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
REQUIREMENT FOR UNITY OF INVENTION
As provided in 37 CFR 1.475(a), a national stage application shall relate to one invention only or to a group of inventions so linked as to form a single general inventive concept (“requirement of unity of invention”). Where a group of inventions is claimed in a national stage application, the requirement of unity of invention shall be fulfilled only when there is a technical relationship among those inventions involving one or more of the same or corresponding special technical features. The expression “special technical features” shall mean those technical features that define a contribution which each of the claimed inventions, considered as a whole, makes over the prior art.
The determination whether a group of inventions is so linked as to form a single general inventive concept shall be made without regard to whether the inventions are claimed in separate claims or as alternatives within a single claim. See 37 CFR 1.475(e).
When Claims Are Directed to Multiple Categories of Inventions:
As provided in 37 CFR 1.475 (b), a national stage application containing claims to different categories of invention will be considered to have unity of invention if the claims are drawn only to one of the following combinations of categories:
(1) A product and a process specially adapted for the manufacture of said product; or
(2) A product and a process of use of said product; or
(3) A product, a process specially adapted for the manufacture of the said product, and a use of the said product; or
(4) A process and an apparatus or means specifically designed for carrying out the said process; or
(5) A product, a process specially adapted for the manufacture of the said product, and an apparatus or means specifically designed for carrying out the said process.
Otherwise, unity of invention might not be present. See 37 CFR 1.475 (c).
Restriction is required under 35 U.S.C. 121 and 372.
This application contains the following inventions or groups of inventions which are not so linked as to form a single general inventive concept under PCT Rule 13.1.
In accordance with 37 CFR 1.499, applicant is required, in reply to this action, to elect a single invention to which the claims must be restricted.
Group I, claims 1, 3, 5-6, 15-25, 28, and 47-51, drawn to a recombinant vector encoding a chimeric coronavirus spike protein that comprises a spike protein originating from a coronavirus, and a transmembrane domain and a C-terminal domain of a surface glycoprotein originating from a budding virus that buds from a host cell’s plasma membrane (BVpm)) in place of a TMD and a CTD of the coronavirus spike protein; wherein the recombinant vector is a recombinant BVpm, the TMD and the CTD of the surface glycoprotein originate from a virus species that is different from that of the recombinant BVpm, and wherein the coronavirus spike protein originates from an IBV, an immunogenic composition comprising the recombinant vector, and a chimeric coronavirus spike protein that comprises a spike protein originating from an IBV, and a TMD and a CTD of a surface glycoprotein originating from a vesicular stomatitis virus, in place of a TMD and a CTD of the IBV spike protein.
Group II, claims 34-37, drawn to a method for protecting an avian from infectious bronchitis due to an infection of IBV.
The groups of inventions listed above do not relate to a single general inventive concept under PCT Rule 13.1 because, under PCT Rule 13.2, they lack the same or corresponding special technical features for the following reasons:
Group I and Group II lack unity of invention because even though the inventions of these groups require the technical feature of a chimeric coronavirus spike protein that comprises a spike protein originating from IBV, and a TMD and a CTD of a surface glycoprotein originating from a budding virus such as vesicular stomatitis virus, in place of a TMD and a CTD of the IBV spike protein, this technical feature is not a special technical feature as it does not make a contribution over the prior art in view of He, et al. (J Virol. 2012 Dec;86(24):13887-8. doi: 10.1128/JVI.02722-12. PMID: 23166279; hereinafter referred to as "He") in view of Broer, et al. (J Virol. 2006 Feb;80(3):1302-10. doi: 10.1128/JVI.80.3.1302-1310.2006. PMID: 16415007; on IDS, hereinafter referred to "Broer").
He teaches a complete genome sequence of an Infectious Bronchitis Virus (IBV), which is a coronavirus known to infect fowl (Abstract; p. 13887, col. 1, para. 1). However, He does not disclose a chimeric coronavirus spike protein that comprises a spike protein originating from an IBV, and a TMD and a CTD of a surface glycoprotein originating from a budding virus such as vesicular stomatitis virus, in place of a TMD and a CTD of the IBV spike protein.
Broer, et al. disclose severe acute respiratory syndrome coronavirus (SARS-CoV) spike chimeras with the cytoplasmic and transmembrane domains of VSV-G, which was used to study the roles of the transmembrane and cytoplasmic domains of spike in the infectivity and membrane fusion activity of SARS-CoV (Abstract; Figs. 5-7).
It would have been obvious to generate similar IBV spike protein chimeras with a TMD and a CTD of a surface glycoprotein originating from a vesicular stomatitis virus, in place of a TMD and a CTD of the IBV spike protein. One of ordinary skill in the art would have been motivated to do so to study the roles of the transmembrane and cytoplasmic domains of IBV spike protein. Therefore, the shared technical feature is not a special technical feature, and thus unity of invention is lacking.
