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 .
DETAILED ACTION
Disposition of Claims
Claims 1-5, 7-15, 18, 20, 23-24, and 29 were pending. Claims 3, 6-7, 16-17, 19, 21-22, 25-28 are cancelled. New claims 30-31 are acknowledged and entered. Amendments to claims 1, 4-5, 8-10, 12-15, 18, 20, and 29 are acknowledged and entered. Claims 1-2, 4-5, 8-15, 18, 20, 23-24, and 29-31 will be examined on their merits.
It should be noted that Claim 14 has a non-compliant amendment. Limitations were entered into claim 14 that were not present in the 08/18/2023 claim set and were not identified as new limitations via underlining, namely the “wherein the pharmaceutical composition is sterile, and is provided in a sealed sterile container.” However, since this does not preclude examination on the merits, Applicant is being informed of this non-compliant amendment and examination will proceed herein. See MPEP §714.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20230372473A1, Published 11/23/2023. Amendments to the specification presented on 04/30/2026 are 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.
Response to Arguments
Applicant's arguments filed 04/30/2026 regarding the previous Office action dated 10/30/2025 have been fully considered. If they have been found to be persuasive, the objection/rejection has been withdrawn below. Likewise, if a rejection/objection has not been recited, said rejection/objection has been withdrawn. If the arguments have not been found to be persuasive, or if there are arguments presented over art that has been utilized in withdrawn rejections but utilized in new rejections, the arguments will be addressed fully with the objection/rejection below.
Optional Authorization to Initiate Electronic Communications
The written authorization to communicate via email presented on 04/30/2026 is acknowledged and entered.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 04/30/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings and Specification; Sequence Disclosure Requirements
(Objection withdrawn.) The objection to the drawings and specification is withdrawn in light of the amendments to the specification.
Specification
(New objection.) The disclosure is objected to because of the following informalities: all references to “SEQUENCE ID” or “SEQ ID” that refer to a specifically deposited sequence should refer to a “SEQ ID NO:”. For instance, in Table 1, there is “SEQUENCE ID 13”. The correct format is “SEQ ID NO: 13” in all caps with the colon. See MPEP § 2412.04. See Table 1, ¶[0053][0082][0083][0217][0221][0230][0236]. Not all instances have been cited.
Appropriate correction is required.
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 are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Namely the GenBank Accession numbers recited throughout the specification and now relied upon in the claims as essential subject matter must be deposited in the application and assigned a unique SEQ ID NO: See rejections infra. Only those deposits which rely on a specific version number may be properly incorporated into the application without introducing new matter. For instance, “NC_001806.2” is acceptable, but “NC_001806” is NOT, as it does not clearly refer to a specific version of said deposit. Similarly, if the sequence refers to a region of a larger viral genome, that smaller region may be claimed as a specific SEQ ID NO: (e.g. the region 55795-53081 of NC_001806.2 may be deposited with a SEQ ID NO: to represent HSV-1 gB as per Table 1.)
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.
Claim Objections
Claims 1, 8, and 14 are objected to because of the following informalities: “stabilises" should be “stabilizes”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b); Second Paragraph
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection maintained in part and extended – necessitated by amendment.) Claims 1 and 14 and dependent claims 2, 4-5, 8, 10-13, 15, 18, 20, 23-24, and 29 thereof remain 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. Note the rejection is withdrawn with respect to canceled claims 3 and 7 and is extended to include claims 9 and 30. (NB: Claim 9 was referenced in the actual body of the rejection as having a specific rejected issue but was not recited in the heading of the rejection. Regardless, in light of the amendments to the claims, claim 9 is now/remains rejected.)
Claims 1 and 14 remain rejected for claiming the limitation of percent identities to “native” nucleotide coding region to the claimed nucleic acid molecules without providing an appropriate frame of reference for said sequence. As the wild-type or “native” nucleic acid sequences within these viruses comprise different strains and different nucleic acid coding sequences, it is unclear what would be considered the “base” sequence for comparison. For instance, with Epstein-Barr virus (EBV) gp42, wild-type sequences P03205 (Strain GD1, Query) and Q1HVG2 (Strain AG876, Sbjct) only share 97.76% amino acid identity, so 90% nucleotide identity to P0325 may be less than 90% identity to Q1HVG2.
Query 1 MVSFKQVRVPLFTAIA LVIVLLLAYFLPPRVRGGGRVAAAAITWVPKPNVEVWPVDPPPP 60
MVSFKQVRVPLFTAIA LVIVLLLAYFLPPRVRGGGRV+AAAITWVPKPNVEVWPVDPPPP
Sbjct 1 MVSFKQVRVPLFTAIA LVIVLLLAYFLPPRVRGGGRVSAAAITWVPKPNVEVWPVDPPPP 60
Query 61 VNFNKTAEQEYGDKEVKLPHWTPTLHTFQVPQNYTKANCTYCNTREYTFSYKGCCFYFTK 120
VNFNKTAEQEYGDKE+KLPHWTPTLHTFQVP+NYTKANCTYCNTREYTFSYK CFYFTK
Sbjct 61 VNFNKTAEQEYGDKEIKLPHWTPTLHTFQVPKNYTKANCTYCNTREYTFSYKERCFYFTK 120
Query 121 KKHTWNGCFQACAELYPCTYFYGPTPDILPVVTRNLNAIESLWVGVYRVGEGNWTSLDGG 180
KKHTWNGCFQACAELYPCTYFYGPTPDILPVVTRNLNAIESLWVGVYRVGEGNWTSLDGG
Sbjct 121 KKHTWNGCFQACAELYPCTYFYGPTPDILPVVTRNLNAIESLWVGVYRVGEGNWTSLDGG 180
Query 181 TFKVYQIFGSHCTYVSKFSTVPVSHHECSFLKPCLCVSQRSNS 223
TFKVYQIFGSHCTYVSKFSTVPVSHHECSFLKPCLCVSQRSNS
Sbjct 181 TFKVYQIFGSHCTYVSKFSTVPVSHHECSFLKPCLCVSQRSNS 223
Since it is unclear what sequences should be the “base” sequence for comparison, and wild-type or “native” sequences for these nucleic acids which encode these human herpesvirus proteins show variations between strains and isolates, it is unclear as to the metes and bounds of what is, or what is not, encompassed by the claims. Additionally, with claims 8-9, it is unclear what would be considered a “mutation” versus a “wild-type” or “native” sequence, as these claims only provide a positional frame of reference, but not an amino acid reference (e.g. “wherein the arginine (Arg, R) at position 230 is mutated to any other amino acid”, or “wherein the tyrosine (Tyr, Y) at position 90 is mutated to an arginine (Arg, R) or phenylalanine (Phe, F)”, etc.)
