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 .
Election/Restrictions
Applicant's election with traverse of Group I (claims 1-13) in the reply filed on 01/07/2026 is acknowledged. The traversal is on the grounds that Group I is directed to an immunogenic composition comprising an mRNA antigen and a kinetically controllable immune modulator as active ingredients specifically configured to increase an immune response, while Group II (claim 14) is directed to a method that defines the process by which the immune response enhancement is manifested upon administration of the immunogenic composition of claim 1 (Group I), which is inherent in the immunogenic composition of claim 1 (Group I).
This is not found persuasive because the shared technical feature of an immunogenic composition for an mRNA vaccine comprising an mRNA antigen and a kinetically controllable immune modulator, wherein the immune modulator is a complex in which a cleavable linker binds to the active site of said immune modulator, is disclosed in the prior art. As previously set forth, US 2019/0351040 A1 (hereinafter Valiante; of record) discloses an RNA cancer vaccine comprising an mRNA open reading frame encoding at least one cancer antigenic polypeptide or an immunogenic fragment thereof, as well as a polypeptide that enhances the immune response, such as a constitutively active human STING polypeptide (paragraphs [0005]-[0007], [0034], and [0037]), which reads on the instantly claimed “immune modulator” per the definition disclosed at page 13, lines 1-10 of the instant specification. While Valiante is silent as to the claimed cleavable linker, this deficiency is cured by US 2019/0151462 A1 (hereinafter Coffman; as cited in the IDS filed 05/10/2023; of record), which discloses cleavable linkers that promote local release and/or local retention of a bioactive form of the agonist administered therein and also stimulate an effective immune response, which reads on the amended limitation that the claimed composition is immunogenic (abstract; paragraph [0008]). Based on these disclosures it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to connect the mRNA antigen and immune modulator disclosed in Valiante with the cleavable linker disclosed in Coffman to predictably produce a vaccine that facilitates tissue-specific targeting and reduces systemic immune activation. Thus, the shared technical feature of Groups I and II cannot be considered a special technical feature.
Therefore, the requirement is still deemed proper and is therefore made FINAL.
Claim 14 is 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. Applicant timely traversed the restriction (election) requirement in the reply filed on 01/07/2026.
Accordingly, claims 1-13 are pending and under consideration.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55 on 02/02/2023. The earliest effective filing date to which the instant application is entitled is 08/04/2020.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
Receipt of an information disclosure statement on 05/10/2023 is acknowledged. The signed and initialed PTO-1449 has been mailed with this action.
Drawings
The drawings are objected to because:
Figure 1 includes a misplaced label “FIG.1” that blocks part of the figure, thereby hindering interpretation. It would be remedial to remove the misplaced “FIG. 1” label in order to facilitate interpretation of the Figure.
The labeling of Figure 2 is broadly grammatically incorrect. The header label “CONCEPTUAL DIAGRAM OF mRNA VACCINE IN WHICH mRNA ANTIGEN EXPRESSION AND ADJUVANT ACTION OCCUR WITH TIME INTERVAL” is grammatically incorrect. Additionally, the label that reads “too early activation inhibit antigen expression” is grammatically incorrect. It would be remedial to update the labeling of Figure 2 to be grammatically correct.
The image quality of Figure 3 is insufficient to be clearly interpretable. It would be remedial to increase the image quality of Figure 3 such that it is clearly interpretable.
Figure 9 is disclosed to depict the degree of antigen presentation when treated with mRNA and poly I:C, wherein poly I:C is provided at different concentrations. These concentrations are listed both in the Figure itself and in the instant specification as 20, 30, and 40 (page 45, lines 6-12). However, the Figure itself does not clarify that the listed 20, 30, and 40 correspond to poly I:C concentration. Additionally, the units of poly I:C concentration are not disclosed. To facilitate interpretation of the Figure, it would be remedial to clearly indicate what the listed 20, 30, and 40 signify.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 1-3, 6-7, and 11-12 are objected to because of the following informalities:
With regard to claim 1, which recites “an immunogenic composition for an mRNA vaccine, comprising mRNA antigen and a kinetically controllable immune modulator as active ingredients, wherein the immune modulator is a complex in which a cleavable linker binds to the active site of an immune modulator,” this recitation does not comport with standard grammatical and/or linguistic conventions. The recited claim is missing an article (such as “an”) preceding “mRNA antigen.” Additionally, the recitation of “the immune modulator is a complex in which a cleavable linker binds to the active site of an immune modulator” requires substantial grammatical revision. One possible example of a grammatically correct recitation is “the immune modulator is within a complex in which a cleavable linker binds to the active site of the immune modulator” (bolded emphasis added). This is merely a general example set forth by the Examiner and is not intended to be limiting. It would be remedial to amend instant claim 1 such that it comports with standard grammatical and/or linguistic conventions.
With regard to claim 2, which recites “the immunogenic composition of claim 1, wherein, after administration of the immunogenic composition for an mRNA vaccine, translation of mRNA into a protein proceeds, and sequentially the cleavable linker binding to the active site of the immune modulator is cleaved to induce the activation function of the immune modulator,” this recitation also does not comport with standard grammatical and/or linguistic conventions and requires substantial grammatical revision. One possible example of a grammatically correct recitation is “the immunogenic composition of claim 1, wherein translation of mRNA into a protein proceeds after administration of the immunogenic composition, and the cleavable linker binding to the active site of the immune modulator is sequentially cleaved to induce the activation function of the immune modulator.” This is merely a general example set forth by the Examiner and is not intended to be limiting. It would be remedial to amend instant claim 2 such that it comports with standard grammatical and/or linguistic conventions.
With regard to claim 3, which recites “the immunogenic composition of claim 1, wherein the kinetic control appears in the manner that when the cleavable linker is linked to the active site of the immune modulator to maintain an inactive state, and then the cleavable linker blocking the active site is cleaved within 2 to 12 hours after mRNA translation has begun, the activity of the immune modulator is temporally delayed,” this recitation also does not comport with standard grammatical and/or linguistic conventions and requires substantial grammatical revision. The Examiner has interpreted the instant claim to recite that the cleavable linker of the immunogenic composition of claim 1 is cleaved within 2 to 12 hours after translation of the mRNA-encoded antigen has begun, thereby releasing the immune modulator. It would be remedial to amend instant claim 3 such that it comports with standard grammatical and/or linguistic conventions.
With regard to claim 6, which recites “the immunogenic composition of claim 1, wherein the cleavable linker is cleaved at the chemical bond of a binding site due to any one or more factors selected from the group consisting of an enzyme, pH, redox potential, a temperature, ultrasonic wave, magnetic force, and a light source,” this recitation also does not comport with standard grammatical and/or linguistic conventions and requires substantial grammatical revision. The Examiner has interpreted the instant claim to recite that cleavage of the cleavable linker associated with the immune modulator is achieved by enzymatic activity, change in pH, redox potential, or temperature, or administration of an ultrasonic wave, magnetic force, or a light source. It would be remedial to amend instant claim 6 such that it comports with standard grammatical and/or linguistic conventions.