During a telephone conversation with Susanna Benn on 5/26/2026, a provisional election was made without traverse to prosecute the invention of Group I, claims 1, 3, 5-6, 15-25, 28, and 47-51. Affirmation of this election must be made by applicant in replying to this Office action.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
The examiner has required restriction between product or apparatus claims and process claims. Where applicant elects claims directed to the product/apparatus, and all product/apparatus claims are subsequently found allowable, withdrawn process claims that include all the limitations of the allowable product/apparatus claims should be considered for rejoinder. All claims directed to a nonelected process invention must include all the limitations of an allowable product/apparatus claim for that process invention to be rejoined.
In the event of rejoinder, the requirement for restriction between the product/apparatus claims and the rejoined process claims will be withdrawn, and the rejoined process claims will be fully examined for patentability in accordance with 37 CFR 1.104. Thus, to be allowable, the rejoined claims must meet all criteria for patentability including the requirements of 35 U.S.C. 101, 102, 103 and 112. Until all claims to the elected product/apparatus are found allowable, an otherwise proper restriction requirement between product/apparatus claims and process claims may be maintained. Withdrawn process claims that are not commensurate in scope with an allowable product/apparatus claim will not be rejoined. See MPEP § 821.04. Additionally, in order for rejoinder to occur, applicant is advised that the process claims should be amended during prosecution to require the limitations of the product/apparatus claims. Failure to do so may result in no rejoinder. Further, note that the prohibition against double patenting rejections of 35 U.S.C. 121 does not apply where the restriction requirement is withdrawn by the examiner before the patent issues. See MPEP § 804.01.
Applicant’s election of the required species, A) a specific IBV serotype: Massachussetts serotype, B) a specific chimeric coronavirus spike protein: SEQ ID NO: 6, C) a specific recombinant expression vector: a recombinant viral vector, and D) a specific recombinant viral vector: alphavirus RNA replicon particle (RP) in the reply filed on 4/20/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim 22 and 34-37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/20/2026.
Claims 1, 3, 5-6, 15-21, 23-25, 28, and 47-51 are under examination on the merits.
Information Disclosure Statement
The Information Disclosure Statements (IDSs) submitted on 11/21/2025, 6/30/2025, and 4/18/2025 are in compliance with 37 CFR 1.97. Accordingly, the references of the IDSs are being considered by the examiner.
Claim Interpretation
The specification indicates a “transmembrane domain” or “TMD” is a hydrophobic region of a protein that either is or is to be inserted into the cell membrane, and the parts of either side of the transmembrane domain of the protein are on opposite sides of the membrane (p. 25). Based on the definition that a TMD is a hydrophobic region that is inserted into the membrane, then the examiner interprets the broadest reasonable interpretation to be any hydrophobic region, the full TMD or any part of it can be replaced. Regarding the “C-terminal domain” or “CTD”, the specification indicates that it is the portion of a surface glycoprotein of an enveloped virus, that projects into the cytoplasm (p. 25). Based on the definition, the examiner interprets the broadest reasonable interpretation to be the entire CTD.
Specification
The disclosure is objected to because it contains embedded hyperlinks and/or other form of browser-executable code on pp. 4 & 80. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http://, www., or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 1 is objected to because of the following informalities: claim 1 recites “a coronavirus selected from the group consisting of an infectious bronchitis virus (IBV)” on lines 8-9. The language “selected from the group consisting of” is unnecessary, because the Markush group only contains a single member. The examiner suggests amending “a coronavirus selected from the group consisting of an infectious bronchitis virus (IBV)” to instead recite ”an infectious bronchitis virus (IBV)”. Appropriate correction is required.
Claim 16 is objected to because of the following informalities: claim 16 recites “wherein the IBV is an IBV-Ma5 strain” on lines 1-2, instead the claim should recite “wherein the Massachusetts serotype is an IBV-Ma5 strain.” Appropriate correction is required.
Claim 18 is objected to because of the following informalities: claim 18 recites “a pair of proline residues (2P)” at line 6. It is not clear if “(2P)” is meant to be an abbreviation for the pair of prolines, or the mutant protein. Appropriate correction is required.
Claim 19 is objected to because of the following informalities: claim 19 recites “wherein the chimeric coronavirus spike protein further comprises 90% or greater identity with amino acid residues 1092 to 1140 of the amino acid sequence of SEQ ID NOs: 4 or 6, over the same range of amino acid residues” at lines 1-4. However, SEQ ID NOs: 4 and 6 are identical over amino acid residues 1092 to 1140, so the claim listing two alternatives that are identical is a duplicate limitation in the same claim. Appropriate correction is required.
Claims 21 and 28 are objected to because of the following informalities: claims 21 and 28 recite the abbreviations “MV” and “NDV” without fully defining them. The full names of these viruses should be recited prior to their abbreviation in the claims. Appropriate correction is required.
Claim 28 is objected to because of the following informalities: claim 28 recites “the recombinant viral vector selected from the group consisting of [..], a DNA expression plasmid, or a synthetic mRNA, and a pharmaceutically acceptable carrier” at lines 2-6. While it is clear that the pharmaceutically acceptable carrier is not part of the Markush group, it is suggested to split the claims into subpart A) with the Markush group and subpart B) with the pharmaceutically acceptable carrier. Appropriate correction is required.