Additionally, in light of the amendments to the claims, claims 1 and 14 are rejected for not properly incorporating essential subject matter and information into the claim.
In the instant case, claims 1 and 14 refer to “Table 1” to attempt to define the “native herpesvirus polypeptide sequences”. Further, in part (i) and (ii) of each claim, this limitation was placed at the end of the list in each part (e.g. after “K8.1(A/B) of Kaposi's sarcoma associated herpesvirus” in part (i) and after “gL of the respective cognate human herpesvirus” in part (ii)), so it is unclear if this applies only to the last listed protein in the Markush group of parts (i) and (ii) or all herpesvirus proteins listed in parts (i) and (ii).
MPEP § 2173.05(s) discloses that where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant's convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted). As these are sequences for proteins, it is not unreasonable to incorporate a sequence for each protein into the claim.
Further, the claim is indefinite because it is improper to import limitations from the specification into the claims, see MPEP §2111.01.
In light of the Sequence disclosure objection supra and 35 USC 112(a) rejection infra, said sequences from said table should be assigned SEQ ID NOs and appropriately deposited within the application, and said claims should refer to the exact sequences and not a table or GenBank accession numbers.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant claims 1 and 14 are rejected on the grounds of being indefinite. Claims 2, 4-5, 8-15, 18, 20, 23-24, and 29-30 are also rejected since they depend from claim 1 or 14, but do not remedy these deficiencies of claim 1 or 14.
Response to Arguments
Applicant's arguments filed 04/30/2026 have been fully considered but they are not entirely persuasive.
While Applicant has attempted to define the “native” sequences for the claimed herpesvirus (HV) polypeptides, as set forth supra, reference to a Table is improper. Therefore, for at least these reasons, the rejection is maintained.
(New rejection – necessitated by amendment.) Claims 1 and 14 and dependent claims 2, 4-5, 8-13, 15, 18, 20, 23-24, and 29-31 thereof are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1 and 14 recite that the “immunogen coding region for gB comprises a non-conservative substitution mutation in the fusion associated domain I that stabilizes gB polypeptide as a trimer in the fusion conformation” It is unclear what structural conformation is required by “the fusion conformation.” The claim does not specify whether the gB trimer must be stabilized in the prefusion conformation, a postfusion conformation, a fusion-intermediate conformation, or another fusogenic state.
The specification does not resolve this uncertainty. The specification states that the fusion complex “may include forms both prefusion or postfusion, with variants that may stabilize either form” (¶[0030]). The specification further discusses transient transition states between prefusion and postfusion forms (¶[0030]). Later portions of the specification describe mutations that stabilize gB in the “fusion conformation” and said mutations stabilize gB in the postfusion conformation, while other disclosed mutations are described as prefusion-stabilizing mutations (¶[0081-0082]; references at ¶[0130]).
Accordingly, the claim does not provide an objective boundary for determining whether a given gB mutant is stabilized in “the fusion conformation”. It is unclear whether a gB mutant stabilized in the prefusion trimer, postfusion trimer, or an intermediate state falls within the scope of the claim. While specific sequences and examples are provided in dependent claims, those claims are still rejected as the wording of the claim and the guidance of the specification make it unclear if said gB is in isolation, or if that specific example is the only version of “the fusion conformation” that independent claim 1 reads upon. Applicant is required to amend the claims to identify the particular conformation(s) intended, or otherwise provide language that specifically and distinctly identifies the required structural state.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant claims 1 and 14 are rejected on the grounds of being indefinite. Claims 2, 4-5, 8-13, 15, 18, 20, 23-24, and 29-31 are also rejected since they depend from claim 1 or 14, but do not remedy these deficiencies of claim 1 or 14.
(Rejection withdrawn.) The rejection of Claim 3 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the cancellation of said claim.
(Rejection withdrawn.) The rejection of Claims 3-5 and 7-10 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to said claims.
(Rejection maintained in part and extended – necessitated by amendment.) The rejection of Claims 3-4 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to said claims.
(New rejection – necessitated by amendment.) Claim 4 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.
The term “same degree” in claim 4 is a relative term which renders the claim indefinite. The term “same degree” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Previously, the claim provided a means as to how to determine the “degree” of “mRNA stability”, but due to the use of “such as”, it rendered the claim indefinite, and the use of “substantially” was also a relative term/term of degree. Now with the claim amendments, it is unclear how to determine the “same degree” of mRNA stability. One suggestion to overcome this new issue is to amend the claim along the lines of the following:
“4. The pharmaceutical composition of claim 1, wherein each immunogen coding regions is operatively linked to a 3' untranslated region comprising the identical polyadenylation sequence of SEQ ID NO: [insert sequence number here].”
This is only a suggestion, as Applicant is free to amend the claim as they deem necessary in order to overcome this issue.
For at least these reasons, the metes and bounds of claim 4 are unclear.
(New rejection – necessitated by amendment.) Claim 5 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 5 is drawn to the “pharmaceutical composition of claim 1, wherein the one or more nucleic acid molecules are deoxyribonucleic acid (DNA) polynucleotides, plasmid expression vectors or viral vectors; or ribonucleic acid (RNA) polynucleotides, or viral vectors; and optionally, wherein the one or more nucleic acid molecules are deoxyribonucleic acid (DNA) polynucleotides, and each of the immunogen coding regions is operatively linked to a 5' promoter, wherein each coding region operatively linked to a 5' promoter is capable of simultaneous gene expression in the vertebrate cell.”
With the amendments to the claim, the term “viral vectors” is recited twice, and it is unclear if this is meant to read on DNA viral vectors and RNA viral vectors as they appear to be in separate sections. As the claim also recites “or” multiple times, and after multiple groupings, it is unclear what the alternatives are in the claim.
The language following “optionally” recites a number of limitations, and due to the wording of the claim, it is unclear if these are optional limitations or are required elements of the claim, whether they apply only to the DNA alternative or also to the viral vector alternatives, and whether mixtures of DNA and RNA are also encompassed.
Further, the claim recites that each coding region is capable of “simultaneous gene expression in the vertebrate cell.” The claim does not provide antecedent basis for “the vertebrate cell”, and it is unclear whether “each coding region” refers to each immunogen coding region or to every coding region in the composition. The claim also does not identify what constitutes simultaneous gene expression, including whether the required simultaneous expression concerns transcription, mRNA expression, protein expression, or another measurable endpoint.
