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 06/05/2026. Claims 15, 23-25, 27-30, 32-35, 37-40, 42-45, and 47-49 are pending. Claims 45 and 47-49 are withdrawn. Claims 15, 23-25, 27-30, 32-35, 37-40, and 42-44 have been examined on the merits.
This action is made second non-final to allow Applicant to respond to a new 112(a) rejection.
Election/Restrictions
The amendments and arguments of 06/05/2026 did not overcome the prior art rejections of the previous action, mailed 03/20/2026. Thus, the Markush search has not been further extended unnecessarily in this action, per Markush search practice.
The elected species
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, liver cancer neoantigen, and CpG-ODN read on claims 15, 23-25, 27-30, 32-35, 37-40, and 42-44.
Claims 45 and 47-49 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 remains 12/07/2020.
Response to Arguments
Examiner acknowledges receipt of and has reviewed the amendments and remarks of 06/05/2026; no new matter is found.
The objection to claims 17-24 is withdrawn because the resolution of the structures has been improved.
The objections to claims 17-24; 27 and 32, 37, and 42; and 28 and 29, 33-34, 38-39, and 43-44 are each withdrawn because the punctuation and grammatical errors have been rectified.
The 101 rejection of claims 15-44 is withdrawn. Independent claim 15 is amended so that the scope of Formula (I) does not encompass natural products.
The 112(a) written description rejection of claims 15-21 and 25-44 is withdrawn. Independent claim 15 is amended so that the scope of Formula (I) aligns with the scope described in and supported by the instant disclosure.
The 112(b) rejection of claims 17-18 and 21-22 is withdrawn because the claims are canceled. The limitations thereof have been imported into claim 15; the punctuation issues have been rectified.
The 112(b) rejection of claims 40-44 is withdrawn since the method step is now clear: “using… as a raw material.”
The 103 rejection of claims 15-28, 30-33, 35-38, and 40-43 over ZHOU, in view of XU, and further in view of WIRTH is maintained. Applicant's arguments have been fully considered but they are not persuasive.
Applicant argues the artisan would have no motivation/expectation of success in modifying the nanoparticle of ZHOU by replacing the oligonucleotides with a peptide antigen to formulate a nanovaccine. ZHOU does not teach the instant compound of Formula (I) as capable of cross-presentation. XU (Pg. 1-2) discloses the quality of cellular immunity is determined by efficiency of cross-presentation wherein a combination of guanidyl and phenyl groups on XU’s compound DGBA are essential for cell membrane penetration. The instant compound lacks the phenyl groups of DGBA. It is unpredictable if the instant compound is: 1) capable of binding a peptide antigen and 2) penetrating the cell membrane to induce cross-presentation.
Examiner respectfully disagrees for the following reasons laid out in the original rejection of 03/20/2026. First, XU teaches the DGBA compound’s guanidino surface chemistry (i.e.,
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) facilitates formation of DGBA-peptide antigen nanoparticles (Pg. 2 Left ¶3 & Pg. 3 Fig. 1). ZHOU teaches the instant compound uses the same group to bind oligonucleotide cargo (Pg. 5236 Right ¶3). Since XU and ZHOU teach use of the same chemical group to bind their respective cargos, the artisan would expect the guanidino group to be vital for binding cargo, including peptide/protein antigens. Thus, the artisan would have a reasonable expectation of success in utilizing the compound of ZHOU to bind peptide/protein antigens.
Second, while ZHOU is silent as to the instant compound’s ability to induce cross-presentation of antigens, ZHOU teaches the instant compound is a cell-penetrating polydisulfide and, via thiol-mediated uptake, facilitates intracellular cargo delivery (Pg. 5236 Right ¶2; Pg. 5237 Left ¶1). XU also teaches to fabricate effective cancer vaccines it is critical to develop compounds able to shuttle antigens directly into the cytosol of cells to facilitate cross-presentation (Pg. 1 Right ¶1). Since the instant compound is known to be able to penetrate cell membranes and deliver cargo intracellularly, the compound would be expected to be able to induce cross-presentation. Therefore, while XU teaches the importance of phenyl groups in a different compound (DGBA), despite a lack of phenyl groups in the instant compound, the artisan would still have an expectation of success due to the properties taught by ZHOU.