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.
Written Description
Claim 6 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the 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 instant claims above are drawn to a genus of recombinant vectors encoding a chimeric coronavirus spike protein that comprises a central helix that is further stabilized in a prefusion state due to consecutive amino acid residues at the beginning of the central helix being replaced by a pair of proline residues (claim 6). “[A]t the beginning of the central helix” is not defined by the specification, and under the broadest reasonable interpretation, is not limited to the first two residues of the central helix. .
Even if the prior art is aware of such consecutive amino acid residues at the beginning of the central helix being replaced by a pair of prolines that confer a very specific function of stabilizing the prefusion state, the totality of known stabilized central helices would not be representative of the entire genus for the reasons discussed below.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the 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. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
Furthermore, to satisfy the written description requirement for the genus recombinant vectors encoding a chimeric coronavirus spike protein that comprises a central helix that is further stabilized in a prefusion state due to consecutive amino acid residues at the beginning of the central helix being replaced by a pair of proline residues, Applicant must adequately describe representative vectors to reflect the structural diversity of the claimed genus. See Eli Lilly, 119 F.3d at 1568 (“[N]aming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993) (“Claiming all DNA[s] that achieve a result without defining what means will do so is not in compliance with the description requirement; it is an attempt to preempt the future before it has arrived.”).
MPEP § 2163 states that 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, 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 applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, as here in which the antibodies claimed can have incomplete CDR sets, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615. “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” One of skill in this art cannot envision the structure of every recombinant vectors encoding a chimeric coronavirus spike protein that comprises a central helix that is further stabilized in a prefusion state due to consecutive amino acid residues at the beginning of the central helix being replaced by a pair of proline residues. The specification refers to Pallesen, et al. (Proc Natl Acad Sci U S A. 2017 Aug 29;114(35):E7348-E7357. doi: 10.1073/pnas.1707304114. Epub 2017 Aug 14. PMID: 28807998) as an example of a pair of consecutive proline residues that are substituted for two consecutive amino acid residues at the beginning of the central helix of a surface glycoprotein of an enveloped virus, to further stabilize the surface glycoprotein in the prototypical prefusion conformation (spec., p. 25). Pallesen discloses that introduction of two consecutive proline residues at the beginning of the central helix seems to be a general strategy for retaining betacoronavirus S proteins in the prototypical prefusion conformation, and that two consecutive proline substitutions at each of MERS-CoV, SARS-CoV, and HCoV-HKU1 spike proteins increased expression levels of the ectodomains and improved conformational homogeneity (p. E7350, col. 1, para. 1). The specification also discloses that introduction of two prolines and removal of the polybasic cleavage site leads to optimal efficacy of a recombinant spike based SARS-CoV-2 vaccine in a mouse model (spec., p. 4). Additionally, the specification discloses cloning and expression of recombinant vectors encoding IBV spike protein with the 2P substitutions (Examples 1-7). Therefore, since limited species are provided to represent these genera, the claims encompassing the same clearly fail the written description requirement.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. See ABBVIE DEUTSCHLAND GMBH & 2 CO. v. JANSSEN BIOTECH, INC., Appeals from the United States District Court for the District of Massachusetts in Nos. 09-CV-11340-FDS, 10-CV-40003-FDS, and 10-CV-40004-FDS, Judge F. Dennis Saylor, IV. See also Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members.
“Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species.” Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since each genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus. Three species is certainly not adequate. The disclosure does not provide examples of other proline substitutions at other residues of the central helix that confer the required function.
Overall, at the time the invention was made, the level of skill for preparing recombinant vectors was high.
A representative number of species has not been taught to describe these genera; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genera of recombinant vectors encoding a chimeric coronavirus spike protein that comprises a central helix that is further stabilized in a prefusion state due to consecutive amino acid residues at the beginning of the central helix being replaced by a pair of proline residues. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genera.
While applicant has described one or a few species within each of the genera recited, and the art may provide more, the genus is large and would encompass structures that cannot be visualized from the prior art or instant disclosure. One of skill in this art cannot determine the structures encompassed by the claimed genera only defined by function. Any future chimeric spike protein structure may or may not be encompassed, and if it is, it would not have been represented in Applicant’s disclosed species. Thus, the described species cannot be considered representative of the recited genera of recombinant vectors encoding chimeric spike proteins. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, the claims are rejected here.
As discussed above, an applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613. Therefore, it is recommended that the instant claims be amended to recite complete structural information of the claimed recombinant vectors encoding a chimeric coronavirus spike protein that comprises a central helix that is further stabilized in a prefusion state due to consecutive amino acid residues at the beginning of the central helix being replaced by a pair of proline residues, including full sequences and precise positions of the proline substitutions.
Claims 17-19 and 48-50 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 instant claims above are drawn to a genus of chimeric coronavirus spike protein, or recombinant vector encoding the chimeric coronavirus spike protein, with 90% identity with amino acid residues 19 to 1091 of the amino acid sequence of SEQ ID NO: 4 or 6, over the same range of residues, and wherein said chimeric coronavirus spike protein comprises an inactivated furin cleavage site (claims 17-18 and 48-49) or a chimeric coronavirus spike protein with 90% identity with amino acid residues 1092-1140 of the amino acid sequence of SEQ ID NOs: 4 or 6, over the same range of amino acid residues (claims 19 & 50).
