DETAILED ACTION
Replace/Supersede Previous Office Action
This Office action supersedes and replaces the Office action mailed 06/04/2026. The period for reply runs from the mailing date of the present Office action.
Disposition of Claims
Claims 1-3, 5, 7, 9, 11-12, 14, 47, 50, 66, 81-82, 91, 94, 105-106, 110-111, 113-114, and 117 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20240299534A1, Published 09/12/2024.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
This action is resetting the period for response, as the 35 USC 102 rejection in the previously mailed action is withdrawn and a new 35 USC 103 rejection is set forth herein. All objections and/or rejections have been annotated as being “withdrawn”, “new”, or “maintained” herein.
Optional Authorization to Initiate Electronic Communications
The Applicant’s representative may wish to consider supplying a written authorization in response to this Office action to correspond with the Examiner via electronic mail (e-mail). This authorization is optional on the part of the Applicant’s representative, but it should be noted that the Examiner may not initiate nor respond to communications via electronic mail unless and until Applicant’s representative authorizes such communications in writing within the official record of the patent application. A sample authorization is available at MPEP § 502.03, part II. If Applicant’s representative chooses to provide this authorization, please ensure to include a valid e-mail address along with said authorization.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/29/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
(Objection maintained.) The abstract of the disclosure is objected to because of the use of implied phraseology (e.g. “The disclosure provides…” and “The disclosure also provides…” and “The disclosure further provides…”). A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Rejections - 35 USC § 112(b); Second Paragraph
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.
(Rejection maintained.) Claims 1 and 81 and dependent claims 2-3, 5, 7, 9, 11-12, 14, 47, 50, 66, 82, 91, 94, 105-106, 110-111, 113-114, and 117 thereof are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “RBD area” in claim 1 is a relative term which renders the claim indefinite. The term “RBD area” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. While the specification attempts to define “RBD area” at ¶[0134], and notes it refers to a coronavirus (CoV) spike (S) protein receptor binding domain (RBD), as well as a portion of the S1 domain on one or both sides of the RBD, and the specification provides exemplary embodiments in which the RBD area comprises additional S1-domain amino acids adjacent to the RBD, it remains that the “RBD” of all CoV S proteins is not clearly defined and can vary depending on references or citations, and the boundary of what is, and what is not, the “RBD” of a CoV is not clearly defined in the specification or claim. Accordingly, the claim language has multiple reasonable interpretations. For example, an RBD area could be interpreted as: 1) RBD alone; 2) RBD and a short adjacent S1 sequence; 3) an RBD and up to approximately 35-40 adjacent S1-domain amino acids on one or both sides; or 4) an RBD and a larger, undefined portion of the S1 domain. It is unclear which construct falls within the scope of the claims.
Claim 81 is rejected for similar reasoning.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim(s) 1 and 81 are rejected on the grounds of being indefinite. Claims 2-3, 5, 7, 9, 11-12, 14, 47, 50, 66, 82, 91, 94, 105-106, 110-111, 113-114, and 117 are also rejected since they depend from claim(s) 1 or 81, but do not remedy these deficiencies of claim(s) 1 or 81.
Claim Interpretation
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 1 is drawn to a messenger ribonucleic acid (mRNA) comprising: an open reading frame (ORF) encoding a monomeric polypeptide chain comprising a first coronavirus (CoV) spike (S) protein receptor binding domain (RBD) area, a first linker, a hinge, a Fc domain, a second linker, and a second coronavirus spike protein receptor binding domain (RBD) area.
