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 .
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. However, the examiner notes that the certified copy of the foreign priority document is not in English, which is necessary to perfect priority.
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
The earliest potential effective filing date of the claimed inventions is 05-28-2020 based on the filing date of foreign application ESP202030498.
Status of Claims
Claims 1, 9, 12, 15, 17-19, 21, and 23-34 are pending and examined on their merits.
Information Disclosure Statement
The Information Disclosure Statement filed 11-28-2022 is acknowledged and has been considered.
Please note that the listing of references in the specification beginning on page 55 is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, applications, or other information submitted for consideration by the Office, and MPEP § 609.04(a), subsection I. 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.
Drawings
The drawings are objected to because the drawings are indicated by “Figure” rather than “FIG.” as required by 37 C.F.R § 1.84 (u)(1) (see also MPEP § 608.02 (V)). The different views must be numbered in consecutive Arabic numerals, starting with 1, independent of the numbering of the sheets and, if possible, in the order in which they appear on the drawing sheet(s). Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter. View numbers must be preceded by the abbreviation “FIG.” Where only a single view is used in an application to illustrate the claimed invention, it must not be numbered and the abbreviation “FIG.” must not appear.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification on page 14, lines 22-30 are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). It appears that applicant amended other areas of the specification to address this issue in the amendment filed on 12-14-2022 but may have inadvertently missed this instance.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above. Specifically, the ASCII file size is listed in KB instead of bytes as required.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 47 lines 28-29. 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:// or other browser-executable code. This can be accomplished by replacing a “.” with an underscore (e.g., “_com”). See MPEP § 608.01.
Claim Objections
Claims 1, 9, 12, 15, 17, 19, 21, 23-25, 27-29, and 32-34 are objected to because of the following informalities:
Claims 1 and 17 recite “SEQ_ID_1”. This should be amended to read “SEQ ID NO: 1” to conform with US practice/form.
Claims 9 and 32-34 recite the phrase “The RNA replicon according to claim 1, having a size between…”. The claims should be amended to read “The RNA replicon according to claim 1, wherein the RNA replicon is between XX and XX kb in length” or similar wording as applicant sees fit to put the claims in better form.
Claim 12 recites the phrase “wrapped within a VLP-E+”. Please expand on the acronym VLP-E+ (e.g., a virus-like particle expressing envelope protein).
Claim 15 recites a Markush group using the phrase “selected among”. Please amend the claim to read “selected from the group consisting of…” to put the claim in proper Markush group form.
Claim 15 additionally recites: “totally or partially deleting of at least 4 genes…”. Please amend this phrase to read either “totally or partially deleting at least 4 genes” or “total or partial deletion of at least 4 genes” to put the claim in better form.
Claim 15 additionally has an editing error in the second to last line; please amend “rtansfecting" to “transfecting”.
Claim 17 should be amended to read:
“The method according to claim 15 comprising:
partial deletion of the gene encoding the E protein, wherein the last 52 nucleotides of the gene are retained, and
total or partial deletion of at least 4 genes encoding genus accessory proteins selected from the group consisting of 3, 4a, 4b, and 5 of MERS CoV, wherein 39 nucleotides of the gene encoding genus accessory protein 3 corresponding to nucleotides 33409-33447 of SEQ ID NO: 1 are retained”
Or similar wording as applicant sees fit to put the claim in better form.
Claim 19 recites a Markush group using the phrase “is selected between:”. Please amend the claim to read “The method according to claim 15, wherein the total or partial deletion of genes from the genome is accomplished by a process selected from the group consisting of restriction enzyme digestion, vector recombination, and CRISPR editing” or similar wording as applicant sees fit to put the claim in better form.
Claim 21 recites the limitation “the cDNA sequence complementary to the RNA replicon”. There is no antecedent basis for this limitation in the claim because parent claim 1 does not establish a cDNA sequence.
Claim 23 recites a Markush group using the phrase “which is selected from”. Please amend the claim to read “The expression vector according to claim 21 wherein the vector backbone is selected from the group consisting of…” or similar wording as applicant sees fit to put the claim in proper Markush group form.
