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 .
Status of Claims
The preliminary amendment filed on 02/06/2025 amended claims 1, 6, 15, 16, 22-24, 168, and 172, and cancelled claims 8, 9, 11-13, 20-21, 25-167, 169-171, and 173-195. There are no claims withdrawn and no claims added. Claims 1-7, 10, 14-19, 22-24, 168, and 172 are pending and will be examined on the merits.
Information Disclosure Statement
The Information Disclosure Statement filed on 11/27/2024 has been considered. Signed copies are enclosed.
Specification
The disclosure is objected to because of the following informalities: the contents of Table 1 are misaligned with respect to the RNA SEQ ID NOs in column 2 and the Amino Acid SEQ ID NOs in column 3. During the course of examination, Examiner found that SEQ ID NOs 26-31 do not encode SEQ ID NO: 180, as disclosed in Table 1 under TLR5 Agonist 5, but encode SEQ ID NO: 179. Examiner found that SEQ ID NO: 180 is encoded by SEQ ID NOs 32-37, when Table 1 recites that those SEQ ID NOs should encode SEQ ID NO 181. Examiner requests that Applicant check Table 1 for accuracy while being mindful of not introducing new matter.
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.
Claim 24 is 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 24 recites “wherein the RNA adjuvant is in complex with the lipid carrier”. 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 “in complex with” in claim 24 is used by the claim to mean “encapsulated inside,” while the accepted meaning is “in a complex with”, or two things that are adjacent to or interacting with each other. The term is indefinite because the specification does not clearly redefine the term (see below).
Applicant does not provide an explicit definition for “in complex” as recited in claim 24, but paragraph [0078] of the instant specification states “[e]xemplary configurations of carrier-RNA complexes are provided in FIGS. 2A-2D.” Figures 2A-2D illustrate RNAs inside of nanoparticles, and paragraphs [0148]-[0150] recite that Figure 2A-2D show the RNA adjuvants are encapsulated within lipid carriers. Therefore, Examiner is determining “encapsulated” and “in complex” as synonymous, absent evidence to the contrary.
Claim Objections
Claim 24 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 23. As recited above, “encapsulated” and “in complex with” appear to be the same term in the instant specification. Therefore, claims 23 and 24 recite the same relationship between the RNA adjuvant and the lipid carrier. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-3, 14-19, 22-24, 168, and 172 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by WO 2022/051629 A1, De Boer et al., published 03/10/2022.
The instant claims are drawn to a composition comprising an RNA adjuvant encoding a synthetic protein comprising at least a functional fragment of a TLR5 agonist and one or more delivery vehicle formulated for various forms of administration, wherein after administration of the composition in the presence of an antigen, an initial innate immune response is induced.
De Boer et al. teach compositions of circular polyribonucleotides to induce an immune response in a subject upon administration (abstract, whole document, page 1, lines 25-27). These polyribonucleotides, or RNAs, comprise an antigen, or immunogen, and an adjuvant (see page 3, lines 26-29). The composition also includes a diluent, which is a vehicle for a composition, as recited on page 122, lines 29-31, and may be formulated to be administered nasally, orally, topically, and transdermally, among others. Therefore, the compositions of De Boer et al. meet the limitations of instant claims 1 and 14, which recites the vehicle may be a diluent. Additionally, De Boer et al. recite, on page 4, that the adjuvant encoded by the RNA may be a bacterial component, and that the bacterial component may be flagellin, therefore meeting the limitations of instant claims 1-3. De Boer et al. also disclose that more than one immunogen may be on the RNA molecule and that these antigens may target pathogens like virus, bacteria, fungi, and parasites, on page 2, teaching instant claims 15-17. De Boer et al. teach, in embodiment 125 on page 20, that the composition can comprise two RNA molecules, one encoding an antigen and one encoding an adjuvant, thereby teaching instant claim 18. Page 3 of De Boer et al. recites that the polypeptides of the RNA molecule contain a single IRES, indicating the adjuvant and immunogens are operably linked, anticipating instant claim 19.