Thus, the arguments are not persuasive and the rejection is maintained with modifications to account for the claim amendments, below.
The 103 rejection of claims 25, 28-29, 34, 39, and 44 over ZHOU, in view of XU, in view of WIRTH, and further in view of ANSEL is maintained. Applicant's arguments have been fully considered but they are not persuasive for the same reasons stated in ¶15, above.
The anticipatory non-statutory double patenting rejection of claims 15-25 and 35 over co-pending application no. 18/702,267 is withdrawn due to amendment. Applicant has incorporated the limitations of claim 26 into independent claims 15 and 25. Since claim 26 was not rejected previously, and the reference application is drawn to different subject matter than that covered by claim 26, the rejection is withdrawn.
New Rejections – Not Necessitated by Amendment
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.
Claims 40 and 42-44 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treatment of tumor, bacterial infection, and virus infection, does not reasonably provide enablement for prevention of tumor, bacterial infection, and virus infection. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. This is a scope of enablement rejection.
The Wands Factors used in a scope of enablement rejection include (per MPEP 2164.01(a)):
The breadth of the claims:
The claims 40 and 42-44 are drawn to a process of making a medicine, for the treatment of prevention of tumor, bacterial infection, and viral infection, comprising a nano-vaccine comprising a compound of Formula (I) and a polypeptide antigen. The claims are relatively narrow in the scope of Formula (I). The claims are broad with respect to the scope of tumors, bacterial infections, viral infections, and polypeptide antigens.
The nature of the invention:
The invention belongs to pharmaceutical technology. While the objective of the process is to make a medicine, and no steps are taken to treat/prevent the recited diseases, the medicine is expected to have the property of treating/preventing the recited diseases.
The state of the prior art & predictability of the art:
Examiner’s search of the prior art has not found any art anticipating the use of the instant compounds as nano-vaccines. Thus, treatment and prevention of the claimed diseases are not anticipated by the art.
Analogous art XU (Xu, J. et al., Biomaterials, 25 March 2019, 207, 1-9; provided 03/20/2026) discloses use of guanidino surface chemistry (i.e.,
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) to shuttle antigens into the cell cytosol to facilitate cross-presentation, specifically as cancer nano-vaccines (Pg. 1 Right ¶1; Pg. 2 Left ¶3 & Pg. 3 Fig. 1). XU teaches treatment of cancer (Pg. 4-5 Fig. 3-4) and suggests the technology can be used for other disease targets such as viral infection (Pg. 6 Conclusions). Similarly, ZHOU (Zhou J., Angew. Chem. Int. Ed., 26 Feb. 2019, 58, 5236-5240; provided 03/20/2026) discloses a compound of Formula (I) is used to shuttle biomolecule cargo into the cell cytosol via thiol-mediated uptake (Pg. 5236 Right ¶2; Pg. 5237 Left ¶1). Thus, the art supports/suggests use of nano-vaccines and the instant Formula (I) for treatment of the instant diseases.
Further, KUNNUMAKKARA (Kunnumakkara et al., Experimental Biology and Medicine, 2019, 244, 663-689) teaches cancer is a group of more than 200 neoplastic diseases caused by diverse deregulated cell signaling cascades (Pg. 633 Left ¶1); cancer occurs as a result of the dysregulation of as many as 500 different genes which may happen over a very long duration of time (20–30 years) till the symptoms become apparent (Pg. 633 Right last ¶). Therefore, the art is unpredictable regarding prevention of tumors.
In view of the relevant prior art, the artisan would be enabled to use nano-vaccines to treat tumors, bacterial infections, and viral infections. However, there is not art which shows the instant nano-vaccines can prevent these diseases. The art does not provide enablement for prevention of tumors, bacterial infections, and viral infections.