With regard to claim 7, which recites “the immunogenic composition of claim 1, wherein, to an end of the cleavable linker, any one or more materials selected from the group consisting of cholesterol, a lipid, a protein, an amino acid, a peptide and an oligonucleotide is bound,” this recitation also does not comport with standard grammatical and/or linguistic conventions and requires substantial grammatical revision. One possible example of a grammatically correct recitation is “the immunogenic composition of claim 1, wherein any one or more materials selected from the group consisting of cholesterol, a lipid, a protein, an amino acid, a peptide, and an oligonucleotide is/are bound to one end of the cleavable linker.” This is merely a general example set forth by the Examiner and is not intended to be limiting. It would be remedial to amend instant claim 7 such that it comports with standard grammatical and/or linguistic conventions.
With regard to claim 11, which recites “the immunogenic composition of claim 10, wherein, in the drug delivery system, after delivering the mRNA antigen loaded in the drug delivery systems to the cytosol first, the kinetically controllable immune modulator interacts with a receptor on a cell surface, or in an endosome or lysosome,” this recitation also does not comport with standard grammatical and/or linguistic conventions and requires substantial grammatical revision. One possible example of a grammatically correct recitation is “the immunogenic composition of claim 10, wherein the mRNA antigen loaded into the drug delivery system is cytosolically delivered, after which the kinetically controllable immune modulator interacts with a cell surface, endosome, or lysosome receptor.” This is merely a general example set forth by the Examiner and is not intended to be limiting. It would be remedial to amend instant claim 11 such that it comports with standard grammatical and/or linguistic conventions.
With regard to claim 12, which recites “the immunogenic composition of claim 10, the drug delivery system further comprises any one or more immune modulators selected from the group consisting of a toll-like receptor agonist, saponin, an antiviral peptide, an inflammasome inducer, a NOD ligand, a cytosolic DNA sensor (CDS ligand), a stimulator of interferon genes (STING) ligand, an outer wall component of a pathogen, alum, a lipid, a combination thereof, and a derivative thereof,” this recitation also does not comport with standard grammatical and/or linguistic conventions and requires substantial grammatical revision. One possible example of a grammatically correct recitation is “the immunogenic composition of claim 10, wherein the drug delivery system further comprises any one or more immune modulators selected from the group consisting of a toll-like receptor agonist, a saponin, an antiviral peptide, an inflammasome inducer, a NOD ligand, a cytosolic DNA sensor (CDS ligand), a stimulator of interferon genes (STING) ligand, an outer wall component of a pathogen, alum, a lipid, and combination(s) or derivative(s) thereof.” This is merely a general example set forth by the Examiner and is not intended to be limiting. It would be remedial to amend instant claim 12 such that it comports with standard grammatical and/or linguistic conventions.
Appropriate correction is required. The instant claim set requires substantial grammatical revision in order to be in good condition.
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 1-13 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.
Claims 1-13 are drawn to a set of immunogenic compositions for an mRNA vaccine, said compositions comprising an mRNA-encoded antigen (see section Claim Rejections - 35 USC § 112(b)) and a kinetically controllable immune modulator bound to a cleavable linker. The rejected claims thus comprise a set of immunogenic compositions for an mRNA vaccine that encompass any mRNA-encoded antigen and any kinetically controllable immune modulator bound to any cleavable linker. Thus, the claims are drawn to a genus of compounds solely defined by the ability to function to modulate the immune response.
While claim 8 further limits the immune modulator to a toll-like receptor agonist, claim 8 nonetheless encompasses a genus of immune modulators defined solely or primarily by function, as the claimed toll-like receptor agonist is defined solely by the ability to function as an immune modulator acting on toll-like receptors. Furthermore, toll-like receptor agonists are one possible class of the broadly/functionally claimed immune modulators and are known to be structurally diverse, as reviewed in Dowling, 2018 (cited in the IDS filed 05/10/2023).
Additionally, while claim 9 further limits the toll-like receptor agonist to any one or more selected from the group consisting of a toll-like receptor 1 agonist, a toll-like receptor 2 agonist, a toll-like receptor 3 agonist, a toll-like receptor 4 agonist, a toll-like receptor 5 agonist, a toll-like receptor 6 agonist, a toll-like receptor 7 or 8 agonist, and a toll-like receptor 9 agonist, claim 9 nonetheless encompasses a genus of immune modulators defined solely or primarily by function, as the claimed toll-like receptor agonists are defined solely by the ability to function as immune modulators acting on specific toll-like receptors. As set forth above, toll-like receptor agonists are known to be structurally diverse, as reviewed in Dowling, 2018 (cited in the IDS filed 05/10/2023).
Claim 12 further limits the immune modulator to any one or more selected from the group consisting of a toll-like receptor agonist, saponin, an antiviral peptide, an inflammasome inducer, a NOD ligand, a cytosolic DNA sensor (CDS ligand), a stimulator of interferon genes (STING) ligand, an outer wall component of a pathogen, alum, a lipid, a combination thereof, and a derivative thereof. However, claim 12 nonetheless encompasses a genus of immune modulators defined solely or primarily by function, as the claimed immune modulators are all structurally diverse despite sharing the function of modulating the immune response.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification describes proof-of-principle mRNA vaccine compositions comprising OVA mRNA (encoding albumin-see TriLink CleanCap® OVA mRNA product page as indicated at page 40, lines 3-4 of the instant specification) and cholesterol-toll-like receptor agonist complexes, wherein said toll-like receptor agonists include polyinosinic-polycytidylic acid (poly I:C)as a toll-like receptor 3 agonist, Lipopolysaccharide (LPS) as a toll-like receptor 4 agonist, and resiquimod (R-848) as a toll-like receptor 7 or 8 agonist (Example 12). The specification further discloses saponin immune modulators at Example 11.3 and delivery of immunogenic compositions via nanoparticle at Example 11. No description is provided of any other mRNA-encoded antigen or of any kinetically controllable immune modulators bound to any cleavable linker other than the limited subset of immune modulators (i.e. toll-like receptor agonists) bound to cholesterol set forth above. Furthermore, no additional working example of delivery via a vehicle other than nanoparticles (as recited at claim 10) is provided.