Further limitations on the mRNA of claim 1 are wherein the mRNA is comprising: an open reading frame (ORF) encoding a monomeric polypeptide chain comprising a first coronavirus (CoV) spike (S) protein RBD, a first linker, a hinge, a Fc domain, a second linker, and a second coronavirus spike protein RBD (claim 2); wherein the mRNA further comprises a 5′ untranslated region (5′-UTR)(claim 3); wherein the mRNA further comprises a 3′ untranslated region (3′-UTR)(claim 5); wherein the mRNA further comprises a poly(A) tail (claim 7); wherein the mRNA further comprises a 5′ cap or 5′ cap analog (claim 9); wherein the mRNA comprises a chemical modification (claim 11); wherein the mRNA further comprises a ribonucleotide sequence encoding a signal peptide (claim 12), wherein the signal peptide is a coronavirus spike protein signal peptide (claim 14); wherein the first coronavirus spike protein receptor binding domain (RBD) is a SARS-CoV-2 spike (S) protein receptor binding domain (RBD)(claim 47); wherein the second coronavirus spike protein RBD is a SARS-CoV-2 S protein RBD (claim 50); wherein the mRNA encodes from 5′ to 3′: the first coronavirus spike protein receptor binding domain, the first linker, the hinge, the Fc domain, the second linker, and the second coronavirus spike protein receptor binding domain (claim 66); a composition comprising the mRNA of claim 1 formulated in a lipid nanoparticle (claim 110); and a vaccine comprising the mRNA of claim 1 and a pharmaceutically acceptable carrier (claim 111).
Claim 81 is drawn to a monomeric polypeptide chain comprising a first CoV S protein RBD area, a first linker, a hinge, a Fc domain, a second linker, and a second CoV S protein receptor RBD.
Further limitations on the monomeric polypeptide chain of claim 81, comprising, from N-terminus to C-terminus, the first coronavirus spike protein receptor binding domain, the first linker, the hinge, the Fc domain, the second linker, and the second coronavirus spike protein receptor binding domain (claim 82); wherein the first coronavirus spike protein receptor binding domain is a SARS-CoV-2 S protein RBD (claim 91); and wherein the second coronavirus spike protein receptor binding domain is a SARS-CoV-2 spike protein receptor binding domain (claim 94).
Claim 105 is drawn to an antigenic protein comprising two monomeric polypeptide chains, wherein each monomeric polypeptide chain is as described in claim 81, wherein the antigenic protein is capable of eliciting in a subject an immune response to a coronavirus.
Further limitations on the antigenic protein of claim 105 are wherein the monomeric polypeptide chain comprises a hinge, and cysteine residues in the hinge form interchain disulfide bonds between the two monomeric polypeptide chains (claim 106).
Claim 113 is drawn to a method for eliciting an immune response in a subject in need thereof, the method comprising: providing to the subject the vaccine of claim 111.
Claim 114 is drawn to a method for preventing and/or treating a coronavirus infection in a subject in need thereof, the method comprising administering to the subject a vaccine comprising the mRNA of claim 1.
Claim 117 is drawn to a method for preventing the occurrence of COVID-19 in a subject in need thereof, the method comprising administering to the subject a vaccine comprising an mRNA comprising an open reading frame encoding a monomeric polypeptide chain comprising a first coronavirus spike protein RBD area, a first linker, a hinge, a Fc domain, a second linker, and a second coronavirus spike protein RBD area.
Claim Rejections - 35 USC § 112(a); First Paragraph
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.
(Rejection maintained.) Claims 1-3, 5, 7, 9, 11-12, 14, 47, 50, 66, 81-82, 91, 94, 105-106, 110-111, 113-114, and 117 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 certain exemplified lipid nanoparticle (LNP)-formulated mRNA constructs encoding selected SARS-CoV-2 double RBD-Fc fusion polypeptides, does not reasonably provide enablement for the full scope of the claimed mRNAs, monomeric polypeptide chains, antigenic proteins, compositions, vaccines, and methods comprising the claimed coronavirus double RBD-Fc fusion constructs. 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 and/or use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. The claims are drawn to mRNAs encoding double-ended coronavirus (CoV) spike (S) protein receptor binding domain (RBD) -Fc fusion polypeptides (e.g. RBD-Fc-RBD), the corresponding polypeptide chains encoded from said mRNAs, dimeric antigenic proteins, lipid nanoparticle (LNP) compositions, vaccines, and methods of eliciting an immune response or preventing/treating CoV infections through the delivery of vaccines encoding said mRNAs.
“Coronavirus” is broadly drawn to any member of the Coronaviridae family of enveloped, positive-stranded RNA viruses. The family Coronaviridae is organized in 3 subfamilies, 6 genera, 28 sub-genera, and 54 species. The subfamily Orthocoronavirinae includes Middle East respiratory coronavirus (MERS CoV) and severe acute respiratory coronavirus (types 1 and 2; SARS CoV-1 and SARS CoV-2). All members of the family Coronaviridae encode a spike (S) protein that is the prominent structural protein which protrudes from the viral envelope, giving the virus its characteristic "crown" or halo-like appearance.