One suggestion is to amend the claim along the lines of the following:
“5. The pharmaceutical composition of claim 1, wherein the one or more nucleic acid molecules comprise one or more deoxyribonucleic acid (DNA) polynucleotide(s) and/or ribonucleic acid (RNA) polynucleotide(s), wherein said DNA and/or RNA polynucleotide(s) are selected from the group consisting of expression vectors and viral vectors.”
This is one suggestion, as Applicant is free to amend the claim however they deem necessary in order to overcome this rejection.
For at least these reasons, claim 5 is rejected on the grounds of being indefinite.
(Rejection withdrawn.) The rejection of Claim 12 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claim.
(New rejection – necessitated by amendment.) Claim 12 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.
In light of the clarification to claim 12 with the amendments, the use of the term “optionally” now causes confusion because it is unclear if “optionally” means that 1) an immunomodulator is required, and it must be CCL5 or a sequence with at least 95% identity to SEQ ID NO: 135 (iciU83A or VIT)(e.g. “optionally” is being used similarly to “such as” in this instance); 2) an immunomodulator is required, but CCL5 and a sequence with at least 95% identity to SEQ ID NO: 135 are merely examples of other, unstated immunomodulators; 3) the immunomodulator itself is optional, despite the preceding affirmative recitation that the nucleic acid “encodes an immunomodulator”.
The repeated “and/or” alternatives further obscure whether the claimed composition must include an encoded immunomodulator, a separately included immunomodulator, an adjuvant, supercoiled DNA, aggregated nucleic acid, bupivacaine, or any combination thereof.
One suggestion to overcome these issues is to amend the claim along the lines of the following:
“12. The pharmaceutical composition of claim 1, wherein the composition further comprises one or more of the following:
(a) an immunomodulator coding region encoding an immunomodulator selected from CCL5 and a sequence with at least 95% identity to SEQ ID NO: 135 (iciU83A or VIT), wherein the immunomodulator coding region is capable of expressing said immunomodulator when introduced into the vertebrate cell;
(b) an adjuvant;
(c) one or more nucleic acid molecules comprising supercoiled DNA;
(d) an aggregating agent, wherein the aggregating agent aggregates the one or more nucleic acid molecules; and
(e) bupivacaine.”
This is just a suggestion, as Applicant is free to amend the claim however they deem necessary in order to overcome the rejection.
For at least these reasons, claim 12 is rejected as being indefinite.
(Rejection withdrawn.) The rejection of Claims 18 and 29 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The rejection of Claim 20 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claim.
Claim Rejections - 35 USC § 112(d); Fourth Paragraph
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claims 13 and 15 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is withdrawn in light of the amendments to the claims.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1 is drawn to a pharmaceutical composition comprising:
one or more nucleic acid molecules comprising a plurality of immunogen coding regions which collectively encode a plurality of herpesvirus polypeptides,
wherein the one or more nucleic acid molecules are capable of expressing the plurality of herpesvirus polypeptides in the form of a herpesvirus fusion complex when introduced into a vertebrate cell,
wherein each of the plurality of immunogen coding regions has at least 90% sequence identity to a native coding region for a corresponding native full-length herpesvirus polypeptide from the same herpesvirus species,
wherein the plurality of native herpesvirus polypeptides are:
(a) gD of herpes simplex virus 2 (HSV2) or herpes simplex virus 1 (HSV1);
(b) gE or gI of varicella zoster virus (VZV);
(c) gp350 or gp42 of Epstein Barr virus (EBV);
(d) gO selected from genotypes 1-8 of human cytomegalovirus (HCMV);
(e) gO of human herpesvirus 6A (HHV-6A);
(f) gO of human herpesvirus 6B (HHV-6B);
(g) gO of human herpesvirus 7 (HHV-7); or
(h) K8.1(A/B) of Kaposi's sarcoma associated herpesvirus (KSHV) as defined in Table 1; and
(ii) gB, gH and gL of the respective cognate human herpesvirus as defined in Table 1; and
wherein the gB polypeptide encoded by the immunogen coding region for gB comprises a non-conservative substitution mutation in the fusion associated domain I that stabilizes gB polypeptide as a trimer in the fusion conformation, wherein the substitution mutation is at a position corresponding to position 262 of SEQ ID NO: 9, position 267 of YP 009137102.1, position 273 of NP 040154.2, position 202 of YP 401713.1, position 202 of YP 001129508.1, position 246 of YP 081514.1, position 193 of NP050220.1, position 190 of YP 073779.1, or position 218 of YP 001129354.1, wherein the substituting amino acid is alanine or isoleucine; and
wherein the pharmaceutical composition is sterile, and is provided in a sealed sterile container.
Further limitations on the pharmaceutical composition of Claim 1 are wherein each of the plurality of immunogen coding regions has a codon usage, a CpG bias and/or a G+C content which is substantially the same as the codon usage, CpG bias and/or G+C content of the native coding region for the corresponding native full-length herpesvirus polypeptide (claim 2); wherein each of the immunogen coding regions is operatively linked to a 3' untranslated region (UTR) which permits the same degree of mRNA stability of the immunogen coding region or transcript thereof (claim 4); wherein the one or more nucleic acid molecules comprise one or more deoxyribonucleic acid (DNA) polynucleotide(s) and/or ribonucleic acid (RNA) polynucleotide(s), wherein said DNA and/or RNA polynucleotide(s) are selected from the group consisting of expression vectors and viral vectors (claim 5); wherein the gB polypeptide encoded by the immunogen coding region for gB comprises a substitution mutation in the gB structure domains III and/or IV which stabilizes gB in a trimer in the prefusion conformation, wherein the substitution mutation is at a position corresponding to one or more of the substitutions in the encoded polypeptides of SEQ ID NOs: 67 to 90 or 132 to 134; or
wherein the gD polypeptide encoded by the immunogen coding region for gD comprises a substitution mutation which lowers interaction with the HVEM receptor, wherein the substitution mutation is at a position corresponding to position 52 of SEQ ID NO: 64 or SEQ ID NO: 65 (claim 8); wherein each of the plurality of immunogen coding regions possesses at least 95% sequence identity, at least 97% sequence identity, at least 99% sequence identify, at least 99.5% sequence identify or 100% sequence identity to the native coding region for the corresponding native full-length herpesvirus polypeptide; or to a coding region for a variant gB polypeptide which differs from the native coding region for the corresponding native full-length gB polypeptide only in the codon corresponding to position 262 of SEQ ID NO: 9 in the encoded variant gB polypeptide (claim 9); wherein the gD, gH and gL encoded by the immunogen coding regions have the amino acids sequences of SEQ ID NOs 10, 6 and 7 respectively, and the gB encoded by the immunogen coding region has the amino acids sequence of SEQ ID NO 8 or 9; or wherein the gD, gH and gL immunogen coding regions have the nucleotide sequences of SEQ ID NOs 5, 1 and 2 respectively, or SEQ ID NOs 18, 15 and 16 respectively; and the gB immunogen coding region has the nucleotide sequence of SEQ ID NOs: 3, 4 or 17 (claim 10); wherein the herpesvirus polypeptides encoded by the one or more nucleic acid molecules are limited to those forming the fusion complex, and optionally also a herpesvirus immunomodulator (claim 11); wherein the composition further comprises one or more of the following:
(a) an immunomodulator coding region encoding an immunomodulator selected from CCL5 and a sequence with at least 95% identity to SEQ ID NO: 135 (iciU83A or VIT), wherein the immunomodulator coding region is capable of expressing said immunomodulator when introduced into the vertebrate cell;
(b) an adjuvant;
(c) one or more nucleic acid molecules comprising supercoiled DNA;
(d) an aggregating agent, wherein the aggregating agent aggregates the one or more nucleic acid molecules; and
(e) bupivacaine (claim 12); wherein the pharmaceutical composition further comprises one or more additional infectious agent antigens (claim 13); wherein the gB polypeptide encoded by the immunogen coding region has at least 95% sequence identity to SEQ ID NOs: 17, 91, 92, 93, 94, 95, 96, 97, 98 or 99 (claim 30); and wherein the gD, gH and gL encoded by the immunogen coding regions have at least 95% sequence identity to the nucleotide sequences of SEQ ID NOs: 18, 15 and 16 respectively; and the gB immunogen coding region has at least 95% sequence identity to the nucleotide sequence of SEQ ID NO: 17 (claim 31).
