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 of species E in the reply filed on November 17, 2025 is acknowledged. Applicant submits that there would be no undue burden to search additional species.
Upon review of the restriction mailed September 17, 2025, it is noted that the instant species requirement is similar to the species restriction mailed July 14, 2022 in the parent case, 17/698,300, now US 11,613,561, where applicant correctly elected each alphabetized species grouping with traverse. In the last paragraph on page 2 of the October 20, 2022 Office Action in the parent case, applicant’s traversal of the species requirement was found persuasive and the species election was withdrawn. For consistency, the instant species requirement between species A-E, is also withdrawn. The examiner apologizes for any inconsistency. However, the instant species requirement of (F), requiring an election of (1) a viral pathogen or (2) an antigenic protein to treat cancer, remain patentably distinct for the reasons set forth in the September 17, 2025 restriction: The heterologous proteins recited in F(1) and F(2) are structurally and functionally distinct. F(1) antigens related to viral infection and F(2) antigens related to cancer diseases, characterized by uncontrolled cell growth do not share common structures or functions. Due to the unique requirements of F(1) and F(2), a separate search is required for each. In addition, these species are not obvious variants of each other based on the current record. Since no election was made for species (F), the examiner called applicant’s representative to request an election of F(1) or F(2), but an automated message stating that no messages could be saved, was received. In the interest of compact prosecution, examination of the viral pathogen of F(1), encompassing claims 14-20 and 26 (SEQ ID NOs: 40, 32, ad 33) are under consideration. Claims 21-23 are also reasonably encompassed within species group F(1).
In conclusion, claims 1-27 are pending; claims 24 and 25 are withdrawn due to non-elected subject matter; and claims 1-23, 26, and 27 are under consideration.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 8/18/2025 has been considered by the examiner.
Specification
The use of the term GenBank in paragraphs [0093 and 0225] and Table 1; and BLAST in paragraph [0250] in the instant published disclosure, USPgPub 2023/0295241, each if which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Applicant' s cooperation is requested in correcting any errors of which applicant may become aware in the specification. Applicant is required to properly annotate all trade names and/or marks present in the instant specification, if any additional trade names and/or marks are discovered.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-23, 26, and 27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
Claim 1 is drawn to a method of preventing or inhibiting or treating a disease or condition by administering a synthetic alphavirus-derived replicon nucleic acid molecule comprising:
a first nucleic acid encoding alphavirus nonstructural proteins nsP1, nsP2, nsP3, and nsP4, and comprising at least one silent mutation introduced at any position within a region from nt 503 to nt 658, nt 658 to nt 1620, nt 1620 to nt 2560, nt 2560 to nt 3954, nt 3954 to nt 4120, nt 6381 to nt 7083, and nt 6966 to nt 7526 in the sequence of the alphavirus genome as set forth in SEQ ID NO: 17; and
a second nucleic acid comprising a modified subgenomic open reading frame (ORF) and administering the alphavirus-derived replicon to the subject.
However, there is no adequate written description for the genus of silent mutations encompassed by the instant claims. Instant working examples 3-5 and 7-9 demonstrate subgenomic ORF expression when a series of silent mutations is introduced between:
nt 6381-7083, construct C01;
nt 503-658, construct C02;
nt 3694-3954, construct C03;
nt 3954-4120, construct C04;
nt 1620-2560, construct C05;
nt 658-1620, construct C06; and
nt 2560-3954, construct C07
in a genome set forth in SEQ ID NO: 17.
However, there is no working example demonstrating subgenomic ORF expression when a series of silent mutations is introduced between 6966-7526, as asserted in line 7 of claim 1.
Instant paragraph [0215] of the instant published disclosure USPgPub 2023/0295241, states:
The successful editing of the nsP gene region of alphavirus replicons to reduce homology to wild-type virus, and incorporate novel biological function into the early phase of self-amplification of such artificial replicons that precedes translation of subgenomically encoded transgenes is reported herein. This is accomplished by identifying key stretches of nucleotides in the nsP region that can be safely edited without disrupting conserved structural elements, and appending additional sequences to the natural terminus of the nsP. This disclosure shows how such modifications can be performed without impairing the self-amplifying functionality of the replicon. Therefore, this disclosure provides a new method to generate safer replicons equipped with additional functionality to modify cellular and immunological parameters of the host cell.
However, the skilled artisan would unable to predict which residues within the between 6966-7526 region recited could endure the inclusion of silent mutations without functional detriment to the alphavirus replicon and generate safer constructs, as asserted by paragraph [0215] and the instant claims. “…[A] vague functional description and an invitation for further research” to determine which single and combination of residues within the instant regions claimed does not satisfy written disclosure, see Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co., 598 F.3d 1336, 1341 (Fed. Cir. 2010) (en banc).