Even if the prior art is aware of such chimeric coronavirus spike proteins, the totality of known chimeric coronavirus spike proteins would not be representative of each entire genus for the reasons discussed below.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the 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. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
Furthermore, to satisfy the written description requirement for the genera chimeric coronavirus spike proteins, or recombinant vector encoding the chimeric coronavirus spike protein, with 90% identity with amino acid residues 19 to 1091 of the amino acid sequence of SEQ ID NO: 4 or 6, over the same range of residues, and wherein said chimeric coronavirus spike protein comprises an inactivated furin cleavage site (claims 17-18 and 48-49) or a chimeric coronavirus spike protein with 90% identity with amino acid residues 1092-1140 of the amino acid sequence of SEQ ID NOs: 4 or 6, over the same range of amino acid residues (claims 19 & 50), Applicant must adequately describe representative chimeric coronavirus spike proteins to reflect the structural diversity of the claimed genus. See Eli Lilly, 119 F.3d at 1568 (“[N]aming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993) (“Claiming all DNA[s] that achieve a result without defining what means will do so is not in compliance with the description requirement; it is an attempt to preempt the future before it has arrived.”).
MPEP § 2163 states that 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, 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 applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, as here in which the claimed chimeric coronavirus spike proteins can have 107 and 4 amino acid changes, respectively, which can occur at any of 1072 and 48 amino acid positions, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615. “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” One of skill in this art cannot envision the structure of all chimeric coronavirus spike proteins encompassed by the claims. Therefore, since a small number of species is provided to represent these genera, the claims encompassing the same clearly fail the written description requirement.
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since each genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus. Several species is certainly not adequate.
Overall, at the time the invention was made, the level of skill for preparing chimeric coronavirus spike proteins and then selecting those proteins with desired functional properties was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify chimeric coronavirus spike proteins with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”) Absent the structure provided by a complete amino acid sequences, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what a chimeric coronavirus spike protein with a particular set of functional properties would look like structurally.
Since few chimeric coronavirus spike proteins are shown to be capable of functioning, the instant claims above clearly fail the written description requirement. A representative number of species has not been taught to describe these genera. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genera.
As discussed above, an applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613. Therefore, it is recommended that the instant claims be amended to recite complete structural information of the claimed chimeric coronavirus spike proteins, including full amino acid sequences.
Scope of Enablement
Claims 17-19 and 48-50 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 chimeric coronavirus spike protein with 100% identity with amino acid residues 19 to 1091 of the amino acid sequence of SEQ ID NO: 4 or 6, over the same range of residues, and wherein said chimeric coronavirus spike protein comprises an inactivated furin cleavage site (claims 17-18 and 48-49) or a chimeric coronavirus spike protein with 100% identity with amino acid residues 1092-1140 of the amino acid sequence of SEQ ID NOs: 4 or 6, over the same range of amino acid residues (claims 19 & 50), does not reasonably provide enablement for chimeric coronavirus spike proteins that comprise 90% or greater identity with amino acid residues 19 to 1091 of the amino acid sequence of SEQ ID NO: 4 or 6, over the same range of residues or amino acid residues 1092-1140 of the amino acid sequence of SEQ ID NOs: 4 or 6, over the same range of amino acid residues. 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 or use the invention commensurate in scope with these claims.
The breadth of the claims is found in claims 17-19 and 48-50.
The nature of the invention is a chimeric coronavirus spike protein, or recombinant vector encoding the chimeric coronavirus spike protein, with 90% identity with amino acid residues 19 to 1091 of the amino acid sequence of SEQ ID NO: 4 or 6, over the same range of residues, and wherein said chimeric coronavirus spike protein comprises an inactivated furin cleavage site (claims 17-18 and 48-49) or a chimeric coronavirus spike protein with 90% identity with amino acid residues 1092-1140 of the amino acid sequence of SEQ ID NOs: 4 or 6, over the same range of amino acid residues (claims 19 & 50).
The level of skill of one skilled in this art is high.
The specification teaches a number of chimeric coronavirus spike proteins with at least 90% identity with amino acid residues 19 to 1091 of the amino acid sequence of SEQ ID NO: 4 or 6, over the same range of residues, and wherein said chimeric coronavirus spike protein comprises an inactivated furin cleavage site, or 90% identity with amino acid residues 1092-1140 of the amino acid sequence of SEQ ID NOs: 4 or 6, over the same range of amino acid residues. See e.g., Example 1. These teachings do not enable the full breadth of the claims because they allow for 107 and 4 amino acid changes, respectively, which can occur at any of 1072 and 48 amino acid positions, with no indication that this very broad genus of possible chimeric coronavirus proteins maintains its immunogenic function.