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims with regard to structure and function, the examples are only representative of proof-of-principle mRNA vaccine compositions comprising OVA mRNA (encoding albumin-see TriLink CleanCap® OVA mRNA product page as indicated at page 40, lines 3-4 of the instant specification) and cholesterol-toll-like receptor agonist complexes, wherein said toll-like receptor agonists include polyinosinic-polycytidylic acid (poly I:C)as a toll-like receptor 3 agonist, Lipopolysaccharide (LPS) as a toll-like receptor 4 agonist, and resiquimod (R-848) as a toll-like receptor 7 or 8 agonist (Example 12). The results are not necessarily predictive of a set of immunogenic compositions for an mRNA vaccine that encompass any mRNA-encoded antigen and any kinetically controllable immune modulator bound to any cleavable linker. Thus, it is impossible for one to extrapolate from the few examples described herein those immunogenic compositions for an mRNA vaccine that would necessarily meet the structural/functional characteristics of the rejected claims.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of immunogenic compositions for an mRNA vaccine that encompass any mRNA-encoded antigen and any kinetically controllable immune modulator bound to any cleavable linker.
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 1-13.
Claim 13 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: Claim 13 is drawn to a composition for the prevention or treatment of any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease. The nature of the invention is complex in that one must be able to prevent or treat any of the claimed diseases, all of which have different causes and different mechanisms of pathogenesis, with the immunogenic composition disclosed therein.
Breadth of the claims: The claims broadly encompass the administration of compositions defined solely or primarily by function (as set forth above), where the compositions must be effective to prevent or treat any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease. The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification and existence of working examples: While the specification broadly envisions prevention or treatment of any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease by administering the immunogenic compositions for an mRNA vaccine disclosed therein (page 7, lines 5-17), it does not teach prevention or treatment of any disease. As set forth above, the specification describes proof-of-principle mRNA vaccine compositions comprising OVA mRNA (encoding albumin-see TriLink CleanCap® OVA mRNA product page as indicated at page 40, lines 3-4 of the instant specification) and cholesterol-toll-like receptor agonist complexes, wherein said toll-like receptor agonists include polyinosinic-polycytidylic acid (poly I:C)as a toll-like receptor 3 agonist, Lipopolysaccharide (LPS) as a toll-like receptor 4 agonist, and resiquimod (R-848) as a toll-like receptor 7 or 8 agonist (Example 12). The specification further discloses saponin immune modulators at Example 11.3 and delivery of immunogenic compositions via nanoparticle at Example 11. No description is provided of prevention or treatment of any disease, including an infectious disease, cancer, metabolic syndrome, an autoimmune disease, or a rare disease, as is instantly claimed.
Predictability and state of the art: Regarding the claimed disease prevention, the claims explicitly encompass preventing any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease in a subject. Looking to the prior art for guidance, a search of the prior art did not identify any methods which utilized an immunogenic composition for an mRNA vaccine that could effectively prevent any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease in a subject. In fact, no prior art was identified which taught effective prevention of any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease using any agent similar to the agents utilized in the instant claims. The specification also does not provide any working example demonstrating prevention of any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease in a subject. Therefore, given the lack of knowledge present in the prior art and the lack of guidance provided in the specification with respect to preventing any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease, further experimentation would be required. Considering that the additional experimentation would require de novo experimentation without a guarantee of success, and further considering that any positive results (i.e., successful prevention of any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease in a subject) would amount to a significant advancement in the state of the art, the additional experimentation required is considered undue.
Furthermore, in In re Vaeck, 947 F.2d 488,495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991), the Court ruled that a rejection under 35 U.S.C. 112, first paragraph for lack of enablement was appropriate given the relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims. Such is the case here where there is a relatively incomplete understanding in the biotechnological field involved, as described above, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims.
Therefore, it is appropriate to reject the claims under 35 USC 112(a) for not being enabled for prevention of any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease.
Additionally, while mRNA vaccines are known to have utility as anticancer therapy (reviewed in Kaczanowska et al., 2013), the instant specification is entirely silent as to the design and use of the immunogenic compositions for an mRNA vaccine as disclosed therein for treatment of any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease. All of these diseases develop via different mechanisms of pathogenesis. For example, cancer is a proliferative disease wherein cancer cells undergo continual unregulated proliferation (reviewed in Cooper, 2000), while autoimmune diseases are generally liked to the failure of the immune system to distinguish self from nonself, although different autoimmune diseases present with different symptoms and are treated differently (reviewed in Wang et al., 2015). While design of therapeutic mRNA vaccines and experimentation thereof are both within the realm of experimentation by those of ordinary skill in the art, the breadth of diseases encompassed by the instant claim set would require substantial and repeated experimentation for numerous, disparate diseases such that the additional experimentation required is considered undue, particularly in the absence of any guidance provided in the instant specification.
Amount of experimentation necessary: As set forth above, the quantity of experimentation required to make and use the full scope of the claimed invention would be large. While the required experimentation is theoretically within the realm of experimentation by those of ordinary skill in the art, the breadth of diseases encompassed by the instant claim set would require substantial and repeated experimentation for numerous, disparate diseases such that the additional experimentation required is considered undue, particularly in the absence of any guidance provided in the instant specification.
Other than contemplating the utility of the claimed immunogenic composition for an mRNA vaccine in preventing or treating any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease, the specification does not disclose how to design or use any of the mRNA-encoded antigen (see section Claim Rejections - 35 USC § 112(b)) required to treat a subject in need thereof using the instantly claimed vaccine composition. As clearly stated in Genentech Inc. v. Novo Nordisk NS (CAFC) 42 USPQ2d 1001: “Patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable. Tossing out the mere germ of an idea does not constitute an enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” See also Brenner v. Manson, 383 U.S. 519, 536, 148 USPQ 689, 696 (1966), stating in the context of the utility requirement that “a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.” Applicant cannot rely on the knowledge of one skilled in the art to supply information on the novel aspects of the claimed invention, to which the instantly filed disclosure is largely silent, as set forth above.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claim 13 is not considered to be enabled by the instant disclosure.
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 1-13 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.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “mRNA antigen” in claim 1 is used by the claim to mean “mRNA-encoded antigen,” as per the instant specification (page 4, lines 1-8; page 8, lines 1-8; page 11, lines 20-22). However, the term “antigen” is a term of the art itself, meaning any substance that causes the body to make an immune response against that substance (NIH Definition). Thus, someone of ordinary skill in the art would interpret the term “mRNA antigen” to mean that the mRNA itself is the antigen, rather than the protein encoded by the mRNA. It would be remedial to amend the instant claim language such that one of ordinary skill in the art would be reasonably apprised of the type of antigen claimed therein.