The level of one of ordinary skill:
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 physician with a M.D. degree and several years of experience. This factor is outweighed, however, by the unpredictable nature of the art (established above). It is well established that "the scope of enablement varies with the degree of unpredictability of the factors involved" and physiological activity is considered to be an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved).
The amount of direction provided by the inventor and the existence of working examples:
Inventors have provided direction as to making the instant nano-vaccine (see Pg. 14-17 of the instant Specification). The nano-vaccines, in vitro, internalize in dendritic cells (Pg. 17 A. ¶92), induce dendritic cell maturation (Pg. 18 B. ¶95), and activate T cell maturation and proliferation (Pg. 18 B. ¶96). In vivo, the nano-vaccine is shown to inhibit growth of transplanted liver tumors (Pg. 19 D. ¶97 & Fig. 12).
Notably, the only disease model utilized is for liver tumor. Inventors have not provided any working examples wherein other tumors, bacterial infections, or virus infections are inhibited. Further, the inhibition of liver tumor growth, while enabling for treatment of liver tumor, does not show prevention of tumor (e.g., Fig. 12 still shows a slight increase in tumor growth from baseline). While the instant data supports activation of immune response and therefore treatment of tumor, bacterial infections, and viral infections, the data does not show prevention thereof.
Thus, Applicants have guidance/enablement in their Specification for treating tumor, bacterial infections, and viral infections, but not prevention thereof, especially in view of the state of the prior art.
The quantity of experimentation needed to make or use the invention:
Applicants’ invention comprising “prevention” requires a high level/quantity of experimentation. While Applicants have provided guidance in their Specification for treating tumor and activating dendritic cells/immune response, they have not provided enough evidence that the claimed “nano-vaccine” can be used to prevent the scope of tumors, bacterial infections, and viral infections per the BRI of the instant claims. At best, the Specification, in view of the prior art, does provide enablement/guidance for treatment of tumors, bacterial infections, and viral infections.
Therefore, claims 40 and 42-44 are rejected under 35 USC 112(a) for lacking scope of enablement for “prevention”. Note, withdrawn claims 45 and 47-49 would be similarly rejected.
To render moot this scope of enablement rejection: Applicants should delete “prevent” and/or “prevention”/”preventing” from the claims.
Response to Amendment – Necessitated by Amendment
Claim Objections
Claim 29 is objected to because of the following informalities: please strike the word “from” in each of the three recited ranges: i.e., “(. 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.
Claims 23-24 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 23 recites L is 1)
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, 2)
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, 3)
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, 4)
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, or 5)
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. These moieties lack sufficient antecedent basis in the claim. For each of 1)-5), L is closest to the parent claim 15 L
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. For 1), R is not present; however, by parent claim 15 R must be present. For 2), n is 5 and R is almost
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, but an extra -CH2- is present at the dashed arrow. For 3) and 4), n is 4 and R is almost
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; however, the attachment of R to the L core is not through either of the wavy-bonds shown on the parent claim R (see dashed arrows in 3) & 4) for the attachment point) and the parent claim R does not comprise the N3 of 3) (solid arrow) or the C≡CH of 4) (solid arrow). For 5), n is 4 and R is almost
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; however, the final -CH2-CH2- (dashed arrow) is not allowed by the parent claim R. The R of 5) comprises m=2 repeating units of (-CH2-CH2-O-) and an extra, unsupported -CH2-CH2-. Thus, the metes and bounds of the claim are undefined rendering the claim indefinite.