Claim 24 recites a Markush group using the phrase “selected from the group of:”. Please amend the claim to read “selected from the group consisting of:” to put the claim in proper Markush group form.
Claim 25 should be amended to read “A vaccine composition that induces protection against infection by a coronavirus in a subject, wherein the vaccine composition comprises an RNA replicon according to claim 1 and, optionally, at least one pharmaceutically acceptable excipient and/or at least one chemical or biological adjuvant or immunostimulant” or similar wording as applicant sees fit to put the claim in better form.
Claims 27 and 28 recite the limitation “immunostimulator”. This should be amended to “immunostimulant” for consistency with claim 25.
Claim 29 should be amended to read “The vaccine composition according to claim 25, wherein the vaccine composition is a liquid or lyophilized” or similar wording as applicant sees fit to put the claim in better form.
Appropriate correction of all claim rejections is required.
Claim Rejections - 35 USC § 112(b)
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.
Claims 1, 9, 12, 15, 17-19, 21, and 23-34 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.
Claim 1 reads:
An RNA replicon derived from a coronavirus to which it has been deleted comprising:
- partially the gene encoding the E protein retaining the last 52 nucleotides of the sequence of this gene and
- total or partially at least 4 genes encoding genus accessory proteins selected from 3, 4a, 4b and 5 of MERS CoV retaining 39 nucleotides of the sequence of the gene encoding genus accessory protein 3, said 39 nucleotides are located in position 33409-33447 of SEQ ID 1, and
- an identity of at least 95% or 96% or 97% or 98% or 99% with respect to the sequence SEQ ID 1, namely with respect to the fragment comprised from nucleotides 7890 to 35838.
This claim is generally narrative and indefinite; it is unclear if all of the claimed limitations are deleted from the RNA replicon and/or if the limitations define what the replicon is (i.e., rather than what is deleted).
Additionally, the limitation “namely with respect to the fragment comprised from nucleotides 7890 to 35838” is indefinite because it is unclear if Applicant is claiming 95% identity to SEQ ID NO: 1 overall or specifically to nucleotides 7890 to 35838 of SEQ ID NO: 1. For the purposes of compact prosecution and applying prior art, the examiner has interpreted the claim to be drawn to at least 95% identity to nucleotides 7890 to 35838 of SEQ ID NO: 1.
Based on the information about preparing the RNA replicon in the specification on page 4 paragraph 2, the examiner has interpreted claim 1 as follows:
An RNA replicon derived from a coronavirus comprising:
partial deletion of the gene encoding the coronavirus E protein, wherein the last 52 nucleotides of the gene are retained, and
total or partial deletion of at least 4 genes encoding genus accessory proteins selected from the group consisting of 3, 4a, 4b, and 5 of MERS CoV, wherein 39 nucleotides of the gene encoding genus accessory protein 3 corresponding to nucleotides 33409-33447 of SEQ ID NO: 1 are retained, and
a sequence with at least 95% identity to nucleotides 7890 to 35838 of SEQ ID NO: 1.
Claim 12 recites the limitation “the RNA replicon is wrapped within a VLP-E+”. It is unclear what “wrapped within” means in the context of a VLP, and the specification does not define this limitation. For the purposes of compact prosecution and applying prior art, the examiner has interpreted this limitation to be drawn to “the RNA replicon is packaged in a VLP-E+”.
Claim 15 recites the limitations “the full-length cDNA” and “the upstream expression vector”. There is no antecedent basis for these limitations in the claim as parent claim 1 does not establish cDNA or an upstream expression vector.
Claim 17 recites the limitation “comprising total or partial deletion of the gene encoding E protein retaining the last 52 nucleotides of the sequence of this gene…”. It is unclear how the E gene can simultaneously be totally deleted and also retain the last 52 nucleotides of the sequence. For the purposes of compact prosecution and applying prior art, the examiner has interpreted claim 17 to be drawn to partial deletion of the E gene.
Claim 18 recites the limitation “several fragments”. This limitation is indefinite because the metes and bounds of “several” is unclear. For the purposes of compact prosecution and applying prior art, the examiner has interpreted “several” to mean more than 1 fragment.
