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 .
Restriction/Election of Species
Examiner required a Restriction in the previous Office Action mailed out on 24 March 2026.
In their Response filed on 24 June 2026, Applicant elected Group I, Claims 1-4, 11, 14, 16-17, and 43, with traverse.
Examiner also required an Election of Species in the previous Office Action mailed out on 24 March 2026.
In their Response filed on 24 June 2026, Applicant elected the following species, with traverse: HSV-2; a first ICP0 polypeptide sequence of SEQ ID NO: 1 and the corresponding nucleotide sequence; a first non-ICP0 sequence being present and having the polypeptide sequence of SEQ ID NO: 3 and the corresponding nucleotide sequence; a second ICP0 polypeptide sequence of SEQ ID NO: 2 and the corresponding nucleotide sequence; a second non-ICP0 sequence being present and having the polypeptide sequence of SEQ ID NO: 4 and the corresponding nucleotide sequence; the ICP0 region not comprising a RING domain; and a full-length mutant fusion polypeptide of SEQ ID NO: 5 and the corresponding nucleotide sequence of SEQ ID NO: 6.
Claims 1-4, 11, 14, 16-18, 26-29, 36, 39, and 41-44 are currently pending, with Claims 18, 26-29, 36, 39, 41-42, and 44 withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction and election of species requirement in the reply filed on 24 June 2026.
Response to Arguments
Applicant’s election with traverse of the Restriction and Election of Species Requirement in the reply filed on 24 June 2026 is acknowledged. The traversal is on the grounds that “the modified RL2 gene sequence of claim 1 is related to the mutant ICPO polypeptide of claim 26, such that it would not be a serious burden for the examiner to examine Group I, Group III, and Group IV claims in this application” and that the “restriction requirement be withdrawn” (see Page 2 of Remarks, First Paragraph). Applicant's arguments have been fully considered but they are not persuasive. This is not found persuasive because the search burden criteria for the Restriction and Election of Species Requirement are irrelevant in the case of the instant application. The “search burden” criteria are only relevant for Restriction and Election of Species Requirements for applications examined under U.S. practice (i.e., 111(a) applications). The instant application, however, is a 371 national stage application. As such, the criteria used for determining the necessity of a Restriction and Election of Species Requirement is Unity of Invention, which is what Examiner addressed. In fact, Examiner did not mention search burden in the Restriction and Election of Species Requirement mailed on 24 March 2026, so Applicant’s argument is found to be unpersuasive.
As such, the Restriction and Election of Species Requirement is still deemed proper and therefore made FINAL.
Response to Amendment/Disposition of Claims
Claims 1-4, 11, 14, 16-18, 26-29, 36, 39, and 41-44 are pending. Claims 3, 11, and 36 have been amended. Claims 5-10, 12-13, 15, 19-25, 30-35, 37-38, and 40 have been cancelled. No new claims have been added. Claims 18, 26-29, 36, 39, 41-42, and 44 withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions, as noted above.
Accordingly, Claims 1-4, 11, 14, 16-17, and 43 will be examined on their merits.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US 2024/0174986 A1, Published 30 May 2024. Applicant’s amended Specification as presented on 16 September 2024 is acknowledged and entered.
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.
Information Disclosure Statement
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.
The information disclosure statement (IDS) submitted on 27 September 2024 has been considered by the examiner.
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 - 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 file size should be given in bytes, not KB. See MPEP 2413.04.
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.
Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures are located in Paragraph 0058 of the PGPub of the instant application, specifically with regard to instant SEQ ID NOs: 5 and 10. A sequence alignment (see attached) confirmed that these sequences are 100% identical to each other and the exact same length (i.e., they are the same sequence). It appears this sequence has been duplicated in the Sequence Listing. Additionally, the nucleotide sequences which encode the elected polypeptide sequences all have at least 10 specifically defined and enumerated bases. As such, they are all required to have their own unique SEQ ID NOs.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also 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;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Specification
The abstract of the disclosure is objected to because it contains sentence fragments or incomplete sentences. It is suggested that it be amended to instead recite “Compositions and methods related to a mutant herpesvirus and a mutant ICP0 are provided. Vaccine compositions comprising the mutant herpesvirus and/or mutant ICP0 are also provided. Methods of treatment using the mutant herpesvirus and/or mutant ICP0 are additionally provided.”
