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 .
Current Status
This action is responsive to the amended claims of 01/13/2026. Claims 15-49 are pending. Claims 45-49 have been withdrawn. Claims 15-44 have been examined on the merits.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 15-44) and species:
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, liver cancer neoantigen, and CpG-ODN in the reply filed on 01/13/2026 is acknowledged.
A search for the elected species retrieved art (see SEARCH 6 of the attached search notes). Therefore, per Markush search practice, the Markush search will not be extended unnecessarily to additional species in this Office Action.
The elected species read on claims 15-44.
Claims 45-49 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/13/2026.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
The effective filing date is 12/07/2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/20/2022 and 10/31/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
Claims 17-24, 27-29, 32-34, 37-39, and 42-44 are objected to because of the following informalities. Appropriate correction is required.
Claims 17-24 are objected to due to the low resolution of the chemical structures. Please provide higher resolution structures to improve readability of the claims.
Claims 17-24 are further objected to due to improper punctuation. Please add a comma following the second to last structure in each list in each claim. Further, in claim 23, please add the word “and” before the recitation of “the L is:”.
Claim 27 is objected to due to improper punctuation. Please add a comma following the second to last option in each list: i.e., after testicular cancer, influenza virus antigen, and meningococcal antigen. Further, please add the word “or” between each of the groups from which the antigen is chosen, placed directly after each semicolon. Dependent claims 32, 37, and 42 are similarly objected since they do not rectify the underlying issue.
Claim 28 is objected to over the recitation of “CpG-ODN, Poly I:C”. While it is clear these are two different species from which the nucleic acid adjuvant is chosen, it is preferred if Applicant replace the current drafting with “CpG-ODN or Poly I:C”. Dependent claims 29, 33-34, 38-39, and 43-44 are similarly objected since they do not rectify the underlying issue.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 15-44 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. The claims recite: (1) a method of mixing two-three natural products – a polypeptide antigen, a compound A-L-F, and a nucleic acid adjuvant – to form a nanoparticle nanovaccine; and (2) a nanoparticle nanovaccine comprising the same two natural products. This judicial exception (JE) is not integrated into a practical application because the claims only add insignificant extra-solution activities (e.g., adjuvants) and suggestions to apply it (e.g., intended use), but do not impose a meaningful limit on the JE such as using the JE to effect a particular treatment. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims represent well-understood, routine, and conventional (“WURC”) steps and components routinely utilized in preparation of nanoparticles and medicines by the artisan.
Step 1: Is the claim drawn to a process, machine, manufacture, or composition of matter?
Yes, the broadest reasonable interpretation (BRI) of the claims as a whole are drawn to (1) a process of mixing two-three natural products – a polypeptide antigen, a compound A-L-F, and a nucleic acid adjuvant – to form a nanoparticle nanovaccine (claims 15-24, 30-34, and 40-44); and (2) a composition of matter comprising the same two-three natural products in the form of a nanoparticle nanovaccine (claims 25-29 and 35-39).
Revised Step 2A:
Prong One: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
Yes, the BRI of the claims 15-44 are all drawn to natural phenomenon.
The BRI of claims 25-29 and 35-39 include nanoparticle nanovaccine comprising two-three natural products:
The compound A-L-F is very broadly defined and includes at least one natural product, lipoid acid. As evidenced by LODGE (Lodge & Packer, Antioxidant Food Supplements in Human Health, Academic Press, 1999, pg. 121-134, ISBN 9780125435901), lipoic acid is a common constituent of normal animal and plant tissues and is synthesized by such (Pg. 121 ¶1).
Further, as evidenced by NIH (NIH, NCI Dictionary of Cancer Terms, 22 April 2018, retrieved from web.archive.org/web/20180422233531/https://www.cancer.gov/publications/dictionaries/cancer-terms/def/antigen on 03/09/2026), antigens include bacteria and viruses and are also present in body tissues and cells such as cancers. Thus, the instant polypeptide antigens are understood to be naturally occurring compounds. Note, even if the instant antigens are synthetically made versions of natural antigens (e.g., a liver cancer antigen), the synthetic version is not markedly different from the natural product since “synthetic” denotes a source not a change in the chemical structure.
