LED ACTION
Non-Final Rejection
Notice of Pre-AIA or AIA Status
1. 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
2. Applicant’s election without traverse of Group II claim 87 along with newly added claims 98-115 are encompassed by this election in the reply filed on 06/29/2026 is acknowledged.
Species election:
An RNA molecule: Applicant elected a self-amplifying RNA molecule comprising a nucleotide sequence encoding HCV E1 and HCV E2 polypeptide. Claim 87 and new claims 98-115 encompass the elected species.
A heterologous polypeptide (encoded by RNA sequence): Applicant elected an RNA molecule comprising a nucleotide sequence encoding HCV E1 and HCV E2 polypeptide and a nucleotide sequence encoding a heterologous polypeptide, TP35-NS3, having the amino acid sequence of SEQ ID NO:102.
Applicant elected modified nucleotide of Formula la, wherein U is 0; R1', R2', R3, R4, and R5 are H; each of Y2, and Y3 are 0; Y4 is H; Y5 is 0; and B is a nucleobase.
Applicant indicated that claim 87 and new claims 98-115 encompass the elected species.
Examiners Response to Elected Species:
The Applicant has elected species SEQ ID NO: 102 and Formula la that are recited in the specification but has not specifically claimed in the instant elected claims 87 and newly added 98-115 (Group II).
The instant claims 109-110 are withdrawn from examination because applicants’ elected species SEQ ID NO: 102 (a heterologous polypeptide) is not claimed and recited as one of the species in the Markush grouping of species of a heterologous polypeptide SEQ ID NOs in instant claims 87 and 98-115.
The instant claims 103 is withdrawn from examination because applicants’ elected species, a modified nucleotide of Formula la, is not claimed and recited in claims 87 and 98-115. The instant claim 103 recites Formula I.
Compact prosecution: Although the elected species were not recited in the elected claims 87 and 98-115, the elected species were searched and examined for the purpose of compact prosecution.
The search was extended to Markush group listing of non-elected species only to the extent of SEQ ID NO: 219 of claims 109-110 for compact prosecution.
The search was extended to Markush group listing of non-elected modified nucleoside only to the extent of Formula I of claim 103 for compact prosecution.
Status of Claims
3. Claims 87 and 98-115 are pending as per claim listing amended on 06/29/2026.
4. Claims 1-9, 11, 15, 17-21, 24, 80, and 83 drawn to unelected Group I are cancelled by the applicant as per claim listing amended on 06/29/2026.
5. Claims 87 and 98-115 are under examination.
Priority
6. This application is a continuation of PCT Application No. PCT/CA2022/050946 which
claims the benefit of U.S. Provisional Patent Application No. 63/210,722, filed June 15, 2021, U.S. Provisional Patent Application No. 63/212,877, filed June 21, 2021, U.S. Provisional Patent Application No. 63/323,434, filed March 24, 2022, and U.S. Provisional Patent Application No. 63/345,799, filed May 25, 2022.
Information Disclosure Statement
7. The information disclosure statement (IDS) submitted on 03/28/2024 and 10/02/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
8. 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.
This is a Written Description Rejection.
Claims 107-112 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.
The claims 107-112 are directed to a functional limitation “induction of immune response to HCV” by administering a composition comprising RNA encoding HCV E1 and E2 and a genus of a heterologous polypeptide comprising T-cell epitope present in an HCV protein other than HCV E1 and E2. The claims 109 and 110 recite TP35-NS3 T-cell epitope SEQ ID NO: 219 which is a formula comprising eight variant amino acids and can accommodate 20% variability. There is no reference sequence provided without a variation that would identify the broad genus of heterologous TP35-NS3 T-cell epitope sequence without any variation. The variant SEQ ID NO: 219 would produce thousands of different species because of variability at eight different positions in instant SEQ ID NO: 219 (instant claims 109-110) see below:
i) a TP35-NS3 T-cell epitope polypeptide comprising an amino acid sequence having at least 80% amino acid sequence identity to: KSTKVPX1AYX2X3QGYX4VLVLNPSVAATLGFGX5X6X7SX8 (SEQ ID NO: 134), wherein X, is A or Y; X2 is A or V; X3 is A or S; X4 is K or N; X5 is A or S; Xe is Y or F; X7 is M or L; and X8 is K or R, wherein the TP35-NS3 T-cell epitope polypeptide has a length of from 28 amino acids to 35 amino acids (SEQ ID NO: 219).