The state of the prior art is such that substitution of a single residue in a viral immunogen can render the vaccine ineffective (see Kodihalli, et al. J Virol. 1995 Aug;69(8):4888-97. doi: 10.1128/JVI.69.8.4888-4897.1995. PMID: 7609057 ; title; abstract).
Thus, the state of the art recognized that it would be highly unpredictable that a specific immunogen lacking precise sequence would have immunogenic function. The minimal structure which the skilled artisan would consider predictive of the function of eliciting an immune response would be a complete amino acid sequence. One of skill in the art would neither expect nor predict the appropriate functioning of the immunogens as broadly as currently claimed.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by Kodihalli, the lack of guidance and direction provided by applicants, and the absence of working examples, undue experimentation would be required to make and use functional immunogens with possible variations of 107 and 4 amino acid changes, respectively, which can occur at any of 1072 and 48 amino acid positions, respectively, with a reasonable expectation of success, absent a specific and detailed description in applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the chimeric spike proteins are functional, commensurate in scope with the claimed invention.
Not knowing, absent further experimentation, which modifications function and which do not, when, as set forth above, even a single change of an encoded amino acid can unpredictably affect immunogen structure and function, leads to one having no predictability or expectation of success for the function of any given chimeric spike protein modification. Such random experimentation to identify at a later time what structure or fragment or modification is or is not functional and is embraced by Applicant’s claims is undue experimentation.
Moreover, claims not containing elements critical or essential to the practice of the invention, such as immunogens not containing a complete sequence, are not enabled by the disclosure. See In re Mayhew, 527 F.2d 1229, 188 USPQ 356 (CCPA 1976).
Note that an enabling disclosure for the preparation and use of only a few analogs of a product does not enable all possible analogs where the characteristics of the analogs are unpredictable. See Amgen Inc. v. Chugai Pharmaceutical Co. Ltd. (18 USPQ 2d 1027 (CAFC 1991)).
Claims 1, 3, 5-6, 15-20, and 51 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 an isolated nucleic acid or recombinant vector encoding a chimeric coronavirus spike protein that comprises a spike protein originating from a coronavirus, and a transmembrane domain and a C-terminal domain of a surface glycoprotein originating from a budding virus that buds from a host cell’s plasma membrane (BVpm)) in place of a TMD and a CTD of the coronavirus spike protein; wherein the recombinant vector is a recombinant BVpm, the TMD and the CTD of the surface glycoprotein originate from a virus species that is different from that of the recombinant BVpm, and wherein the coronavirus spike protein originates from an IBV, does not reasonably provide enablement for all nucleic acids or recombinant vectors encoding a chimeric coronavirus spike protein that comprises a spike protein originating from a coronavirus, and a transmembrane domain and a C-terminal domain of a surface glycoprotein originating from a budding virus that buds from a host cell’s plasma membrane (BVpm)) in place of a TMD and a CTD of the coronavirus spike protein; wherein the recombinant vector is a recombinant BVpm, the TMD and the CTD of the surface glycoprotein originate from a virus species that is different from that of the recombinant BVpm, and wherein the coronavirus spike protein originates from an IBV. 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 or use the invention commensurate in scope with these claims.
Applicant broadly claims a recombinant vector or nucleic acid encoding a chimeric coronavirus spike protein that comprises a spike protein originating from a coronavirus, and a transmembrane domain and a C-terminal domain of a surface glycoprotein originating from a budding virus that buds from a host cell’s plasma membrane (BVpm)) in place of a TMD and a CTD of the coronavirus spike protein; wherein the recombinant vector is a recombinant BVpm, the TMD and the CTD of the surface glycoprotein originate from a virus species that is different from that of the recombinant BVpm, and wherein the coronavirus spike protein originates from an IBV. The claim reads on a cell within a transgenic animal or a transgene therein given that the term "isolated" is not denoted in describing the host cell, nucleic acid, or vector.
With respect to the unisolated transgenes as “nucleic acids” or “vectors “of the instant claims discussed above, the state of the art at the time of filing was such that one of skill could not predict the phenotype of transgenics. The art of transgenic animals has for many years stated that the unpredictability lies, in part, with the site or sites of transgene integration into the target genome and that "the position effect" as well as unidentified control elements are recognized to cause aberrant expression of a transgene (Wall et al., Theriogenology, Vol. 45, Pg. 57-68, 1996).
The elements of the particular construct used to make transgenic animals are also held to be critical, and they must be designed case by case without general rules to obtain good expression of a transgene; e.g., specific promoters, presence or absence of introns, etc. (Houdebine et al., Journal of Biotechnology, Vol. 34, Pg. 269- 287, 1994). Furthermore, transgenic animals are regarded to have within their cells, cellular mechanisms that prevent expression of the transgene, such as methylation or deletion from the genome (Kappell et al., Current Opinions in Biotechnology, Vol. 3, Pg. 548-553, 1992). Houdebine (Comparative Immunology, Microbiology, and Infectious Diseases, Vol. 32, Pg. 107-121, 2009) teaches progress has been made in the field of transgenic animals for production of foreign proteins (Abstract); however, constructing an efficient expression vector to produce a therapeutic protein is not a standard operation (Pg. 116, Paragraph, second). Therefore, undue experimentation is required to make and use a transgene and transgenic animal to produce the proteins of the instant claims.
