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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on February 16, 2023 has been considered by the examiner.
Specification
The use of the term “Tween 80”, which is a trade name or a mark used in commerce, has been noted in this application in paragraph [0091] of the instant published disclosure, USPgPub 2023/0321219. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Applicant is required to properly annotate all trade names and/or marks present in the instant specification, if any additional trade names and/or marks are discovered. Applicant' s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
The specification is additionally objected to for failing to adhere to the requirements of the sequence rules, see paragraph [0168] of the instant published disclosure. Applicant must append SEQ ID NOs. to all mentions of specific sequences comprising four or more amino acids and ten or more nucleic acids in the specification. When a sequence is presented in a drawing, the sequence must still be included in the sequence listing if the sequence falls within the definition set forth in 37 CFR 1.821(a), and the sequence identifier ("SEQ ID NO:X") must be used, either on the drawing itself or in the Brief Description of the Drawings. Applicant is required to append a SEQ ID NO. to any sequence applicable to the rule. See 37 CFR § 1.821 (a)-(d) and MPEP § 2422. Appropriate correction is required.
Claim Objections
Claim 22 is objected to because of the following informalities: “RRAR” and “SGAS” are not designated by a SEQ ID NO, as required by 37 CFR § 1.821 (a)-(d). Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 2-4, 8, and 22 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.
Claims 2-4, 8, and 22 require specific cysteine substitutions at particular position numbers, but it cannot be determined what the positions are relative to, or what constitutes position 1.
In claim 2 (iii), the first cysteine substitution is: C662C, which would not result in a substitution. The claim is unclear due to this contradiction.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
Claims 1, 5-7, and 9-27 are directed to a SARS-CoV-2 spike (S) VLP, where the S component is modified to include at least one of the following modifications:
linking the S1 and S2 domains via generation of disulfides bonds between the S1 and S2 domains;
linking intra-polypeptide and inter-polypeptide S2 helices of the S2 domain; and
substitution of one or more non-cysteine residues with a cysteine residue to generate one or more disulfide bonds.
The one or more modifications to the S glycoprotein (i) stabilize a prefusion conformation of the S glycoprotein and/or (ii) prohibit a transition to a post-fusion structure.
The "prefusion" limitation is a structural limitation that requires a specific structure. Paragraph [0108] and the amino acid substitution strategy chart below paragraph [0108] of the instant published disclosure, USPgPub 2023/0321219, lists the one or more amino acid substitutions that generate disulfide bridges between the S1 and S2 portions of S to prevent the spike trimer from undergoing a conformational change resulting in a post-fusion structure. These one or more substitutions are recited in instant claims 2-4 and 8, selected from:
A653C at the S1 domain and A694C at the S2 domain;
S659C at the S1 domain and S698C at the S2 domain;
C662C at the S1 domain and M697C at the S2 domain;
V705C and T883C at the S2 domain;
A570C at the S1 domain and V963C at the S2 domain;
D571C at the S1 domain and S967C at the S2 domain;
Y707C and T883C at the S2 domain; and
K558C at the S1 domain and N282C at the S2 domain.
However, there is no showing or teaching suggesting the instant alternative cysteine substitution pairings instantly required would result in a stabilized prefusion spike protein structure, as required and asserted by the instant claims.