Claim 14 is drawn to a pharmaceutical composition comprising a plurality of herpesvirus polypeptides in association with a lipid membrane, wherein the pharmaceutical composition is formed by expressing the plurality of herpesvirus polypeptides in vitro in human cells from one or more nucleic acid molecules comprising a plurality of immunogen coding regions which collectively encode the plurality of herpesvirus polypeptides, wherein each of the plurality of immunogen coding regions has at least 90% sequence identity to a native coding region for a corresponding native full-length herpesvirus polypeptide from the same herpesvirus species,
wherein the plurality of native herpesvirus polypeptides are:
(a) gD of HSV2 or HSV1;
(b) gE or gI of VZV;
(c) gp350 or gp42 of EBV;
(d) gO selected from genotypes 1-8 of HCMV;
(e) gO of HHV-6A;
(f) gO of HHV-6B;
(g) gO of HHV-7; or
(h) K8.1(A/B) of KSHV as defined in Table 1; and
(ii) gB, gH and gL of the respective cognate human herpesvirus as defined in Table 1; and
wherein the gB polypeptide encoded by the immunogen coding region for gB comprises a non-conservative substitution mutation in the fusion associated domain I that stabilizes gB polypeptide as a trimer in the fusion conformation, wherein the substitution mutation is at a position corresponding to position 262 of SEQ ID NO: 9, position 267 of YP 009137102.1, position 273 of NP 040154.2, position 202 of YP 401713.1, position 202 of YP 001129508.1, position 246 of YP 081514.1, position 193 of NP050220.1, position 190 of YP 073779.1, or position 218 of YP 001129354.1, wherein the substituting amino acid is alanine or isoleucine; and
wherein the pharmaceutical composition is sterile, and is provided in a sealed sterile container.
Further limitations on the pharmaceutical composition of claim 14 are wherein the pharmaceutical composition further comprises one or more additional infectious agent antigens; and optionally wherein the plurality of herpesvirus polypeptides in association with a lipid membrane are provided in the form of membranes, membrane vesicles, or whole cells (claim 15)
Claim 18 is drawn to a method of therapy, wherein the method comprises administering to a patient in need thereof the pharmaceutical composition of claim 1.
Further limitations on the method of therapy according to claim 18, wherein the method is for:
(i) inducing an immune response to a herpesvirus; and/or
(ii) preventing or treating a herpesvirus infection, optionally wherein preventing a herpesvirus infection comprises protecting from acute disease and/or infection; protecting from establishing latent infection; protecting from reactivating latent infection and/or viral transmission; and/or protecting from latent viral recurrence and disease; optionally wherein treating a herpesvirus infection comprises protecting from establishing latent infection; protecting from reactivating latent infection and/or viral transmission; and/or protecting from latent viral recurrence and disease; and/or
(iii) inducing an immune response to one or more infectious agent antigens; and/or
(iv) preventing or treating an infection caused by an infectious agent which comprises one or more infectious agent antigens (claim 20).
Claim 23 is drawn to the method of making the pharmaceutical composition of claim 1, the method comprising formulating the one or more nucleic acid molecules as defined in claim 1 with one or more physiologically acceptable diluents or excipients as a sterile composition, and optionally formulating the pharmaceutical composition with one or more infectious agent antigens, and/or an immunomodulator, and/or an adjuvant.
Claim 24 is drawn to a method of making the pharmaceutical composition of claim 14, comprising:
introducing the one or more nucleic acid molecules as defined in Claim 14 into human cells in vitro,
allowing the human cells to express the plurality of herpesvirus polypeptides from the one or more nucleic acid molecules, thereby obtaining the plurality of herpesvirus polypeptides in association with a lipid membrane and
optionally, wherein the method further comprises collecting membrane vesicles or whole cells comprising the plurality of herpesvirus polypeptides in association with a lipid membrane, and optionally purifying the membrane vesicles or whole cells and/or formulating the pharmaceutical composition with one or more infectious agent antigens, and/or an immunomodulator, and/or an adjuvant.
Claim 29 is drawn to a method of therapy, wherein the method comprises: administering to a patient in need thereof the pharmaceutical composition of claim 14.
Claim Rejections - 35 USC § 101
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claims 1-5, 7-15, 18, 20, 23-24, and 29 under 35 U.S.C. 101 is withdrawn in light of the amendments to the claims.
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.
(New rejection – necessitated by amendment.) Claims 1-2, 4-5, 8-15, 18, 20, 23-24, and 29-31 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.