Claim 24 recites the limitation “preferably” in lines 3, 4, and 6. “Preferably” is indefinite because it is unclear if the claim encompasses the preferred embodiments. Thus, the metes and bounds of the claim are unclear.
Claim 25 contains an erroneous period after “and/or” in line 4. This renders the claim indefinite because the metes and bounds of the claim are unclear.
Claim 34 is drawn to the RNA replicon of claim 1 wherein the replicon is between 22 and 24 kb in size. Claim 1 establishes that the RNA replicon is at least 95% identical to nucleotides 7890 to 35838 of SEQ ID NO: 1; the fragment comprising nucleotides 7890 to 35838 of SEQ ID NO: 1 is 27948 bp. Deletion or addition of portions of the RNA replicon to retain 95% identity to nucleotides 7890 to 35838 of SEQ ID NO: 1 would result in a replicon that is 26551 - 29345 bp in size. Thus, it is unclear how the replicon can be between 22 and 24 kb in size and still retain 95% identity to nucleotides 7890 to 35838 of SEQ ID NO: 1.
Claims 9, 19, 21, 23, 26-29, and 30-33 are rejected due to their dependence on claim 1.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 26-27 and 31 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 oral, subcutaneous, or intramuscular vaccine administration, does not reasonably provide enablement for topical vaccine administration. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Nature of the invention/ breadth of the claims/ level of skill in the art. Claims 26-27 and 31 are drawn to a vaccine comprising the RNA replicon of claim 1 (claims 26-27) or a method of using the RNA replicon of claim 1 as a vaccine (claim 31) wherein the vaccine is administered topically, intranasally, orally, subcutaneously, or intramuscularly.
The level of one of ordinary skill in the art of this invention is high, minimally requiring an advanced degree to understand the nuance of vaccine design and administration.
State and predictability of the art. CDC (Vaccine Administration 2025- see attached form 892) teaches that vaccines can be administered orally, intranasally, subcutaneously, or intramuscularly (Site and Route Selection). Goldman (Stanford Medicine News Center 2024- see attached form 892) teaches the development of a topical vaccine candidate (engineering a living vaccine). However, this vaccine was developed in 2024 (i.e., after the EFD of the instant application) and has only been tested in mice (see section “look, ma, no limits”).
Working examples and guidance in the specification. The specification provides working examples and guidance on intranasal vaccine administration. However, no guidance or working examples are provided for topical vaccine administration.
Amount of experimentation necessary. Given, inter alia, the unpredictability in the art and the limited working examples/directions in the specification, extensive experimentation and research would be needed to assess if topical vaccine administration would successfully induce an immune response against MERS-CoV.
As such, claims 26-27 and 31 contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 9, 12, 15, 17-19, 21, 23-24, and 32-34 are rejected under 35 U.S.C. 103 as being unpatentable over Almazán et al (mBio 2013- included on IDS) as evidenced by Wang et al (GenBank accession number U51113.1 and BioTechniques 1997- included on IDS) and van Boheemen et al (GenBank accession number JX869059.2 and mBio 2012- included on IDS).
Claim 1 is drawn to:
An RNA replicon derived from a coronavirus comprising:
partial deletion of the gene encoding the coronavirus E protein, wherein the last 52 nucleotides of the gene are retained, and
total or partial deletion of at least 4 genes encoding genus accessory proteins selected from the group consisting of 3, 4a, 4b, and 5 of MERS CoV, wherein 39 nucleotides of the gene encoding genus accessory protein 3 corresponding to nucleotides 33409-33447 of SEQ ID NO: 1 are retained, and
a sequence with at least 95% identity to SEQ ID NO: 1.