Examples in the literature aptly demonstrate that even closely related species carrying the same transgene construct can exhibit widely varying phenotypes. Mullins (1993, Hypertension, Vol. 22, No. 4, pp. 630-633) states that not all animals express a transgene sufficiently to provide a model for a disease as the integration of a transgene into different species of animal has been reported to give divergent phenotypes. For example, several animal models of human diseases have relied on transgenic rats when the development of mouse models was not feasible. Mullins (1990, Nature, Vol. 344, 541-544) produced outbred Sprague-Dawley x WKY rats with hypertension caused by expression of a mouse Ren-2 renin transgene. Hammer (1990, Cell, Vol. 63, 1099- 1112) describes spontaneous inflammatory disease in inbred Fischer and Lewis rats expressing human class I major histocompatibility allele HLA-B27 and human 02- microglobulin transgenes. Both investigations were preceded by the failure to develop human disease-like symptoms in transgenic mice expressing the same transgenes that successfully caused the desired symptoms in transgenic rats (Mullins, 1989, EMBO J., Vol. 8, pages 4065-4072). Thus, the use of nonmurine species for transgenesis will continue to reflect the suitability of a particular species for the specific questions being addressed, bearing in mind that a given construct may react very differently from one species to another.
The examiner notes here, in addition to these issues, even assuming arguendo PHOSITA could make a host organism with functional transgene that encodes the nucleic acid or recombinant vector, there is no predictability that the host will survive its expression. The transgene depends on the host for function and harm to the host, including death, renders the transgene nonfunctional and thus not enabled.
At the time of filing, the phenotype of a transgene within any animal was unpredictable. The claims as written, encompassing a transgene in a transgenic animal, is not adequately described in the specification as to prevent excessive experimentation by the public to generate and use the invention. Applicants can obviate the instant rejection by amending the claim to recite the term "isolated" before the recitation, "recombinant vector" and “nucleic acid” and by amending the polynucleotide claims to specify they are not in a transgenic animal. Applicant may consider using purified in such claims if description is appropriate for such a term and it is not redefined away from standard meaning. Method claims using these products should also carry the appropriate adjectives above.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use functional recombinant vectors encoding a chimeric coronavirus spike protein, specifically related to transgenes and transgenic animals encompassed by the instant claims, with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed recombinant vectors, nucleic acids, and encoded chimeric coronavirus spike protein are functional, commensurate in scope with the claimed invention. Thus, the claims are rejected here.
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 18 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 18 recites “wherein the alanine (A) residue at position 859 and the isoleucine (I) residue at position 860 of SEQ ID NO: 6 are replaced by a pair of proline residues (2P)” on lines 5-6. However, according to the sequence listing, SEQ ID NO: 6 already possesses prolines at positions 859 and 860. It is unclear whether the claimed chimeric coronavirus spike protein is supposed to have alanine and isoleucine residues, or proline and proline residues, at positions 859 and 860, respectively.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 5-6, 15-21, 23-25, 28, and 47-51 are rejected under 35 U.S.C. 103 as being unpatentable over Broer, et al. (J Virol. 2006 Feb;80(3):1302-10. doi: 10.1128/JVI.80.3.1302-1310.2006. PMID: 16415007), Brandao, et al. (Brandao, et al. Genome Announc. 2017 Jun 8;5(23):e00201-17. doi: 10.1128/genomeA.00201-17. PMID: 28596385) as evidenced by GenBank accession: KY626045 (4/24/2017), Anderson (WO 2013068847 A2, published 5/16/2013), Pallesen, et al. (Proc Natl Acad Sci U S A. 2017 Aug 29;114(35):E7348-E7357. doi: 10.1073/pnas.1707304114. Epub 2017 Aug 14. PMID: 28807998), Rappuoli, et al. (WO 2004092360 A2, published 10/28/2004), and Yamada, et al. (J Virol. 2009 Sep;83(17):8744-58. doi: 10.1128/JVI.00613-09. Epub 2009 Jun 24. PMID: 19553314).
The claimed invention encompasses a recombinant vector encoding a chimeric coronavirus spike protein that comprises a spike protein originating from a coronavirus, and a transmembrane domain (TMD) and a C-terminal domain (CTD) of a surface glycoprotein originating from a budding virus that buds from a host cell’s plasma membrane (BVpm), in place of a TMD and a CTD of the coronavirus spike protein; wherein when the recombinant vector is a recombinant BVpm, the TMD and CTD of the surface glycoprotein originate from a virus species that is different from that of the recombinant BVpm, and wherein the coronavirus spike protein originates from a coronavirus selected from the group consisting of an infectious bronchitis virus (claim 1).
The Prior Art
Broer, et al. disclose severe acute respiratory syndrome coronavirus (SARS-CoV) spike chimeras with the cytoplasmic and transmembrane domains of VSV-G, which was used to study the roles of the transmembrane and cytoplasmic domains of spike in the infectivity and membrane fusion activity of SARS-CoV (Abstract; Figs. 5-7). Broer also discloses vectors for expressing the spike proteins (p. 1303, col. 2; p. 1304; col. 1), and incorporation of the chimeric S proteins into pseudotyped particles (p. 1305, col. 1).