Claim 28 introduces a nucleic acid adjuvant to the nanoparticle nanovaccine, such as CpG-ODN and Poly(I:C). CpG-ODN, as evidenced by KLINMAN (Klinman D. M., Nat. Rev. Immunol., 2004, 4, 1-10), are considered to comprise natural products. KLINMAN discloses bacterial DNA comprises unmethylated CpG motifs; synthetic ODNs comprise these CpG motifs (Pg. 1 ¶2-3). Poly(I:C), as evidenced by BILBO (Bilbo, S.D. & Schwarz J.M., Front. Neuroendocrinol., 2012, 33, 267-286), is a synthetic-version of viral double stranded RNA (Pg. 269 sect. 3.1.1). Similar to the antigen above, these synthetic analogs are not markedly different by virtue of being synthetically made. Thus, both CpG-ODN and Poly(I:C) are understood to be natural products.
The claims allow for the compound A-L-F and the polypeptide to be non-covalently linked (see claim 25). Further, claim 28 merely recite the nanoparticle further comprises the nucleic acid adjuvant – under the BRI this adjuvant is also not covalently bound to the other two components. In this case, the two-three components are merely floating near each other in a composition. Since the individual components are not covalently bound to each other, the components are not chemically/structurally different from their natural counterparts. Mixing natural products does not make the component products any less natural. Note, in the case of covalent-linkage, the resulting nanoparticle would be markedly different from the corresponding natural products since these components were not found by the Examiner’s search to naturally bond together.
The BRI of process claims 15-24, 30-34, and 40-44 includes mixing the nanoparticle components together which is not considered to be substantially different from the product claims wherein the components are inherently mixed/added together. No further steps are introduced, so, based on the analysis above, the process of mixing to afford a non-covalently bound nanoparticle would not be markedly different. Further, this process of mixing per se does not serve as a markedly different characteristic to distinguish the method claims from naturally occurring phenomena; e.g., these components may naturally associate with each other in close (non-covalent) proximity since they all can naturally occur in an organism.
Prong Two: Does the Claim Recite Additional Elements that Integrate the Judicial Exception (JE) into a Practical Application?
No, the BRI of claims 15-44 contain no additional elements that would integrate the JE into a practical application. Prong 2 requires an additional element or combination of elements to use the JE in a manner that imposes a meaningful limit on the JE.
Claims 15-29 do not add any additional elements; claim 29 merely provides broadly defined ratios for the components. Claims 30-34 recite the solution in which the nanoparticle components are mixed; however, this element falls under WURC techniques (see next section) and does not provide an actual use for the JE. Claims 35-39 only add insignificant extra-solution activities to the product in the form of adjuvants; these adjuvants do not apply the JE to a practical application. Claims 40-44 recite a suggestion to apply the JE (e.g., intended use) in the form of the phrase “a medicine for prevention and/or treatment of a tumor”. However, the claims are drawn to a process of making such medicine and not actually using such medicine for such application. Thus, the suggestion is merely an intended use and not an actual application. The claims do not impose a meaningful limit on the JE such as using the JE to effect a particular treatment.
Step 2B: Does the claim recite additional elements that amount to significantly more than the JE?
No, the BRI of the claims does not recite additional elements that amount to significantly more than the JE.
Dependent claims 28-39 recite the addition of a nucleic acid adjuvant or an adjuvant, in general. It is a well-understood, routine, and conventional (WURC) technique to add adjuvants to vaccines. In the general case, it is common practice to add adjuvants (e.g., excipients) to pharmaceutical compositions to affect delivery of a drug/vaccine. Further, evidenced by KLINMAN (cited above), nucleic acid adjuvants like CpG-ODN are recognized as having utility in vaccines and cancer therapy by triggering the innate immune response (Pg. 2 Fig. 1). Thus, these elements do not amount to significantly more.