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).
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. 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. See MPEP § 608.01. The hyperlink in question is https://bip.weizmann.ac.il/education/materials/gcg/fasta.html (Paragraph 0132).
The use of the terms DMEM, Merck Adjuvant 65, MF59, Montanide, AS02, AS04, ISCOM, AS-2, MPL, BLAST, the GAP program, Genetics Computing Group/GCG, and Bayer Advia 120, which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms, as applicable.
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.
The disclosure is objected to because of the following informalities: In Paragraph 0091, it should say “AS02” and “AS04” instead of “ASO2” and “ASO4”, respectively.
In Paragraph 0039, it should say “…and ICP0 with a GFPΔ19-104 mutation (panel B)” instead of “…and ICP0 with a GPFΔ19-104 mutation (panel B)”. It currently says “GPF” instead of “GFP”.
Appropriate correction is required.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claims 1, 4, 11, and 14 are objected to for the following reason: Claims are only allowed to have one period, as stated in MPEP § 608.01(m). The claims which do not adhere to this rule are Claims 1, 4, 11, and 14. Regarding these claims, the various subparts should utilize parentheses instead of periods to separate them from the claim language itself.
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.
Claim 11 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding Claim 11, it recites the limitation “wherein…b. the first non-ICP0 sequence comprises or consists of a green fluorescent protein (GFP) sequence”. The use of “a” in the phrase “a green fluorescent protein (GFP) sequence” renders the claim indefinite because it is unclear if Applicant is referring to a partial GFP sequence or the full-length GFP sequence. As currently written, this claim reads on any dipeptide sequence that happens to occur in the GFP sequence. It is suggested that the claim be amended to recite “the green fluorescent protein (GFP) sequence”, which would require that the entire sequence be present, but Applicant is free to amend the claim as they deem necessary.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim 14 is rejected on the grounds of being indefinite.
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 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.
Claims 1-4, 11, 14, 16-17, and 43 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a mutant herpesvirus comprising a modified RL2 gene sequence, wherein the modified RL2 gene sequence encodes a polypeptide comprising one or more fragments of infected cell protein 0 (ICP0), wherein the polypeptide comprises or consists of, from the N-terminus to the C-terminus: a) a first ICP0 sequence comprising a sequence having 100% sequence identity to SEQ ID NO: 1 and comprising no more than 30 amino acids; b) optionally, a first non-ICP0 sequence; c) a second ICP sequence comprising a sequence having 100% sequence identity to SEQ ID NO: 2 and comprising no more than 30 amino acids; and, d) optionally, a second non-ICP0 sequence; wherein the first and second non-ICP0 sequences have less than 10% sequence identity to ICP0, and wherein the mutant herpesvirus is substantially avirulent and immunogenic; wherein: a) the polypeptide does not comprise the first non-ICP0 sequence or the second non-ICP0 sequence; b) the polypeptide has 100% sequence identity to SEQ ID NO: 7; c) the polypeptide comprises the second non-ICP0 sequence and does not comprise the first non-ICP0 sequence; d) the polypeptide has 100% sequence identity to SEQ ID NO: 8; e) the polypeptide comprises the first non-ICP0 sequence and does not comprise the second non-ICP0 sequence; f) the polypeptide has 100% sequence identity to SEQ ID NO: 9; or g) the polypeptide comprises the first non-ICP0 sequence and the second non-ICP0 sequence; wherein: a) the first non-ICP0 sequence comprises at least 200 amino acids; b) the first non-ICP0 sequence comprises or consists of a green fluorescent protein (GFP) sequence; or c) the first non-ICP0 sequence has 100% sequence identity to SEQ ID NO: 3; wherein: a) the second non-ICP0 sequence