As taught in Greenspan et al (Nature Biotechnology. 17; 10:936-937 (1999), defining epitopes is not as easy as it seems (page 937). Epitopes have been defined in terms of the spacial organization of residues that make contact with a ligand and the structural characterization of the molecular interface for the binding of the molecules to define the epitope boundaries (page 937 middle of page). The epitope defined in this manner will likely include residues that contact the ligand but are energetically neutral or even destabilizing to binding. “In addition, a priori it will not include any residue that makes no contact with a ligand but whose substitution may profoundly affect ligand recognition through influence on the stability of the free form of the macromolecule, or participation in long-range allosteric effects”. “Even when the residues making contacts with ligands are known with certainty, say from the crystal structure of the complex, the question remains with regard to the energetic involvement of each residue (page 936 right column, first paragraph). Therefore, “amino acids should be recognized to have multiple ways of contributing to a noncovalent interaction” (page 937, middle of page). The specification teaches epitope mapping of the F5 and C1 using competition assay (page 69, lines 25-26 and figure 2), however, the results are not clear that the antibodies do in fact bind the same epitope. As evidenced by Greenspan et al a number of factors not primarily related to the contours of the contacts of the molecules contribute to the free energy change, sometimes profoundly.
It has been well known in the art that minor structural differences even among structurally related compounds or compositions can result in substantially different biological or pharmacological activities. It is known in the art that the substitution of amino acids within the protein sequence may cause the loss of function of the protein.
Vas-Cath Inc. V. Mahurkar, 19USPQ2d 1111, clearly states "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 [he or she] invented what is claimed." (See Vas-Cath at page 1116). Conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers V. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
The instant specification does not have written description support by reduction to practice of example(s) showing that that the applicant possesses the claimed “genus of a heterologous polypeptide comprising T-cell epitope present in an HCV protein other than HCV E1 and E2” that is required to be satisfied through sufficient description of a representative number of species by actual reduction to practice showing similar induction of immune response against HCV.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021). See MPEP 2163 “Written Description Guidelines”.
The Federal Circuit has clarified the application of the written description requirement to inventions in the field of biotechnology. See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568,43 USPQ2d l398, 1406 (Fed. Cir. 1997). The Court stated that a written description of an invention requires a precise definition, one that defines the structural features of the chemical genus that distinguishes it from other chemical structures. A definition by function does not suffice to define the genus because it is only an indication of what the genus does, rather than what it is. Further, the Court held that to adequately describe a claimed genus, an applicant must describe a representative number of species of the claimed genus, and that one of skill in the art should be able to “visualize or recognize the identity of the members of the genus.”
Amgen Inc. vs Sanofi (2017-1480, Fed Cir, 2017) states that "an adequate written description must contain enough information about the actual makeup of the claim products - a precise definition such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other material," which may be present in "function "terminology "when the art has established a correlation between structure and function" (page 17,1st paragraph). Therefore, one of the ordinary skills in the art has interpreted that the applicant and inventors at the time the application was filed, had no possession of the full scope of claimed invention as claimed in claims 107-112. Because there is no variant species of a heterologous polypeptide comprising T-cell epitope present in an HCV protein other than HCV E1 and E2 or there are insufficient representative species and/or identifying characteristics to place applicant in possession of the generic scope of the claimed invention with a demonstrated reduction to practice with entire scope of a claimed genus commensurate to a claimed full scope of the functional limitation induction of immune response against HCV. The specification do not 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.
Claim Interpretation
9. The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 87: The instant claim 87 is interpreted to be directed to a method of inducing an immune response to hepatitis C virus (HCV) in an individual, the method comprising administering to the individual an effective amount of a composition of comprising an RNA or mRNA molecule vaccine expressing HCV full length proteins E1 and E2 and comprising an adjuvant, the composition delivered as a nano-emulsion or VLP that packages the mRNA.
Claims 103 (dependent on claim 87): The instant claim 103 is interpreted to be directed to the method with added limitation, wherein at least one of the one or more RNA molecules comprises a modified nucleotide (e.g. Formula I, Formula Ia).
Claims 107-112: The instant claims 107-112 (dependent on claim 87) are interpreted to be directed to a method of inducing an immune response to hepatitis C virus (HCV) in an individual, inter alia, comprising two or more heterologous polypeptides comprising a T-cell epitope present in an HCV protein other than HCV E1 and E2 polypeptides to induce broader T cell immune response.
Claim Rejections - 35 USC § 103
10. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
11. Claims 87, 102, 104-108, 113, and 114-115 are rejected under 35 U.S.C. 103 as being unpatentable over Houghton et al 2019 (WO2019173925A1 published 09/19/2019 with an earlier priority of 03/16/2018 to US 62/644,140 provisional application), and further in view of Sharifnia et al 2019 (Iranian biomedical journal, 23(1), 57), Pardi et al 2018 (Nature reviews Drug discovery, 17(4), 261-279) and Ho et al 2021 (Advanced healthcare materials, 10(8), 2001812 published 01/18/2021).