The dependent claims 30-34 recite a buffer, water, and a temperature used to prepare a solution of the nanoparticles (including the non-covalently bound ones). It is a well-understood, routine, and conventional (WURC) technique to prepare nanoparticle in a buffer and water. This is evidenced by ZHOU (Zhou J., Angew. Chem. Int. Ed., 26 Feb. 2019, 58, 5236-5240): the supplemental information (Pg. 5) describes how a buffer solution and water are used to prepare nanoparticles comprising the A-L-F compound
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(i.e., that of instant claim 24 and falling under claims 15 and 25). Thus, these elements do not amount to significantly more.
Hence, the claims 15-44 are not patent eligible specifically regarding the non-covalently bound nanoparticle comprising the JE.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 15-21 and 25-44 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
MPEP 2163(I) states “The written description requirement has several policy objectives. "[T]he ‘essential goal’ of the description of the invention requirement is to clearly convey the information that an applicant [inventor] has invented the subject matter which is claimed." In re Barker, 559 F.2d 588, 592 n.4, 194 USPQ 470, 473 n.4 (CCPA 1977). Another objective is to convey to the public what the applicant claims as the invention. See Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1566, 43 USPQ2d 1398, 1404 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089 (1998). "The ‘written description’ requirement implements the principle that a patent must describe the technology that is sought to be patented; the requirement serves both to satisfy the inventor’s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee [inventor] was in possession of the invention that is claimed." Capon v. Eshhar, 418 F.3d 1349, 1357, 76 USPQ2d 1078, 1084 (Fed. Cir. 2005). Further, the written description requirement promotes the progress of the useful arts by ensuring that patentees adequately describe their inventions in their patent specifications in exchange for the right to exclude others from practicing the invention for the duration of the patent’s term.”
Factors to be considered in making the determination as to whether one skilled in the art would recognize that the applicant was in possession of the claimed invention as a whole at the time of filing include: (a) Actual reduction to practice; (b) Disclosure of drawings or structural chemical formulas; (c) Sufficient relevant identifying characteristics such as: (i) Complete structure, (ii) Partial structure, (iii) Physical and/or chemical properties or (iv) Functional characteristics when coupled with a known or disclosed correlation between function and structure; (d) Method of making the claimed invention; (e) Level of skill and knowledge in the art and (f) Predictability in the art. While all of these factors are considered, a sufficient number for a prima facie case are discussed below.
The Instant Disclosure:
The claims are very broadly drawn to a nanovaccine/nanoparticle comprising compounds of Formula (I) A-L-F wherein A is any heterocyclic group comprising at least 2 S atoms, L is a linking group which may or may not be present, and F is any group capable of covalent or non-covalent association with a polypeptide antigen. Claims 15 and 25-44 do not attempt to define the structure A-L-F any further than this – a very broad genus encompassing a multitude of heterocyclic groups bound (by any possible atom/molecular linkage) to any group able to interact with a peptide (i.e., basically any atom which can covalently bond to a C, N, S etc. and/or form H-bonds or van der waals-type associations with the peptide). Further, L and F are defined purely by function.
Claims 16-21 begin to define the individual parts of the compound A-L-F, but fail to define a fully realized genus of A-L-F (i.e., at least one portion of the compound is left as broadly claimed in parent claim 15). Claims 22-23 define fully realized genera of A-L-F by providing structural limitations to all parts of the Formula (I) and claim 24 defines species thereof, thus, these claims are not included in this rejection.
Claim 24 and the specification (see Pg. 12-13 ¶69-74) disclose only 3 relatively structurally similar species of compound A-L-F and methods of making thereof. Further, the specification only provides methods of making the claimed nanoparticle and nanovaccine with the same 3 species of A-L-F (Pg. 14-17). Claims 22-23 provide a clearer picture of the genus of compound A-L-F which would properly “convey to the public what the applicant claims as the invention” (MPEP 2163(I)) and is closer aligned with the exemplary species. Further, claims 16-21, would accomplish the same if they were taken together (and not how they are currently related by dependence). Currently, the disclosure does not “demonstrate that the patentee [inventor] was in possession of the invention that is claimed" (MPEP 2163(I)) since the disclosed species do not support the breadth of A-L-F recited in the rejected claims.
