/10/2026 have been fully considered but they are not persuasive Applicants argue that given the presented arguments below, the attempted combination of Compans, Li and Zhang is improper and rejection under 35 U.S.C. 103 based on such combination should be withdrawn ( see pg. 15, bottom page, filed 11/10/2025).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In this case, the applicants argue that with respect to Claims 1-7, 9, 11-15, 18-21, and 27 that were rejected under 35 U.S.C 103, that “to replace the VLP-forming influenza sequence in Compans with hepatitis B core protein would change its principle of operation as Compans, Li and Zhang all teach away from such a replacement (see pg. 8, Section A, filed 11/10/2025). Specifically, Applicants argue that the Compans fusion protein is a complex system where enveloped VLPs are formed in contrast to the fusion protein recited in presently amended claims 1 and 27 of the current instant application where the fusion protein would self-assemble with a multitude of other fusion proteins of the same kind to form a VLP. Applicants argue that there is a fundamental difference in the principle of operation between Compans and the present disclosure as well as Li and Zhang (see pg. 9) . Applicants argue that Li or Zhang do not supply any assurance or reasonable expectation that their fusion protein could work in Compan’s vaccine system (see pg. 10). Applicants further argue that Li cautions against unpredictability surrounding VLPs from hepatitis B virus core protein and that if Zhang has not outright taught away one of ordinary skill in the art it does not provide any reasonable expectation of success for adopting HBc-VLPs (see pg. 11-12). The Examiner does not find the arguments persuasive as the arguments focus on a mode of operation and not on the broadest reasonable interpretation of structure outlined in the claim limitations of the composition which is presented in the current claims of the instant application. Additionally, according the MPEP 2145 (IV), “One cannot show nonobviousness by attacking references individually where the rejections are based on a combination of references”. The Examiner does not find the arguments that Compans, Li, and Zhang teach away from the composition recited in claim 1 (and claims dependent on) persuasive in light of the broadest reasonable interpretation of the composition of claim 1.
With respect to claim 1, Compans teaches a recombinant formation of a fusion protein comprising both the D0 and D1 domains of a flagellin protein, and an amino acid sequence for a polypeptide, that in aggregate would form a VLP (Compans [23]; [49]; [86]). Although Compans does not teach that the fusion protein comprises an amino acid sequence for a VLP-forming polypeptide that consists of either a full-length or a substantial portion of a hepatitis virus core protein, it would have been obvious to one of ordinary skill in the art before the effective filing date of the current instant application to modify the fusion protein and VLP taught by Compans, by replacing the M1 influenza virus forming protein, with the hepatitis B core-OVA fusion protein taught by Li (Li, Fig. 5; pg. 2, section 2.2). The motivation would come from the teaching of Li which highlights advantages offered by utilizing a hepatitis B core protein which has high immunogenicity and allows for the insertion of up to 300 amino acids at the c/e1 loop without affecting its ability to self-assemble (Li, pg. 1, [1]). Therefore, the combined teachings of Compans, Li, and Zhang meet the claim limitations recited in claim 1 (and claims dependent on) according to the broadest reasonable interpretation of the claim. Although, Applicants argue that the Compans system adopts “membrane-anchored” VLPs (see pg. 9) which differ from the current instant application, the claim limitations recited in claim 1 (and claims dependent on) do not recite such a limitation. According to MPEP 2145 (VI), “although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims”.
Applicants also argue that despite clear potential and huge amount of work on HBc-VLP vaccine candidates by many groups, limitations soon emerged. Applicants argue that in the Affidavit by Dr. Chen filed with the current instant application, Dr. Chen highlights the failure of others in utilizing the known immunity-enhancing property of the flagellin proteins ( see pg. 13). The Examiner does not find the arguments persuasive as they focus on intended use of the composition and not on the structure of the composition as presented in the claims.
Applicants also argue that they have made improvement far more than the predictable use of prior art elements. Applicants state the present application discloses successful creation of high-density displays of flagellin on HBc-VLP surface which reduces TLR5 activation, systematic cytokine release and rectal temperature increase in murine models caused by flagellin and dramatically improves the safety profile of the resulting F-H VLP platforms for use in vaccine development (see pg. 14-15). The Examiner does not find these arguments persuasive as they focus on use of the composition and not the structure of the composition as described in the claims of the current instant application.
Applicants also argue that while the c/e1 loop of HBc, as widely known in the prior art, can only accommodate relatively short antigenic epitopes. Applicants argue that in the present disclosure, they provide for the successful display of an immunogenic sequence well over 450 amino acids long on VLPs to affect a highly immunogenic yet surprisingly safe vaccine system and argue that the unexpected result goes beyond “predictable results” from combinations of know elements ( see pg. 15). The Examiner does not find the arguments persuasive since in, claim 5, the claim recites “the fusion protein of claim 3 wherein (a) is recombinantly inserted to replace part or all of the c/e1 loop (N75-L84) of the HBc protein or the substantial portion thereof” does not define a specific size of the inserted protein due to the use of the term “substantial portion”. As stated in the 103 rejection, with respect to claim 5, Li teaches that the HBc protein has high immunogenicity and allows for the insertion of up to 300 amino acids at the c/e1 loop without affecting its ability to self-assemble (Li, pg. 1, [1]). .
The Applicants’ arguments have been considered but are not persuasive. The rejection is modified in light of Applicant’s amendment and is maintained.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GEORGE T LOUNTOS whose telephone number is (571)272-0502. The examiner can normally be reached Monday-Friday 8:00 am - 5:00 pm.
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/GEORGE THEMISTOCLIS LOUNTOS/ Examiner, Art Unit 1652
/ROBERT B MONDESI/ Supervisory Patent Examiner, Art Unit 1652