comprises at least 100 amino acids; or b) the second non-ICP0 sequence has 100% sequence identity to SEQ ID NO: 4; and wherein the polypeptide has 100% sequence identity to SEQ ID NO: 5, does not reasonably provide enablement for a mutant herpesvirus comprising a modified RL2 gene sequence, wherein the modified RL2 gene sequence encodes a polypeptide comprising one or more fragments of infected cell protein 0 (ICP0), wherein the polypeptide comprises or consists of, from the N-terminus to the C-terminus: a) a first ICP0 sequence comprising a sequence having at least 80% sequence identity to SEQ ID NO: 1 and comprising no more than 30 amino acids; b) optionally, a first non-ICP0 sequence; c) a second ICP sequence comprising a sequence having at least 80% sequence identity to SEQ ID NO: 2 and comprising no more than 30 amino acids; and, d) optionally, a second non-ICP0 sequence; wherein the first and second non-ICP0 sequences have less than 10% sequence identity to ICP0, and wherein the mutant herpesvirus is substantially avirulent and immunogenic; wherein: a) the polypeptide does not comprise the first non-ICP0 sequence or the second non-ICP0 sequence; b) the polypeptide has at least 80% sequence identity to SEQ ID NO: 7; c) the polypeptide comprises the second non-ICP0 sequence and does not comprise the first non-ICP0 sequence; d) the polypeptide has at least 80% sequence identity to SEQ ID NO: 8; e) the polypeptide comprises the first non-ICP0 sequence and does not comprise the second non-ICP0 sequence; f) the polypeptide has at least 80% sequence identity to SEQ ID NO: 9; or g) the polypeptide comprises the first non-ICP0 sequence and the second non-ICP0 sequence; wherein: a) the first non-ICP0 sequence comprises at least 200 amino acids; b) the first non-ICP0 sequence comprises or consists of a green fluorescent protein (GFP) sequence; or c) the first non-ICP0 sequence has at least 80% sequence identity to SEQ ID NO: 3; wherein: a) the second non-ICP0 sequence comprises at least 100 amino acids; or b) the second non-ICP0 sequence has at least 80% sequence identity to SEQ ID NO: 4; and wherein the polypeptide has at least 80% sequence identity to SEQ ID NO: 5. 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 a mutant herpesvirus comprising a modified RL2 gene sequence, wherein the modified RL2 gene sequence encodes a polypeptide comprising one or more fragments of infected cell protein 0 (ICP0), wherein the polypeptide comprises or consists of, from the N- terminus to the C-terminus: a) a first ICP0 sequence comprising a sequence having at least 80% sequence identity to SEQ ID NO: 1 and comprising no more than 30 amino acids; b) optionally, a first non-ICP0 sequence; c) a second ICP sequence comprising a sequence having at least 80% sequence identity to SEQ ID NO: 2 and comprising no more than 30 amino acids; and, d) optionally, a second non-ICP0 sequence; wherein the first and second non-ICP0 sequences have less than 10% sequence identity to ICP0, and wherein the mutant herpesvirus is substantially avirulent and immunogenic; wherein: a) the polypeptide does not comprise the first non-ICP0 sequence or the second non-ICP0 sequence; b) the polypeptide has at least 80% sequence identity to SEQ ID NO: 7; c) the polypeptide comprises the second non-ICP0 sequence and does not comprise the first non-ICP0 sequence; d) the polypeptide has at least 80% sequence identity to SEQ ID NO: 8; e) the polypeptide comprises the first non-ICP0 sequence and does not comprise the second non-ICP0 sequence; f) the polypeptide has at least 80% sequence identity to SEQ ID NO: 9; or g) the polypeptide comprises the first non-ICP0 sequence and the second non-ICP0 sequence; wherein: a) the first non-ICP0 sequence comprises at least 200 amino acids; b) the first non-ICP0 sequence comprises or consists of a green fluorescent protein (GFP) sequence; or c) the first non-ICP0 sequence has at least 80% sequence identity to SEQ ID NO: 3; wherein: a) the second non-ICP0 sequence comprises at least 100 amino acids; or b) the second non-ICP0 sequence has at least 80% sequence identity to SEQ ID NO:4; and wherein the polypeptide has at least 80% sequence identity to SEQ ID NO: 5.