Level of Skill and Knowledge in the Art:
The relative skill of those in the art is high, generally that of an M.D. or Ph.D. The artisan using Applicant’s invention would generally be a collaborative team of synthetic chemists and/or health practitioners, possessing commensurate degree level and/or skill in the art, as well as several years of professional experience. The factor is outweighed, however, by the unpredictable nature of the pharmaceutical art. It is noted that each embodiment of the invention is required to be individually assessed for physiological activity by in vitro or in vivo screening to determine which compounds exhibit the desired pharmacological activity.
Examiner cites ZHANG (Zhang, P. et al., Adv. Mater., 2017, 29, 1702311) and HAYAT (Hayat, S.M.G. et al., J. Cell. Physiol., 2019, 12530-12536) to represent the knowledge in the relevant nanoparticle-nanovaccine art.
ZHANG discloses nanocarriers for tumor targeting therapy in vivo (title). ZHANG also discloses the surface chemistry of these nanocarriers plays a vital role in and poses a great challenge to crossing physical and biological barriers in vivo; thus, tailoring the physicochemical properties of the nanomaterials (e.g., size, shape, and especially surface chemistry) plays a vital role in mediating cell interaction, enhancing delivery efficiency, and improving therapeutic efficacy (Pg. 1 Abstract & Right Col. ¶1).
HAYAT discloses nanovaccines are vaccines that utilize nanoparticles as carriers (Pg. 12530 Abstract). HAYAT discloses the size and distribution, shape, surface charge, composition of said nanoparticles affects the cellular uptake and bioavailability of the nanoparticles (Pg. 12533 sect. 5.1-5.4).
Together, ZHANG and HAYAT disclose and reinforce that it is common knowledge in the art that the chemical properties of a nanoparticle are vital to the utility of said nanoparticle as a nanovaccine. Since the instant claims are drawn to a nanoparticle as a nanovaccine, and since the instant disclosure does not support the full breadth of the rejected claims, in view of the teachings of ZHANG and HAYAT, the artisan would not be properly informed of the A-L-F structures which provide the necessary chemical properties to act as nanovaccines.
As recited above, “the written description requirement promotes the progress of the useful arts by ensuring that patentees adequately describe their inventions in their patent specifications in exchange for the right to exclude others from practicing the invention for the duration of the patent’s term” (MPEP 2163(I)). In view of ZHANG and HAYAT, the instant invention is not adequately described because the structure of the compound A-L-F (and therefore the chemical properties thereof) are not adequately described by the instant disclosure. The rejected claims provide mostly functional properties of the instant compound A-L-F and very little chemical definition.
Conclusions:
Due to the breadth of genus Formula (I), the lack of direction given in the claims/specification regarding embodiments of the full scope of Formula (I) which show the desired activity, and the challenges presented in the art, the artisan would not be able to immediately envisage the breadth of compounds encompassed by the scope of Formula (I). The instant specification fails to provide guidance to overcome the complexity and difficulties known to the artisan, as discussed above. Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
Thus, claims 15-21 and 25-44 are rejected as lacking written description for the full scope of Formula (I). To overcome this rejection, Applicants are encouraged to incorporate structural limitations from the dependent claims (e.g., claim 23) into claim 15.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 17-18 and 21-22 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.
Claims 17 and 18 recite wherein L is chosen from a series of structures; however, the punctuation and ordering of the listing makes the listing unclear. See:
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; here, the inconsistent use of commas, a semicolon, and lack of punctuation makes it unclear which moieties are being further defined by the “wherein n=1~5…”. Further, the comma between -H and C1-5 alkyl group leaves it unclear whether R is chosen from H or C1-5 alkyl or if R can only be H and L can be a C1-5 alkyl. See also:
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; here, the semicolon between the final structure and “m=1~50” leaves it unclear whether the definition of m is meant to define the final structure or is applied to the genus L. Since the punctuation and resulting L groups are unclear, the metes and bounds of the claim are undefined rendering the claim indefinite. Dependent claims 21-22 are similarly rejected since they do not rectify the underlying issue.