“Fc domain” or the Fragment crystallizable domain, is the tail region of an antibody that interacts with cell-surface receptors and complement proteins to elicit an immune response. They are classified into five primary types corresponding to antibody isotypes, alongside engineered variants designed for therapeutics. In humans, Fc domains are defined by their heavy-chain constant regions (CH2 and CH3) domains, namely IgG, IgE, IgA, IgD, and IgM. The type of Fc domain determines as to which immune system receptors it may bind.
As set forth supra, the “RBD” is broadly defined and unclear across the scope of the claims. For SARS CoV-2 RBD, for instance, is generally considered to be located between amino acid residues 319 and 541, but varies depending on the sequence/isolate of the S protein and the citing literature as to the boundaries of this functional region. The primary function of the Receptor-Binding Domain (RBD) in SARS-CoV-2 is to facilitate viral entry into human cells by binding to the Angiotensin-Converting Enzyme 2 (ACE2) receptor on the host cell.
The recitation of “preventing a CoV infection" is interpreted to encompass the complete blockade of any individual cell within the subject from any CoV infection.
The scope of the claims is substantially broader than the tested embodiments. Claims 1 and 81, for instance, are not limited to SARS CoV-2 S protein RBDs, but any RBD from any CoV. The claims additionally encompass any amount of undefined flanking RBD sequence, different variant pairings, different relative arrangements of RBD areas, different linkers (e.g. lengths, compositions, sequences, etc.), different hinge sequences, different Fc domains, and combinations thereof. The method claims also are drawn to eliciting an immune response and/or treating/preventing infection against any CoV and does not require the RBD eliciting the therapeutic immune response to be derived from the same CoV being treated under the claimed method.
State of the prior art/Predictability of the art. At the time of filing of the instant invention, the art established that mRNA vaccines, tandem coronavirus RBD antigens, and Fc-fusion vaccine antigens were known. However, the art did not establish that the varied components encompassed by the claims could be substituted interchangeably while retaining adequate expression, stability, antigen presentation, immunogenicity, neutralizing antibody activity, or therapeutic efficacy.
Pardi et. al. (Pardi N, et. al. Nat Rev Drug Discov. 2018 Apr;17(4):261-279. Epub 2018 Jan 12.) describes mRNA vaccines as a promising platform while explaining that mRNA-vaccine development requires optimization of translation, innate and adaptive immunogenicity, stability, and delivery. Pardi notes that while animal models of mRNA vaccination were promising, the results viewed in these models did not always translate to the clinical studies.
Dai et. al. (WO2021159648A1) teaches beta-CoV antigens comprising tandem single-chain RBD dimers, including RBD sequences joined through ser/gly linkers. Dai further proposes a beta-CoV mRNA vaccine comprising an mRNA sequence encoding the antigen, and provides mouse immunogenicity data for selected 2019-nCoV and SARS CoV RBD constructs. While Dai supports the general feasibility of tandem RBD antigens, it fails to provide a general rule that enables selection of operable double-ended RBD-linker-hinge-Fc-linker-RBD constructs throughout the scope presently claimed. Zion et. al. (US20210346490A1) teaches constructs which are encompassed by the instant claims, but Zion confirms that the identification of suitable constructs requires empirical evaluation. Ren et. al. (Ren W, et. al. Vaccine. 2020 Jul 31;38(35):5653-5658. Epub 2020 Jun 24.) teach that a recombinant SARS CoV-2 spike S1 Fc-fusion protein induced neutralizing responses in mice, rabbits, and nonhuman primates. Ren supports the general feasibility of SARS-CoV-2 S-Fc fusion antigens, but does not establish that any CoV RBD area, linker, hinge, Fc domain, or double-ended arrangement will predictably provide an operable vaccine construct.