Furthermore, the term “active site of an immune modulator” in claim 1 is used by the claim to mean “critical moiety of an immune modulator,” as per the instant specification (page 8, lines 19-24). However, the term “active site” is a term of the art itself, meaning the site of an enzyme that binds to and acts on the substrate (reviewed in Robinson, 2015). As set forth above, immune modulators are a structurally diverse genus of molecules, not all of which are enzymes. For example, peptidoglycan is an immune modulator that is a toll-like receptor agonist (reviewed in Kaczanowska et al., 2013) and is not an enzyme. Thus, someone of ordinary skill in the art would not reasonably be able to interpret the term “active site of an immune modulator,” as not all immune modulators are enzymes with active sites. While the specification broadly suggests that the active site refers to a critical moiety of an immune modulator (page 8, lines 19-24), the term is not clearly redefined. It would be remedial to either amend the instant claim language or to clearly redefine the term “active site” in the specification such that one of ordinary skill in the art would be reasonably apprised of the bounds of the claimed invention.
Dependent claims 2-13 do not remedy the basis of the indefiniteness rejection of instant claim 1 set forth above and therefore inherit the rejection thereof.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-13 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0351040 A1 (hereinafter Valiante; of record), US 2019/0151462 A2 (hereinafter Coffman; as cited in the IDS filed 05/10/2023; of record), and Abraham et al., 2017 (hereinafter Abraham), as evidenced by Kaczanowska et al., 2013 (hereinafter Kaczanowska).
With regard to claim 1, which recites “an immunogenic composition for an mRNA vaccine, comprising [an] mRNA antigen and a kinetically controllable immune modulator as active ingredients, wherein the immune modulator is a complex in which a cleavable linker binds to the active site of an immune modulator,” Valiante discloses an RNA cancer vaccine comprising an mRNA open reading frame encoding at least one cancer antigenic polypeptide or an immunogenic fragment thereof, as well as a polypeptide that enhances the immune response, such as a constitutively active human STING polypeptide (paragraphs [0005]-[0007], [0034], and [0037]). Per the definition disclosed on page 13, lines 1-10 of the instant specification, the STING polypeptide to enhance the immune response disclosed in Valiante reads on the instantly claimed "immune modulator."
However, Valiante is silent as to the claimed cleavable linker connecting the mRNA antigen and the immune modulator. This deficiency is cured by Coffman, which discloses cleavable linkers that promote local release and/or local retention of a bioactive form of the TLR7/8 agonist administered therein and also stimulate an effective immune response (abstract; paragraphs [0002] and [0008]). Coffman specifically discloses that the subject matter taught therein relates to methods for preparation of a therapeutic agent or vaccine adjuvant (paragraphs [0158] and [0401]) capable of targeting specific tissues, thereby reducing unwanted systemic immune activation (paragraph [0007]). Additionally, Coffman explicitly discloses that the cleavable, self-eliminating linkers taught therein maintain the TLR7/8 agonist in a relatively inactive state prior to cleavage of said linker, after which the TLR7/8 agonist is released in its active form (paragraphs [0006] and [0364]). This disclosure of a cleavable linker blocking activity of an immune modulator when bound to said immune modulator and restoring activity of said immune modulator upon cleavage of said linker is considered to read on the instantly claimed cleavable linker bound to the active site of an immune modulator. Furthermore, Figure 4 of Coffman illustrates the kinetic control of the immune modulator (IMDQ-a TLR7/8 agonist), wherein said immune modulator is released over several hours (see also paragraph [0657]).
With regard to claim 2, which recites “after administration of the immunogenic composition for an mRNA vaccine [of claim 1], translation of mRNA into a protein proceeds, and sequentially the cleavable linker binding to the active site of the immune modulator is cleaved to induce the activation function of the immune modulator,” as set forth above, Valiante discloses an RNA cancer vaccine comprising an mRNA open reading frame encoding at least one cancer antigenic polypeptide or an immunogenic fragment thereof, as well as a polypeptide that enhances the immune response, such as a constitutively active human STING polypeptide (paragraphs [0005]-[0007], [0034], and [0037]). Valiante specifically discloses that mRNA vaccines are superior to other vaccine technology, as they are better designed to produce the appropriate antigenic protein conformation upon translation by co-opting natural cellular machinery (paragraph [0006]). Thus, Valiante discloses translation of the antigenic mRNA, as in instant claim 2. Furthermore, as set forth above, Coffman discloses kinetic control of an immune modulator such as IMDQ (a TLR7/8 agonist) by attaching said immune modulator to a cleavable linker such that the cleavable linker blocks activity of the immune modulator until the linker is cleaved, after which the immune modulator is released in its active form as a vaccine adjuvant (abstract; paragraphs [0002], [0006], [0008], [0364], and [0657]; Figure 4).
With regard to claim 3, which recites “the kinetic control [of the immunogenic composition of claim 1] appears in the manner that when the cleavable linker is linked to the active site of the immune modulator to maintain an inactive state, and then the cleavable linker blocking the active site is cleaved within 2 to 12 hours after mRNA translation has begun, the activity of the immune modulator is temporally delayed,” as set forth above, the Examiner has interpreted instant claim 3 to recite that the cleavable linker of the immunogenic composition of claim 1 is cleaved within 2 to 12 hours after translation of the mRNA-encoded antigen has begun, thereby releasing the immune modulator. As set forth above regarding instant claim 2, Valiante discloses an RNA cancer vaccine comprising an mRNA open reading frame encoding at least one cancer antigenic polypeptide or an immunogenic fragment thereof, said antigenic polypeptide or immunogenic fragment thereof being translated by co-opting natural cellular machinery, as well as a polypeptide that enhances the immune response, such as a constitutively active human STING polypeptide (paragraphs [0005]-[0007], [0034], and [0037]). Furthermore, as set forth above, Coffman discloses kinetic control of an immune modulator such as IMDQ (a TLR7/8 agonist) by attaching said immune modulator to a cleavable linker such that the cleavable linker blocks activity of the immune modulator until the linker is cleaved, after which the immune modulator is released in its active form as a vaccine adjuvant, said release being delayed several hours after administration of the vaccine (abstract; paragraphs [0002], [0006], [0008], [0364], and [0657]; Figure 4). The time course of IMDQ release depicted in Figure 4 of Coffman reads on the instantly claimed range of 2 to 12 hours after mRNA translation has begun following administration of the vaccine (per Valiante).
With regard to claim 4, which recites “the cleavable linker [of the immunogenic composition of claim 1] comprises any one or more bonds selected from the group consisting of disulfide, carbamate, hydrazine, ester, peptide, azide, amide, hydrazone, thioether, phosphodiester, thioketal bonds, and a combination thereof,” Coffman further discloses that the cleavable linkers taught therein may be dimethyl disulfide cleavable linkers (Figure 3; paragraphs [0090], [0382], [0391], and [0395]) comprising disulfide bonds, as instantly claimed.