To overcome the rejection: Applicant may consider rearranging the claim so that each of the moieties from which L is chosen are listed (separated by commas with an “or” preceding the final structure) and then followed by a wherein clause defining each of the variables introduced by the structures, e.g.,:
“[insert structures here];
wherein n is 1~5, R is -H or C1-5 alkyl, and m is 1~50.”
Claims 40-44 recite methods of preparing a medicine “comprising: adding the nanovaccine”. Use of the word “adding” implies the nanovaccine is combined with some other component; however, the claim only recites a step of adding the nanovaccine and no other steps to the method or structural elements of the prepared medicine. As written, the method step is incomplete and it is unclear what the nanovaccine is added to. Thus, the metes and bounds of the claim are undefined rendering the claim indefinite.
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.
Claims 15-28, 30-33, 35-38, and 40-43 are rejected under 35 U.S.C. 103 as being unpatentable over ZHOU (Zhou J., Angew. Chem. Int. Ed., 26 Feb. 2019, 58, 5236-5240), in view of XU (Xu, J. et al., Biomaterials, 25 March 2019, 207, 1-9), and further in view of WIRTH (Wirth, T.C. & Kuhnel, F., Frontiers in Immunology, 2017, 8, 1-16).
Determining the Scope and Contents of the Prior Art:
ZHOU teaches endocytosis-independent pathways, such as thiol-mediated uptake, exhibit great potential for the direct cytosolic delivery of biomolecules; cell-penetrating polydisulfides facilitate intracellular cargo delivery (Pg. 5236 Right ¶2). ZHOU teaches guanidinium (Gu+)-containing disulfide monomers were polymerized onto oligonucleotides (ON) via interaction between the Gu+ and the ON to form nanoparticles (Pg. 5236 Right ¶3). The disulfide monomer is:
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(Pg. 5238 Fig. 2a) which reads on instant Formula (I) wherein A is
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, L is
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(n=4, R=C2 alkyl), and F is
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. ZHOU teaches the nanoparticles could gain direct and efficient access into the cytosol and upon uptake the oligomers are rapidly depolymerized by endogenous GSH, leading to disassembly of the nanoparticle and release of the ON for gene regulation (Pg. 5237 Left ¶1). The key advantages of ZHOU’s nanoparticles are facile assembly without additional assistance, rapid cell uptake with no endo- or lysosomal trapping, and controlled intracellular release of cargo by GSH-assisted depolymerization (Pg. 5239-5240 last-first ¶).
The supplemental information of ZHOU teaches the nanoparticles were assembled by mixing the ONs and disulfide monomers for 15 min at 37°C in Tris-HCl (TM) buffer; the nanoparticles were removed by dialysis in water (Pg. 4 ¶1).
XU teaches to fabricate effective cancer vaccines it would be critical to develop antigen carriers that are able to shuttle antigens directly into cytosols of antigen-presenting cells to facilitate antigen cross-presentation (Pg. 1 Right ¶1). XU teaches cationic dendrimers can efficiently condense nucleic acids, peptides, and proteins into nanoparticles – in particular dendrimers comprising guanidino-groups (Gu) showed high ability in protein/peptide binding and endosomal disruption to achieve efficient delivery of such proteins/peptides to cell cytosol (Pg. 1-2 first-last ¶). XU teaches dendrimers with guanidino surface chemistry (i.e.,
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) were mixed with a protein antigen ovalbumin to form dendrimer-antigen nanoparticles (Pg. 2 Left ¶3 & Pg. 3 Fig. 1). Further, CpG-ODN, which acts as an immune adjuvant to enhance the immunogenicity of antigens and immune response, was mixed with the dendrimer-antigen nanoparticle to form dendrimer-antigen-(CpG-ODN) nanoparticles by electrostatic interaction (Pg. 2 Right ¶3). The resulting nanovaccine was tested in vivo and achieved cell uptake, antigen cross-presentation, and immune T cell response (Pg. 4 Fig. 3). Thus, XU teaches a nanovaccine formulation comprising guanidino-dendrimer+CpG+antigen which is assembled by simple mixing of all components (Pg. 6 Conclusions). XU teaches the nanovaccine was suspended in cold saline buffer for administration (Pg. 8 sect. 4.6), i.e., an acceptable adjuvant. Further, XU teaches this technology can be extended to other types of vaccines including those for viral infection (Pg. 6 Conclusions).