Diamos et. al. (Diamos AG, et. al. Front Immunol. 2020 Dec 4;11:576012.) describes empirical optimization of IgG-fusion vaccine candidates and reports that modifications affected expression, solubility, stability, and immunogenicity. Diamos further demonstrates that IgG-fusion vaccine design is not “plug-and-play”, but requires empirical validation to determine which protein components from both the Fc and virus can be utilized, as Diamos shows that known antibodies against Zika virus envelope domain recognized different variations of said envelope domain fused to different Fc portions of an antibody (Fig. 1). Kontermann (Kontermann RE. Curr Opin Biotechnol. 2011 Dec;22(6):868-76. Epub 2011 Aug 20.) teaches recombinant fusion proteins in which an Fc domain is used as a central scaffold and is genetically fused to functional protein domains through hinge regions and peptide linkers. Kontermann establishes the general technical feasibility of constructing Fc-centered fusion proteins containing multiple functional domains and linker elements. However, Kontermann fails to identify a structural rule sufficient to predict which CoV RBD-linker-hinge-Fc-linker-RBD fusion constructs will express adequately, remain stable, elicit the desired therapeutic or preventative immune response, or otherwise treat or prevent any CoV infection.
The state of the art therefore provided methods for constructing and screening candidate mRNA and Fc-fusion vaccine constructs, but did not provide a predictable structure-function relationship that would allow a person skilled in the art to identify operable embodiments throughout the claimed genus without empirical screening.
Working examples. The specification provides working examples for selected SARS CoV-2 mRNA constructs; Example 1 starting at ¶[0193] describes the construction of polynucleotides encoding RBD-linker IgG4 Fc, IgG4 Fc-linker-RBD, and RBD-linker-IgG4 Fc-linker-RBD constructs (¶[0195]). The expression yields of these different constructs were analyzed in Example 2 (starting at ¶[0199]) with certain constructs producing little to no detectable protein (Tables 4-6). Example 3 starting at ¶[0205] analyzes the ability for the polynucleotide constructs to be expressed in vivo, while Example 4 starting at ¶[0207] describes preparation of pseudouridine-containing, capped, polyadenylated mRNA, wherein said mRNA was formulated in an LNP comprised of an unknown ionizable lipid, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, and unidentified PEG-lipid (with molar ratios of 50:10:38.5:1.5)(¶[0209]).
The working examples demonstrate that construct performance varies materially depending on the selected components and their relative arrangement. Example 5 reports different in vitro and in vivo expression levels for RBD-Fc fusion proteins having different lengths, with at least one construct expressing at levels similar to internal saline and GFP controls (Fig. 4). Example 6 reports that Fc-RBD fusion protein expression was higher and maintained for a longer period than RBD-Fc fusion protein expression (Fig. 5), while Example 7 reports that a double-ended RBD_Delta-Fc-RBD_WT fusion protein exhibited higher in vivo expression than the reverse RBD_WT-Fc-RBD_Delta arrangement (Fig. 6). Example 8 reports that linker length affected expression of RBD-Fc fusion proteins, with longer linkers producing higher expression for the tested configurations (Fig. 8). Example 9 reports that the hinge affected stability of both double-ended RBD-Fc and single-ended RBD-Fc fusion proteins (Figs. 9-10). Example 10 assessed in vitro and in vivo expression levels of RBD-Fc fusion proteins with IgG1 and IgG4 Fc, and as shown in FIG. 11A, IgG4-Fc (F234A/L235A double mutant) fused antigens have similar in vitro expression levels compared to IgG1-Fc fused proteins. However, as shown in FIG. 11B, IgG4-Fc (F234A/L235A double mutant) fused antigens have significantly higher in vivo expression levels than IgG1-Fc fused proteins, and longer in vivo half-life. Examples 12-18 report LNP-mRNA vaccination studies in mice, wherein these studies evaluated selected SARS-CoV-2 constructs and measured antigen expression, anti-RBD antibody levels, and assessed pseudovirus neutralization titers against selected SARS CoV-2 variants, including Delta, Omicron BA.1, and Omicron BA.2.
The specification does not provide working examples demonstrating operability throughout the full scope of the claims. The specification only provides working examples for SARS CoV-2 RBD S protein sequences and constructs, and does not show any studies with any other RBD from any other CoV. It is unclear as to the construct of LNPs which delivered the mRNA, and no other LNP formulations appear to have been studied for their efficacy in delivering and expressing the mRNA. The specification fails to provide sufficient guidance regarding the breadth of RBD “areas”, linker sequences, hinge sequences, Fc domains, RBD-area pairings, or combinations thereof encompassed by the claims. The animal model did not appear to utilize a human ACE2-expressing animal model, so prevention or inhibition of SARS CoV-2 infection in a challenge study was not performed or assessed, nor were any other CoV infections tested, nor were any cross-reactive immune responses assessed.
