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 are pending.
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.
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.
Optional Authorization to Initiate Electronic Communications
The Applicant’s representative may wish to consider supplying a written authorization in response to this Office action to correspond with the Examiner via electronic mail (e-mail). This authorization is optional on the part of the Applicant’s representative, but it should be noted that the Examiner may not initiate nor respond to communications via electronic mail unless and until Applicant’s representative authorizes such communications in writing within the official record of the patent application. A sample authorization is available at MPEP § 502.03, part II. If Applicant’s representative chooses to provide this authorization, please ensure to include a valid e-mail address along with said authorization.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/22/2023, 04/10/2023, and 04/06/2023 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
This application contains sequence disclosures that are encompassed by 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 through 1.825 for the reason(s) set forth below.
The drawings and specification are objected to because Figures 1 and 3-5 comprise sequence that does not identify said sequence with a corresponding SEQ ID NO: within the figure itself or within the figure legend of the specification.
The objection to the drawings will not be held in abeyance. Applicants must comply with sequence rules in order to be considered a complete response to this Office Action; a complete response would be to either submit corrected drawing sheets as noted below or to amend the specification to include the SEQ ID NO:s within the figure legend.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action.
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.
Claims 1, 7-8, and 14 and dependent claims 2-5, 10-13, 15, 18, 20, 23-24, and 29 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 are 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 7-9, 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.)
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant claims 1, 7-10, and 14 are rejected on the grounds of being indefinite. Claims 2-5, 11-13, 15, 18, 20, 23-24, and 29 are also rejected since they depend from claim 1, 7-10, or 14, but do not remedy these deficiencies of claim 1 or 14.
Claim 3 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 3 provides a limitation of a “Kozak sequence” and a related function (e.g. capable of permitting initiation of translation with a specific efficiency), but it is unclear how the Kozak sequence provides the initiation of translation with a specific type of efficiency, as Kozak sequences are not the only elements in DNA that are required for initiation of translation and/or have an effect on translation efficiency. It is unclear what structural elements of the “Kozak sequence” are, or are not required (e.g. specific type of Kozak sequence used) and/or what other elements are, or are not, required to achieve the translational efficiency claimed.
For at least these reasons, claim 3 is rejected on the grounds of being indefinite.
Claims 3-5 and 7-10 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.
Regarding claims 3-5 and 7-10, the phrase "such as" renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
For at least these reasons, the metes and bounds of claims 3-5 and 7-10 are unclear.
Claims 3-4 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “substantially” in claims 3-4 is a relative term which renders the claims indefinite. The term “substantially” 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. Note the definition of “substantially” is provided for in the specification with respect to codon usage, CpG bias, and G+C content, which is why claim 2 is NOT included in this rejection. However, it is unclear what is, and what is not, “substantially the same” with respect to initiation of translation efficiency and/or to mRNA stability.
For at least these reasons, the metes and bounds of claims 3-4 are unclear.
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.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “VIT” in claim 12 is used by the claim to mean “iciU83A-N, a novel cDNA from a new spliced transcript variant from parent genes integrated at the human telomere as described from archaic HHV-6A genome” (¶[0091]) while the accepted meaning in the biological arts could mean a number of things, such as “vitreous humor” or “vacuolar iron transporter” or “vitellogenin”. The term is indefinite because the specification provides a partial definition that is not clear what is, and what is not, VIT, and does not clearly redefine the term. It is suggested that the sequences for “VIT” be claimed or written along the lines of the following so that the definition and metes and bounds are clear (e.g. “…optionally CCL5 or VIT (iciU83A-N, SEQ ID NO: 135)…” or “…optionally CCL5 or a sequence with at least 95% identity to SEQ ID NO: 135 (iciU83A-N or VIT)…”).
For at least these reasons, claim 12 is rejected on the grounds of being indefinite.
Claims 18 and 29 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 18 provides for a method wherein a pharmaceutical composition is administered to a patient in need thereof, and the claim provides two options as to the composition of the pharmaceutical composition. However, the first option is identical to the composition as set forth in instant claim 1, and the second option is “optional” and provides that the composition is as defined in claim 1. This is confusing as the composition does not appear to be “optional” with respect to being the same as that which is provided for in claim 1, and the composition of claim 1 is required in claim 18. Claim 29 is rejected for the same reasoning, because the composition as drafted in the claim must have all the components of the composition of claim 14, but then claim 29 also recites that it is optional that the composition comprise the components of claim 14.