Claim 1 recites, inter alia, the following regarding the gB polypeptide “…wherein the gB polypeptide encoded by the immunogen coding region for gB comprises a non-conservative substitution mutation in the fusion associated domain I that stabilises gB polypeptide as a trimer in the fusion conformation, wherein the substitution mutation is at a position corresponding to position 262 of SEQ ID NO: 9, position 267 of YP 009137102.1, position 273 of NP 040154.2, position 202 of YP 401713.1, position 202 of YP 001129508.1, position 246 of YP 081514.1, position 193 of NP050220.1, position 190 of YP 073779.1, or position 218 of YP 001129354.1, wherein the substituting amino acid is alanine or isoleucine…”. The residues of gB are defined relative to the following GenBank accession numbers: YP 009137102.1, NP 040154.2, YP 401713.1, YP 001129508.1, YP 081514.1, NP050220.1, YP 073779.1, and YP 001129354.1. Claim 14 recites a nearly identical limitation regarding gB. The claimed residue position, and therefore the identity of the claimed gB mutant, cannot be determined from the disclosure without consulting the referenced GenBank records. The sequence information in those records supplies the amino acid sequence and coordinate system necessary to identify the residue at the recited position and the resulting substituted gB polypeptide.
Additionally, as set forth supra in the 35 USC 112b rejection, Applicant appears to be referencing subject matter in Table 1 of the specification, which also refers to GenBank Accession numbers and ranges within said accession. Similarly, the identity of these sequences which refer to human herpesvirus (HHV) proteins, cannot be determined from the disclosure without consulting the referenced GenBank records. The sequence information in those records supplies the amino acid sequence and coordinate system necessary to identify the claimed HHV polypeptide.
Accordingly the referenced GenBank sequence information is essential material. It is necessary to provide a written description of the claimed gB variants and to identify the particular amino acid substitutions or genomic positions now relied upon to distinguish the claimed invention. The information is not merely background material or an indication of the state of the art.
The specification does not set forth the complete relevant sequences as SEQ ID NOs, nor does it otherwise provide sufficient identifying structural information to establish the precise residue positions or polypeptide sequences recited in the claims. To the extent the application relies on the GenBank accession numbers or Table 1 to supply that sequence information, such reliance is not an effective incorporation by reference only to a U.S. patent or a U.S. patent application publication that does not itself incorporate the essential material by reference. See MPEP §608.01(p). A GenBank database record is not a U.S. Patent or U.S. Patent application publication.
Therefore, absent the externally referenced GenBank sequence information, the specification does not describe the claimed gB polypeptides with the recited substitutions or the “native” HHV proteins with sufficient structural specificity to reasonably convey possession of those particular variants as of the filing date. The claims are not adequately supported by the written description.
Applicant may overcome this rejection by amending the claims to rely on sequence information adequately disclosed in the application as filed, such as an applicable SEQ ID NO:, or by otherwise establishing that the specific claimed gB sequence and residue positions are adequately described in the originally filed disclosure. Any attempt to add the previously absent sequence must comply with 37 CFR 1.57(g) and must not introduce new matter.
(New rejection – necessitated by amendment.) Claims 1-2, 4-5, 8-15, 18, 20, 23-24, and 29-31 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 specific plasmids encoding proteins of an HSV-2 fusion complex, and the use of said plasmids as a vaccine against HSV-2, does not reasonably provide enablement for the HHV fusion complexes with proteins comprising the at least 90% identity claimed and the use of said complexes in methods of treating or preventing any herpesvirus or pathogenic infection. 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 set forth in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). The factors to be considered include: (1) the breadth of the claims; (2) the nature of the invention; (3) the state of the prior art; (4) the level of one of ordinary skill; (5) the level of predictability in the art; (6) the amount of direction provided by the inventor; (7) the existence of working examples; and (8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. The factors are considered as a whole in determining whether any necessary experimentation would have been undue.
Nature of the invention and breadth of the claims. The claimed invention is directed to compositions, products, and methods of making and using said compositions, wherein the compositions comprise nucleic acids encoding the HHV antigens of parts (i) and (ii) of claims 1 or 14 with at least 90% identity to sequences listed in Table 1 (a corresponding native full-length coding region) and are able to form fusion complexes, or be present in the corresponding membrane-associated product. The claims also required a gB stabilized as a trimer in a “fusion conformation”. The claims are directed towards the therapeutic use of the compositions comprising the nucleic acids encoding said HHV proteins or the fusion complexes of said HHV proteins. The independent “method of therapy” is broadly and generically claimed and does not require the “patient in need thereof” to have any defining characteristics (e.g. at risk of any infection from any HHV or other pathogen, or having any active pathogen or HHV infection, etc.) The therapeutic methods claimed when delivering the nucleic acids broadly encompass said therapeutic method to read upon the induction of any immune response and/or the treatment or prevention of any homologous or heterologous HHV infection or any other pathogenic infection.
The specification describes the generation of specific HSV-2 (HHV-2) gB, gD, gH, and gL antigens (SEQ ID NOs: 15-18) expressed from a plasmid to form a fusion complex, wherein said HHV-2 gB is stabilized by a T262A mutation into a trimer conformation. The specification describes testing said plasmids as a DNA vaccine in guinea pig animal models for the ability to inhibit HSV-2 latency establishment, HSV-2 asymptomatic and symptomatic disease and/or viral shedding, or to inhibit reactivation of HSV-2 from latency (Examples 1-8; ¶[0211-0274]). However, the claims are not limited to the disclosed embodiments. The claims also encompass subunit vaccines with said fusion complexes and nucleic acid vaccines of other formats (e.g. viral vectors, RNA-based formats, etc.). The claims also encompass the proteins having at least 90% identity to the native protein sequences of Table 1, and also claim other fusion complex proteins from all other HHVs at the at least 90% identity to the native protein sequences of Table 1 and the compositions comprising either subunit antigens or nucleic acids encoding said antigens. The specification does not identify which protein variants can still form the fusion complexes as claimed. The claimed methods also encompass the nucleic acid vaccination methods to treat against homologous or heterologous pathogen infection. The claimed scope therefore extends beyond the embodiments described in the specification.
State of the prior art and predictability of the art. At the time the application was filed, it was known that HHV required a complex of glycoproteins to initiate fusion and viral entry with the target host cell membrane, and that gB and gH/gL provide a conserved fusion core among herpesviruses, but that said complexes and proteins therein differed for each HHV. The complexes in each HHV being different resulted in different cell types and receptors being targeted, and made for changes in productive entry for each HHV. The art therefore did not provide a general rule that a coding region having at least 90% sequence identity to a reference antigen would remain compatible with the other selected proteins and retain the claimed fusion-complex properties.
