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 .
Claims 1-10 and 12-21 are pending. Claims 1-5, 8-9, 12-16 and 21 are under examination. Claims 6-7, 10 and 17-20 are withdrawn.
Election/Restrictions
Applicant’s election of Group I claims 1-16 and 21 and the species fungi, influenza and PPP in the reply filed 06/29/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Regarding the election of an adjuvant, Applicants amend claim 15 to restrict to only CpG ODN based adjuvants and state that it would be impractical and unreasonable to require Applicant select a single type of CpG ODN because thousands are known in the art and it would be impractical and unreasonable to specify a specific CpG for prosecution and that certain CpG ODNs are more effective in certain organisms than others, for example CpG1826 works well as an adjuvant in mice but not so in humans and adjuvants like CpG1018 may work well in humans, but Applicant cannot conduct human testing without approval from the Food and Drug Administration.
Applicants statement has been carefully considered. The non-election of a type of CpG ODN adjuvant would be regarded as an incomplete response. As set forth in the restriction requirement Applicant is advised that the reply to this requirement to be complete must include (i) an election of a species to be examined even though the requirement may be traversed (37 CFR 1.143) and (ii) identification of the claims encompassing the elected species or grouping of patentably indistinct species, including any claims subsequently added.
The species election for an adjuvant is maintained. The election of CpG ODN based adjuvant is not deemed responsive because there are several CpG ODN adjuvant set forth in claim 15-16. There would be a serious search and examination burden for all the patentably distinct CpG species because the species require a different field of search. For example, employing different search queries for each adjuvant.
Since Applicants have not elected a species of adjuvant as directed in the restriction requirement, CpG 1018 and CpG 1826 will be searched and examined for initial examination.
Claims 6-7, 10 and 17-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected method and species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/29/2026.
Priority
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/536,695 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The provisional application only discloses CpG 1018. Therefore, claims directed to CpG 1018 are assigned the effective filing date of the provisional application which is 9/5/2023 and claims directed to all other CpG ODN adjuvants are assigned the filing date of the instant application which is 9/5/2024.
Information Disclosure Statement
The information disclosure statement filed 03/25/2026 has been considered and an initialed copy is enclosed.
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 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.
Claim(s) 1-3, 5, 8-9 and 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Von Andrian et al. WO 2009/051837 4/23/2009 in view of Wu et al. Growth Factors, December 2011; 29(6):290-297.
Claim 1: Von Andrian et al disclose a vaccine comprising nanoparticles that comprise the antigen and the adjuvant (paragraph 6: the synthetic nanocarriers comprise one or more of an immunomodulatory agent, an immunostimulatory agent; paragraph 8: the antigen is physically 'bound' to the nanocarrier by covalent or noncovalent means. Noncovalently bound includes, for example, ionic bonding, hydrophobic bonding, physical entrapment, and the like; paragraph 78: in some embodiments, an immunomodulatory agent is an antigen. In some embodiments, an immunomodulatory agent is used for vaccines. In some embodiments, an immunomodulatory agent is any protein and/or other antigen derived from a pathogen. The pathogen may be a virus, bacterium, fungus, protozoan, parasite, etc.; paragraph 66 the immunostimulatory agent (adjuvant) is CpG immunostimulatory oligonucleotides);
wherein the nanoparticles are hollow (paragraph 101) and comprise an outer surface and an accessible inner cavity (paragraph 101: nanocarriers may be solid or hollow and may comprise one or more layers), where the antigen and/or the adjuvant is conjugated to the outer surface of the nanoparticles, and/or where the antigen and/or the adjuvant is conjugated or loaded into the inner cavity of the nanoparticles (paragraph 29: In some embodiments, the immunostimulatory agent is on the surface of the nanocarrier or is both on the surface of the nanocarrier and encapsulated within the nanocarrier; paragraph 38: in some embodiments of any of the nanocarriers provided herein, an immunostimulatory agent is encapsulated within the nanocarrier. In some of these embodiments, the immunostimulatory agent is R848, a TLR9 agonist (e.g., a CpG/CpG- containing nucleic acid) ; paragraph 78: In certain embodiments, immunomodulatory agents presented on nanocarrier surfaces stimulate B cells, and immunomodulatory agents encapsulated within the nanocarriers are processed and presented to T cells; paragraph 84: in some embodiments, the immunomodulatory agent is embedded within the polymer, associated with the interior surface of the polymer, and/or encapsulated within the polymer of a vaccine nanocarrier, and, in some embodiments, at least one type of immunomodulatory agent is embedded within the polymer, associated with the interior surface of the polymer, and/or encapsulated within the polymer of a vaccine nanocarrier; paragraph 101: in some embodiments, one, a few, or all of the different layers (*of the nanoparticle) may comprise one or more immunomodulatory agents, targeting moieties, immunostimulatory agents, and/or combinations thereof; paragraph 108).