Claims 87, 102, 104-108, 113, and 114-115. Houghton et al 2019 is in the art and is directed to an immunogenic composition and a method comprising administering the immunogenic composition inter alia comprising one or more nucleic acids (an RNA) comprising nucleotide sequences encoding the T-cell epitope polypeptide(s), the HCV E1/E2 heterodimeric polypeptide to an individual for inducing an immune response in an individual against a hepatitis C virus (HCV) (See, claims 25-27, abstract, para [0038], [00198]). A method for inducing an immune response to HCV in an individual comprises administering to the individual an effective amount of a nucleic acid(s) comprising nucleotide sequences encoding 1) an HCV E1/E2 heterodimer and a T-cell epitope polypeptide; 2) an HCV E2 polypeptide and a T-cell epitope polypeptide; or 3) an HCV El polypeptide and a T-cell epitope polypeptide. Nucleic acid is an RNA comprising nucleotide sequences encoding a polypeptide of the present disclosure (e g., an HCV E1/E2 heterodimer; an HCV El polypeptide; an HCV E2 polypeptide; a T-cell epitope polypeptide. An RNA (e.g., a single mRNA molecule; or 2 mRNA molecules; or 3 mRNA molecules) comprising nucleotide sequences encoding a polypeptide of the present disclosure is formulated with a liposome (reads on a lipid), an RNA (e.g., a single mRNA molecule; or 2 mRNA molecules) comprising nucleotide sequences encoding a polypeptide of the present disclosure is complexed with protamine (see, para [00452]). The disclosure further provides a nucleic acid comprising a nucleotide sequence encoding a fusion polypeptide of the present disclosure (e.g., a T-cell epitope polypeptide comprising 2, 3, 4, or 5 of the aforementioned T-cell epitope polypeptides in a single polypeptide chain) (See, para [00198]). The immunogenic composition comprises cationic nano emulsion (see para [00378], [00337], [00377]). The HCV E1 and E2 polypeptides are from HCV genotype 1, HCV genotype 2, or HCV genotype 3 are disclosed for inducing immune response against HCV (instant claim 113 limitation) (See, para [0068], [0071], [0274]- [0285], [0460], [0035]).
Claim 106. Houghton et al 2019 teaches a polypeptide (also referred to herein as a "T-cell epitope polypeptide" or an "HCV T-cell epitope polypeptide") comprising T-cell epitopes (e.g., CD4+ and CD8+ T-cell epitopes that are conserved among some HCV genotypes and that are presented through one or multiple HLA alleles common within the human population) present in an HCV protein other than E1 and E2, the structural proteins comprise a core protein forming the viral nucleocapsid (See, para [0004]), the core-El-E2 coding regions of a HCV genotype 1 (para [0008]-[0011]), an immunogenic composition when administered to an individual in need thereof, induces production of HCV core-specific CD4+ T cells and/or CD8+ T cells in the individual, where the number of HCV core-specific CD4+T cells and/or CD8+ T cells is increased (para [063]) (instant claim 106 limitation).
Claims 107-108. Houghton et al 2019 teaches a “heterologous” is used in the context of a polypeptide, where the polypeptide includes operably linked amino acid sequences that can be derived from one or more different polypeptides, e.g., amino acid sequences that are not operably linked to the polypeptide in nature. A composition comprises an HCV E1/E2 heterodimer and a “heterologous” polypeptide, the “heterologous polypeptide is a polypeptide other than HCV El or HCV E2 (See, para [0040]). The disclosure provides an immunogenic composition comprising: a) a polypeptide that comprises one or more T-cell epitopes (e.g., CD4+ and/or CD8+ T-cell epitopes that are conserved between or among two or more EICV genotypes and that are presented through one or multiple HLA alleles common within the human population) present in an HCV protein other than E1 and E2; and b) a pharmaceutically acceptable excipient. The disclosure provides an immunogenic composition comprising: a) 1) a hepatitis C vims (HCV) heterodimeric polypeptide that includes HCV E1 and E2 polypeptides; ii) an HCV E1 polypeptide; or hi) an HCV E2 polypeptide; b) a heterologous polypeptide (also referred to herein as a“T-cell epitope polypeptide” or an“HCV T-cell epitope polypeptide”) comprising T-cell epitopes (e g., CD4+ and/or CD8+ T-cell epitopes that are conserved between or among two or more HCV genotypes and that are presented through one or multiple HLA alleles common within the human population) present in an HCV protein other than E1 and E2; and c) a pharmaceutically acceptable excipient. The present disclosure provides a method of inducing an immune response in an individual to an HCV polypeptide (see, [0048], [0051], [0053]). An HCV E1/E2 heterodimer can be generated using a method that involves an HCV El or an HCV E2 polypeptide comprising a heterologous proteolytically cleavable linker (e.g. Gly-Pro, Ser, Gly, or Gly-Ser) (See, para [00285]-[0290]). In some cases, the T-cell epitope polypeptide is part of a fusion polypeptide (See, para [0080]-[0081]).
Houghton et al 2019 although teaches an mRNA or RNA do not explicitly disclose at least one 5' cap structure and/or a 5' untranslated region (5' UTR) and/or a 5' internal ribosome entry site (IRES).