With respect to HSV-1 (HHV-1), Hilterbrand et. al. (Hilterbrand AT, et. al. PLoS Pathog. 2019 May 9;15(5):e1007660.; CITED IN IDS) explains that HSV-1 entry requires coordinated functions of multiple viral glycoproteins and describes the entry mechanisms as “complex and incompletely understood.” Hilterbrand further explains that receptor engagement by gD triggers conformational changes involving gH/gL and gB, with entry routes varying by cell type and viral context. Fan et. al. (Fan Q, et. al. J Virol. 2014 Jun;88(11):6470-82. Epub 2014 Mar 26.) evaluated replacement of HSV-1 entry glycoproteins with homologs from samiriine herpesvirus 1, and despite the reported sequence similarity between those viruses, the substitutions resulted in “complete loss of fusion function” in certain constructs and the gH/gL heterodimers were “not interchangeable”. Vollmer et. al. (Vollmer B, et. al. Sci Adv. 2020 Sep 25;6(39):eabc1726.) reported that HSV gB is “highly unstable” and readily converts to its postfusion form. The authors used structural analysis and molecular dynamics work to devise a particular stabilizing mutation; the work does not provide a general rule by which one could predict stabilization from sequence identity alone.
With respect to HCMV (HHV-5), Ciferri et. al. (Ciferri C, et. al. PLoS Pathog. 2015 Oct 20;11(10):e1005230.) reports that the virus uses “two distinct glycoprotein complexes” namely gH/gL/gO and gH/gL/UL128/UL130/UL131a. The former complex is required for entry into fibroblasts, while the latter complex is required for entry into endothelial and epithelial cells. Ciferri further explains that gO and the UL128/UL130/UL131a components form “mutually exclusive cell entry complexes” and mutations in the UL128-UL131a loci could eliminate endothelial/epithelial cell tropism after only a few passages in fibroblasts. Thus, even HCMV proteins sharing gH/gL are not interchangeable across entry contexts.
With respect to Varicella-zoster virus (VZV, HHV-3), VZV does not use the HSV gD-based entry arrangement. Maresova et. al. (Maresova L, et. al. J Virol. 2001 Oct;75(19):9483-92.) states that “VZV lacks a gD homologous protein” and reports that VZV gB and gE coexpression, rather than gB or gE alone, induced extensive fusion in their assay. Krummenacher et. al. (Krummenacher C, et. al. Adv Exp Med Biol. 2013;790:178-95.) likewise explained that VZV diverges from other alphaherpesviruses because it lacks gD, while gE plays an essential role in virus-cell fusion and may serve as the receptor-binding protein. Accordingly, HSV-2 gD based examples do not supply a predictable model for selecting or varying the VZV entry-associated antigens.
Epstein-Barr virus (HHV-4; EBV) used different glycoprotein requirements depending on the target cell. Sathiyamoorthy et. al. (Sathiyamoorthy K, et. al. PLoS Pathog. 2014 Aug 21;10(8):e1004309.) report that EBV B-cell entry involves at least gp350/220, gH, gL, gp42, and gB, with gH/gL/gp42 engaging HLA class II as the triggering receptor. In contrast, gH, gL, and gB are required for fusion with epithelial cells, while gp42 is indispensable for B-cell fusion. The same proteins therefore operate differently depending on host-cell context, which does not permit prediction that a 90% identity variant of gp350, gp42, gH, gL, or gB will preserve the claimed multi-protein fusion complex function.
HHV-6 employs a distinct gH/gL/gQ1/gQ2 tetramer. Tang et. al. (Tang H, et. al. J Virol. 2011 Nov;85(21):11121-30. Epub 2011 Aug 17.) explains that this complex is a viral ligand for the HHV-6 receptor CD46, and that all four glycoproteins were required for receptor binding and complex trafficking. Tanaka et. al. (Tanaka Y, et. al. J Virol. 2013 Oct;87(19):10900-3. Epub 2013 Jul 24.) further demonstrated that gB together with gH/gL/gQ1/gQ2 were the minimum components required for HHV-6 membrane fusion. In addition, CD134 was identified as a receptor specific for HHV-6B, rather than HHV-6A, further showing that the entry requirements depend on the viral species and the particular glycoprotein complex.
HHV-7 also does not provide a predictable extension of the HSV-2 example. Krummenacher et. al. (Krummenacher C, et. al. Adv Exp Med Biol. 2013;790:178-95.) states that HHV-7 likely attaches through gB interaction with heparan sulfate and that CD4 appears to participate in T-cell infection, although its role regarding attachment or fusion remained unclear. Krummenacher also explained that the gQ gene is unique to HHV-6 and HHV-7, and that the third component associated with the gH/gL complex may determine cell tropism. The limited understanding of HHV-7 entry at the relevant time would have required additional experimentation to identify which variants of the claimed HHV-7 proteins remained compatible and functional.
Kaposi’s sarcoma associated herpesvirus (KSHV, HHV-8) provides a further distinct entry example with respect to viral glycoproteins. Pertel (Pertel PE. J Virol. 2002 May;76(9):4390-400.) showed that KSHV gB, gH, and gL could mediate fusion, but optimal fusion depended on the target cell type and on a truncated gB construct having improved cell surface expression. KSHV also uses additional attachment and entry interactions, including K8.1 and integrin-associated pathways, rather than HSV gD receptor-triggering pathway.
Even the highly similar HSV-1 and HSV-2 (HHV-2) do not establish that sequence similarity reliably predicts equivalent fusion behavior. Atanasiu et. al. (Atanasiu D, et. al. J Virol. 2016 Nov 14;90(23):10535-10544.) reported that wild type HSV-2 glycoproteins produced fusion approximately twice as fast as HSV-1 glycoproteins, and identified gH/gL as the principal determinant of that difference. Although the HSV-2 proteins could replace HSV-1 proteins without an apparent qualitative change in syncytium formation, the reference shows that the activation state of gH/gL could alter the fusion potential of gB mutants and overcome restrictions otherwise imposed by gB structure. Thus, even closely related HSV proteins require context-dependent interactions that are not identified merely by percentage identity.
The art was not sufficiently predictable to support extrapolation from the limited HSV-2 gB, gD, gH, and gL DNA plasmid vaccination embodiments with homologous viral challenge to any of the claimed HHV proteins with the percent identity and the noted gB “fusion conformation” mutations claimed, especially in methods to treat any homologous or heterologous pathogen. Accordingly, the results obtained using the HSV-2 DNA vaccine examples would not have reasonably established that the broader claimed scope could be practiced without further experimentation.
Level of skill in the art. One skilled in the art would have been familiar with the basic molecular biology techniques required to generate HHV mutants, such as BAC recombineering, plaque selection, sequencing of resulting isolates, plaque assays to determine fusion complex formation, and basic in vivo inoculation techniques, such as which animal models could be used for immunological studies and, if possible, for viral challenge, infection, and/or latency/reactivation studies. However, the existence of known methods for preparing and testing candidate embodiments does not establish that one skilled in the art would have known, without further experimentation, which additional HHV protein mutants at the claimed percent identity would satisfy the claimed limitations.