Claim 24 recites the compound of Formula (I) is
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. There is insufficient antecedent basis for this in the claim. The A (circled) and F (outlined) portions are supported by parent claim 15; however, the L (remaining) portion is not. L is
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. This L is closest to
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wherein n is 4 and R is almost
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; however, the final -CH2-CH2- (dashed arrow) is not allowed by parent claim 15. The R of claim 24 comprises m=2 repeating units of (-CH2-CH2-O-) and an extra, unsupported -CH2-CH2-. Thus, the metes and bounds of the claim are undefined rendering the claim indefinite.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 23-24 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 23-24 recite chemical moieties for L and compound of Formula (I), respectively, which do not fall within the scope of the compound A-L-F/Formula (I) as defined by parent claim 15. See ¶23-24, above. Thus, the claims 23-24 do not properly further limit parent claim 15. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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, 23-25, 27-28, 30, 32-33, 35, 37-38, 40, and 42-43 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; provided 03/20/2026), in view of XU (Xu, J. et al., Biomaterials, 25 March 2019, 207, 1-9; provided 03/20/2026), and further in view of WIRTH (Wirth, T.C. & Kuhnel, F., Frontiers in Immunology, 2017, 8, 1-16; provided 03/20/2026).
The instant claims are drawn to: a method of preparing a nano-vaccine comprising mixing a compound of Formula (I) and a polypeptide tumor antigen (15 & 23-24); a nanoparticle comprising a compound of Formula (I) and a polypeptide liver-tumor antigen (25 & 27) and a further nucleic acid adjuvant (28); a method of preparing the nanoparticle comprising mixing the ingredient (30 & 32-33); a nano-vaccine comprising the nanoparticle and an acceptable adjuvant (35 & 37-38); and a method of preparing a medicine for treatment of tumor using the nano-vaccine as a raw material (40 & 42-43).
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 nano-vaccine was tested in vivo and achieved cell uptake, antigen cross-presentation, and immune T cell response (Pg. 4 Fig. 3). Thus, XU teaches a nano-vaccine formulation comprising guanidino-dendrimer+CpG+antigen which is assembled by simple mixing of all components (Pg. 6 Conclusions). XU teaches the nano-vaccine 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 nano-vaccine.
XU does not teach the thiol compound of Formula (I).
WIRTH does not teach the instant nano-vaccine.
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 nano-vaccines 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 nano-vaccines 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 nano-vaccine, in view of XU’s nanoparticle nano-vaccine. 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 nano-vaccine 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 and 23-24, 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 nano-vaccine is obvious by the logic above, the method of preparing such nano-vaccine 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 claim 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, 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 nano-vaccine 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 nano-vaccine 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 nano-vaccine by simple mixing and would enhance the efficacy thereof.
Regarding claims 30 and 32-33, 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 nano-vaccine, 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 and 37-38, the nano-vaccines of claims 25 and 27-28 are obvious, above. Since XU teaches the nano-vaccine 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 nano-vaccine comprising the nanoparticle and an acceptable adjuvant, such as saline.
Regarding claims 40 and 42-43, by the above logic, the instant nanoparticle and nano-vaccine thereof further comprising an acceptable adjuvant is obvious. XU teaches the nano-vaccine is for treatment of cancer (Pg. 1 Right ¶1) and suspension of the nano-vaccine in saline buffer (Pg. 8 sect. 4.6), thus XU teaches preparation of a medicine for treatment of a tumor comprising the nano-vaccine as a raw material. In view of this and the logic above regarding the instant nanoparticle nano-vaccine, the instant claims are made obvious. XU also teaches treatment in vivo (Pg. 4 Fig. 3); thus, the “medicine” is for treatment of tumor.
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; provided 03/20/2026), in view of XU (Xu, J. et al., Biomaterials, 25 March 2019, 207, 1-9; provided 03/20/2026), and in view of WIRTH (Wirth, T.C. & Kuhnel, F., Frontiers in Immunology, 2017, 8, 1-16; provided 03/20/2026) 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; provided 03/20/2026).
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 nano-vaccine and possesses the technical knowledge necessary to make adjustments to the nanoparticle to optimize/enhance the nano-vaccine. 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 ¶30.
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.”
Here, 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). 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. Absent any evidence demonstrating the contrary, the determination of the optimum or workable ratios of these components would have been well within the practice of 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 ¶30), the instant claims are found obvious.
Conclusion
Claims 15, 23-25, 27-30, 32-35, 37-40, and 42-44 are rejected.
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/S.E.B./Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625
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