Sharifnia et al 2019 is in the art teaches to design and development of modified mRNA encoding core antigen of hepatitis C virus vaccine and disclosed a method of inducing an immune response to HCV in an individual by administering RNA encoding hepatitis C virus (HCV) core antigen. The RNA is designed such that it comprises a 5' UTR, a 5' IRES and 3' UTR as part of the RNA molecule.
Pardi et al 2018 is in the art and reviewed mRNA vaccines against infectious diseases including a human virus - a new era in vaccinology and disclosed optimization of mRNA translation and stability that 5ʹ UTR and 3ʹ UTR elements flanking the coding sequence profoundly influence the stability and translation of mRNA both of which are critical concerns for mRNA vaccines and these regulatory sequences can be derived
from viral or eukaryotic genes and half-life and expression of therapeutic mRNA (See, p. 262 col 2 last para). A 5ʹ cap structure is required for efficient protein production from mRNA (See, p. 26 col 1). The poly(A) tail also plays an important regulatory role in mRNA translation
and stability; thus, an optimal length of poly(A)24 must be added to mRNA (instant claims 99-100 limitation). Delivery methods for mRNA vaccines cationic nanoemulsion, mRNA in a cationic lipid nanoparticle ( for example, 1,2‑dioleoyloxy‑3‑trimethylammoniumpropane (DOTAP) or dioleoylphosphatidylethanolamine (DOPE) lipids), mRNA complexed with cationic lipids, cholesterol and PEG-lipid (instant claim 104 limitation), mRNA associated with a chemically modified dendrimer and complexed with polyethylene glycol (PEG)-lipid, mRNA associated with a cationic polymer such as polyethylenimine (PEI) (instant claim 105 limitation) (See, p.264 col 1 last para, Fig 2 and legends, p.266 col 1 section on Cationic lipid and polymer-based delivery, p.262 Table 1 col 1). Liposome-complexed mRNA (instant claim 115 limitation) encoding influenza virus nucleoproteins elicited CTL responses in mice (See, p. 268 col 1, Table 3 col 2, p.272 col 1). Nucleoside modification (instant claim 102 limitation), the incorporation of chemically modified nucleosides, such as pseudouridine, 1‑methylpseudouridine, 5‑methylcytidine and others, into mRNA transcripts, usually to suppress innate immune
sensing and/or to improve translation (See, p. 264). Self-amplifying mRNA (SAM) vaccines, The SAM platform enables a large amount of antigen production from an extremely small dose of vaccine owing to intracellular replication of the antigen-encoding RNA (See, p. 267 col 2).
Ho et al 2021 is in the art and teaches virus-like particles (VLPs), VLPs can load small molecules, proteins as well as nucleic acids and have been utilized to deliver nucleic acid vaccines (instant claim 87 limitation) (See, p.11 col 1 last para section 3.3, p. 12 col 1 last para).
Claim 114. Ho et al 2021 teaches added limitation of instant claim 114, wherein the RNA is a self-amplifying RNA comprising a nucleotide sequence encoding an RNA-dependent RNA polymerase (RdRP) by disclosing that the self-amplifying mRNAs are termed replicons, and are derived from RNA viruses where the structural viral proteins are replaced with mRNA encoding
antigens and RNA polymerases. Self-amplifying mRNAs code for the antigens of interest as well as the RNA dependent polymerase for replicon amplification [See, page 2 col 2).
It would have been obvious to one of ordinary skill in the art to modify the prior art teachings of Houghton et al 2019 on Hepatitis C virus mRNA nucleic acid immunogenic composition with additional teachings of Sharifnia et al 2019, Pardi et al 2018 and Ho et al 2021 regarding teachings on mRNA vaccine features 5' cap structure and/or a 5' untranslated region (5' UTR) and/or a 5' internal ribosome entry site (IRES) to arrive at the invention of claim 87 with an express motivation of the prior art Houghton et al 2019 to develop a method to induce immune response to HCV by administering to the individual an effective amount of a composition of an RNA or mRNA molecule composition comprising polypeptide-encoding region comprising a nucleotide sequence encoding a full- length hepatitis C virus (HCV) E1 polypeptide and a full-length HCV E2 polypeptide formulated in a suitable lipid nano-emulsion as a vaccine and suggestion and teachings of Sharifnia et al 2019, Pardi et al 2018 and Ho et al 2021 on 5' cap structure and/or a 5' untranslated region (5' UTR) and/or a 5' internal ribosome entry site (IRES) features to comprise in RNA or mRNA molecule(s) for stability and IRES expression of more than one encoding sequence E1 or E2. One of the ordinary skills in the art would have a reasonable expectation of success given the applied combined prior art teachings to develop the instant method of claim 87 for developing an efficacious HCV vaccination method for commercial success. Further modification of combined prior art teachings as applied to claim 87 above with additional teachings of Sharifnia et al 2019, Pardi et al 2018 and Ho et al 2021 as recited supra rendered obvious claims 102, 104-105, 107, 113, and 114-115 to develop a method to induce efficacious immune response against HCV genotypes 1-3 by administering the HCV RNA or mRNA vaccine ad claimed in the instant claims 102, 104-105, 107, 113, and 114-115. This is analogous to some teaching, suggestions, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 87 and 102, 104-105, 113, 114-115. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
See, MPEP 2143 Examples of Basic Requirements of a Prima Facie Case of Obviousness.