With regard to claim 5, which recites “the cleavable linker [of the immunogenic composition of claim 1] further comprises ethylene oxide or ethylene glycol at one or both ends thereof,” Coffman further discloses that the cleavable linkers taught therein may comprise ethylene oxide or ethylene glycol species at the N-terminus (paragraphs [0146] and [0671]; claims 1, 77, and 86).
With regard to claim 6, which recites “the cleavable linker [of the immunogenic composition of claim 1] is cleaved at the chemical bond of a binding site due to any one or more factors selected from the group consisting of an enzyme, pH, redox potential, a temperature, ultrasonic wave, magnetic force, and a light source,” Coffman further discloses that the cleavable linkers taught therein may be cleaved by a proteolytic enzyme such as Cathepsin B (paragraph [0383]).
With regard to claim 7, which recites “to an end of the cleavable linker [of the immunogenic composition of claim 1], any one or more materials selected from the group consisting of cholesterol, a lipid, a protein, an amino acid, a peptide and an oligonucleotide is bound,” Coffman further discloses that the cleavable linkers taught therein may be peptide-based cleavable linkers comprising amino acid residues and amino acid motifs (paragraph [0383]). Such peptide-based cleavable linkers must necessarily have amino acid residues bound at their ends, as instantly claimed.
With regard to claims 8 and 9, which respectively recite “the immune modulator [of the immunogenic composition of claim 1] is a toll-like receptor agonist” and “the toll-like receptor agonist [of the immunogenic composition of claim 8] is any one or more selected from the group consisting of a toll-like receptor 1 agonist, a toll-like receptor 2 agonist, a toll-like receptor 3 agonist, a toll-like receptor 4 agonist, a toll-like receptor 5 agonist, a toll-like receptor 6 agonist, a toll-like receptor 7 or 8 agonist, and a toll-like receptor 9 agonist,” as set forth above, Coffman discloses kinetic control of an immune modulator such as IMDQ (a TLR7/8 agonist) by attaching said immune modulator to a cleavable linker such that the cleavable linker blocks activity of the immune modulator until the linker is cleaved, after which the immune modulator is released in its active form as a vaccine adjuvant, said release being delayed several hours after administration of the vaccine (abstract; paragraphs [0002], [0006], [0008], [0364], and [0657]; Figure 4).
With regard to claim 10, which recites “the mRNA antigen and the kinetically controllable immune modulator [of the immunogenic composition of claim 1] are loaded into any one or more drug delivery systems selected from the group consisting of a nanoliposome, a nanoemulsion, a nanomicelle, a hydrogel, a scaffold, a solid nanoparticle, and a polymeric nanoparticle,” while both Valiante and Coffman disclose delivery systems such as lipid nanoparticles (Valiante, paragraph [0201]), they do not explicitly disclose the specific species of the instantly claimed drug delivery systems. However, Abraham cures this deficiency by disclosing that nanoliposomes facilitate safe and efficient therapeutic mRNA delivery, such as mRNA vaccines (abstract).
With regard to claim 11, which recites “after delivering the mRNA antigen loaded in the drug delivery systems [of instant claim 10] to the cytosol first, the kinetically controllable immune modulator interacts with a receptor on a cell surface, or in an endosome or lysosome,” as set forth above, Valiante specifically discloses that mRNA vaccines are superior to other vaccine technology, as they are better designed to produce the appropriate antigenic protein conformation upon translation by co-opting natural cellular machinery (paragraph [0006]) within the cytoplasm (or cytosol) of cells (Abraham: page 162, column 1, paragraph 1). Furthermore, Coffman further discloses that the TLR7/8 agonist taught therein interacts with toll-like receptors that are transmembrane proteins (paragraphs [0003] and [0005]). While Coffman does not specifically disclose that the TLR7/8 agonist taught therein interacts with cell surface, endosomal, or lysosomal receptors, it is known in the art that TLR7/8 localizes to endosomal membranes (Kaczanowska: Table 1).
With regard to claim 12, which recites “the drug delivery system [of the immunogenic composition of claim 10] further comprises any one or more immune modulators selected from the group consisting of a toll-like receptor agonist, saponin, an antiviral peptide, an inflammasome inducer, a NOD ligand, a cytosolic DNA sensor (CDS ligand), a stimulator of interferon genes (STING) ligand, an outer wall component of a pathogen, alum, a lipid, a combination thereof, and a derivative thereof,” as set forth above, Abraham discloses that nanoliposomes facilitate safe and efficient therapeutic mRNA delivery, such as the mRNA vaccines disclosed by Valiante (abstract). Furthermore, Valiante discloses that the mRNA vaccines taught therein further comprise a constitutively active STING polypeptide to further potentiate the immune response (paragraph [0015]).
With regard to claim 13, which recites “the composition for an mRNA vaccine [of claim 1] is used for prevention or treatment of any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease,” Valiante discloses that the mRNA vaccines taught therein are suitable for treating cancer (abstract; paragraph [0006]). Coffman also discloses that the vaccines comprising cleavable linkers attached to TLR agonists taught therein are suitable for treating cancer (paragraph [0002]).
Given that Valiante discloses an mRNA vaccine comprising at least one mRNA antigen and an immune modulator; that Coffman discloses cleavable linkers relevant to vaccine preparation that facilitate tissue-specific targeting and release of said immune modulator over several hours following administration; and that Abraham discloses that nanoliposomes facilitate safe and efficient therapeutic mRNA delivery (i.e. mRNA vaccines), it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to connect the mRNA antigen and immune modulator disclosed in Valiante with the cleavable linker attached to an immune modulator (i.e. a TLR7/8 agonist) disclosed in Coffman and delivered via nanoliposomes as disclosed in Abraham to predictably produce a vaccine that facilitates tissue-specific targeting and reduces systemic immune activation by controlling the release of the immune modulator, thereby treating diseases such as cancer. One would have been motivated to make such a modification in order to receive the expected benefit of reducing unwanted systemic immune activation, thereby treating diseases such as cancer.
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.
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Claims 1, 4, 6-10, and 13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-12, and 17 of copending Application No. 17/391,224 (reference application; corresponds to US 2022/0008411 A1). Although the claims at issue are not identical, they are not patentably distinct from each other, as set forth below.