Guidance in the specification. The specification provides guidance for preparing and evaluating selected mRNA constructs. It identifies exemplary RBD sequences, linker sequences, hinge sequences, Fc domains, untranslated regions (UTRs), signal peptides, nucleoside modifications, and LNP components. It also describes assays for measuring in vitro/in vivo expression, antigen stability, antibody levels, and pseudovirus neutralization titers. However, the specification fails to identify a structural characteristic common to the claimed genus that reliably predicts adequate expression, stability, immunogenicity, neutralizing-antibody activity, or therapeutic efficacy. The disclosed examples instead demonstrate that changes in RBD length, RBD orientation/order, RBD pairing, linker length/sequence, hinge presence/sequence, and Fc-domain type can materially affect performance. The specification fails to provide criteria sufficient to determine, without empirical testing, which additional CoV RBD areas may be used, how much adjacent S1 domain sequence may be included within an RBD area, which first and second RBD area combinations are suitable, which linker and/or hinge sequences are useful, and which Fc domains should be utilized, or which resulting constructs will elicit a sufficient immune response to prevent or treat any CoV infection.
Amount of experimentation necessary. Additional research is required in order to determine which constructs within the claimed genus are operable and suitable for the claimed uses.
In light of the Supreme Court decision in Amgen Inc. et al. v. Sanofi et al., 143 S. Ct. 1243 (2023) (hereafter Amgen), updated guidelines were provided regarding the assessment of enablement (Federal Register, pp. 1563-1566; Pub. Jan. 10, 2024.) In Amgen, the Supreme Court unanimously affirmed that a genus of monoclonal antibodies were not enabled because when a range within a genus is claimed, there must be reasonable enablement of the scope of the range. The Court found in Amgen that due to the large number of possible candidates within the scope of the claims and the specification's corresponding lack of structural guidance, it would have required undue experimentation to synthesize and screen each candidate to determine which compounds in the claimed class exhibited the claimed functionality. In the instantly claimed invention, the claims encompass a broad genus of mRNAs and encoded fusion proteins having variable CoV RBD areas, RBD-area boundaries, linker sequences, hinge sequences, Fc domains, RBD orders/pairings, and combinations thereof. The specification does not identify a structural characteristic common to the claimed genus that reliably predicts expression, stability, immunogenicity, neutralizing-antibody activity, or therapeutic efficacy. Instead, the working examples demonstrate the large amount of empirical validation that must be performed for each of these structural elements, which amounts to an undue amount of experimentation for the CoV RBD and Fc-fusion protein elements claimed.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to make and/or use the claimed products and methods.
(Rejection maintained.) Claims 105-106, 111, and 113-114 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 following quotation from section 2163 of the Manual of Patent Examination Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirements for a generic claim covering several distinct inventions:
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 applicant was in possession of the claimed genus... See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Thus, when a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed.
Claims 105-106, 111, and 113-114 are rejected as lacking adequate descriptive support for the claimed genus of antigenic proteins capable of eliciting an immune response in any subject to any CoV, the claimed genus of vaccines comprising the mRNA of claim 1 and for methods of eliciting any immune response against any CoV using said vaccines, and the claimed genus of methods of eliciting any immune response with said mRNA vaccines that prevents and/or treats any CoV.