I. EXAMPLES OF RATIONALES, E. "Obvious To Try" – Choosing From a Finite Number of Identified, Predictable Solutions, With a Reasonable Expectation of Success. Example 3, In re Kubin, 561 F.3d 1351, 90 USPQ2d 1417 (Fed. Cir. 2009), affirmed the Office’s determination in Ex parte Kubin, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007).
12. Claims 98-101 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Houghton et al 2019 (WO2019173925A1 published 09/19/2019 with an earlier priority of 03/16/2018 to US 62/644,140 provisional application), Sharifnia et al 2019 (Iranian biomedical journal, 23(1), 57), Pardi et al 2018 (Nature reviews Drug discovery, 17(4), 261-279) and Ho et al 2021 (Advanced healthcare materials, 10(8), 2001812 published 01/18/2021) as applied to claim 107 above and further in view of Bancel et al 2016 (US9254311B2, 02/09/2016).
Claims 98-101. The combined prior art teachings of Houghton et al 2019, Sharifnia et al 2019, Pardi et al 2018 and Ho et al 2021 rendered obvious instant claim 87 as recited supra. Sharifnia et al 2019, Pardi et al 2018 taught RNA molecules include at least one 5' cap structure as recited supra. However, do not teach the added limitations of instant claims 98-101.
Claim 98. Bancel et al 2016 is in the art and discloses compositions and methods for the preparation, manufacture and therapeutic use of polynucleotides, primary transcripts and modified mRNA molecules. Bancel et al 2016 taught added limitation of instant claim 98, wherein the one or more RNA molecules comprises a 5' cap structure and a 5' UTR, wherein the 5'UTR is 3' of the 5' cap structure (See, claim 5, columns 42-47).
Claim 99. Bancel et al 2016 is in the art and discloses compositions and methods for the preparation, manufacture and therapeutic use of polynucleotides, primary transcripts and modified mRNA molecules. Bancel et al 2016 taught added limitation of instant claim 99, wherein the one or more RNA molecules comprises a 3' UTR and/or a 3' tailing sequence (See, claim 5, Column 42-43).
Claim 100. Bancel et al 2016 is in the art and discloses compositions and methods for the preparation, manufacture and therapeutic use of polynucleotides, primary transcripts and modified mRNA molecules. Bancel et al 2016 taught added limitation of instant claim 100, wherein the 3' tailing sequence is a poly(adenosine) (poly-A) sequence (See, claim 2, Column 48 lines 26-34).
Claim 101. Bancel et al 2016 is in the art and discloses compositions and methods for the preparation, manufacture and therapeutic use of polynucleotides, primary transcripts and modified mRNA molecules. Bancel et al 2016 rendered obvious the added limitation of claim 103 by disclosing wherein the mRNA comprises at least one 5′ terminal cap and wherein the at least one 5′ terminal cap is selected from the group consisting of Cap0, Cap1, ARCA, inosine, N1-methyl-guanosine, 2′fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, and 2-azido-guanosine (See, claim 4).
It would have been obvious to one of ordinary skill in the art to modify the combined prior art teachings of Houghton et al 2019, Sharifnia et al 2019, Pardi et al 2018, Ho et al 2021 with additional express teachings of Bancel et al 2016 on 5 ' capping , 5’ and 3’ UTRs of RNA or mRNA transcripts for stability of mRNA molecule for improved translation and expression to arrive at the invention of claims 98-101. One of the ordinary skills in the art would have a reasonable expectation of success given the applied combined prior art teachings to develop the instant method of claims 98-101 for developing an efficacious HCV vaccination method for commercial success. This is analogous to some teaching, suggestions, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 98-101. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
13. Claim 103 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Houghton et al 2019 (WO2019173925A1 published 09/19/2019 with an earlier priority of 03/16/2018 to US 62/644,140 provisional application), Sharifnia et al 2019 (Iranian biomedical journal, 23(1), 57), Pardi et al 2018 (Nature reviews Drug discovery, 17(4), 261-279) and Ho et al 2021 (Advanced healthcare materials, 10(8), 2001812 published 01/18/2021) as applied to claim 87 above and further in view of Bancel et al 2016 (US9254311B2, 02/09/2016).
Claim 103. (dependent on claim 87): The combined teachings of Houghton et al 2019, Sharifnia et al 2019, Pardi et al 2018, and Ho et al 2021 teaches claim 87 as recited supra. However, Houghton et al 2019 or the combined prior art teachings as applied to claim 87 above do not teach the elected species a nucleoside of Formula Ia of instant claim 103.