The instant specification recites, in paragraph [0118], “the lipid carrier is a cationic lipid nanoparticle, an ionizable lipid nanoparticle, a polyethylene glycol (PEG) lipid carrier, a polymeric lipid nanoparticle, a polymer-conjugated lipid carrier, a synthetic vesicle, a liposome, an exosome, an endosome, a lipoplex, a lipidoid, a derivative, variant, or any combination thereof.” De Boer et al. teach, in embodiment [250] on page 29, a lipid nanoparticle comprising the compositions of RNA molecules encoding antigens and an adjuvant. Page 137, line 4-5, discloses that the RNA may be encapsulated within the nanoparticle, or associated with the nanoparticle, thereby teaching instant claims 23 and 24. Finally, claim 59 of De Boer et al. discloses a pharmaceutical composition comprising the circular RNA and a pharmaceutically acceptable excipient, as recited in instant claim 168, and pages 12-13 of De Boer et al. disclose methods of inducing an immune response comprising administering a compound comprising an RNA encoding an immunogen and an adjuvant, and a method of maintaining or enhancing an immune response comprising administering a compound comprising an RNA encoding an immunogen and an adjuvant, therefore teaching instant claim 172. Therefore, De Boer et al. anticipate instant claims 1-3, 14-19, 22-24, 168, and 172.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-7, 10, 14-19, 22-24, 168, and 172 is/are rejected under 35 U.S.C. 103 as being unpatentable over De Boer et al. in view of Gudkov et al., US 10,336,793 B2 (07/02/2019).
The instant claims are drawn to a composition comprising an RNA adjuvant encoding a synthetic protein comprising at least a functional fragment of a TLR5 agonist and one or more delivery vehicle formulated for various forms of administration, wherein after administration of the composition in the presence of an antigen, an initial innate immune response is induced.
De Boer et al. teach compositions of circular polyribonucleotides to induce an immune response in a subject upon administration (abstract, whole document, page 1, lines 25-27). These polyribonucleotides, or RNAs, comprise an antigen, or immunogen, and an adjuvant (see page 3, lines 26-29). The composition also includes a diluent, which is a vehicle for a composition, as recited on page 122, lines 29-31, and may be formulated to be administered nasally, orally, topically, and transdermally, among others. Therefore, the compositions of De Boer et al. meet the limitations of instant claims 1 and 14, which recites the vehicle may be a diluent.
Additionally, De Boer et al. recite, on page 4, that the adjuvant encoded by the RNA may be a bacterial component, and that the bacterial component may be flagellin, therefore meeting the limitations of instant claims 1-3. De Boer et al. also disclose that more than one immunogen may be on the RNA molecule and that these antigens may target pathogens like virus, bacteria, fungi, and parasites, on page 2, teaching instant claims 15-17. De Boer et al. teach, in embodiment 125 on page 20, that the composition can comprise two RNA molecules, one encoding an antigen and one encoding an adjuvant, thereby teaching instant claim 18. Page 3 of De Boer et al. recites that the polypeptides of the RNA molecule contain a single IRES, indicating the adjuvant and immunogens are operably linked, anticipating instant claim 19.
The instant specification recites, in paragraph [0118], “the lipid carrier is a cationic lipid nanoparticle, an ionizable lipid nanoparticle, a polyethylene glycol (PEG) lipid carrier, a polymeric lipid nanoparticle, a polymer-conjugated lipid carrier, a synthetic vesicle, a liposome, an exosome, an endosome, a lipoplex, a lipidoid, a derivative, variant, or any combination thereof.” De Boer et al. teach, in embodiment [250] on page 29, a lipid nanoparticle comprising the compositions of RNA molecules encoding antigens and an adjuvant. Page 137, line 4-5, discloses that the RNA may be encapsulated within the nanoparticle, or associated with the nanoparticle, thereby teaching instant claims 23 and 24. Finally, claim 59 of De Boer et al. discloses a pharmaceutical composition comprising the circular RNA and a pharmaceutically acceptable excipient, as recited in instant claim 168, and pages 12-13 of De Boer et al. disclose methods of inducing an immune response comprising administering a compound comprising an RNA encoding an immunogen and an adjuvant, and a method of maintaining or enhancing an immune response comprising administering a compound comprising an RNA encoding an immunogen and an adjuvant, therefore teaching instant claim 172.