State of the prior art/Predictability of the art. The art teaches that protein chemistry is probably one of the most unpredictable areas of biotechnology. For example, replacement of a single “lysine” residue at position 118 of acidic fibroblast growth factor by “glutamic acid” led to the substantial loss of heparin binding, receptor binding and biological activity of the protein (Burgess et al., J of Cell Bio. 111:2129-2138, 1990). In transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen (Lazar et al. Molecular and Cellular Biology 8:1247-1252, 1988). As these references illustrate, it is unpredictable that a polypeptide variant of a known target protein binder will also bind said target. It is also unpredictable that they would bind said target in the same way, having the same effect on the target (i.e. inhibit or activate). Ju (Proceedings of the National Academy of Sciences, U.S.A., Vol. 88, Pg. 2658-2662, 1991) teaches that the interleukin 1 receptor (IL-1R) antagonist IL-1ra is a naturally occurring protein with no agonist activity in vitro or in vivo (Abstract). However, substitution of a single amino acid lysine145 to aspartic acid changes the property of this peptide to a partial agonist of IL-1R (Abstract). Thus, even a single substitution can change the biological property of a peptide.
This substitution need not be at a position where said residue would contact the target protein. Baker (Immunity, Vol. 13, Pg. 475-484, 2000) teaches that Tax-peptide is an agonist of the of T cell activity (Abstract). However, mutation of proline at position 6 of this peptide to alanine creates a T cell antagonist (Abstract). Importantly, this residue does not contact the T cell receptor (Abstract).
In another case, Huang (The Journal of Biological Chemistry, Vol. 272, No. 43, Pg. 27155-27159, 1997) teaches that conjugation of peptides to other proteins can change their biological properties. They teach that multiple conjugation of the peptide TGFβ1 (residues 41-65) to carrier proteins enhances its antagonist activity but also confers partial agonist activity as well (Abstract). Thus, the chemical context of a biologically active peptide is also important.
Truncation of proteins can also lead to adverse effects on protein structure and thus protein function. Martindale (Nature Genetics, Vol. 18, Pg. 150-154, 1998) teaches that truncation of huntingtin leads to aggregate development which compromises cell viability (Abstract). Nonaka (Human Molecular Genetics, Vol. 18, No. 18, Pg. 3353-3364, 2009) teaches that truncation of TDP-43 to its C-terminal fragments causes abnormally phosphorylated and ubiquitinated inclusions of the protein (Abstract). Taken together, not just any truncation of a protein will yield a soluble, functional, protein fragment.
In summary, these examples teach that the biological function of peptide variants is unpredictable because even a single mutation can abolish activity or give a different function. For example, agonist and antagonist peptides can be interconverted through conjugation or mutagenesis. Importantly, binding can still occur after mutation or conjugation in the literature examples provided above, illustrating that a simple show of binding is not predictive of the nature of a peptide’s biological activity. This point is underlined by Montrose-Rafizadeh (The Journal of Biological Chemistry, Vol. 272, Pg. 21201-21206, 1997) who teaches that receptor binding does not predict agonist or antagonist activity (Pg. 21205, Column 2, Paragraph, first full, Sentence, first).
Working examples. No working examples of the claimed variants are disclosed in the specification. Example 1 discloses a mutant HSV-2 strain MS having a mutant ICP0 (see Figure 2C) wherein the sequences comprising the mutant ICP0 are presumably 100% identical to instant SEQ ID NOs: 1-4, with the full-length sequence is presumably 100% identical to instant SEQ ID NO: 5 and encoded by instant SEQ ID NO: 6 (see Paragraph 0141; Table 1). Example 2 discloses an HSV-2 vaccine comprising the mutant ICP0 sequence described in Example 1, which corresponds to instant SEQ IDNO: 5) (see Paragraph 0143), while Example 3 discloses the efficacy of said HSV-2 vaccine comprising the mutant ICP0 sequence described in Example 1 (see Paragraph 0171).