Almazán et al teaches a RNA replicon system for MERS-CoV wherein viral accessory genes 3, 4a, 4b, and 5 and the envelope protein are totally or partially deleted (abstract). Specifically, Almazán et al teaches the replicon rMERS-CoV-ΔE wherein the E gene is deleted except for the last 49 nucleotides (Generation of a rMERS-CoV mutant lacking the structural E protein gen and Figure 4A), rMERS-CoV-Δ3 wherein the gene encoding accessory protein 3 is deleted except for the last 41 nucleotides, rMERS-CoV-Δ4ab wherein the genes encoding accessory proteins 4a and 4b are deleted except for the last 81 nucleotides of gene 4b, and rMERS-CoV-Δ5 wherein the entire gene encoding accessory protein 5 is deleted (Rescue of infectious rMERS-CoVs lacking accessory genes 3, 4a and 4b, and 5 and Figure 3A). Almazán et al does not specifically teach a replicon wherein both the E gene and the genes encoding the accessory proteins are totally or partially deleted or that the replicon is at least 95% identical to SEQ ID NO: 1.
However, Almazán et al provides motivation to arrive at the replicon of claim 1. Almazán et al teaches that rMERS-CoV-ΔE is a safer vaccine candidate compared to live attenuated virus because the recombinant virus does not propagate in the absence of E protein expression, which prevents a potential reversion to virulence (Discussion paragraph 10). Additionally, Almazán et al teaches that the accessory proteins are not required for viral replication (Figure 3B) and that their absence in combination with the rMERS-CoV-ΔE recombinant virus could serve as a marker for vaccinated patients compared to patients that were naturally infected with MERS (Discussion paragraph 12).
Regarding SEQ ID NO: 1, the specification indicates that SEQ ID NO: 1 includes: “pBAC sequence (nucleotides 1 to 7889), RNA replicon (nucleotides 7890 to 35838) and pBAC sequence (nucleotides 35839 to 36179)" (page 53 lines 2-3). Almazán et al teaches that the MERS recombinant viruses were assembled in the pBeloBAC11 backbone taught by Wang et al (GenBank accession number U51113.1) (plasmids and bacteria strains) based on the MERS-CoV-EMC12 sequence (GenBank accession number JX869059 taught by van Boheemen et al) (Construction of a full-length cDNA clone of MERS-CoV). Sequence alignment indicates that the first approximately 7 kb of SEQ ID NO: 1 is identical to the pBeloBAC11 sequence taught by Wang et al (see partial alignment below). Additionally, the portion of SEQ ID NO: 1 beginning at nucleotide 7890 aligns to the MERS CoV sequence taught by van Boheemen et al (see partial alignment below). Thus, Almazán et al in view of Wang et al and van Boheemen et al provide a clear teaching, suggestion, and motivation to arrive at the sequence disclosed by SEQ ID NO: 1.
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It would have been prima facie obvious to a person with ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Almazán et al as evidenced by Wang et al and van Boheemen et al to arrive at a coronavirus RNA replicon comprising partial deletion of the E gene and total or partial deletion of the genes encoding accessory proteins 3, 4a, 4b, and 5, and wherein the replicon is at least 95% identical to SEQ ID NO: 5. One would have been motivated to do so for the advantage of producing an RNA replicon that could be used as an attenuated vaccine candidate for MERS as taught by Almazán et al. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Claim 9 is drawn to the replicon of claim 1 wherein the replicon is between 18 and 29 kb in size.
Claim 32 is drawn to the replicon of claim 1 wherein the replicon is between 20 and 27 kb in size.
Claim 33 is drawn to the replicon of claim 1 wherein the replicon is between 22 and 26 kb in size.
Claim 34 is drawn to the replicon of claim 1 wherein the replicon is between 22 and 24 kb in size.
Almazán et al teaches replicons greater than 25.8 kb in length (Figure 1C). The courts have found that in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists (i.e., claims 9, 32, and 33) (In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976)) and “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” (i.e., claim 34) (In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)). See MPEP 2144.05 II. One of ordinary skill in the art would have been free to test different replicon lengths/sizes with a reasonable expectation of success. Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
Claim 12 is drawn to the replicon of claim 1 wherein the RNA replicon is packaged in a VLP-E+. The specification evidences that packaging within a VLP is an inherent property of the RNA replicons: “the replicon will begin to replicate inside the cell, but the new RNAs and proteins encoded by genes that have not been deleted will be able to form Virus-like particles (VLPs) that will protect the RNA that forms the replicon genome against degradation” (page 4 lines 16-19). As such, absent evidence to the contrary, the RNA replicon taught by Almazán would be packaged into a VLP after transfection into a host cell.