In support of the claimed genera (any antigenic CoV RBD-Fc-RBD proteins, any method of eliciting any immune response, any method of preventing/treating any CoV infection), the application discloses selected SARS CoV-2 RBD-Fc fusion constructs and select LNP formulated mRNAs encoding such constructs. The working examples evaluated selected SARS CoV-2 RBD sequences, including wild-type, Delta, Omicron BA.1, and Omicron BA.2 sequences. The application reports antibody levels and pseudovirus neutralization titers for selected SARS CoV-2-Fc constructs in a mouse model. However, these limited examples (discussed in more detail supra in the 35 USC 112a scope of enablement rejection) does not provide representative number of examples across the full scope of the claimed genera. For instance, the only RBD from any CoV tested was from SARS CoV-2; no RBD from MERS-CoV, SARS CoV, huCoV 229e, etc. were tested in any of the Fc fusion protein formats. Only a limited number of Fc domains were tested; said Fc domains were limited to human Fc and did not include Fc from any other species or any synthetic or chimeric Fc domains. Only a limited number of linkers were tested, and only specific hinge regions were tested. As set forth supra, the metes and bounds of “RBD area” are unclear, so it is not clear as to what sequences from SARS CoV-2 S proteins should, or should not be tested, and it is also equally unclear what other RBD areas from other CoV should be tested. The breadth of further limitations was not tested, as it is unclear how changing signal domains, UTRs, 5’ caps, 3’ polyA tails, and chemically modified mRNA would affect the claimed methods. Only a generically recited LNP was tested, and it is unclear as to the nature of the “ionizable lipid” and the “PEG lipid” used in the LNPs, as these can also affect the overall function of the methods. Thus, the application fails to provide a sufficient number of examples of species within the broadly claimed genera.
Further, while the claims provide both a general structure and function, the application fails to establish a sufficient correlation between the two. The application does not identify structural characteristics common to the claimed genus that allow a person skilled in the art to determine which double-ended RBD-linker-hinge-Fc-linker-RBD constructs will elicit an immune response to any CoV. Applicant’s own data demonstrates that, with respect to the mRNA, selected structural variables affect expression, stability, and persistence. There is no correlation between the broadly recited double-ended RBD-Fc fusion protein and the claimed therapeutic functions. The ability of selected SARS CoV-2 constructs to elicit antibodies and pseudovirus neutralization titers following prophylactic administration does not, without more, reasonably convey possession of the broader genus of methods for treating any existing CoV infection or for preventing any CoV infection in any subject. The application therefore fails to establish a reliable correlation between the broadly claimed structures and the claimed functions said structures are to perform.
Thus, in view of the above, there would have been significant uncertainty as to which antigenic RBD-Fc fusion proteins would be able confer the claimed function of eliciting any immune response to any CoV. Additionally, there would have been significant uncertainty as to which mRNAs and encoded fusion proteins would elicit any immune response against any CoV in the methods claimed, or would be useful to prevent or treat any CoV infection in any subject claimed. In view of this uncertainty and the lack of sufficient examples of the broadly claimed genera, the claims are rejected for lack of adequate written description support.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
(Rejection withdrawn.) The rejection of Claims 81-82, 91, 94, and 105-106 under 35 U.S.C. 102(a)(2) as being anticipated by Zion et. al. (US20210346490A1, Priority 04/10/2020; hereafter “Zion”) is withdrawn in light of the new 35 USC 103 rejection herein.
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.
(Rejection withdrawn.) The rejection of Claims 1-3, 5, 7, 9, 11-12, 14, 47, 50, 66, 110-111, 113-114, and 117 under 35 U.S.C. 103 as being unpatentable over Zion as applied to claims 81-82, 91, 94, and 105-106 above, and further in view of Dai et. al. (WO2021159648A1; Priority 02/10/2020; hereafter “Dai”; NB: WIPO publication is not in English, so citations refer to the USPGPub of this application, US20220305113A1, Pub. 09/29/2022), Mumm et. al. (US20190241659A1, Pub. 08/08/2019; hereafter “Mumm”), and Stewart-Jones (WO2021159040A2, Pub. 08/12/2021; hereafter “Stewart-Jones”) is withdrawn in light of the new 35 USC 103 rejection set forth herein.
(New rejection.) Claims 1-3, 5, 7, 9, 11-12, 14, 47, 50, 66, 81-82, 91, 94, 105-106, 110-111, 113-114, and 117 are rejected under 35 U.S.C. 103 as being unpatentable over Zion et. al. (US20210346490A1, Priority 04/10/2020; hereafter “Zion”), and further in view of Dai et. al. (WO2021159648A1; Priority 02/10/2020; hereafter “Dai”; NB: WIPO publication is not in English, so citations refer to the USPGPub of this application, US20220305113A1, Pub. 09/29/2022), Mumm et. al. (US20190241659A1, Pub. 08/08/2019; hereafter “Mumm”), and Stewart-Jones (WO2021159040A2, Pub. 08/12/2021; hereafter “Stewart-Jones”.)