Copending claim 10 recites “a vaccine composition comprising the adjuvant composition of [copending] claim 9 and an antigen,” which recites “an adjuvant composition comprising the toll-like receptor 7/8 agonist-cholesterol complex of [copending] claim 1.” Copending claim 11 further recites that the antigen of the vaccine composition of copending claim 10 is selected from a group of antigen species, including a polynucleotide, which reads on the instantly claimed “mRNA antigen” (instant claim 1). Furthermore, copending claim 1 recites “a toll-like receptor 7/8 agonist-cholesterol complex, in which cholesterol is linked to an active site of a toll-like receptor 7/8 agonist, wherein the linkage is made in a separable form, and wherein the separable linkage is made by at least one selected from the group consisting of a carbamate, a disulfide, an ester, a peptide, an azide, and a combination thereof.” Thus, copending claims 1, 9, and 10 recite a vaccine composition comprising an adjuvant composition, which is itself comprised of a toll-like receptor 7/8 agonist-cholesterol complex in which cholesterol is linked to an active site of a toll-like receptor 7/8 agonist, as well as a polynucleotide-based antigen.
This linkage is explicitly recited as being made in a separable form, wherein the separable linkage is made by at least one specified chemical bond, such as a disulfide, carbamate, ester, peptide, azide, or combination thereof. The toll-like receptor 7/8 agonist of the copending application is limited to specific species at copending claims 4 and 5. The separable linkage of the copending application is recited to be cleaved “in response to a tumor microenvironment, a temperature, an endosomal enzyme, a lysosomal enzyme, or pH in cells” at copending claim 6. Furthermore, the composition of the copending application is recited to be packaged into a nanoparticle composition (copending claim 7), “wherein the nanoparticle comprises at least one selected from the group consisting of a nanoliposome, a nanoemulsion, a nanomicelle, a solid nanoparticle, and a polymer nanoparticle” (copending claim 8).
Finally, the composition of the copending application is recited to be useful “for controlling an immune function or preventing or treating a cancer” at copending claim 12 as well as for inhibiting cancer proliferation at copending claim 17 (which reads on treatment of cancer under broadest reasonable interpretation).
In comparison, instant claim 1 recites “an immunogenic composition for an mRNA vaccine,” said composition comprising an antigen encoded by mRNA and a kinetically controllable immune modulator in a complex bound to a cleavable linker, said cleavable linker comprising “any one or more bonds selected from the group consisting of disulfide, carbamate, hydrazine, ester, peptide, azide, amide, hydrazone, thioether, phosphodiester, thioketal bonds, and a combination thereof,” (as recited at instant claim 4) and additionally comprising cholesterol bound to an end of said cleavable linker (as recited at instant claim 7). The kinetically controllable immune modulator recited at instant claim 1 is further limited to a toll-like receptor agonist at instant claim 8, specifically a toll-like receptor 7 or 8 agonist at instant claim 9. The specific species of toll-like receptor 7 or 8 agonists recited in the copending application all read on the generically claimed toll-like receptor 7 or 8 agonists recited in the instant application. The cleavable linker of the instant application is recited to be cleaved “due to any one or more factors selected from the group consisting of an enzyme, pH, redox potential, a temperature, ultrasonic wave, magnetic force, and a light source” at instant claim 6. The instantly claimed immunogenic composition is “loaded into any one or more drug delivery systems selected from the group consisting of a nanoliposome, a nanoemulsion, a nanomicelle, a hydrogel, a scaffold, a solid nanoparticle, and a polymeric nanoparticle” as recited at instant claim 10. Finally, the instantly claimed immunogenic composition is recited to be “used for prevention or treatment of any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease” at instant claim 13.
Thus, while the instant and copending applications do not recite identical limitations, the subject matter claimed therein is not patentably distinct, as both applications recite an immunogenic composition for a vaccine, said immunogenic composition comprising a polynucleotide-based antigen and a toll-like receptor 7/8 agonist attached via a cleavable linker for the treatment of diseases such as cancer.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 4, 6-10, and 12-13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 6, 8-12, and 14-15 of copending Application No. 17/909,066 (reference application; corresponds to US 2023/0346924 A1). Although the claims at issue are not identical, they are not patentably distinct from each other, as set forth below.
Copending claim 11 recites “a vaccine composition comprising the adjuvant composition of [copending] claim 10 and an antigen as active ingredients,” which recites “an adjuvant composition comprising nano-molecule of [copending] claim 1.” The nano-molecule of claim 1 is recited to comprise a toll-like receptor 7 or 8 agonist, wherein the toll-like receptor 7 or 8 agonist is in an inactive state by binding a lipid to an activation site, wherein the binding between the toll-like receptor agonist and the lipid is cleavable (copending claim 1). Copending claim 12 further recites that the antigen of the vaccine composition of copending claim 10 is selected from a group of antigen species, including a polynucleotide, which reads on the instantly claimed “mRNA antigen” (instant claim 1). The cleavable bond recited at copending claim 1 is further recited to be “selected from the group consisting of a carbamate bond, a disulfide bond, an ester bond, a peptide bond, an azide bond, an amide bond, a hydrazone bond, a thioether bond, a phosphodiester bond, a thioketal bond, and any combination thereof” at copending claim 4. Thus, copending claims 1, 4, and 10-12 collectively recite a vaccine composition comprising an adjuvant composition, which is itself comprised of a toll-like receptor 7/8 agonist bound to a lipid, in which said lipid linked to an active site of a toll-like receptor 7/8 agonist, as well as a polynucleotide-based antigen.
This linkage is explicitly recited as being made in a separable form, wherein the separable linkage is made by at least one specified chemical bond, such as a disulfide, carbamate, ester, peptide, azide, or combination thereof. Cleavage of this separable linkage is recited to occur “in response to a tumor microenvironment, or enzymes and pH of endosomes and lysosomes in cells” (copending claim 6).
The composition of the copending application is recited to comprise a nano-molecule (copending claim 1), wherein the nano-molecule “is any one or more selected from the group consisting of a nanoliposome, a nanoemulsion, a nanomicelle, and a polymer nanoparticle” (copending claim 8). Additionally, the composition of the copending application is recited to further comprise “a toll-like receptor agonist, a saponin, an antiviral peptide, an inflammasome inducer, a NOD ligand, a cytosolic DNA sensor (CDS) ligand, a stimulator of interferon genes (STING) ligand, an antigen, alum, a chemotherapeutic agent, an immune checkpoint inhibitor, and any combination thereof” at copending claim 9.
Finally, the composition of the copending application is recited to be useful “for preventing or treating cancer” at copending claim 14 as well as for inhibiting cancer proliferation at copending claim 15 (which reads on treatment of cancer under broadest reasonable interpretation).