Bancel et al 2016 is in the art and discloses compositions and methods for the preparation, manufacture and therapeutic use of polynucleotides, primary transcripts and modified mRNA molecules comprising modified nucleosides. Bancel et al 2016 disclosed a modified nucleoside Formula IIa (recited below) that is identical to the instant elected modified nucleoside Formula Ia and with identical limitations on the elected Formula Ia variable organic group residues identification (See, US9254311B2, Col 96 lines 6-24, 45-64).
PNG
media_image1.png
246
438
media_image1.png
Greyscale
Bancel et al 2016 additionally teaches the non-elected species (a genus) of modified nucleoside Formula I recited in instant claim 103 as recited as Formula Ia with identical limitations on the Formula I variable organic group residues identification (See, US9254311B2, Col 86 lines 55-67).
PNG
media_image2.png
302
452
media_image2.png
Greyscale
Bancel et al 2016 also disclosed additional different species / genera of modified nucleoside (See, Columns 86-106).
It would have been obvious to one of ordinary skill in the art to modify the combined prior art teachings of Houghton et al 2019, Sharifnia et al 2019, Pardi et al 2018, and Ho et al 2021 as applied to claim 87 with additional express teachings of Bancel et al 2016 on modified nucleoside of Formula Ia or Formula I and incorporate in the RNA or mRNA molecule(s) to arrive at the invention of claim 103 with express teachings of the prior art Pardi et al 2018 (page 263 Box 1) that modified nucleosides decrease innate immune activation and increase stability and translation and reduce inflammatory response (Blancel et al 2016). One of the ordinary skills in the art would have a reasonable expectation of success given the applied combined prior art teachings to develop the instant method of claim 103 for developing an efficacious HCV mRNA molecule encoding full length E1 and E2 polypeptides as a vaccine or immunogenic composition for vaccination method against HCV for commercial success. This is analogous to some teaching, suggestions, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claim 103. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
14. Claims 109-111 are rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Houghton et al 2019 (WO2019173925A1 published 09/19/2019 with an earlier priority of 03/16/2018 to US 62/644,140 provisional application), Sharifnia et al 2019 (Iranian biomedical journal, 23(1), 57), Pardi et al 2018 (Nature reviews Drug discovery, 17(4), 261-279) and Ho et al 2021 (Advanced healthcare materials, 10(8), 2001812 published 01/18/2021) as applied to claim 107 above and further in view of Barnes et al 2021 (US20210138063A1, 05/13/2021).
Claims 109-110 (dependent on claim 107): The combined teachings of Houghton et al 2019, Sharifnia et al 2019, Pardi et al 2018, and Ho et al 2021 teaches claim 107 as recited supra. However, Houghton et al 2019 or other applied prior arts do not teach elected species of heterologous polypeptide SEQ ID NO: 102.
Claim 109. Houghton et al 2019 teaches added limitation of instant claim 109 by disclosing a) one or more T-cell epitope polypeptides selected from:
i) a TP35-NS3 T-cell epitope polypeptide comprising an amino acid sequence having at least 80% amino acid sequence identity to: KSTKVPX1AYX2X3QGYX4VLVLNPSVAATLGFGX5X6X7SX8 (SEQ ID NO: 134), wherein X, is A or Y; X2 is A or V; X3 is A or S; X4 is K or N; X5 is A or S; Xe is Y or F; X7 is M or L; and X8 is K or R, wherein the TP35-NS3 T-cell epitope polypeptide has a length of from 28 amino acids to 35 amino acids. The prior art SEQ ID NO: 134 has 100% identity with instant SEQ ID NO: 219 (see, claim 1).
Barnes et al 2021 (US20210138063A1, 05/13/2021) is in the art and disclosed the elected species of heterologous polypeptide SEQ ID NO: 102 (Qy) that has 100% identity with prior art SEQ ID NO: 163.
Query Match 100.0%; Score 173; Length 45;
Best Local Similarity 100.0%;
Matches 35; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 KSTKVPAAYAAQGYKVLVLNPSVAATLGFGAYMSK 35
|||||||||||||||||||||||||||||||||||
Db 10 KSTKVPAAYAAQGYKVLVLNPSVAATLGFGAYMSK 44
Claim 110: Houghton et al 2019 teaches added limitation of instant claim 110, wherein fusion polypeptide comprises from 2 to 10 T- cell epitope polypeptide selected from: i) a TP35-NS3 T-cell epitope polypeptide comprising an amino acid sequence having at least 80% amino acid sequence identity to: KSTKVPX1AYX2X3QGYX4VLVLNPSVAATLGFGX5X6X7SX8 (SEQ ID NO: 134), wherein X, is A or Y; X2 is A or V; X3 is A or S; X4 is K or N; X5 is A or S; Xe is Y or F; X7 is M or L; and X8 is K or R, wherein the TP35-NS3 T-cell epitope polypeptide has a length of from 28 amino acids to 35 amino acids (e.g., the T-cell epitope polypeptide has a length of 28 amino acids (aa), 29 aa, 30 aa, 31 aa, 32 aa, 33 aa, 34 aa, or 35 aa). In some cases, the T-cell epitope polypeptide has a length of 35 amino acids. In some cases, the T-cell epitope polypeptide is part of a fusion polypeptide. The prior art SEQ ID NO: 134 has 100% identity with instant SEQ ID NO: 219 (see, claim 1, para [0081], [0080], [0040] a fusion polypeptide comprises: a) a T-cell epitope polypeptide).