The Prior Art
Zion teaches SARS-CoV-2 RBD-Fc fusion proteins comprising a SARS-CoV-2 RBD fragment, an optional peptide linker, and an Fc fragment, and pharmaceutical compositions comprising said RBD-Fc fusion protein to treat and inhibit COVID-19 disease (entire document; see abstract; Figs. 1-2). Zion teaches these fusion proteins may be homodimers (reference claim 5) and that the Fc region would comprise a hinge region (¶[0006]; instant claims 82, 91, 94). Zion teaches that these constructs may be in further multimeric form, such as dimers (¶[0132]; instant claim 105). Zion teaches that disulfide bridges may form bonds between the two monomeric polypeptide chains (¶[0006]; instant claim 106).
While Zion teaches RBD-Fc domain fusion proteins of the instant claims, and teaches nucleic acids encoding said proteins (¶[0013]), Zion does not explicitly teach that the nucleic acid encoding said proteins is mRNA, or that the RBD is at the N- and C-terminus of the protein, sandwiching the Fc domain between the two RBD domains. While Zion teaches the mRNA vaccines against SARS CoV-2 and that said vaccines are an mRNA-LNP platform that deliver S protein antigens to the host (¶[0116]), Zion does not teach delivery of their protein constructs using said mRNA-LNP platform. However, motivation to use the mRNA which expresses the protein of Zion was present in the art at the time of filing, as well as generating RBD-Fc-RBD fusion proteins, as evidenced by Dai, Mumm, and Stewart-Jones.
Dai teaches antigens of β-coronaviruses, preparation methods and uses thereof, wherein the amino acid sequence of the antigen of the β-coronavirus includes an amino acid sequence arranged in a (A-B)-(A-B) pattern or an amino acid sequence arranged in a (A-B)-C-(A-B) pattern or an amino acid sequence arranged in a (A-B)-(A-B′) pattern or an amino acid sequence arranged in a (A-B)-C-(A-B′) pattern. The antigen of the β-coronavirus has a single-chain dimer structure and can be used in vaccines to elicit high-titer neutralizing antibodies (entire document; see abstract.) Dai teaches that each (A-B) portion comprises a partial or complete amino acid sequence of a receptor binding region of a β-coronavirus spike protein and (C) comprises a linking amino acid sequence (¶[0012]). Dai further teaches that the linking amino acid sequence may comprise a ser-gly linker of (GGS)n (¶[0014]) and teaches tandem receptor binding domain (RBD) sequences connected through peptide linkers (¶[0019][0036][0038-0040]; Fig. 1.) Dai teaches a β-coronavirus mRNA vaccine comprising an mRNA sequence encoding said β-coronavirus antigens (¶[0067]). Dai teaches that a sequence encoding a signal peptide would be added to the 5’ terminal of the mRNA, wherein said signal peptide may be a signal peptide from a coronavirus spike protein (¶[0061][0148]; instant claims 12, 14). Dai teaches that the first and second RBD may be SARS-CoV-2 S protein RBDs (¶[0147]; instant claims 47, 50).
Mumm teaches bispecific fusion proteins comprising: a single chain fusion protein comprising a first binding region specific for a first cell surface target, an Fc monomer, and a second binding region specific for a second cell surface target, wherein the first binding region and the second binding region are covalently linked to the Fc monomer via a peptide linker, and wherein the bispecific fusion protein is capable of binding the first cell surface target and the second cell surface target at the same time (entire document; see abstract; reference claim 1.) Mumm teaches that the binding regions would preferably bind to a cell-surface receptor (¶[0015][0129-0131]). The two receptor binding domains are joined by the Fc domain, wherein the Fc domain comprises a hinge region (SEQ ID NOs: 6, 9; reference claim 9; ¶[0020][0115-0116]) and a peptide linker (¶[0116][0130][0137]). Said bispecific proteins can be administered within pharmaceutically acceptable compositions (¶[0118]).