The middle row of Figure 1 of Hsieh et al. (Current Opinion in Structural Biology. 2022 Jun 1; 74: 102385) depicts examples of engineered trimeric spikes in the prefusion conformation. Under “Stabilized spike antigens”, Hsieh et al. teach four strategies used to design 100 various spike substitutions, including proline, disulfide bond, salt bridge, and cavity-filling, to determine which strategies result in a stabilized prefusion conformation. Of the 100 recombinant spike proteins characterized, “HexaPro”, carrying six proline substitutions throughout the region between the fusion peptide and HR1, resulted conserved stability under heat and physical stress. In the same section, Hsieh et al. review many additional modifications, based on “HexaPro”, added by other research groups, including cysteine substitutions Y707C and T883C (recited in instant claims 3(i) and 8 (vii)). In the first paragraph under “Stabilized spike antigens”, Hsieh et al. teach, “two proline substitutions at residues 986 and 987” are used “to stabilize the SARS-CoV-2 spike. This prefusion-stabilized construct, referred to as S-2P, facilitated rapid COVID-19 vaccine development, and is the antigen used in the Pfizer-BioNTech BNT162b2, Moderna mRNA-1273, and Janssen/J&J Ad.26.COV2.S vaccines”. In the first paragraph under, “Part 2”, Byrne and McLellan (Current Opinion in Immunology. 2022; 77: 102209) state that of the five vaccine formulations recommended by WHO, four comprise tandem proline substitutions at residues 986 and 987 (recited in claim 22 (vi)) to stabilize the prefusion-stabilizing conformation.
Therefore, the art teaches that the SARS-CoV-2 spike protein is not stable in the prefusion conformation unless it is stabilized in a particular manner and that not all mutants stabilize the prefusion structure. Without guidance provided by the instant specification or the art, the skilled artisan would be unable to predict which substitution along the entire SARS-CoV-2 S protein, or any one or more combination of substitutions recited in the claims, would result in a stabilized prefusion conformation recited. Therefore, the genus of substitutions encompassed by the instant claims are not adequately described to satisfy the written description requirement.
Under, “The best designs are the ones that work”, Byrne and McLellan state:
“The complex and unpredictable nature of protein folding can lay waste to the best-laid rational designs. Successful application of these principles therefore depends on rigorous experimental testing, since stabilizing substitutions must ultimately preserve a particular protein conformation without disfiguring the antigen’s surface. Indeed, many designs fail to achieve their intended
effect.” This teaching clearly indicates that even if structures “look” correct, they still need testing to determine if they work as intended, i.e., to “stabilize a prefusion conformation of the S glycoprotein and/or (ii) prohibit a transition to a post-fusion structure”, recited in the last clause of instant claim 1.
The applicable standard for the written description requirement can be found in MPEP 2163; University of California v. Eli Lilly, 43 USPQ2d 1398 at 1407; PTO Written Description Guidelines; Enzo Biochem Inc. v. Gen-Probe Inc., 63 USPQ2d 1609; Vas- Cath Inc. v. Mahurkar, 19 USPQ2d 1111; and University of Rochester v. G.D. Searle & Co., 69 USPQ2d 1886 (CAFC 2004). To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In this case, the only requirement provided in instant claims 1, 5-7, and 9-27 to achieve asserted prefusion stabilization of the S protein is selected from at least one of the following:
linking the S1 and S2 domains via generation of disulfides bonds between the S1 and S2 domains (at any one or more, at any location);
linking intra-polypeptide and inter-polypeptide S2 helices of the S2 domain (at any one or more, at any location); and
substitution of one or more non-cysteine residues with a cysteine residue to generate one or more disulfide bonds (at any one or more, or any location).
The skilled artisan would be unable to recognize which of the one or more modifications, selected from an infinite quantity of possibilities, would result in a stabilized prefusion spike protein structure and/or prohibit transition of the prefusion spike protein to a post-fusion structure, as required. There is no teaching in the instant disclosure that any one or more of the modifications recited achieves a stabilized prefusion spike protein conformation.
Instant claims 2-4 and 8 further define the modifications of (i-iii) as selected from one or more of the following substitution pairs to result in a stabilized prefusion spike protein structure:
A653C at the S1 domain and A694C at the S2 domain;
S659C at the S1 domain and S698C at the S2 domain;
C662C at the S1 domain and M697C at the S2 domain;
V705C and T883C at the S2 domain;
A570C at the S1 domain and V963C at the S2 domain;
D571C at the S1 domain and S967C at the S2 domain;
Y707C and T883C at the S2 domain; and
K558C at the S1 domain and N282C at the S2 domain.