Barnes et al 2021 (US20210138063A1, 05/13/2021) is in the art and disclosed the elected species of heterologous polypeptide SEQ ID NO: 102 (Qy) that has 100% identity with prior art SEQ ID NO: 163.
Query Match 100.0%; Score 173; Length 45;
Best Local Similarity 100.0%;
Matches 35; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 KSTKVPAAYAAQGYKVLVLNPSVAATLGFGAYMSK 35
|||||||||||||||||||||||||||||||||||
Db 10 KSTKVPAAYAAQGYKVLVLNPSVAATLGFGAYMSK 44
Claim 111. Houghton et al 2019 teaches added limitation of instant claim 110, wherein the polypeptide-encoding region comprises one or more nucleotide sequences encoding two or more heterologous polypeptides comprising a T- cell epitope present in an HCV protein other than HCV E1 and E2 polypeptides (see, abstract, para [0007], [0048]).
It would have been obvious to one of ordinary skill in the art to modify the combined prior art teachings of Houghton et al 2019, Sharifnia et al 2019, Pardi et al 2018, Ho et al 2021, with additional express teachings of Barnes et al 2021 on a heterologous polypeptide sequence that has 100% identity with instant SEQ ID NO: 102 to develop a method to arrive at the invention of claims 109-110 to induce immune response to HCV genotypes. One of the ordinary skills in the art would have a reasonable expectation of success given the applied combined prior art teachings to develop the instant method of claims 109-110 for developing an efficacious HCV vaccination method for commercial success. This is analogous to some teaching, suggestions, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claim 109-110. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
15. Claim 112 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Houghton et al 2019 (WO2019173925A1 published 09/19/2019 with an earlier priority of 03/16/2018 to US 62/644,140 provisional application), Sharifnia et al 2019 (Iranian biomedical journal, 23(1), 57), Pardi et al 2018 (Nature reviews Drug discovery, 17(4), 261-279) and Ho et al 2021 (Advanced healthcare materials, 10(8), 2001812 published 01/18/2021), Barnes et al 2021 (US20210138063A1, 05/13/2021) as applied to claim 111 above and further in view of Wong et al 2002 (Gene therapy, 9(5), 337-344) and Bancel et al 2016 (US9254311B2, 02/09/2016).
Claim 112: The combined teachings of Houghton et al 2019, Sharifnia et al 2019, Pardi et al 2018, Ho et al 2021, Barnes et al 2021 and teaches claim 111 as recited supra. Both Sharifnia et al 2019 and Pardi et al 2018 teaches IRES for mRNA molecule as recited supra. However, do not teach different IRES (first IRES and second IRES).
Wong et al 2002 is in the art and teaches improved co-expression of multiple genes in vectors containing more than one internal ribosome entry sites (IRESes) for improved co-expression of multiple genes (See, Wong et al 2002, abstract, entire article).
Bancel et al 2016 is in the modified mRNA art and teaches multicistronic nucleic acid molecules or mRNA molecules and internal ribosome entry site (IRES) sequences derived from different viruses and disclosed when polynucleotides, primary constructs or modified mRNA are provided with an IRES, further optionally provided is a second translatable region. Examples of IRES sequences that can be used according to the invention include without limitation, those from picornaviruses (e.g. FMDV), pest viruses (CFFV), polio viruses (PV), encephalomyocarditis viruses (ECMV), foot-and-mouth disease viruses (FMDV), hepatitis C viruses (HCV), classical swine fever viruses (CSFV), murine leukemia virus (MLV), simian immune deficiency viruses (SIV) or cricket paralysis viruses (CrPV) (See, column 48) that can be incorporated in mRNA construct of instant claim 112.
As recited supra, the added limitations of the instant claim 112 other than first and second IRES, wherein the one or more RNA molecules comprises: a) a first internal ribosome entry site (IRES) between i) the nucleotide sequence encoding the HCV E1 and E2 polypeptides; and ii) the nucleotide sequence encoding the first of the two or more heterologous polypeptides; and b) a second IRES between i) the nucleotide sequence encoding the first of the two or more heterologous polypeptides; and ii) the nucleotide sequence encoding the second of the two or more heterologous polypeptides, wherein the first IRES and the second IRES are the same or different.