Guidance in the specification. The specification provides guidance towards variants comprising substitution mutations, but does not disclose which regions of the claimed sequences can tolerate such changes. This also applies to the insertion and deletion mutations recited in the Specification. The Specification does not even specify that the substitution mutations are conservative substitutions. The instant Specification also fails to identify the essential or critical residues of the claimed amino acid sequences. Paragraph 0070 of the instant Specification states that “the mutant ICP0 is any of the mutant or modified ICP0 disclosed herein, or a variant or fragment thereof” while Paragraph 0135 states that the “term ‘variant’ or ‘mutant’ as used herein encompasses a mutant of a reference polynucleotide or polypeptide sequence, for example a native polynucleotide or polypeptide sequence, i.e., having less than 100% sequence identity with the reference polynucleotide or polypeptide sequence” and that “a variant or mutant comprises at least one amino acid difference (e.g., amino acid substitution, amino acid insertion, amino acid deletion) relative to a reference polynucleotide sequence, e.g., a native polynucleotide or polypeptide sequence”.
Amount of experimentation necessary. Since the art teaches that it is unpredictable whether or not peptide variants of known sequences will function as intended, and the specification does nothing to ameliorate these concerns, one would be burdened with undue experimentation to use the products of the instant claims as broadly as they are currently claimed.
Claim 43 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for an isolated mouse, guinea pig, neonatal mouse or guinea pig, cotton rat, primate, or human cell, does not reasonably provide enablement for just any isolated cell comprising the mutant herpesvirus of claim 1. 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 a cell comprising the mutant herpesvirus of claim 1.
State of the prior art/Predictability of the art. The teachings of the art show that not all animals can be used to model HSV-2 infection. Hussain et al. (Hussain MT, Stanfield BA, Bernstein DI. Small Animal Models to Study Herpes Simplex Virus Infections. Viruses. 2024 Jun 27;16(7):1037.) teach that mice, guinea pigs, neonatal mice, neonatal guinea pigs and cotton rats have all been used in small animal models for studying herpes simplex virus, specifically HSV-2, but that animals such as rabbits, transgenic rabbits, tree shrews, and zebrafish have only been used for HSV-1 (see Table 1). Wang et al. (Wang K, Jordan T, Dowdell K, Herbert R, Moore IN, Koelle DM, Cohen JI. A nonhuman primate model for genital herpes simplex virus 2 infection that results in vaginal vesicular lesions, virus shedding, and seroconversion. PLoS Pathog. 2024 Sep 3;20(9):e1012477.) teach that the most commonly used animal models for evaluating the efficacy of HSV-2 candidate vaccines are mice and guinea pigs and that while numerous HSV-2 vaccine candidates have been tested in these animals and were effective in reducing disease and mortality, these results did not predict the effectiveness of the vaccines in human trials (see Abstract). Wang et al. also teach that infection of rhesus macaques rarely results in lesions or HSV-2 specific antibody responses. Wang et al. found that Cebus appella, a New World primate, has the potential to serve as a model for evaluating the efficacy of prophylactic vaccines, antivirus, or monoclonal antibodies to HSV-2 (see Abstract).
Working examples. Only one working example of an animal or cell being infected by the claimed mutant herpesvirus is disclosed. Example 2 discloses an HSV-2 vaccine comprising the mutant ICP0 sequence described in Example 1, which corresponds to instant SEQ IDNO: 5), being intradermally administered to CD-1 mice (see Paragraph 0143), while Example 3 discloses the efficacy of said HSV-2 vaccine comprising the mutant ICP0 sequence described in Example 2 in said CD-1 mice (see Paragraph 0171).