For the purpose of examination, claim 18 will be interpreted as being drawn to the following:
“18. A method of therapy, wherein the method comprises administering to a patient in need thereof a pharmaceutical composition, wherein the pharmaceutical composition is as defined in claim 1.”
For the purpose of examination, claim 29 will be interpreted as being drawn to the following:
“29. A method of therapy, wherein the method comprises:
administering to a patient in need thereof a pharmaceutical composition,
wherein the pharmaceutical composition comprises a plurality of herpesvirus polypeptides in association with a lipid membrane,
wherein the pharmaceutical composition is the pharmaceutical composition of claim 14.”
For at least these reasons, claims 18 and 29 are rejected on the grounds of being indefinite.
Claim 20 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 20 recites the limitation "the one or more infectious agent antigens" and related “infectious agent” in lines 12-14. There is insufficient antecedent basis for these limitations in the claim.
Claim Rejections - 35 USC § 112(d); Fourth Paragraph
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 13 and 15 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 13 is drawn to the pharmaceutical composition of claim 1, wherein the one or more nucleic acid molecules encode one or more infectious agent antigens, wherein the one or more nucleic acid molecules are capable of expressing the one or more infectious agent antigens when introduced into the vertebrate cell; and/or wherein the pharmaceutical composition further comprises one or more infectious agent antigens. However, claim 1 already comprises “infectious agent antigens”, as the “infectious agent antigens” of claim 13 is a broader genus of the “immunogen coding regions” which comprise “herpesvirus polypeptides” which can “form a herpesvirus fusion complex when introduced into a vertebrate cell” of claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. Claim 15 is rejected for similar reasoning. One suggestion is to amend claims 13 and 15 to state that the nucleic acid molecules encode additional antigens and specify whether or not said antigens are heterologous to said herpesvirus or derived from said herpesvirus (e.g. wherein the herpesvirus is CMV, and the fusion protein antigens are gO, gB. gH, and gL, and the additional CMV antigens are pp65 and IE-1).
For at least these reasons, claims 13 and 15 are rejected for not further limiting the claim upon which it depends.
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 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); and
(ii) gB, gH and gL of the respective cognate human herpesvirus; 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 plurality of immunogen coding regions comprises a Kozak sequence which is capable of permitting initiation of translation of the herpesvirus polypeptide in the vertebrate cell with an efficiency which is substantially the same as the efficiency with which the Kozak sequence of the native coding region for the corresponding native full-length herpesvirus polypeptide permits initiation of translation in the vertebrate cell, such as wherein the Kozak sequence of each of the plurality of immunogen coding regions is identical to the Kozak sequence of the native coding region for the corresponding native full-length herpesvirus polypeptide (claim 3); wherein each of the immunogen coding regions is operatively linked to a 3' untranslated region (UTR) which permits substantially the same degree of mRNA stability of the immunogen coding region or transcript thereof, such as by virtue of comprising an identical 3' polyadenylation sequence (claim 4); wherein the one or more nucleic acid molecules are deoxyribonucleic acid (DNA) polynucleotides, such as plasmid expression vectors or viral vectors; or ribonucleic acid (RNA) polynucleotides, such as 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, such as by virtue of each coding region being linked to an identical 5' promoter (claim 5); wherein the gB polypeptide encoded by the immunogen coding region for gB comprises a mutation which stabilizes gB polypeptide as a trimer in the fusion conformation, such as a mutation in the fusion associated domain I, such as a substitution at a position corresponding to position 262 of SEQ ID NO 9, such as wherein the substitution is a non- conservative substitution; or a substitution at a position corresponding to position 267 of SEQ ID 91, position 273 of SEQ ID 92, position 202 of SEQ ID 93, position 202 of SEQ ID 94, position 246 of SEQ ID 95, position 193 of SEQ ID 97, position 190 of SEQ ID 98, position 218 of SEQ ID 99, such as wherein the substitution is a non-conservative substitution (claim 7); wherein the gB polypeptide encoded by the immunogen coding region for gB comprises a mutation which stabilizes gB in a trimer in the prefusion conformation, such as a mutation in the gB structure domains III and/or IV, such as a substitution at a position corresponding to one or more of the substitutions in the encoded polypeptides of SEQ IDs 67 to 90 or 132 to 134; or wherein the gD polypeptide encoded by the immunogen coding region for gD comprises a mutation which lowers interaction with the HVEM receptor, such as a substitution at a position corresponding to position 52 of SEQ ID 64 or SEQ ID 65 (claim 8); wherein each of the plurality of immunogen coding regions possesses at least 95% sequence identity, such as 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; such as 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 NO 3, 4 or 17 (claim 10); 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 the vertebrate cell, or 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 one or more nucleic acid molecules encodes an immunomodulator, optionally CCL5 or VIT, wherein the one or more nucleic acid molecules are capable of expressing the immunomodulator when introduced into the vertebrate cell; and/or wherein the composition comprises an immunomodulator, optionally CCL5 or VIT; and/or wherein the composition comprises an adjuvant; and/or wherein the one or more nucleic acid molecules are supercoiled DNA; and/or wherein the nucleic acid molecules are aggregated with an aggregating agent; and/or wherein the composition comprises bupivacaine (claim 12); wherein the one or more nucleic acid molecules encode one or more infectious agent antigens, wherein the one or more nucleic acid molecules are capable of expressing the one or more infectious agent antigens when introduced into the vertebrate cell; and/or wherein the pharmaceutical composition further comprises one or more infectious agent antigens (claim 13)
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 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; and
(ii) gB, gH and gL of the respective cognate human herpesvirus.