Working examples. The specification provides working examples directed to DNA plasmids encoding HSV-2 gB, gD, gH, and gL (encode the proteins SEQ ID NOs: 15-18) that are able to form a fusion complex and has a gB with a trimer stabilizing mutation of T262A. See Example 1 starting at ¶[0212]. This DNA vaccine formulation was used with or without additional cytokines (CCL5 or VIT) to inoculate a guinea pig animal model and determine the efficacy of said composition on inhibition of homologous viral challenge (Examples 2-8 starting at ¶[0217]).
The specification does not provide working examples directed to any of SEQ ID NOs: 15-18 with less than 100% but greater than 90% sequence identity, nor does it show that the immune response was specific to any other herpesvirus aside from HSV-2 or any other pathogen that is not a herpesvirus. No other herpesvirus fusion complexes with 90% or greater identity to those proteins in Table 1 or claims 1 or 14 were generated or tested in any capacity. The disclosed examples therefore do not establish enablement across the full scope of the claims.
Guidance in the specification. The specification provides guidance regarding the generation of a specific HSV-2 fusion complex with gB, gD, gH, and gL proteins forming said complex, and expressing said proteins from specific DNA plasmids with specific regulatory elements, and using said DNA plasmids as a vaccine composition in a guinea pig model to determine the effectiveness against HSV-2 primary or latent infection. However, the specification does not provide sufficient guidance regarding the use of these proteins as a subunit vaccine, or the use of any other type of nucleic acid platform to deliver and express said proteins in a host. No other variants of these HSV-2 proteins within the claimed sequence identity were generated or tested. No other herpesvirus fusion complexes were generated as nucleic acids or proteins with the percent identity claimed, and tested in any capacity to determine if they formed the fusion complex and if they were immunogenic against homologous or heterologous pathogen challenge. In particular, the specification does not explain what proteins from parts (i) and (ii) of claims 1 and 14 can be generated with the claimed percent identity and still form fusion complexes that are also immunogenic, nor has the specification detailed what other mutations to gB can be tolerated or should be made in order to form the trimer as claimed. For instance, in subunit vaccines with gB, depending on the source of gB, there is a furin cleavage site that must be mutated in order to maintain the structural integrity of the resulting gB, as well as potentially deleting the transmembrane regions of certain herpesvirus glycoproteins in order to allow said proteins to be soluble and isolated from solution, if to be used in a subunit protein formulation. No guidance in the examples was provided for any of these conditions.
Quantity of experimentation necessary. To practice the full scope of the claims, one skilled in the art would need to identify additional variants of the glycoproteins of parts (i) and (ii) of the independent claims, test to see if said variants form the fusion complexes properly, determine if said fusion complexes are still immunogenic in a manner to be useful in a therapeutic against a homologous or heterologous pathogen, and determine what nucleic acid platform can efficiently express said variants and also allow them to be useful therapeutically. Such experimentation would not merely involve the routine application of known methods to embodiments reasonably expected to work. Instead, one skilled in the art would need to prepare and test additional embodiments to determine whether they satisfy the claimed function of maintaining gB trimeric stability and allow said gB to form fusion complexes with the other herpesvirus glycoprotein sequence variants. Although the individual methods used to prepare and test candidate embodiments may have been known in the art, the relevant inquiry is not whether one skilled in the art could perform the required assays. The relevant inquiry is whether the specification provides sufficient guidance to identify and practice the embodiments falling within the full scope of the claims without undue experimentation. Here, one skilled in the art would need to prepare and test additional glycoprotein variants for each of the 8 HHVs to determine which embodiments satisfy the ability to stabilize the gB trimer and formulate fusion complexes.
Amgen. The Supreme Court has explained that a specification need not describe with particularity how to make and use every embodiment within a claimed class. However, the disclosure must enable one skilled in the art to make and use the full scope of the claimed invention. A reasonable amount of experimentation may be permissible depending on the nature of the invention and the underlying art. Amgen Inc. v. Sanofi, 598 U.S. 594, 610-13 (2023).
In the instantly claimed invention, the specification describes one specific HSV-2 embodiment of a DNA vaccine encoding HSV-2 gB, gD, gH, and gL that fall within the scope of the claims, but the claims also encompass not only sequence variants of these HSV-2 glycoproteins, but sequence variants of every other HHV and the use of either a protein or nucleic acid vaccine comprising said glycoproteins in a therapeutic setting. The specification does not identify a general quality or provide sufficient guidance that would allow one skilled in the art to practice that broader scope without undue experimentation.
Conclusion. For the reasons discussed above, the specification does not enable one skilled in the art to make and/or use the full scope of the invention recited in the claims without undue experimentation.
(New rejection – necessitated by amendment.) Claims 1-2, 4-5, 8-15, 18, 20, 23-24, and 29-31 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The written description requirement is separate and distinct from the enablement requirement. To satisfy the written description requirement, the specification must reasonably convey to one skilled in the relevant art that the inventor had possession of the claimed invention as of the filing date. Possession may be shown by a description of the complete structure of the claimed invention, a representative number of species falling within the scope of a claimed genus, or relevant identifying characteristics sufficient to show that the inventor had possession of the claimed subject matter.
The claims recite pharmaceutical compositions or methods comprising immunogen coding regions collectively encoding the herpesvirus polypeptides of parts (i) and (ii), wherein each coding region has at least 90% sequence identity to a corresponding native full-length coding region and the encoded polypeptides form a herpesvirus fusion complex. The compositions either comprise the nucleic acids encoding said fusion complexes or the protein fusion complex itself. Claims 23 and 24 incorporate the same composition requirements, and the dependent claims continue to encompass that genus.
The specification describes reference strains and coding regions for human herpesviruses (HHV) in Table 1. The specification describes these HHV as “representative examples” of herpesviruses (¶[0058-0059]; Table 1), and the specification further describes variants as proteins containing amino acid insertions, deletion, or substitutions, including non-conservative substitutions (¶[0045]). The specification describes a HSV-2 VLM construct using gD, gH, gL, and mutated gB from the HG52 reference strain, and tests said strain in a guinea pig model system for immunogenicity, including for the ability of the construct to prevent asymptomatic and symptomatic shedding, induction of dorsal root ganglion latency, and topical lesions (Examples 1-7; ¶[0211-0274])
However, the scope of the claims is not limited to the embodiments described in the specification. The claims broadly encompass any HHV coding region for any of the listed HHV proteins which form an entry fusion protein complex, namely gB, gD, gH, and gL, along with other HHV-specific entry glycoproteins, so long as said proteins are at least 90% identical to a specific reference sequence and that the gB comprises a mutation in domain I that stabilizes the gB into a “fusion conformation”. The construction includes a cell-binding component for each HHV as claimed in part (i) of claims 1 and 14, and the respective gB, gH, and gL components for the same HHV in part (ii). The claimed scope extends across structurally distinct HHV proteins from alpha-, beta-, and gamma- HHV, while requiring that the resulting variants co-express as the claimed fusion complex.