Claim 5: Von Andrian et al disclose the immunomodulatory agent is an antigen from a virus. See paragraph 78.
Claim 8: Von Andrian et al disclose the antigen is from influenza virus. See paragraph 78.
Claim 9: Von Andrian et al disclose the antigen is from influenza virus. See paragraph 78.
Von Andrian et al does not disclose a vaccine depot formulation for the simultaneous delivery of an antigen and adjuvant comprising biodegradable thermosensitive hydrogel that has been loaded or embedded with the nanoparticles that comprise the antigen and the adjuvant, wherein the vaccine depot formulation is suitable for injection by the biodegradable thermosensitive hydrogel being in a liquid state at normal ambient temperatures but solidifying into a gel like state at a normal body temperature; wherein the biodegradable thermosensitive hydrogel is PCL-PEG-PCL.
Wu et al teaches that it is well known that particulate antigens are more immunogenic than soluble antigens and therefore nanoparticles (NP) were proposed as a novel adjuvant for protein antigens. See p. 290 column 2. Wu et al disclose that as a vaccine delivery system, NPs can traverse cellular membranes to mediate antigen delivery, and they are also less susceptible to reticuloendothelial system clearance owing to their small size, which means that NPs have better penetration into cells and tissues.
Wu et al disclose that thermosensitive hydrogel was also introduced as a vaccine delivery system to enhance the immune response of antigens. See p. 291 column 1 first paragraph. Wu et al disclose that antigen-loaded hydrogel could induce strong humoral immunity, which indicated that the thermosensitive hydrogel was a promising vaccine delivery system. See p. 291 column 1 second paragraph.
Wu et al disclose that a novel vaccine delivery system, biodegradable NPs in thermosensitive hydrogel, was developed to further improve the humoral immunity of protein antigens, which combined the advantages of particulate antigens and hydrogel-controlled delivery system. See p. 291 column 1 paragraph 3. Wu et al disclose an example of a thermosensitive hydrogel such as PCL-PEG-PCL, PCEC. See p. 291 column 1 2nd paragraph. Wu et al disclose the nanoparticle is loaded and encapsulated by the hydrogel. See p. 292 under “preparation and characterization of bFGF-NPs”.
Wu et al disclose that they prepared a novel vaccine delivery system for protein antigen, biodegradable NPs in thermosensitive hydrogel, which combined the advantages of particulate antigens and hydrogel-controlled delivery system. Wu et al disclose their exemplary antigen-NP/hydrogel composite that is obtained is an injectable free-flowing sol at ambient temperature and converts into a non-flowing gel at body temperature by acting as an antigen depot.
Wu et al disclose that the antigen could be sustained when released from the NPs/hydrogel composite in an extended period in vitro. Wu et al disclose that the in vivo test suggested that the immunogenicity of the antigen was improved significantly after being encapsulated in the NPs/hydrogel composition and strong humoral immunity was maintained for longer than 12 weeks.
Wu et al disclose that NPs/hydrogel composite might be a potential candidate as a vaccine delivery system for the protein antigen. See p. 296 under conclusions.
It would have been prima facie obvious to a person of ordinary skill in the art as of the effective filing date of the instant invention to have modified the nanoparticle of Von Andrian et al by loading or embedding said nanoparticle in a biodegradable thermosensitive hydrogel as taught by Wu et al, thus resulting in the instant invention with a reasonable expectation of success.
The motivation to do so is that Wu et al disclose that a novel vaccine delivery system, biodegradable NPs in thermosensitive hydrogel, was developed to further improve the humoral immunity of protein antigens, and combines the advantages of particulate antigens and hydrogel-controlled delivery system and that the exemplary antigen-NP/hydrogel composite that is obtained is an injectable free-flowing sol at ambient temperature and converts into a non-flowing gel at body temperature by acting as an antigen depot and that the antigen could be sustained when released from the NPs/hydrogel composite in an extended period in vitro and that the in vivo test suggested that the immunogenicity of the antigen was improved significantly after being encapsulated in the NPs/hydrogel composition and strong humoral immunity was maintained for longer than 12 weeks and that NPs/hydrogel composite might be a potential candidate as a vaccine delivery system for the protein antigen.