WIRTH teaches clinical studies on personalized vaccinations targeting neoepitopes revealed the therapeutic potential of personalized, neoantigen-directed immunotherapies and their potential in cancer immunotherapy (Pg. 1 Abstract). WIRTH teaches tumors in general acquire mutations during carcinogenesis and progression, resulting in altered proteins that may serve as neoantigens (Pg. 3 Left ¶2). WIRTH also teaches certain cancers, such as liver cancer, are much more resistant to immunotherapies such as T-cell stimulation and checkpoint inhibition, revealing space for tumor antigen-targeting therapies (Pg. 2 Right ¶3).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
ZHOU does not teach the thiol compound of Formula (I) is associated with a polypeptide antigen in the nanoparticle as a nanovaccine.
XU does not teach the nanovaccine comprises the thiol compound of Formula (I).
WIRTH does not teach the instant nanovaccine.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of nanoparticles useful for nanovaccines and possesses the technical knowledge necessary to make adjustments to the nanoparticle to optimize/enhance the vaccine’s properties. Said artisan has also reviewed the problems in the art regarding thiol-mediated uptake and nanovaccines and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references ZHOU, in view of XU, and further in view of WIRTH.
The artisan would be motivated to modify the nanoparticle of ZHOU by replacing the oligonucleotides (ON) with a peptide/protein antigen (polypeptide antigen) to formulate a nanovaccine, in view of XU’s nanoparticle nanovaccine. Both ZHOU and XU are directed to methods of biomolecule cargo delivery to the cytosol of cells via nanoparticles (see all teachings above). The artisan would be motivated to modify ZHOU’s nanoparticle to a nanovaccine since: ZHOU’s nanoparticles have advantageous assembly, rapid cellular uptake with no trapping, and endogenously controlled intracellular release of cargo thanks to the poly(disulfide) component (Pg. 5239-5240 last-first ¶). Further the artisan would have an expectation of success in forming a nanoparticle nanovaccine between the disulfide monomer
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and a polypeptide antigen since: 1) ZHOU’s nanoparticle is polymerized via interaction between the disulfide’s Gu+ moiety and the ON (Pg. 5236 Right ¶3); and 2) XU teaches cationic dendrimers particularly those comprising guanidino-groups (Gu) effectively bind proteins/peptides for efficient delivery of such to cell cytosol (Pg. 1-2 first-last ¶). Thus, both ZHOU and XU teach use of cationic guanidino/guanidinium to bind cargo for delivery. Therefore, the artisan would expect the disulfide of ZHOU to be capable of binding a polypeptide antigen.
Regarding claims 15-24, both ZHOU (Pg. 4 ¶1) and XU (Pg. 2 Left ¶3 & Pg. 3 Fig. 1) teach the nanoparticle is made by mixing the components. Thus, since the instant nanoparticle nanovaccine is obvious by the logic above, the method of preparing such nanovaccine by mixing a compound of formula (I)
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and a polypeptide antigen is further obvious.
Regarding claim 25, the nanoparticle comprising the compound of formula (I), above, and a polypeptide antigen is obvious by the logic above.
Regarding claims 26-27, the nanoparticle of claim 25 is obvious. Since WIRTH teaches tumors produce neoantigens (Pg. 3 Left ¶2) and liver cancer is a prime target for tumor antigen-targeting therapies (Pg. 2 Right ¶3), the artisan would be motivated to choose the polypeptide antigen from a liver tumor antigen.
Note, further regarding claim 26, since XU teaches this technology can be extended to other types of vaccines including those for viral infection (Pg. 6 Conclusions), the artisan would also have motivation to choose a virus antigen.
Regarding claim 28, the artisan would be motivated to add the nucleic acid adjuvant CpG-ODN to the nanovaccine since XU teaches CpG-ODN enhances the immunogenicity of antigens and immune response (Pg. 2 Right ¶3). The artisan would have an expectation of success in adding CpG-ODN, since XU teach CpG-ODN was simply mixed with the nanoparticle nanovaccine and associated with it by electrostatic interaction (Pg. 2 Right ¶3). Therefore, due to the similarities between ZHOU and XU discussed above, the artisan would expect that the CpG-ODN would also associate with the instant nanoparticle nanovaccine by simple mixing and would enhance the efficacy thereof.