The applicable standard for the written description requirement can be found in MPEP § 2163; University of California v. Eli Lilly, 43 USPQ2d 1398 at 1407; PTO Written Description Guidelines; Enzo Biochem Inc. v. Gen-Probe Inc., 63 USPQ2d 1609; Vas- Cath Inc. v. Mahurkar, 19 USPQ2d 1111; and University of Rochester v. G.D. Searle & Co., 69 USPQ2d 1886 (CAFC 2004). 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 complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In this case, the only factor present in the specification are the C01-C07 constructs. There is no disclosure of sufficient characteristics of the claimed genus of alphavirus replicon variants comprising one or more silent mutations within a region from nt 6966 to nt 7526 in the sequence of the alphavirus genome as set forth in SEQ ID NO: 17. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
The court clearly states in Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not clearly allow persons of ordinary skill in the art to recognize that the inventors invented what is claimed. As discussed above, the skilled artisan cannot envision the distinguishing, identifying characteristics of the encompassed genus of silent mutations between nt 6966-7526 of the alphavirus replicon claimed. The full breadth of the claims does not meet the written description provision of 35 U.S.C. 112(a). Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Claims 1-23, 26, and 27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a synthetic alphavirus-derived replicon comprising subgenomic ORF expression when a series of silent mutations is introduced between:
nt 6381-7083, construct C01;
nt 503-658, construct C02;
nt 3694-3954, construct C03;
nt 3954-4120, construct C04;
nt 1620-2560, construct C05;
nt 658-1620, construct C06; and
nt 2560-3954, construct C07
in a genome set forth in SEQ ID NO: 17,
does not reasonably provide enablement for introducing silent mutations at nt 6966 to nt 7526 in the sequence of the alphavirus genome as set forth in SEQ ID NO: 17 for use in the instant method. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
Claim 1 is drawn to a method of preventing or inhibiting or treating a disease or condition by administering a synthetic alphavirus-derived replicon nucleic acid molecule comprising:
a first nucleic acid encoding alphavirus nonstructural proteins nsP1, nsP2, nsP3, and nsP4, and comprising at least one silent mutation introduced at any position within a region from nt 503 to nt 658, nt 658 to nt 1620, nt 1620 to nt 2560, nt 2560 to nt 3954, nt 3954 to nt 4120, nt 6381 to nt 7083, and nt 6966 to nt 7526 in the sequence of the alphavirus genome as set forth in SEQ ID NO: 17; and
a second nucleic acid comprising a modified subgenomic open reading frame (ORF) and administering the alphavirus-derived replicon to the subject.
There is no adequate written description for the genus of silent mutations encompassed by the instant claims. The instant working examples demonstrate subgenomic ORF expression when a series of silent mutations is introduced between:
nt 6381-7083, construct C01;
nt 503-658, construct C02;
nt 3694-3954, construct C03;
nt 3954-4120, construct C04;
nt 1620-2560, construct C05;
nt 658-1620, construct C06; and
nt 2560-3954, construct C07
in a genome set forth in SEQ ID NO: 17.
However, there is no working example demonstrating subgenomic ORF expression when a series of silent mutations is introduced between 6966-7526 in the sequence of the alphavirus genome as set forth in SEQ ID NO: 17, as asserted in line 7 of claim 1.
Instant paragraph [0215] of the instant published disclosure USPgPub 2023/0295241, states:
The successful editing of the nsP gene region of alphavirus replicons to reduce homology to wild-type virus, and incorporate novel biological function into the early phase of self-amplification of such artificial replicons that precedes translation of subgenomically encoded transgenes is reported herein. This is accomplished by identifying key stretches of nucleotides in the nsP region that can be safely edited without disrupting conserved structural elements, and appending additional sequences to the natural terminus of the nsP. This disclosure shows how such modifications can be performed without impairing the self-amplifying functionality of the replicon. Therefore, this disclosure provides a new method to generate safer replicons equipped with additional functionality to modify cellular and immunological parameters of the host cell.
However, the skilled artisan would unable to predict which residues within the 6966-7526 region recited could endure the inclusion of silent mutations without functional detriment to the alphavirus replicon and generate safer constructs, as asserted by paragraph [0215] and the instant claims, as evidenced by Sharma et al. (Viruses. 2019 Feb 18; 11 (2): 164). In the last paragraph on page 8, Sharma et al. state that nsp4 has not been specifically studied and that analogous studies in Sindbis and Simliki viruses show that nsp4 is an RNA dependent RNA polymerase (RdRp) and may also have an auto proteinase activity. It is unknown which residues within the 6966-7526 region recited could endure the inclusion of silent mutations without functional detriment to the alphavirus replicon. For these reasons, it is determined that an undue quantity of experimentation would be required of the skilled artisan to make the invention commensurate with the scope of the claims.