Claim(s) 3-4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Von Andrian et al. WO 2009/051837 4/23/2009 and Wu et al. Growth Factors, December 2011; 29(6):290-297 as applied to claims 1-3, 5, 8-9, and 21 above, further in view of Shah et al. US 6,451,346 9/17/2002.
The combination of Von Andrian et al and Wu et al is set forth above but does not disclose that the biodegradable thermosensitive hydrogel is PLGA-PEG-PLGA (PPP).
Shah et al disclose biodegradable thermosensitive hydrogels, whereby an effective amount of a biologically active agent is incorporated in a polymeric matrix of the hydrogel and is capable of providing for the sustained-release of the biologically active agent. See column 3 lines 52-62. Shah et al disclose that administering biologically active agent in a biodegradable polymeric matrix to a warm blooded animal forms a gel depot within the body of said animal and the biologically active agent is released from the depot at a controlled rate concomitant with biodegradation of the polymeric matrix. See column 4 lines 1-12. Shah et al disclose an example of the biodegradable thermosensitive hydrogel is PLGA-PEG-PLGA (PPP). See whole of Shah et al for context especially figure 3, column 4 lines 22-30 and column 11 lines 26-28.
It would have been prima facie obvious to a person of ordinary skill in the art as of the effective filing date of the instant invention to have modified the vaccine depot formulation of the combination of Von Andrian et al and Wu et al, by substituting the biodegradable thermosensitive hydrogel with PPP as disclosed by Shah et al, thus resulting in the instant invention with a reasonable expectation of success.
The motivation to do so is that Shah et al disclose PPP can be also be used for delivery of biologically active agent and forms a gel depot within the body of said animal and the biologically active agent is released from the depot at a controlled rate concomitant with biodegradation of the polymeric matrix.
Claim(s) 15-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Von Andrian et al. WO 2009/051837 4/23/2009 and Wu et al. Growth Factors, December 2011; 29(6):290-297 as applied to claims 1-3, 5, 8-9, and 21 above, further in view of Appel et al. WO 2021/231942 11/18/2021.
The combination of Von Andrian et al and Wu et al does not disclose that the CpG ODN is CpG 1018 or CpG 1826.
Appel et al disclose that injectable nanoparticle hydrogel prolongs the co-delivery of vaccine components to the immune system and that hydrogels exhibit unique delivery characteristics whereby physiochemically distinct compounds (such as antigen and adjuvant) could be co-delivered over the course of weeks and that the nanoparticle hydrogel platform improved the efficacy an influenza hemagglutinin subunit vaccine. See paragraphs 3, 5, 94-97, 163-166, 173 and claims 1-25. Appel et al disclose that CpG 1018 is a clinically approved CpG ODN and is an adjuvant. See paragraph 164. Apel et al disclose other CpG ODN adjuvant such as CpG 1826 (Class B CpG) and CpG 2395 (Class C Cpg). See paragraph 169 and 173. Appel et al disclose vaccine comprising a nanoparticle loaded hydrogel wherein the nanoparticle comprises toll like receptor 9 (TLR9) agonist such as CpG as the adjuvant. See paragraphs 3-10.
It would have been prima facie obvious to a person of ordinary skill in the art as of the effective filing date of the instant invention to have used the TLR9 agonist CpG such as 1018 and 1826 as the CpG adjuvant in the vaccine depot formulation of the combination of Von Andrian et a and Wu et al, as taught by Appel et al, thus resulting in the instant invention with a reasonable expectation of success.
The motivation to do so is that Appel et al disclose the CpG adjuvants can be co-delivered with antigen such as influenza antigen in a nanoparticle/hydrogel platform and discloses CpG adjuvants known in the art such as CpG 1018 which is approved for human use and other known CpG adjuvants such as CpG 1826.
Claim(s) 12-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Von Andrian et al. WO 2009/051837 4/23/2009 and Wu et al. Growth Factors, December 2011; 29(6):290-297 as applied to claims 1-3, 5, 8-9, and 21 above, further in view of Dalmau et al. Biotechnology and Bioengineering, vol. 101, No. 4, page 654-664 November 2008.