In comparison, instant claim 1 recites “an immunogenic composition for an mRNA vaccine,” said composition comprising an antigen encoded by mRNA and a kinetically controllable immune modulator in a complex bound to a cleavable linker, said cleavable linker comprising “any one or more bonds selected from the group consisting of disulfide, carbamate, hydrazine, ester, peptide, azide, amide, hydrazone, thioether, phosphodiester, thioketal bonds, and a combination thereof,” (as recited at instant claim 4) and additionally comprising a lipid bound to an end of said cleavable linker (as recited at instant claim 7). The kinetically controllable immune modulator recited at instant claim 1 is further limited to a toll-like receptor agonist at instant claim 8, specifically a toll-like receptor 7 or 8 agonist at instant claim 9. The cleavable linker of the instant application is recited to be cleaved “due to any one or more factors selected from the group consisting of an enzyme, pH, redox potential, a temperature, ultrasonic wave, magnetic force, and a light source” at instant claim 6. The instantly claimed immunogenic composition is “loaded into any one or more drug delivery systems selected from the group consisting of a nanoliposome, a nanoemulsion, a nanomicelle, a hydrogel, a scaffold, a solid nanoparticle, and a polymeric nanoparticle” as recited at instant claim 10. Instant claim 12 further recites that the delivery system “further comprises any one or more immune modulators selected from the group consisting of a toll-like receptor agonist, saponin, an antiviral peptide, an inflammasome inducer, a NOD ligand, a cytosolic DNA sensor (CDS ligand), a stimulator of interferon genes (STING) ligand, an outer wall component of a pathogen, alum, a lipid, a combination thereof, and a derivative thereof.” Finally, the instantly claimed immunogenic composition is recited to be “used for prevention or treatment of any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease” at instant claim 13.
Thus, while the instant and copending applications do not recite identical limitations, the subject matter claimed therein is not patentably distinct, as both applications recite an immunogenic composition for a vaccine, said immunogenic composition comprising a polynucleotide-based antigen and a toll-like receptor 7/8 agonist attached via a cleavable linker for the treatment of diseases such as cancer.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 4-6, 8-9, and 13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5-9, 14, and 16 of copending Application No. 18/040,323 (reference application; corresponds to US 2023/0277525 A1). Although the claims at issue are not identical, they are not patentably distinct from each other, as set forth below.
Copending claim 1 recites “a toll-like receptor 7/8 agonist-functional drug complex, in which the functional drug and the active site of the toll-like receptor 7 or 8 agonist are connected via a cleavable linker,” said cleavable linker comprising “any one or more bonds selected from the group consisting of carbamate, disulfide, hydrazine, ester, peptide, azide, β-glucuronide bonds, and a combination thereof” (copending claim 5) as well as ethylene oxide or ethylene glycol (copending claim 6), and being “cleaved at the chemical bond of a binding site due to any one or more factors selected from the group consisting of an enzyme, pH, redox potential, a temperature, ultrasonic wave, magnetic force, and a light source” (copending claim 3). The generically-recited toll-like receptor 7/8 agonist is limited to specific species at copending claim 7, all of which read on the generically-recited toll-like receptor agonist of instant claims 8 and 9.
The functional drug of the copending application is limited to “any one or more selected from the group consisting of an antibody, an antibody fragment, a single-stranded antibody, an anticancer agent, an antigen, a cytokine, a protein, a peptide, an amino acid, an oligonucleotide, an enzyme, a lipid, a low-molecular compound, a glycoprotein, and a targeting ligand” at copending claim 8 or to “any one or more selected from the group consisting of an antibody, a protein-based drug, a sensitizer, and an anticancer agent” at copending claim 9. As set forth above, the recitation of an antigenic polynucleotide reads on the instantly claimed “mRNA antigen” of instant claim 1. Furthermore, given that the mRNA antigen of the instant application must be translated into a protein product in order to achieve therapeutic effect, it is further considered that the recitation of a protein-based drug also reads on the instantly claimed antigen expressed from mRNA.
Finally, copending claim 14 recites “a method of preventing or treating cancer, comprising: administering the pharmaceutical composition comprising the complex of claim 1 as an active ingredient to a subject,” wherein “the pharmaceutical composition inhibits cancer proliferation, metastasis, recurrence, or resistance to an anticancer therapy” (copending claim 16), which reads on treatment of cancer under broadest reasonable interpretation.
In comparison, instant claim 1 recites “an immunogenic composition for an mRNA vaccine,” said composition comprising an antigen encoded by mRNA and a kinetically controllable immune modulator in a complex bound to a cleavable linker, said cleavable linker comprising “any one or more bonds selected from the group consisting of disulfide, carbamate, hydrazine, ester, peptide, azide, amide, hydrazone, thioether, phosphodiester, thioketal bonds, and a combination thereof,” (as recited at instant claim 4) and “ethylene oxide or ethylene glycol at one or both ends thereof” (as recited at instant claim 5). The kinetically controllable immune modulator recited at instant claim 1 is further limited to a toll-like receptor agonist at instant claim 8, specifically a toll-like receptor 7 or 8 agonist at instant claim 9. The cleavable linker of the instant application is recited to be cleaved “due to any one or more factors selected from the group consisting of an enzyme, pH, redox potential, a temperature, ultrasonic wave, magnetic force, and a light source” at instant claim 6. Finally, the instantly claimed immunogenic composition is recited to be “used for prevention or treatment of any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease” at instant claim 13.
While the copending application does not explicitly recite that the pharmaceutical composition claimed therein is a vaccine composition, under broadest reasonable interpretation, a pharmaceutical composition reads on a vaccine composition. Furthermore, the subject matter claimed therein is not patentably distinct, as both applications recite a pharmaceutical composition, said composition comprising a polynucleotide-based antigen and a toll-like receptor 7/8 agonist attached via a cleavable linker for the treatment of diseases such as cancer.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3, and 4-13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 and 14-17 of copending Application No. 18/040,328 (corresponds to US 2023/0355750 A1) in view of US 2019/0351040 A1 (hereinafter Valiante; of record) and Abraham et al., 2017 (hereinafter Abraham).
Copending claim 14 is drawn to a kinetically acting adjuvant ensemble composition comprising a first and second adjuvant, wherein the second adjuvant “is a complex in which a cleavable linker binds to its active site” (copending claim 1), said composition being used for “prevention or treatment of any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease” (copending claim 14) as well as for inhibiting “cancer growth, metastasis, recurrence, or resistance to anticancer therapy” (copending claim 17), which reads on treatment of cancer under broadest reasonable interpretation. The claimed adjuvant ensemble composition “further comprises an antigen” (copending claim 15), wherein the antigen is “one or more selected from the group consisting of a protein, a recombinant protein, a glycoprotein, a gene, a peptide, a polysaccharide, a lipopolysaccharide, a polynucleotide, a cell, a cell lysate, a bacterium, and a virus” (copending claim 16). As set forth above, the recitation of an antigenic polynucleotide reads on the instantly claimed “mRNA antigen” of instant claim 1. Additionally, while the copending application does not explicitly recite that the composition claimed therein is a vaccine composition, under broadest reasonable interpretation, a composition for preventing diseases reads on a vaccine composition, as instantly claimed.