However, Broer does not teach a coronavirus spike protein that originates from an infectious bronchitis virus (IBV).
Brandao teaches the complete genome of Avian coronavirus vaccine strains Ma5 (GI-1, Massachusetts type), including notation of the spike gene (nucleotides 20314 to 23802), and teaches that because vaccination is a core tool for controlling AvCoV infection and due to a range of variables to be considered for this process, the integration of experimental, field, and genomic data could improve the process of developing vaccines and predicting their behavior (Title; p. 1, paras 1-2; p. 2, para. 2).
Anderson discloses compositions and methods useful for treating HCMV infection, based on development of immunogenic compositions that include virus-like particles (Abstract), and teaches an envelope polypeptide from HCMV that includes a transmembrane domain and cytoplasmic domain found in VSV (para. [0079]). Anderson explains that the transmembrane domain of VSV-G functions to target the viral glycoprotein to the cell membrane, and swapping the transmembrane and cytoplasmic domains of VSV-G for the transmembrane and cytoplasmic domains of another protein has been used to direct a protein to the cell membrane (para. [0080]). Anderson further discloses that development of an HCMV vaccine comprising one or more envelope polypeptide antigens presented in their native conformation on the surface of a VLP leads to induction of neutralizing antibodies (para. [0082]). Anderson also teaches that its VLPs may be prepared as DNA vaccines, wherein one or more vectors or plasmids may be administered to a subject such that recipient cells express polypeptides encoded by the vector or plasmid (para. [0106]). Additionally, Anderson teaches a pharmaceutical composition comprising the VLP and a pharmaceutically acceptable carrier (claim 134).
It would have been obvious to one of ordinary skill in the art to generate similar Ma5 strain IBV spike protein chimeras with a TMD and a CTD of a surface glycoprotein originating from a vesicular stomatitis virus, in place of a TMD and a CTD of the IBV spike protein. Regarding claim 51, it would have been obvious to generate nucleic acid vectors encoding the obvious chimeric coronavirus spike proteins for expression, because Broer discloses vectors for expressing its spike proteins. Anderson teaches vaccine compositions with viral envelope proteins where the native transmembrane and cytoplasmic domains are swapped for those of VSV. One of ordinary skill in the art would have been motivated to generate pseudotyped viral particles and direct the chimeric IBV spike protein to the plasma membrane for use in a vaccine. There would be a reasonable expectation of success because similar chimeras and pseudotyped particles had been successfully generated for other coronaviruses. Therefore, claims 1, 3, 15-16, 47, and 51 were prima facie obvious before the priority date of the instant invention.
Broer, Brandao, and Anderson do not disclose a chimeric coronavirus spike protein that comprises an inactivated furin cleavage site or central helix that is further stabilized in a prefusion state due to two consecutive amino acid residues at the beginning of the central helix being replaced by a pair of proline residues (2P).
Pallesen discloses a rationally designed strategy to retain betacoronavirus S proteins in the prefusion conformation, and the prefusion-stabilized MERS-CoV S protein retained high-affinity binding to its dimeric receptor and a panel of neutralizing antibodies, and elicited high titers of neutralizing antibodies in mice (p. E7349, col. 2, para. 2). Pallesen further discloses that introduction of proline substitutions in the loop between the first heptad repeat (HR1) and central helix of HIV-1, RSV, and MERS-CoV restrict premature triggering of the fusion protein and often increase expression yields of prefusion ectodomains (p. E7350, col. 1, para. 1), and that single proline substitutions into a similar region in the MERS-CoV S2 subunit dramatically increased expression levels of the ectodomains, while two consecutive proline substitutions at residues V1060 and L1061 resulted in a >50-fold improvement in yield, with homologous substitutions in the S proteins from SARS-CoV and HCoV-HKU1 also increasing the expression levels of the ectodomains and improved conformational homogeneity (p. E7350, col. 1, para. 1; Fig. 1). Pallesen teaches that the introduction of two consecutive proline residues at the beginning of the central helix seems to be a general strategy for retaining betacoronavirus S proteins in the prototypical prefusion conformation (p. E7350, col. 1, para. 1). Pallesen also discloses that for efficient infection of target cells, the MERS-CoV S protein requires a two-step, protease-mediated activation to facilitate membrane fusion, where furin cleavage at the S1/S2 junction occurs in the virus producing cell, and mutation of the S1/S2 furin site (RSVR) of MERS-CoV-2 spike (pp. E7350-51, bridging para.).