However, there is no showing or teaching suggesting the instant alternative cysteine substitution pairings instantly required would result in a stabilized prefusion spike protein structure, as required and asserted by the instant claims.
There is no disclosure of sufficient characteristics of the claimed genus of SARS-CV2 spike protein modifications to allow persons of ordinary skill in the art to recognize that applicants were in possession of the claimed genus. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus. A definition by function alone is not sufficient because it is only an indication of what a thing does, rather than what it is. Eli Lily, 119 F.3 at 1568, 43 USPQ2d at 1406.
The court clearly states in Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not clearly allow persons of ordinary skill in the art to recognize that the inventors invented what is claimed. As discussed above, the skilled artisan cannot envision the distinguishing, identifying characteristics required of the stabilized prefusion spike proteins claimed. The claims do not meet the written description provision of 35 U.S.C. 112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains 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.
Claims 1, 5-7, and 9-27 are directed to a SARS-CoV-2 spike (S) VLP, where the S component is modified to include at least one of the following modifications:
linking the S1 and S2 domains via generation of disulfides bonds between the S1 and S2 domains;
linking intra-polypeptide and inter-polypeptide S2 helices of the S2 domain; and
substitution of one or more non-cysteine residues with a cysteine residue to generate one or more disulfide bonds.
The one or more modifications to the S glycoprotein are claimed to (i) stabilize a prefusion conformation of the S glycoprotein and/or (ii) prohibit a transition to a post-fusion structure.
The "prefusion" limitation is a structural limitation that requires a specific structure. Paragraph [0108] and the amino acid substitution strategy chart below paragraph [0108] of the instant published disclosure, USPgPub 2023/0321219, lists the one or more amino acid substitutions that generate disulfide bridges between the S1 and S2 portions of S to prevent the spike trimer from undergoing a conformational change resulting in a post-fusion structure. These one or more substitutions are recited in instant claims 2-4 and 8, selected from:
A653C at the S1 domain and A694C at the S2 domain;
S659C at the S1 domain and S698C at the S2 domain;
C662C at the S1 domain and M697C at the S2 domain;
V705C and T883C at the S2 domain;
A570C at the S1 domain and V963C at the S2 domain;
D571C at the S1 domain and S967C at the S2 domain;
Y707C and T883C at the S2 domain; and
K558C at the S1 domain and N282C at the S2 domain.
However, there is no showing or teaching suggesting that any of the one or more modifications, including one or more of the instant alternative cysteine substitution pairings, would result in a stabilized prefusion spike protein structure, as required and asserted by the instant claims.
In the first paragraph under “Stabilized spike antigens”, Hsieh et al. (Current Opinion in Structural Biology. 2022 Jun 1; 74: 102385) teach:
“Introducing two prolines at the short loop connecting the heptad repeat 1 (HR1) region and the
central helix (CH) effectively stabilized the MERS-CoV and SARS-CoV spikes in the prefusion conformation [39,40]. This led several groups to introduce the same two proline substitutions at residues 986 and 987 to stabilize the SARS-CoV-2 spike [41-43]. This prefusion-stabilized construct, referred to as S-2P, facilitated rapid COVID-19 vaccine development, and is the antigen used in the Pfizer-BioNTech BNT162b2, Moderna mRNA-1273, and Janssen/J&J Ad.26.COV2.S vaccines [44-46]. Using the SARS-CoV-2 S-2P cryo- EM structure as a guide, our team designed and characterized 100 spike substitutions…”.
Hsieh et al. reviews additional stabilizing modifications to the spike protein using the SARS-CoV-2 S-2P architecture as the base.
In the first paragraph under, “Part 2”, Byrne and McLellan (Current Opinion in Immunology. 2022; 77: 102209) state that of the five vaccine formulations recommended by WHO, four comprise tandem proline substitutions at residues 986 and 987 (recited in claim 22 (vi)) to stabilize the prefusion-stabilizing conformation.