The specification does not describe a sufficient number of species representative of the claimed scope. The specification also does not describe structural features common to the claimed genus which would allow one skilled in the art to recognize which additional species fall within the scope of the claimed invention. Instead, one skilled in the art would be required to select additional HHV protein sequence variants, including deletion, substitution, and insertion mutants, not described in the specification and determine whether those additional embodiments satisfy the recited limitations. The disclosed HSV-2 coding regions and the reference sequences in Table 1 do not establish possession of the substantially broader group of four-protein combinations that comprise the 90% identity variants for each protein. The disclosure does not identify which substitutions, deletions, insertions, or combinations thereof, may be made in each of the four proteins while retaining the interactions necessary for the claimed fusion complex (“herpesvirus polypeptides in association with a lipid membrane”). Nor does it establish a structural correlation between 90% sequence identity and the ability of the variant proteins to co-express and assemble in the claimed manner.
The specification recognizes that glycoproteins derived from different herpesvirus strain may combine “with different properties” (¶[0059]). This confirms that sequence similarity alone does not identify which variant combinations will retain the claimed complex forming properties. The recited gB stabilization limitation does not cure this deficiency because the claims still encompass uncharacterized 90% identity variants of the remaining fusion-complex components and their combinations with the recited gB variants.
The claimed HHV glycoproteins are defined, at least in part, by the recited function of forming a fusion complex. However, the specification does not establish a correlation between the disclosed structural features and the recited function sufficient to identify the additional HHV protein variants falling within the scope of the claim. The specification describes HSV-2 gB, gD, gH, and gL variants of SEQ ID NOs: 17, 18, 15, and 16, but does not identify structural features common to the broader claimed genus of other HHV fusion complexes with the percent identity claimed which would allow one skilled in the art to recognize other members of the genus. The disclosure of the desired function, without a sufficient description of the claimed genus, does not demonstrate possession of the full scope of the claim.
The specification describes HSV-2 with fusion protein complexes formed from SEQ ID NOs: 15-18. However, the claims are not limited to those constructs. The claims also encompass constructs that differ in percent identity, and encompass variants of SEQ ID NOs: 15-18, and the claims also encompass HHV fusion protein complexes from other HHV with at least 90% identity to proteins listed in Table 1. The specification does not describe representative examples across that scope or identify structural features sufficient to show possession of the broader group of constructs.
The specification describes specific sequences for HSV-2 and the other HHV claimed. However, the claims also encompass additional sequences having at least 90% sequence identity, which includes any mutation that still allows for that overall percent identity while also satisfying the recited function of forming fusion protein complexes. The specification does not identify which positions may be altered while retaining the recited function, describe representative variants across the claimed scope, or identify structural features sufficient to distinguish operative variants from other sequences. Accordingly, the disclosure does not demonstrate possession of the broader claimed group of sequences.
The specification also describes the use of these HSV-2 SEQ ID NO: 15-18 fusion complex to inoculate a guinea pig model against HSV-2, with or without the addition of the cytokines CCL5 or VIT. However, the claims broadly encompass the use of any of the HHV fusion complexes for therapeutic methods, including inducing any immune response to any herpesvirus (the method is not limited to only inducing an immune response against the HHV whose proteins are in the compositions) or to any other infectious agent antigens, or for preventing or treating any infection from any herpesvirus or other infectious agent. The specification does not describe representative embodiments across that scope or otherwise demonstrate possession of the broader claimed method. The disclosure of the in vivo guinea pig model data with the use of CCL5 or VIT as adjuvanting agents does not reasonably convey possession of methods using any of the claimed HHV fusion complexes with the percent identities claimed to treat or prevent homologous or heterologous HHV infections or to treat or prevent any infection from any pathogenic agent by raising any immune response against any antigen from said pathogenic agent.
Accordingly, the disclosure does not reasonably convey to one skilled in the art that the inventor had possession of the full scope of the subject matter recited in the claims at the time the application was filed.
Claim Rejections - 35 USC § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claims 1-3, 5, 9, 11, 13, 18, 20, and 23 under 35 U.S.C. 102(a)(1) as being anticipated by Cui et. al. (US20190367561A1; Pub. 12/05/2019; hereafter “Cui”) is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The rejection of Claims 1-5, 12-13, 18, 20, 23-24, and 29 under 35 U.S.C. 102(a)(1) as being anticipated by Ciaramella et. al. (US20200069793A1; Pub. 03/05/2020; hereafter “Ciaramella”) is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The rejection of Claims 1-5, 12-13, 18, 20, 23-24, and 29 under 35 U.S.C. 102(a)(1) as being anticipated by John et. al. (US20200054737A1; Pub. 02/20/2020; hereafter “John”) is withdrawn in light of the amendments to the claims.
NB: The reference citation for “John” was incorrectly provided as US20200069793A1; Pub. 03/05/2020.
(Rejection withdrawn.) The rejection of Claims 1-2, 5, 11-15, 18, 20, 23, and 29 under 35 U.S.C. 102(a)(1) as being anticipated by Fairman et. al. (US20130171234A1, Pub. 07/04/2013; hereafter “Fairman”) is withdrawn in light of the amendments to the claims.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claims 7-8, 10, and 24 under 35 U.S.C. 103 as being unpatentable over John as applied to claims 1-5, 12-13, 18, 20, and 23 above, and Cui as applied to claims 1-3, 5, 9, 11, 13, 18, 20, and 23 above, and Fairman as applied to claims 1-2, 5, 11-15, 18, 20, 23, and 29 above,
and further in view of
Stuve et. al. (Stuve LL, et. al. Glycoprotein B precursor. UniProtKB/Swiss-Prot: Q89920. Dep. 11/28/2006; hereafter “Q89920”); and
Vollmer et. al. (Vollmer B, et. al Sci Adv. 2020 Sep 25;6(39):eabc1726.; hereafter “Vollmer”) is withdrawn in light of the amendments to the claims.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RACHEL B GILL whose telephone number is (571)272-3129. The examiner can normally be reached on M to F 8:00 AM to 5:00 PM Eastern.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL ALLEN can be reached on 571-270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/RACHEL B GILL/
Primary Examiner, Art Unit 1671
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