It would have been obvious to one of ordinary skill in the art to modify the combined prior art teachings of Houghton et al 2019, Sharifnia et al 2019, Pardi et al 2018, Ho et al 2021, and Barnes et al 2021 with additional express teachings of Wong et al 2002 and Bancel et al 2016 on improved co-expression of multiple genes in modified mRNA or vectors containing more than one internal ribosome entry sites (IRESes) for improved co-expression of multiple genes in a vector (reads on RNA or mRNA molecule) to arrive at the invention of claim 112 to develop a method of claim 112 to induce immune response to HCV. One of the ordinary skills in the art would have a reasonable expectation of success given the applied combined prior art teachings to develop the instant method of claim 112 for developing an efficacious HCV vaccination method for commercial success. This is analogous to some teaching, suggestions, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claim 112. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
Double Patenting
16. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
17. Claims 87 and 109-100 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over Claims 1 and 39 of copending Application No. 18/391,501 in view of Houghton et al 2019 (WO2019173925A1 published 09/19/2019 with an earlier priority of 03/16/2018 to US 62/644,140 provisional application), and further in view of Sharifnia et al 2019 (Iranian biomedical journal, 23(1), 57), Pardi et al 2018 (Nature reviews Drug discovery, 17(4), 261-279) and Ho et al 2021 (Advanced healthcare materials, 10(8), 2001812 published 01/18/2021).
Both the instant claims 87 and 109-100 and co-pending claims 1 and 39 are directed to an immunogenic composition and a method to induce immune response against Hepatitis C virus effectively encoding same proteins T cell epitope polypeptide a TP35-NS3 with the same amino acid sequence.
The instant claims 87 and 109-100 are directed to an RNA encoding a TP35-NS3. However, the co-pending claims 1 and 39 are directed to a polypeptide TP35-NS3.
In view of combined prior art teachings of Houghton et al 2019, Sharifnia et al 2019), Pardi et al 2018 and Ho et al 2021 as applied and recited supra incorporated here in entirety, it would have been obvious to modify the co-pending claims 1 and 39 to comprise RNA encoding polypeptide TP35-NS3 to arrive at the instant claims 87 and 109-100 invention to develop RNA vaccine for commercial success with a reasonable expectation of success.
See, MPEP 2143 Examples of Basic Requirements of a Prima Facie Case of Obviousness.
I. EXAMPLES OF RATIONALES, E. "Obvious To Try" – Choosing From a Finite Number of Identified, Predictable Solutions, With a Reasonable Expectation of Success. Example 3, In re Kubin, 561 F.3d 1351, 90 USPQ2d 1417 (Fed. Cir. 2009), affirmed the Office’s determination in Ex parte Kubin, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007).
This is a provisional nonstatutory double patenting rejection.
18. Claims 87 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over Claim 81-82 of copending Application No. 18/975,849 in view of Houghton et al 2019 (WO2019173925A1 published 09/19/2019 with an earlier priority of 03/16/2018 to US 62/644,140 provisional application), and further in view of Sharifnia et al 2019 (Iranian biomedical journal, 23(1), 57), Pardi et al 2018 (Nature reviews Drug discovery, 17(4), 261-279) and Ho et al 2021 (Advanced healthcare materials, 10(8), 2001812 published 01/18/2021).
Both the instant claims 87 and co-pending claims 81 and 82 are directed to an immunogenic composition and a method to induce immune response against Hepatitis C virus effectively encoding same HCV E1 and E2 polypeptides.
Instant claim 87 is directed to a method that comprise a composition comprising an RNA encoding HCV E1 and E2 proteins. However, the co-pending claims 81-82 are directed to nucleic acid (reads on RNA) HCV E1 and E2 polypeptides.
In view of combined prior art teachings of Houghton et al 2019, Sharifnia et al 2019), Pardi et al 2018 and Ho et al 2021 as applied and recited supra incorporated here in entirety, it would have been obvious to modify the co-pending claims 81-82 to comprise nucleic acid RNA or mRNA encoding HCV E1 and E2 polypeptide to arrive at the instant claim 87 invention to develop RNA or mRNA vaccine for commercial success with a reasonable expectation of success.
See, MPEP 2143 Examples of Basic Requirements of a Prima Facie Case of Obviousness.
I. EXAMPLES OF RATIONALES, E. "Obvious To Try" – Choosing From a Finite Number of Identified, Predictable Solutions, With a Reasonable Expectation of Success. Example 3, In re Kubin, 561 F.3d 1351, 90 USPQ2d 1417 (Fed. Cir. 2009), affirmed the Office’s determination in Ex parte Kubin, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007).
This is a provisional nonstatutory double patenting rejection.
Conclusion
19. No claim is allowed.
20. Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMADHAN J JADHAO whose telephone number is (703)756-1223. The examiner can normally be reached M-F 8:00-5:00.
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, Thomas J Visone can be reached at 571-270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SAMADHAN JAISING JADHAO/Examiner, Art Unit 1672
/BENNETT M CELSA/Primary Examiner, Art Unit 1600
Prosecution Insights