Stewart-Jones teaches RNA vaccines that encode domains and subunits of coronavirus (CoV) proteins (entire document; see abstract; Fig. 1). Stewart-Jones teaches messenger ribonucleic acid (mRNA) comprising an open reading frame (ORF) that encodes at least two domains of a SARS-CoV-2 Spike (S) protein, and less than the full length spike protein, wherein at least one domain is a RBD of the S protein (reference claims 1, 2, 26). Stewart-Jones teaches that the domains can be linked through linkers (reference claims 8-9), and that the ORF encodes a signal peptide (reference claim 11) that is linked to the RBD (reference claim 13). Stewart-Jones teaches the mRNA may comprise functional regions, such as a 5’ cap (reference claim 45; NB: there are two claim 45s, this is the second; instant claim 9) a 3’ poly A tail (reference claim 46; instant claim 7), or a 5’ and/or 3’ UTR (reference claims 120-121; instant claims 3, 5). Stewart-Jones further teaches chemical modifications to the mRNA, such as the use of 1-methyl-pseudouridine to replace the uridines in the mRNA (reference claims 47-48; instant claim 11). Stewart-Jones teaches the mRNA may be formulated in a lipid nanoparticle (LNP)(reference claims 64-68; instant claim 110) or vaccine compositions comprising pharmaceutically-acceptable carriers (p. 17, ¶2; p. 19, ¶2; p. 118, ¶2; p. 2, ¶1; abstract; instant claim 111). Stewart-Jones teaches that the mRNA compositions may be used in methods to elicit immune responses in a subject in need thereof through the administration of the mRNA vaccines, wherein said administration may happen in a prophylactically effective dose to prevent infection with the virus at a clinically acceptable level (p. 121, ¶2-6; instant claims 113-114). Stewart-Jones teaches the disease associated with SARS-CoV-2 infection is COVID-19, so inhibition of SARS-CoV-2 infection with methods of administration of the mRNA vaccines would inhibit the occurrence of COVID-19 (p. 5, ¶1; instant claim 117).
Given the teachings of Zion, a skilled artisan would be apprised as to the usefulness of a protein which presented multiple SARS-CoV-2 antigens in a multimeric format, such as the highly antigenic RBD, as said region would not only sterically inhibit the entry of virus into its target cell through competitive inhibition, but would also elicit a therapeutic immune response against this region on the Spike protein. Given the teachings of Dai and Mumm, one would further find it obvious to generate a bispecific fusion protein joined by a Fc region, as Mumm teaches joining receptor binding domains through a Fc domain and Dai teaches attaching a Fc to SARS-CoV-2 RBD. Delivering this biological therapeutic as a protein is taught by Zion, but delivering it as an mRNA vaccine would also be an obvious modification, given the teachings of Stewart-Jones and Dai. Given the prior art, arriving at the limitations of instant claims 1-3, 5, 7, 9, 11-12, 14, 47, 50, 66, 81-82, 91, 94, 105-106, 110-111, 113-114, and 117 would be obvious to a skilled artisan, given the teachings of Zion, Dai, Mumm, and Stewart-Jones.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Zion in order to deliver the RBD-Fc fusion protein homodimer in a different format, such as delivering a nucleic acid, such as mRNA, which encodes said protein. One would have been further motivated to have both copies of the RBD expressed as a single monomeric peptide to aid in expression and to avoid the necessity of making the homodimers of Zion. One would have been motivated to make such changes, given the suggestion by Stewart-Jones and Dai that delivery of mRNA encoding therapeutic proteins was known in the art. There would have been a reasonable expectation of success, given the knowledge that Stewart-Jones teaches delivery of mRNA encoding SARS-CoV-2 RBD antigens in lipid nanoparticles with specific structures/modifications to stabilize the mRNA, and also given the knowledge that RBD-Fc-RBD fusion peptides were known in the art as a therapeutic modality, as taught by Mumm, and that presenting multiple forms of RBD at once was suggested in the art, as taught by Zion. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure and is listed below.
Gauthier et. al. (US20170210802A1, Pub. 07/27/2017; hereafter “Gauthier”). Teaches antigen binding proteins joined by linkers, Fc domain, and hinges. Not utilized as rejection would be redundant to those set forth supra.
Shin HJ, et. al. Int J Biol Sci. 2021 Aug 28;17(14):3786-3794. Teaches SARS-CoV-2 S protein RBD-Fc fusion protein. Not utilized as rejection would be redundant to those set forth supra.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RACHEL B GILL whose telephone number is (571)272-3129. The examiner can normally be reached on M to F 8:00 AM to 5:00 PM Eastern.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671
Prosecution Insights