Therefore, the art recognizes that the SARS-CoV-2 spike protein is not stable in the prefusion conformation unless it is stabilized in a particular manner. The essential stabilizing modifications to the S protein of two proline substitutions at residues 986 and 987, are not required in the instant claims. Instant claim 22 (vi) encompasses one or more amino acid mutations at positions 986 and 987 in a delta variant, followed by, where the one or more mutations are from KV to PP. However, while claim 22 (vi) recites the art-recognized SARS-CoV-2 S-2P stabilized prefusion conformation, SARS-CoV-2 S-2P construct is not a requirement in any of the stabilized spike prefusion conformations claimed since it is recited as an alternative selection.
Under, “The best designs are the ones that work”, Byrne and McLellan state:
“The complex and unpredictable nature of protein folding can lay waste to the best-laid rational designs. Successful application of these principles therefore depends on rigorous experimental testing, since stabilizing substitutions must ultimately preserve a particular protein conformation without disfiguring the antigen’s surface. Indeed, many designs fail to achieve their intended
effect.” This teaching clearly indicates that even if structures “look” correct, they still need testing to determine if they work as intended, i.e., to “stabilize a prefusion conformation of the S glycoprotein and/or (ii) prohibit a transition to a post-fusion structure”, recited in the last clause of instant claim 1. There is no guidance or working example provided in the instant specification showing that any of the modifications recited result in stabilized prefusion conformations.
There is no teaching or data provided in the instant disclosure demonstrating stabilization of that the requisite spike protein in a pre-fusion conformation with at least one of the following modifications encompassed by instant claims 1, 5-7, and 9-27:
linking the S1 and S2 domains via generation of disulfides bonds between the S1 and S2 domains;
linking intra-polypeptide and inter-polypeptide S2 helices of the S2 domain; and
substitution of one or more non-cysteine residues with a cysteine residue to generate one or more disulfide bonds.
There is also no teaching or data provided in the instant disclosure indicating that prefusion stabilization of the spike protein is achieved by introduction of one or more modifications selected from:
A653C at the S1 domain and A694C at the S2 domain;
S659C at the S1 domain and S698C at the S2 domain;
C662C at the S1 domain and M697C at the S2 domain;
V705C and T883C at the S2 domain;
A570C at the S1 domain and V963C at the S2 domain;
D571C at the S1 domain and S967C at the S2 domain;
Y707C and T883C at the S2 domain; and
K558C at the S1 domain and N282C at the S2 domain,
recited in instant claims 2-4 and 8.
There is no evidence provided in the instant specification or the state of the art that any one or more of the modifications claimed results in a stabilized spike prefusion conformation and/or prohibits transition to a post-fusion structure, as asserted by the instant claims. For these reasons, it is determined that an undue quantity of experimentation would be requires to make and use the invention as claimed.
Conclusion
The prior art made of record, and not relied upon, is considered pertinent to applicant's disclosure:
Xu et al. (Frontiers in Bioengineering and Biotechnology. 2020 Jul 30; 8: 862, cited in the IDS) teach construction of SARS-CoV-2 Virus-Like Particles made by a plasmid expressing human codon optimized sequences of genes encoding spike, membrane, envelope, and nucleoproteins in HEK-293T cells and Vero E6 cells, see “Plasmid Construction and Molecular
Cloning” and “Synthesis and Purification of VLPs”.
Wrapp et al. (Science. 13 March 2020; 367 (6483): 1260-1263) achieve a recombinant prefusion-stabilized SARS-CoV-2 spike protein comprising two proline substitutions at residues 986 and 987 and a “GSAS” substitution of residues 682-685 in the furin cleavage site, “RRAR”. (Examiner query: Is “SGSA” recited in line 9 of claim 22 intended to recite “GSAS”?)
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHANON A FOLEY whose telephone number is (571)272-0898. The examiner can normally be reached M-F, generally 5:30 AM-5 PM, flexible.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Allen can be reached at 571-270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Shanon A. Foley/ Primary Examiner, Art Unit 1671