De Boer et al. do not teach the specific flagellin protein limitations of instant claims 4-7 and 10, wherein the TLR5 agonist is a truncated or secreted form of flagellin, a D0 and D1 region, a D0, D1, and D2 region, or a D0, D1, D2, and D3 region of flagellin, or is 85% identical to any one of SEQ ID NO: 2-37.
Gudkov et al. teach flagellin-derived constructs and methods for use in vaccination, including flagellin based adjuvants. Gudkov et al. teach that the adjuvant may comprise domains D0, D1, D2, and D3, in column 6, paragraph 5, and in column 7, paragraph 7 (lines 49-54). Instant claims 5, 6, and 7 recite that the adjuvant comprises either a D0 and D1, a Do, D1, and D2, or a D0, D1, D2, and D3 region of the flagellin – therefore, Gudkov et al. teaches instant claims 5-7. Additionally, Gudkov et al. teach a truncated flagellin protein or protein domain in column 7, line 42 and 63-64, teaching instant claim 4, which recite the adjuvant is a truncated form of a flagellin protein. Finally, Gudkov et al. teach Gudkov SEQ ID NO: 2, 42, and 150. Gudkov SEQ ID NO: 2 has 100% identity to the protein encoded by instant SEQ ID NO: 26-31, Gudkov SEQ ID NO: 42 has 100% identity to the protein encoded by instant SEQ ID NO: 20-25, and Gudkov SEQ ID NO: 150 has 100% identity to the protein encoded by instant SEQ ID NO: 14-19 (see attached alignments). As is considered well understood, routine, and conventional in the art, RNA sequences encode protein sequences, and multiple RNA sequences may encode the same proteins, depending on which codons are used (Alberts et al., Molecular Biology of the Cell. 4th edition, 2002). One of ordinary skill in the art would know what codons correspond to what amino acid and would be easily able to derive different RNA sequences that encode the same protein. The instant specification does not provide any reason the specific RNA sequences that encode the protein of Gudkov et al. are advantageous over any other RNA sequence. Therefore, the RNA sequences encoded by SEQ ID NOs: 14-31 are considered obvious variants of an RNA encoding Gudkov et al. SEQ ID NO:2, 42, and 150. Thus, the proteins disclosed in Gudkov et al. teach instant claim 10.
It would be obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to encode the adjuvant presented by Gudkov et al. in the form of RNA for administration via the method and compositions of De Boer et al. One would be motivated to do so as Gudkov et al. disclose TLR5 agonist molecules that function as adjuvants in vaccines against various antigens (see Examples 9 and 10) that have the advantage of removal of epitopes that generate neutralizing anti-flagellin antibodies, allowing for surprisingly effective adjuvant properties (see column 7, lines 28-34). One would have reasonable expectation of success, as DeBoer et al. already disclose RNA encoding flagellin as an adjuvant in their compositions; the flagellin of Gudkov et al. simply provides a more robust adjuvant response with fewer neutralizing antibodies generated. Therefore, it would be obvious to one of ordinary skill in the art to substitute an RNA encoding the adjuvant of Gudkov et al. into the RNA compositions of De Boer et al. in order to obtain better adjuvant properties. Thus, claims 1-7, 10, 14-19, 22-24, 168, and 172 are obvious over De Boer et al. in view of Gudkov et al.
Conclusion
No claims are allowed.
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/AMELIA STEPHENS/Examiner, Art Unit 1645
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683
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