Regarding the cleavable linker of the copending application set forth above, the cleavable linker is recited to comprise “any one or more bonds selected from the group consisting of disulfide, carbamate, hydrazine, ester, peptide, azide, amide, hydrazone, thioether, phosphodiester, thioketal, and a combination thereof” at copending claim 3. Furthermore, the cleavable linker of the copending application “is bound to the active site of the second adjuvant to maintain an inactive state, and then the cleavable linker blocking the active site is cleaved within 2 to 12 hours,” thereby temporally delaying the activity of the immune activating material (copending claim 2). The cleavable linker of the copending application “further comprises ethylene oxide or ethylene glycol at one or both ends thereof” (copending claim 4), “is cleaved at the chemical bond of a binding site due to any one or more factors selected from the group consisting of an enzyme, pH, redox potential, a temperature, ultrasonic wave, magnetic force, and a light source” (copending claim 5), and is bound to “cholesterol, a lipid, a protein, an amino acid, a peptide [or] an oligonucleotide” at an end (copending claim 6).
The adjuvant ensemble composition of the copending application is further recited to be “loaded in any one or more drug delivery systems selected from the group consisting of a nanoliposome, a nanoemulsion, a nanomicelle, a hydrogen, a scaffold, a solid nanoparticle and a polymeric nanoparticle” at copending claims 7 and 8. Additionally, the adjuvant ensemble composition and drug delivery system of the copending application “further comprises a ligand that is able to react with a receptor present on the surface of immune cells or in an endosome or cytosol” (copending claim 9) or “any one or more immune activating material selected from the group consisting of a toll-like receptor agonist, saponin, an antiviral peptide, an inflammasome inducer, a NOD ligand, a cytosolic DNA sensor (CDS ligand), a stimulator of interferon genes (STING) ligand, an outer wall component of a pathogen, alum, a lipid, a combination thereof, and a derivative thereof” (copending claims 10-12).
In comparison, instant claim 1 recites “an immunogenic composition for an mRNA vaccine,” said composition comprising an antigen encoded by mRNA and a kinetically controllable immune modulator in a complex bound to a cleavable linker, said cleavable linker comprising “any one or more bonds selected from the group consisting of disulfide, carbamate, hydrazine, ester, peptide, azide, amide, hydrazone, thioether, phosphodiester, thioketal bonds, and a combination thereof,” (as recited at instant claim 4) and additionally comprising cholesterol, a lipid, a protein, an amino acid, a peptide, or an oligonucleotide bound to an end of said cleavable linker (as recited at instant claim 7). Cleavage of this linker occurs within 2 to 12 hours after translation of the mRNA antigen has begun, thereby temporally delaying the activity of the claimed immune modulator (as recited at instant claim 3). The kinetically controllable immune modulator recited at instant claim 1 is further limited to a toll-like receptor agonist at instant claim 8, specifically a toll-like receptor 7 or 8 agonist at instant claim 9. The cleavable linker of the instant application is recited to be cleaved “due to any one or more factors selected from the group consisting of an enzyme, pH, redox potential, a temperature, ultrasonic wave, magnetic force, and a light source” at instant claim 6. The instantly claimed immunogenic composition is “loaded into any one or more drug delivery systems selected from the group consisting of a nanoliposome, a nanoemulsion, a nanomicelle, a hydrogel, a scaffold, a solid nanoparticle, and a polymeric nanoparticle” as recited at instant claim 10. Furthermore, the claimed delivery system is recited to deliver the mRNA antigen to the cytosol, after which the kinetically controllable immune modulator interacts with a receptor on a cell surface, or in an endosome or lysosome” (instant claim 11). Instant claim 12 further recites that the delivery system “further comprises any one or more immune modulators selected from the group consisting of a toll-like receptor agonist, saponin, an antiviral peptide, an inflammasome inducer, a NOD ligand, a cytosolic DNA sensor (CDS ligand), a stimulator of interferon genes (STING) ligand, an outer wall component of a pathogen, alum, a lipid, a combination thereof, and a derivative thereof.” Finally, the instantly claimed immunogenic composition is recited to be “used for prevention or treatment of any one or more diseases selected from the group consisting of an infectious disease, cancer, metabolic syndrome, an autoimmune disease, and a rare disease” at instant claim 13.
The claims of the copending application set forth above read on the claims of the instant application set forth above, with the exception of the limitations of instant claim 3 regarding cleavage of the cleavable linker within 2 to 12 hours after translation of the mRNA antigen has begun as well as the limitation of instant claim 11 regarding delivery of the mRNA antigen to the cytosol. However, this deficiency is cured by Valiante and Abraham. As set forth above, Valiante discloses an RNA cancer vaccine comprising an mRNA open reading frame encoding at least one cancer antigenic polypeptide or an immunogenic fragment thereof, said antigenic polypeptide or immunogenic fragment thereof being translated by co-opting natural cellular machinery, as well as a polypeptide that enhances the immune response, such as a constitutively active human STING polypeptide (paragraphs [0005]-[0007], [0034], and [0037]). Valiante specifically discloses that mRNA vaccines are superior to other vaccine technology, as they are better designed to produce the appropriate antigenic protein conformation upon translation by co-opting natural cellular machinery (paragraph [0006]) within the cytoplasm (or cytosol) of cells (Abraham: page 162, column 1, paragraph 1).
Given that copending application ‘328 discloses an adjuvant ensemble composition for the prevention of diseases such as cancer, said adjuvant ensemble composition comprising an immune modulator linked to a cleavable linker and a polynucleotide antigen, wherein the immune modulator is cleaved within 2 to 12 hours, that the instant application discloses an immunogenic mRNA vaccine composition for the prevention of diseases such as cancer, said adjuvant ensemble composition comprising an immune modulator linked to a cleavable linker and a polynucleotide antigen, wherein the immune modulator is cleaved within 2 to 12 hours, and further that Valiante discloses that mRNA vaccines are superior to other vaccine technology, as they are better designed to produce the appropriate antigenic protein conformation upon translation by co-opting natural cellular machinery within the cytoplasm (or cytosol) of cells (as taught by Abraham), it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to specifically utilize an mRNA-based antigen as the claimed polynucleotide antigen to predictably translate said mRNA-based antigen within the cytosol of cells and release the immune modulator linked in a complex by a cleavable linker. One would have been motivated to make such a modification in order to receive the expected benefit of producing an antigen with the appropriate antigenic protein conformation within the cytosol of cells followed by release of an immune modulator tethered by a cleavable linker.
Conclusion
No claims are allowed.
Claims 1-3, 6-7, and 11-12 are objected to.
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/SARAH E ALLEN/ Examiner, Art Unit 1637
/J. E. ANGELL/ Primary Examiner, Art Unit 1637