Regarding claims 30-33, ZHOU teaches a method of making the disulfide nanoparticles comprising: mixing the cargo and disulfide monomers for 15 min at 37°C in Tris-HCl (TM) buffer and dialyzing in deionized water (Pg. 4 ¶1). XU also teaches simple mixing of all nanoparticle components (Pg. 6 Conclusions). Thus, since the artisan is modifying the nanoparticle of ZHOU to create a nanovaccine, the artisan would be motivated to utilize the mixing conditions taught by ZHOU. They would further have an expectation of success in adding the nucleic acid adjuvant by simple mixing in view of XU.
Regarding claims 35-38, the nanovaccines of claims 25-28 are obvious, above. Since XU teaches the nanovaccine was formulated in saline buffer for administration (Pg. 8 sect. 4.6), the artisan would have motivation with an expectation of success to formulate the nanovaccine comprising the nanoparticle and an acceptable adjuvant, such as saline.
Regarding claims 40-43, by the above logic, the instant nanoparticle and nanovaccine thereof further comprising an acceptable adjuvant is obvious. XU teaches the nanovaccine is for treatment of cancer (Pg. 1 Right ¶1) and suspension of the nanovaccine in saline buffer (Pg. 8 sect. 4.6), thus XU teaches preparation of a medicine for treatment of a tumor comprising adding the nanovaccine. In view of this and the logic above regarding the instant nanoparticle nanovaccine, the instant claims are made obvious. Note, the instant phrase “for prevention and/or treatment of a tumor, a bacterial infection and/or a virus infection” is understood as an intended use. Nothing precludes the nanoparticle nonvaccine from this use.
Claims 25, 28-29, 34, 39, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over ZHOU (Zhou J., Angew. Chem. Int. Ed., 26 Feb. 2019, 58, 5236-5240), in view of XU (Xu, J. et al., Biomaterials, 25 March 2019, 207, 1-9), and in view of WIRTH (Wirth, T.C. & Kuhnel, F., Frontiers in Immunology, 2017, 8, 1-16) as applied to claims 25 and 28 above, and further in view of ANSEL (Ansel, H.C. et al. Pharmaceutical Dosage Forms and Drug Delivery Systems, Lippincott Williams & Wilkins, 7th ed., 1999, pages 48-53).
Determining the Scope and Contents of the Prior Art:
ZHOU, XU, and WIRTH teach the limitations of claims 25 and 28, above. ZHOU further teaches a ratio of compound of formula (I) to cargo is (45 uM – 180 uM):(0.5 uM) and that these ratios were optimized by varying the concentrations (Supp. Info. Pg. 4 ¶1-2). XU further teaches a weight ratio of dendrimer compound:CpG-ODN:antigen is 10:0.4:10 (Pg. 2 Right ¶3); these components were mixed at “optimal weight ratios” (Pg. 8 sect. 4.2).
ANSEL teaches the safe and effective dose of a drug depends on a number of factors including characteristics of the drug, the dosage form, and a variety of patient factors (Pg. 48 Left Col. para 2) and the effective dose may be different for different patients (Pg. 48 Left Col. para 4).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
ZHOU, XU, and WIRTH do not teach the instant molar ratio of the compound of Formula (I), the nucleic acid adjuvant, and the polypeptide antigen.
ANSEL does not teach the instant nanoparticle.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of a nanoparticle useful for a nanovaccine and possesses the technical knowledge necessary to make adjustments to the nanoparticle to optimize/enhance the nanovaccine. Said artisan has also reviewed the problems in the art regarding optimization of nanoparticle component ratios and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references ZHOU, in view of XU, in view of WIRTH, and further in view of ANSEL. Claims 25 and 28 are made obvious, above ¶27.
Regarding claim 29, the artisan would be motivated to optimize the ratio of compound of Formula (I):nucleic acid adjuvant:polypeptide antigen.