Rappuoli discloses nucleic acids and proteins from SARS coronavirus that can be used in the preparation and manufacture of vaccine formulations, diagnostic reagents, kits, etc. (Abstract). Rappuoli teaches that antigens it discloses may be expressed in vivo or in vitro by polynucleotides encoding the antigens, and the expression and delivery of the polynucleotides of the invention may be facilitated via viral vectors and/or viral particles (p. 140). Rappuoli also teaches that gene-based delivery systems derived from viruses, such as alphaviruses, are useful for administration of heterologous genes, including one or more SARS genes, having therapeutic or prophylactic applications, and polynucleotides encoding SARS virus antigens are incorporated into the gene-based vaccines (p. 140). Further, the most common alphavirus expression vectors have exploited both the positive-stranded nature and modular organization of the RNA genome; these vectors, termed “replicons” due to their property of self-amplification, permit insertion of heterologous sequences in place of the structural polyprotein genes, and chimeric alphavirus vectors and particles derived from divergent virus families have also been described (pp. 140-141). Rappuoli also specifically discloses that the SARS virus spike gene can be incorporated into alphavirus replicon particles derived from a variety of alphaviruses, including Venezuelan equine encephalitis virus (p. 145). Further, Rappuoli discloses examples of alphavirus-based plasmid DNA expressing SARS virus spike for prophylactic or therapeutic immunization, and that SARS spike gene can be delivered using any of the alphavirus-based plasmid DNA replicons (p. 148). Additionally, Rappuoli discloses that its pharmaceutical compositions may also include a pharmaceutically acceptable carrier, such as a diluent or a number of other substances (p. 208).
It would have been obvious to one of ordinary skill in the art to modify the Ma5 IBV chimeric spike protein comprising VSV-G CTD and TM domains to further comprise double proline mutation, and a mutated furin cleavage site, as disclosed as a general strategy for retaining betacoronavirus S proteins in the prototypical prefusion conformation by Pallesen. One of ordinary skill in the art would have been motivated to retain the chimeric IBV spike protein in a prototypical prefusion conformation, improve yield, and stay present as an immunogenic target. There would have been a reasonable expectation of success because Pallesen discloses such mutations as a general strategy for coronavirus spike proteins.
It also would have been obvious to one of ordinary skill in the art to generate a recombinant expression vector that is a recombinant viral vector or a DNA expression vector, or more specifically an alphavirus RNA replicon particle (RP) that is a Venezuelan equine encephalitis virus (VEEV) replicon particle. Rappuoli discloses SARS-CoV spike vaccine formulations, and that gene-based delivery systems derived from viruses, such as alphaviruses, are useful for administration of heterologous genes, including one or more SARS genes, having therapeutic or prophylactic applications, and polynucleotides encoding SARS virus antigens are incorporated into the gene-based vaccines. Rappuoli also specifically discloses that the SARS virus spike gene can be incorporated into alphavirus replicon particles derived from a variety of alphaviruses, including Venezuelan equine encephalitis virus, and further teaches examples of alphavirus-based plasmid DNA expressing SARS virus spike for prophylactic or therapeutic immunization, and that SARS spike gene can be delivered using any of the alphavirus-based plasmid DNA replicons. Rappuoli also teaches that its pharmaceutical compositions may include a pharmaceutically acceptable carrier. Additionally, as further motivation to create a chimeric coronavirus spike protein comprising IBV spike protein with CTD and TMD substituted with other BVpm, because CTD and TM swapping the transmembrane and cytoplasmic domains of VSV-G for the transmembrane and cytoplasmic domains of another protein has been used to direct a protein to the cell membrane, and Anderson teaches generation of other chimeric viral proteins with such substitutions, and contemplates vaccination with such. It would have been obvious to one of ordinary skill in the art that similar compositions could be generated for use as IBV immunogenic compositions. Therefore, claims 1, 3, 5-6, 15-16, 20-21, 23-25, 28, 47, and 51 were prima facie obvious before the priority date of the instant invention.
Yamada discloses the furin cleavage site of IBV spike protein is the sequence RRFRR537/S (Abstract).
Regarding claims 17 and 48, Brandao discloses a full genome sequence of an Ma5 IBV serotype, which is described as GenBank accession: KY626045 (deposited 4/24/2017), which has 99.6% identity with SEQ ID NO: 4 residues 19-1091, see ABSS sequence alignment summary below.
PNG
media_image1.png
134
608
media_image1.png
Greyscale
Although the KY626045 sequence does not contain a mutated furin cleavage site, creating a mutant with a substitution in the furin cleavage site, as taught by Pallesen, would have been obvious to one of ordinary skill in the art. Yamada discloses that the furin cleavage site of IBV spike protein is the sequence RRFRR at position 537 of spike protein. One of ordinary skill in the art would have been motivated to retain the chimeric IBV spike protein in a prototypical prefusion conformation. Therefore, claims 1, 3, 5-6, 15-17, 20-21, 23-25, 28, 47-48, and 51 were prima facie obvious to one of ordinary skill in the art before the priority date of the instant invention.
Conclusion
No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEFFREY MARK SIFFORD whose telephone number is (571)272-7289. The examiner can normally be reached 8:30 a.m. - 5:30 p.m. ET with alternating Fridays off.
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.
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.
/JEFFREY MARK SIFFORD/Examiner, Art Unit 1671 /Michael Allen/Supervisory Patent Examiner, Art Unit 1671
Prosecution Insights