Guidance in the specification. The specification provides guidance towards a cell comprising a mutant herpesvirus and/or mutant ICP0 polypeptide disclosed herein” and can include cells that include genetic material that encodes for the production of the mutant herpesvirus and/or mutant ICP0 polypeptide” (see Paragraph 0081). This paragraph also states that the “cell can be any type of cell: however, it can be preferable for the cell to be a cell type that is capable of being infected with wild type HSV-1 and/or HSV-2” and that “the cell can be a host cell, such as a recombinant eukaryotic cell line containing the gene(s) encoding a mutant herpesvirus and/or mutant ICP0 polypeptide”. Paragraph 0081 also states that “the cell can be a Vero cell, L7 cell, LLC-MK2 cell, or MDCK cell”.
Amount of experimentation necessary. Additional research is required in order to determine how effective the claimed mutant herpesvirus would be at infecting any cell type.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to make and/or use the claimed products.
Claims 1-4, 11, 14, 16-17, and 43 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant application attempts to tie sequence identity to function in the context of a mutant herpesvirus comprising a modified RL2 gene sequence, wherein the modified RL2 gene sequence encodes a polypeptide comprising one or more fragments of infected cell protein 0 (ICP0), wherein the polypeptide comprises or consists of, from the N- terminus to the C-terminus: a) a first ICP0 sequence comprising a sequence having at least 80% sequence identity to SEQ ID NO: 1 and comprising no more than 30 amino acids; b) optionally, a first non-ICP0 sequence; c) a second ICP sequence comprising a sequence having at least 80% sequence identity to SEQ ID NO: 2 and comprising no more than 30 amino acids; and, d) optionally, a second non-ICP0 sequence; wherein the first and second non-ICP0 sequences have less than 10% sequence identity to ICP0, and wherein the mutant herpesvirus is substantially avirulent and immunogenic; wherein: a) the polypeptide does not comprise the first non-ICP0 sequence or the second non-ICP0 sequence; b) the polypeptide has at least 80% sequence identity to SEQ ID NO: 7; c) the polypeptide comprises the second non-ICP0 sequence and does not comprise the first non-ICP0 sequence; d) the polypeptide has at least 80% sequence identity to SEQ ID NO: 8; e) the polypeptide comprises the first non-ICP0 sequence and does not comprise the second non-ICP0 sequence; f) the polypeptide has at least 80% sequence identity to SEQ ID NO: 9; or g) the polypeptide comprises the first non-ICP0 sequence and the second non-ICP0 sequence; wherein: a) the first non-ICP0 sequence comprises at least 200 amino acids; b) the first non-ICP0 sequence comprises or consists of a green fluorescent protein (GFP) sequence; or c) the first non-ICP0 sequence has at least 80% sequence identity to SEQ ID NO: 3; wherein: a) the second non-ICP0 sequence comprises at least 100 amino acids; or b) the second non-ICP0 sequence has at least 80% sequence identity to SEQ ID NO:4; and wherein the polypeptide has at least 80% sequence identity to SEQ ID NO: 5. While the claims recite a percent identity cutoff and the instant Specification provides guidance towards variants comprising substitution mutations, the Specification does not disclose which regions of the claimed sequences can tolerate such changes. This also applies to the insertion and deletion mutations recited in the Specification. The Specification does not even specify that the substitution mutations are conservative substitutions. The instant Specification also fails to identify the essential or critical residues of the claimed amino acid sequences. Paragraph 0070 of the instant Specification states that “the mutant ICP0 is any of the mutant or modified ICP0 disclosed herein, or a variant or fragment thereof” while Paragraph 0135 states that the “term ‘variant’ or ‘mutant’ as used herein encompasses a mutant of a reference polynucleotide or polypeptide sequence, for example a native polynucleotide or polypeptide sequence, i.e., having less than 100% sequence identity with the reference polynucleotide or polypeptide sequence” and that “a variant or mutant comprises at least one amino acid difference (e.g., amino acid substitution, amino acid insertion, amino acid deletion) relative to a reference polynucleotide sequence, e.g., a native polynucleotide or polypeptide sequence”.