MPEP 2144.05(II)(A) provides guidance about the routine optimization of prior art conditions: "Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). "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.").”
Furthermore, MPEP 2144.05(I) provides guidance about overlapping ranges: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists…Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.”
In the instant case, ZHOU teaches the ratio Formula (I):cargo as (45 uM – 180 uM):(0.5 uM) (Supp. Info. Pg. 4 ¶1-2) and XU teaches formula (I):CpG-ODN:antigen is 10:0.4:10 (Pg. 2 Right ¶3). These ratios are considered to overlap with/approach the instantly claimed ratios of (50~100):(0~1):(20~50), wherein the ~ is understood to denote “about”. Since ZHOU teaches optimization of these ratios by varying the concentrations (Supp. Info. Pg. 4 ¶1-2), and since XU teaches optimization of ratios (Pg. 8 sect. 4.2) the artisan would recognize these concentrations as equivalent to the ones recited in the MPEP. Further, the amount of nucleic acid adjuvant and antigen can be seen as similar to a dose of drug since both the adjuvant and antigen affect treatment. Thus, since ANSEL teaches effective dosing is variable (Pg. 48 Left Col. para 2 & 4), the artisan would recognize the “dosage” of these components as a result-effective variable, i.e., a variable that achieves a recognized result. Thus, the ratio of the nanoparticle components is analogous to the “concentration or temperature” recited in the MPEP and may be optimized by routine experimentation. Therefore, the determination of the optimum or workable ratios of these components would have been well within the practice of the artisan. Furthermore, absent any evidence demonstrating a patentable difference between the instant and prior art compositions and the criticality of the claimed ratios, the determination of the optimum or workable ratios given the guidance of the prior art would have been generally prima facie obvious to the artisan.
Regarding claims 34, 39, and 44, since the claim 29 is found obvious (above), by the same logic applied to claims 33, 38, and 43 (above ¶27), the instant claims are found obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 15-25 and 35 are provisionally rejected on the ground of anticipatory nonstatutory double patenting as being unpatentable over claims 1, 4, 9, and 11-12 of copending Application No. 18/702,267 (reference claims of 04/17/2024), evidenced by PETERSEN (Petersen, K.G. et al., Acta Diabetol., 1994, 31, 66-72). Although the claims at issue are not identical, they are not patentably distinct from each other.
The reference claims are drawn to an aggregate comprising a compound A-L-B and insulin (ref. claim 1) wherein the compound A-L-B is
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(ref. claim 4). Reference claim 9 is drawn to method of producing said aggregate by incubating the insulin with the A-L-B compound, i.e., mixing the two components. Reference claims 11-12 are drawn to an oral formulation of the aggregate further comprising an acceptable excipient, i.e., an adjuvant.
The above species of A-L-B are species of the instant A-L-F. Insulin is considered a polypeptide antigen, as evidenced by PETERSEN: “Insulin is considered to be one of the target antigens of the autoimmune process in type I diabetes” (Pg. 66 Intro. ¶1). The disclosure of Application No. 18/702,267 is referred to in order to understand the definition of “aggregate”, in accordance with MPEP 804(II)(B)(1): “those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application (as distinguished from an obvious variation of the subject matter disclosed in the reference patent or application). In re Vogel, 422 F.2d 438, 441-42, 164 USPQ 619, 622 (CCPA 1970).” The aggregate is a particle of 10-500 nm in size (Pg. 8 ¶37); i.e., a nanoparticle. Therefore, the reference claims teach a species of instant claim 25.
Instant claims 15-24 refer to the final product of the method as a nanovaccine; the reference claims are silent as to this terminology. However, the reference claims teach a species of the instant nanoparticle and teach the steps of making the nanovaccine comprising the nanoparticle (i.e., mixing A-L-F & antigen). Thus, all structural elements of the instant claims are met by the reference claims. Similarly, instant claim 35 recites a nanovaccine; however, all structural elements (nanoparticle & adjuvant) are taught by the reference claims.
Thus, claims 15-25 and 35 are anticipated by the reference application. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 15-44 are rejected.
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/S.E.B./Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625