The combination of Von Andrian et al and Wu et al disclose the hollow nanoparticle is formed by self-assembly (See Von Andrian et al above and paragraph 14 Von Andrian et al) but does not disclose that the hollow nanoparticles are hollow protein nanoparticles based on the E2 subunit, or a portion thereof, of the pyruvate dehydrogenase complex (PDC) from the Geobacillus stearothermophilus wherein the E2 subunit of the PDC has been recombinantly modified to substitute one or more amino acids with cysteines.
Dalmau et al disclose that self-assembling protein systems which form hollow architectures have shown promise in a wide range of nanotechnology applications including the encapsulation and targeted delivery of therapeutic molecules and loading of foreign DNA for potential gene delivery. See p. 654 under introduction. Dalmau et al disclose the E2 component of pyruvate dehydrogenase from Bacillus stearothermophilus (aka forms Geobacillus stearothermophilus) forms a dodecahedral complex and potentially provides another platform for nanotechnology applications. See p.654 abstract. Dalmau et al disclose that the E2 complex self-associates into a dodecahedron cage that consists of 60 identical subunits, and three-dimensional crystallographic structure shows this assembly is approximately 24 nm in diameter with 12 openings of 5 nm each, leading to a hollow core which can potentially be utilized for molecular encapsulation. See p. 655 column 1 last paragraph.
Dalmau et al disclose the E2 subunit is recombinantly modified to substitute an amino acid with cysteine (D381C) to enable chemical modification of the nanoparticle. See p. 656 column 1, figure 1 and column 2 lines 1-2, p. 660 col. 1 last paragraph.
Dalmau et al disclose that the E2 structural scaffold from the multienzyme complex pyruvate dehydrogenase is robust and has the characteristics of an ideal caged-protein platform for molecular transport and encapsulation and that the truncated core scaffold exhibiting wild-type sequence self-assembles into a structure with icosahedral symmetry and is highly thermostable and that the high tolerance of internal modifications to this system, together with previously demonstrated ability to attach and display multiple foreign peptides on the outside surface suggest that this platform can potentially be a powerful and versatile tool in bio-nanotechnology. See p. 662 under conclusions and p. 663 column first paragraph.
It would have been prima facie obvious to a person of ordinary skill in the art as of the effective filing date of the instant invention to have modified the vaccine depot formulation of Von Andrian et al and Wu et al by using a nanoparticle that forms by self-assembly such as the E2 subunit of the pyruvate dehydrogenase complex from Geobacillus stearothermophilus, wherein the E2 protein has been recombinantly modified to substitute an amino acid with cysteine such as D381C, thus resulting in the instant invention with a reasonable expectation of success.
The motivation to do so is that the combination of Von Andrian et al and Wu et al disclose that the hollow nanoparticle can be formed from self-assembly and Dalmau et al disclose that self-assembling protein systems which form hollow architectures have shown promise in a wide range of nanotechnology application including the encapsulation and targeted delivery of therapeutic molecules and loading of foreign DNA for potential gene delivery and Dalmau et al disclose the E2 component of pyruvate dehydrogenase from Bacillus stearothermophilus (aka forms Geobacillus stearothermophilus) a dodecahedral complex that self-associates into a dodecahedron cage that consists of 60 identical subunits, and three-dimensional crystallographic structure shows this assembly is approximately 24 nm in diameter with 12 openings of 5 nm each, leading to a hollow core which can potentially be utilized for molecular encapsulation. Dalmau et al disclose the E2 subunit can be recombinantly modified to substitute an amino acid with cysteine (D381C) to enable chemical modification of the nanoparticle. Dalmau et al disclose that the E2 structural scaffold from the multienzyme complex pyruvate dehydrogenase is robust and has the characteristics of an ideal caged-protein platform for molecular transport and encapsulation and said E2 truncated core scaffold self-assembles into a structure with icosahedral symmetry and is highly thermostable and that the high tolerance of internal modifications to this system, together with previously demonstrated ability to attach and display multiple foreign peptides on the outside surface suggest that this platform can potentially be a powerful and versatile tool in bio-nanotechnology.
Status of Claims
Claims 1-5, 8-9, 12-16 and 21 are rejected. Claims 6-7, 10 and 17-20 are withdrawn.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to OLUWATOSIN A OGUNBIYI whose telephone number is (571)272-9939. The examiner can normally be reached IFP.
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 5712703497. 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.
/OLUWATOSIN A OGUNBIYI/Primary Examiner, Art Unit 1645
Prosecution Insights