Claims 1-23, 26, and 27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for inducing an immune response against heterologous proteins expressed from the instant alphavirus replicon, does not reasonably provide enablement for preventing, inhibiting, or treating any symptoms of any disease or condition in a subject. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claims 1 and 23 are drawn to a method of preventing or inhibiting or treating a disease or condition by administering a synthetic alphavirus-derived replicon nucleic acid molecule comprising:
a first nucleic acid encoding alphavirus nonstructural proteins nsP1, nsP2, nsP3, and nsP4, and comprising at least one silent mutation introduced at any position within a region from nt 503 to nt 658, nt 658 to nt 1620, nt 1620 to nt 2560, nt 2560 to nt 3954, nt 3954 to nt 4120, nt 6381 to nt 7083, and nt 6966 to nt 7526 in the sequence of the alphavirus genome as set forth in SEQ ID NO: 17; and
a second nucleic acid comprising a modified subgenomic open reading frame (ORF) and administering the alphavirus-derived replicon to the subject.
However, there is no evidence of preventing or inhibiting or treating any disease or any condition by administering a synthetic alphavirus-derived replicon nucleic acid, as asserted by the claims. The instant working examples 3-5, 7-9, and 12 demonstrate subgenomic ORF expression when a series of silent mutations is introduced between:
nt 6381-7083, construct C01;
nt 503-658, construct C02;
nt 3694-3954, construct C03;
nt 3954-4120, construct C04;
nt 1620-2560, construct C05;
nt 658-1620, construct C06; and/or
nt 2560-3954, construct C07
in a genome set forth in SEQ ID NO: 17.
Working examples 13-17 introduce a c-terminal fusion site and a subgenomic promoter expressing (FMDV) 3C protease and P1 structural polypeptide. However, there is no evidence that this construct would prevent or inhibit or treat any disease or any condition by administration. The state of the art is silent regarding preventing or inhibiting or treating any disease or any condition by administering a synthetic alphavirus-derived replicon nucleic acid or administering a synthetic alphavirus-derived replicon nucleic acid expressing one or more heterologous proteins, as claimed. For these reasons, it is determined that an undue quantity of experimentation would be required to use the invention in its full scope.
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.
Claims 1-10, 13, 14, 20, 22, 23, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Kinney et al. (Journal of General Virology. 1992; 73: 3301-3305, hereinafter, “Kinney-1992”), supra, as evidenced by Kinney et al. (Virology. 1986; 152: 400-413, hereinafter, “Kinney-1986”), supra, further in view of Kinney et al. (Virology. 1989; 170: 19-30, hereinafter, Kinney-89) and Polo (WO 02/099035).
Kinney-1992 teach that the VEEV TRD and VEEV 71-80 viruses differ by only 0.3% in genomic sequence, comprising 34 nucleic acid differences, 15 of which are in the non-structural region with nine of the 15 being silent mutations within amino acid positions within the instantly recited regions from nt 503 to nt 658, nt 658 to nt 1620, nt 2560 to nt 3954, nt 6381 to nt 7083, and nt 6966 to nt 7526 in the sequence of the alphavirus genome as set forth in TRD SEQ ID NO: 17, see the second column on page 3302 and Table 1. The 71-80 VEEV strain possesses a second nucleic acid comprising a modified subgenomic open reading frame (ORF), see the first paragraph on 3301 of Kinney-1992, since the structural proteins of 71-80 possess mutations, see Table 1. The 71-80 VEEV strain of Kinney-1992 also possesses at least 90% identity to instant SEQ ID NOs: 21, 25 (recited in claim 4); SEQ ID NOs: 24, 22, 26 (recited in claim 5); SEQ ID NO: 23 (recited in claim 6); SEQ ID NO: 20 (recited in claim 7); SEQ ID NOs: 25, 26 (recited in claim 8); SEQ ID NOs: 22, 20 (recited in claim 9); and SEQ ID NOs: 21, 25, 24, 26, 23, 20 (recited in claim 10) since the 71-80 strain possesses at least 99.7% identity with TRD of Kinney-1986, i.e., instant SEQ ID NO: 17, see the paragraph bridging pages 3302-3303 of Kinney-1992 as well as the sequence alignments of GenEmbl database accession no: EEVNSPEPA Kinney-1986 with: nt 500-7600 of instant SEQ ID NO: 17 and instant SEQ ID NOs: 20-26 (attached).