Furthermore, while it is not explicitly stated, it is assumed that the constructs used in the instant Specification have sequences which are 100% identical to the claimed sequences. Even if that is not the case, the data provided do not explicitly include any claimed variants having as little as 80% sequence identity, or even 81-99% sequence identity, relative to the claimed sequences, raising questions about how effective these claimed variants would be in the data provided. Thus, it is not clear what was tested, it does not appear that any claimed variants were tested, and the essential characteristics of the genera being claimed by Applicant have not been identified or disclosed.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contributions to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle and Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient details that one skilled in the art can reasonably conclude that the invention had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, as here in which the peptide variants can have any sequences which vary from instant SEQ ID NOs: 1-5 and 7-9 by as much as 20%, one must describe a sufficient variety of species to reflect the variation within the genus. However, one of skill in this art cannot envision the structure of any peptide variants with the required sequence identity other than the few species provided by Applicant and the prior art. Therefore, since only a few species are provided to represent the genera, the claims encompassing the same clearly fail the written description requirement.
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014).
Overall, at the time the invention was made, the level of skill for preparing peptide variants and then selecting those peptides which meet the desired percent identity cutoff was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identity peptide variants with the recited percent identity cutoff, the written description provision of 35 U.S.C. 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010). Absent the conserved structure provided by a core peptide sequence, the skilled artisan would not be able to visualize or otherwise predict, a priori, what any peptide which meets the recited percent identity cutoff would look like structurally.
While applicant has described a few species within the genera recited, and the art may provide more, each genus is very large and would encompass peptide structures that cannot be visualized from the prior art or instant disclosure. One of skill in this art cannot determine the peptide structures encompassed by the claimed/recited genera only defined by sequence identity. Any future peptide variants may or may not be encompassed, as if they are, they would not have been represented in Applicant’s disclosed species. Thus, the described species cannot be considered representative of the entire recited genera of peptide variants. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Therefore, the claims are rejected here.
As such, it does not appear Applicant was in possession of the full scope of the claimed invention at the time of filing and thus Claims 1-4, 11, 14, 16-17, and 43 do not meet the written description requirement.
Claim Rejections – Improper Markush Grouping
Claims 4, 11, and 14 are rejected on the basis that they contain improper Markush groupings of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush groupings of sequences comprised by the mutant herpesvirus of claim 1 are improper because the alternatives defined by the Markush groupings do not share both a single structural similarity and a common use for the following reasons: Regarding the alternatives recited in Claim 4, there is no common structure preserved. For options b, d, and f, the variation encompassed by the claimed 80% sequence identity means that there is no conserved sequence between the claimed sequences. For options a, c, e, and g, the non-ICP0 sequence does not provide the function of ICP0 and there is no substantial structural conservation because some options have it and some do not. For Claim 11, option a is so broad that the 200 amino acids claimed for the first non-ICP0 sequence might not have anything in common with option c as the 200 amino acids in question were not specified. Similarly, for Claim 14, option a is so broad that the 100 amino acids claimed for the second non-ICP0 sequence might not have anything in common with option b as the 100 amino acids in question were not specified.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 43 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101). Paragraph 0081 of the instant Specification specifically contemplates an L7 cell, which reads on L7-expressing Purkinje neurons in the human brain, which also reads on an human organism. Additionally, a cell comprising the claimed mutant herpesvirus would have to have been infected by said herpesvirus. Given that the backbone for the mutant herpesvirus is HSV-2, it is assumed that any cell capable of being infected would have to be a human cell or a cell belonging to one of the known animal models used for HSV-2 studies (see Scope of Enablement rejection above). It is suggested that the claim be amended so that it instead recites “An isolated cell”, but Applicant is free to amend the claim as they deem necessary.
Conclusion
No claims are allowed.
The prior art made of record, but not relied upon, and considered pertinent to applicant's disclosure is listed below:
Laquerre and Hermiston (U.S. Patent No. 6,660,259 B2)
Laquerre and Hermiston teach pharmaceutical compositions, kits, and methods of use thereof, comprising a mutant HSV-1 which does not encode a fully functional wild-type ICP0 polypeptide.
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/CAREY ALEXANDER STUART/Examiner, Art Unit 1671 /Michael Allen/Supervisory Patent Examiner, Art Unit 1671
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