Almazán et al teaches complementation of rMERS-CoV-ΔE through growth in a cell line expressing E in trans (i.e., generation of VLP-E+), which rescues viral titer and genome replication in this recombinant virus (Complementation of rMERS-CoV-ΔE in cells expressing E protein in trans and Figure 5). Thus, Almazán et al teaches an RNA replicon packaged in a VLP expressing E since the transfected cells express E.
Claim 15 is drawn to a method for preparing the RNA replicon of claim 1 comprising:
construction of full-length cDNA from the gRNA of a coronavirus and insertion into an expression vector to obtain an infectious clone,
partial deletion of the E gene,
total or partial deletion of at least 4 genes encoding the accessory proteins 3, 4a, 4b, and 5, and
transfecting the expression vector into a host cell
Claim 17 is drawn to the method of claim 15 comprising: partial deletion of the gene encoding the coronavirus E protein, wherein the last 52 nucleotides of the gene are retained and total or partial deletion of at least 4 genes encoding genus accessory proteins selected from the group consisting of 3, 4a, 4b, and 5 of MERS CoV, wherein 39 nucleotides of the gene encoding genus accessory protein 3 corresponding to nucleotides 33409-33447 of SEQ ID NO: 1 are retained.
Claim 18 is drawn to the method of claim 15 wherein the full-length cDNA is obtained by chemically synthesizing fragments and introducing the fragments into an expression vector.
Claim 19 is drawn to the method of claim 15 wherein the genes are deleted through restriction enzyme digest, vector recombination, or CRISPR editing.
Almazán et al teaches construction of a full-length cDNA clone of MERS-CoV through cloning fragments of the MERS-CoV genome into pBeloBAC11 (plasmids and bacteria strains and Construction of a full-length cDNA clone of MERS-CoV). Almazán et al teaches total and partial deletion of the indicated viral genes through PCR-directed mutagenesis and restriction digest (Construction of MERS-CoV cDNA clones lacking accessory genes 3, 4a, 4b, and 5 and Construction of a MERS-CoV cDNA clone lacking the structural E gene). Finally, Almazán et al teaches that the expression vector was transfected into BHK cells to obtain recombinant virus from the RNA replicons (Recovery of recombinant viruses from the cDNA clones).
Claim 21 is drawn to an expression vector comprising a cDNA sequence complementary to the RNA replicon of claim 1.
Claim 23 is drawn to the expression vector of claim 21 wherein the expression vector is selected from the group consisting of a bacterial artificial chromosome, a cosmid, and a P1-derived artificial chromosome.
Claim 24 is drawn to the expression vector of claim 23 further comprising a selection system selected from the group consisting of an antibiotic resistance gene, complementation of auxotrophic markers, toxin/antitoxin, ColE1-based repression, and counter selection with sacB.
Almazán et al teaches construction of a pBeloBAC11-based vector comprising a cDNA sequence of MERS-CoV replicons (Construction of a full-length cDNA clone of MERS-CoV). Wang et al evidences that pBeloBAC11 comprises a chloramphenicol resistance gene for selection (paragraph 2).
Thus, the inventions of claims 1, 9, 12, 15, 17-19, 21, 23-24, and 32-34 as a whole were prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention, especially in the absence of evidence to the contrary.
Claims 25-26 and 29-31 are rejected under 35 U.S.C. 103 as being unpatentable over Almazán et al, as evidenced by Wang et al and van Boheemen et al, as applied to claims 1, 9, 12, 15, 17-19, 21, 23-24, and 32-34 above and further in view of Netland et al (Virology 2010- included on IDS).
Claim 25 is drawn to a vaccine composition capable of inducing protection against coronavirus infection in a subject wherein the vaccine composition comprises the RNA replicon of claim 1 and, optionally, at least one pharmaceutically acceptable excipient and/or at least one chemical or biological adjuvant or immunostimulant. The examiner notes that the broadest reasonable interpretation of an “immunostimulant” includes the RNA replicon of claim 1 in sterile water.