Kinney-1992 does not teach an attenuated VEEV.
Kinney-89 compare the genomic sequences between wild-type VEEV strain TRD and vaccine derivative, TC-83. Kinney et al. teach 11 sequence differences between the parent strain and the attenuated virus, one of which was present in the nonstructural polypeptide and resulted in a conservative mutation from serine to threonine at residue 260 of nsp3, see the abstract; “Deduced amino acid sequences of VEE nonstructural polypeptides” on page 22; “Summary of VEE TC-83 mutations” on page 23; and Figure 2.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have used the TC-83 VEEV of Kinney-89 with a reasonable expectation of success because TC-83 virus elicits VEEV-specific neutralizing antibodies in most humans and was used to vaccinate more than two million horses after a VEE epidemic in 1971, see the paragraph bridging pages 19-20, as required by instant claims 1 and 23.
Kinney-89 do not teach expressing a first heterologous protein, recited in instant claims 2, 13, and 14, and second heterologous antigenic protein from at an altered nsp4, as required by instant claims 3, 14, and 20, or a stimulator of interferon genes (STING), recited in claim 22, and is administered to a human or a cloven-hooved animal, recited in instant claim 27.
Polo teaches expressing one or more heterologous sequences from the nsP4 ORF in the paragraph bridging pages 6-7, where the heterologous antigen is derived from a second alphavirus on page 9, lines 22-24 and another heterologous antigen is derived from stimulators of interferon genes (STING) on page 9, lines 17-21. On page 46, lines 19-28, Polo teaches administering the composition to a human, cow, or sheep to generate an immune response in claim 31.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have expressed the one or more heterologous viral antigens and stimulators of interferon genes, as taught by Polo, in the attenuated VEEV of Kinney-89, to induce an immune response against a second virus and enhance the immune response upon expression of STING. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have expressed the one or more heterologous viral antigens and stimulators of interferon genes, as taught by Polo, in the attenuated VEEV of Kinney-89 because the alphavirus of Polo is also VEEV, see claims 8-12, 14, and 15.
Claims 15, 19, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Kinney-1992, as evidenced by Kinney-1986, combined with the teachings of Kinney-89 and Polo, as applied to claims 1-10, 13, 14, 20, 22, 23, and 27 above, and further in view of Puckette et al. (USPgPub 2018/0066235).
See the teachings of Kinney-1992, as evidenced by Kinney-1986, combined with the teachings of Kinney-89 and Polo above.
None of the references teach a first heterologous protein derived from FMDV O1 Manisa P1, as required by instant claims 15 and 26 and a second heterologous protein derived from 3C protease, recited in claim 19.
Puckette et al. teach an expression cassette encoding the P1 polypeptide precursor that is derived from the O1 Manisa isolate 87 and a mutant nucleotide sequence encoding the L127P mutant FMDV Asia Lebanon 89 3C protease, see paragraph [0030] for example.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have expressed the P1 polypeptide precursor that is derived from the O1 Manisa isolate 87 and a mutant nucleotide sequence encoding the L127P mutant FMDV Asia Lebanon 89 3C protease of Puckette et al. in the attenuated VEEV of Kinney-89 and Polo, to induce an immune response against FMDV and differentiate infected from vaccinated animals, see paragraph [0337] of Puckette et al. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have expressed the L127P mutant FMDV Asia Lebanon 89 3C protease of Puckette et al. in the attenuated VEEV of Kinney-89 and Polo because the VEEV alphavirus vector of Kinney-89 and Polo is attenuated, see the paragraph bridging pages 19-20 of Kinney-89 and expresses one or more heterologous antigens, see the paragraph bridging pages 6-7 of Polo.
Allowable Subject Matter
SEQ ID NO: 18 (recited in claim 12); SEQ ID NO: 19 (recited in instant claim 7); SEQ ID NO: 30 (recited in claim 11); SEQ ID NO: 32 (recited in claim 17); SEQ ID NO: 33 (recited in claim 18); SEQ ID NO: 40 (recited in claim 16); and SEQ ID NO: 42 (recited in claim 21) are free of the art.
Conclusion
The prior art made of record and not relied upon and considered pertinent to applicant's disclosure:
Dubensky, Jr. (USPgPub 2003/0170871) teach a VEEV, see claims 7 and 15, that is used to express a variety of heterologous proteins, such as viral antigens and stimulators of interferon genes (STING), see paragraphs [0011, 0059, 0061, and 0062].
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHANON A FOLEY whose telephone number is (571)272-0898. The examiner can normally be reached M-F, generally 5:30 AM-5 PM, flexible.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Allen can be reached at 571-270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Shanon A. Foley/Primary Examiner, Art Unit 1671