As discussed above, claim 1 was rendered prima facie obvious by the teachings of Almazán et al as evidenced by Wang et al and van Boheemen et al. These references do not teach a coronavirus vaccine comprising the RNA replicon of claim 1.
However, Netland et al teaches a SARS-CoV vaccine based on a recombinant SARS-CoV comprising deletion of E and various accessory proteins (abstract). Netland et al teaches that the vaccine protected mice from SARS-CoV challenge after they were immunized intranasally with the recombinant virus (mouse infections, Figure 1).
It would have been prima facie obvious to a person with ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Almazán et al and Netland et al to arrive at a vaccine comprising the RNA replicon of claim 1. One would have been motivated to do so for the advantage of protecting against MERS-CoV. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by successful generation of the SARS-CoV vaccine built on a similar platform taught by Netland et al.
Claim 26 is drawn to the vaccine of claim 25 wherein the vaccine is administered topically, intranasally, orally, subcutaneously, or intramuscularly.
Claim 31 is drawn to a method of use of the RNA replicon of claim 1 as a vaccine wherein the vaccine is administered topically, intranasally, orally, subcutaneously, or intramuscularly.
Netland et al teaches intranasal administration of the SARS-CoV vaccine to mice (mouse infections).
Claim 29 is drawn to the vaccine of claim 25 wherein the vaccine is liquid or lyophilized.
Netland et al teaches that the recombinant virus was propagated (i.e., grown in cells and collected in liquid supernatant) before intranasal administration to mice (viruses and cells and mouse infections). Thus, Netland et al teaches a liquid vaccine formulation.
Claim 30 is drawn to the vaccine of claim 25 wherein the subject is a mammal selected from a human, dog, or cat.
Almazán et al teaches that the recombinant MERS-CoV virus is a vaccine candidate for use in humans (importance).
Thus, the inventions of claims 25-26 and 29-30 as a whole were prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention, especially in the absence of evidence to the contrary.
Claims 27-28 are rejected under 35 U.S.C. 103 as being unpatentable over Almazán et al, as evidenced by Wang et al and van Boheemen et al, and Netland et al, as applied to claims 25-26 and 29-31 above and further in view of Pallesen et al (PNAS 2017- included on IDS) as evidenced by Sigma (Sigma Adjuvant System- see attached form 82)
Claim 27 is drawn to the vaccine of claim 26 for its administration simultaneously with a chemical or biological adjuvant or immunostimulant.
Claim 28 is drawn to the vaccine composition of claim 25 for its administration before or after the chemical or biological adjuvant or immunostimulant.
The examiner notes that the phrase “for its administration” denotes an intended use of the vaccine. MPEP 2111.02(II) states “statements in the preamble reciting the purpose or intended use of the claimed invention must be evaluated to determine whether or not the recited purpose or intended use results in a structural difference between the claimed invention and the prior art”. The timing of adjuvant/immunostimulant administration does not result impart a structural difference to the claimed vaccine. Thus, the broadest reasonable interpretation is claims 27 and 28 are drawn to the vaccine of claims 25/26 further comprising adjuvant or immunostimulant.
As discussed above, claims 25-26 and 29-31 were rendered prima facie obvious by the teachings of Almazán et al and Netland et al. These references do not teach the administration of an adjuvant or immunostimulant with the vaccine.
However, Pallesen et al teaches immunization of mice with a MERS-CoV vaccine comprising the Sigma Adjuvant System (mouse immunizations), which is an oil emulsion adjuvant derived from bacterial and mycobacterial cell wall components, which provide a potent stimulus to the immune system (Sigma, description).
It would have been prima facie obvious to a person with ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Almazán et al, Netland et al, and Pallesen et al to arrive at a MERS-CoV vaccine comprising an adjuvant. One would have been motivated to do so for the advantage of increasing immune response from vaccination to result in the generation neutralizing antibodies against MERS-CoV as taught by Pallesen et al (Figure 3) and evidenced by Sigma. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Thus, the inventions of claims 27-28 as a whole were prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention, especially in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
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/KATHERINE ARCENEAUX WILLARD/Examiner, Art Unit 1671
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1671