Further limitations on the pharmaceutical composition of claim 14 are wherein the one or more nucleic acid molecules are as defined in claim 1; and optionally further comprises one or more 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 a pharmaceutical composition, wherein the pharmaceutical composition is as defined in 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;
(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 the one or more infectious agent antigens; and/or (iv)preventing or treating an infection caused by an infectious agent which comprises the 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 a pharmaceutical composition,
wherein the pharmaceutical composition comprises a plurality of herpesvirus polypeptides in association with a lipid membrane,
wherein the pharmaceutical composition is the pharmaceutical composition of claim 14.
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.
Claims 1-5, 7-15, 18, 20, 23-24, and 29 are rejected under 35 U.S.C. 101 because the claimed invention is directed to naturally occurring herpesviruses, herpesvirus proteins, herpesvirus genomes, herpesvirus sequences, and methods of herpesvirus replication and infection without significantly more. The claims recite pharmaceutical compositions which comprise nucleic acids which encode glycoproteins from each of the 8 known human herpesviruses that are known to cause fusion complexes between the virion and the target cell. Further claims require the presence of a “lipid membrane” in the compositions. This judicial exception is not integrated into a practical application because, under broadest reasonable interpretation, these compositions are drawn to naturally-occurring viruses, viral sequences, and/or virions without significantly more. The claims does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the limitations do not add meaningful differences to the compositions to impart a marked change to the naturally occurring nucleic acids, sequences, or virions. For instance, the composition being within a “sterile container” does not change the virus or viral nucleic acid sequence or structure. The nucleic acids claimed, under broadest reasonable interpretation, are drawn to naturally-occurring viral genomes which encode known fusogenic proteins (e.g. HSV-2 gD, gB, gH, and gL are known to be important proteins in the viral fusion mechanism to cause the herpesviral lipid envelope to fuse with the lipid membrane of the target cell.) Further limitations in dependent claims do not add marked changes to their naturally occurring counterpart. While some claims comprise elements that would impart marked changes to the naturally occurring viral material (e.g. adjuvants are those components which caused an increased immune response to the antigen within the composition), those elements which could be seen as imparting a difference are either claimed as optional elements or are claimed in the alternative, wherein the alternative elements still read upon naturally occurring viruses, viral sequences, and viral products. Further, in light of the 35 USC 112b rejection supra, it is unclear which elements following the “such as” phrase are exemplary elements or are required at all within the claim. The methods of making the compositions (product-by-process claims) must somehow result in a virus, virion, viral sequence, and/or viral genome that would be markedly distinct from those herpesviruses that would be found in nature. The methods of using the compositions are also recited at such a high level of generality and with optional elements and/or elements in the alternative, that they read upon methods of natural viral replication and natural viral infection without significantly more.
It is suggested that elements that would amount to significantly more than natural viral sequences, such as the inclusion of heterologous sequences in the encoding nucleic acid, or the addition of elements within the composition that would markedly change the viral elements, such as the use of heterologously tagged sequences and/or adjuvants, be employed to impart patent eligibility to the claims. Steps in the method claims could be added to ensure the claims do not read on natural infection, such as a route of administration that could not read on natural infection, or an amount delivered that could not reasonably read upon natural infection, or the delivery of compositions which include the viral components plus additional elements (e.g. unique sequences which do not read upon natural viral sequences, sequences which comprise heterologous elements or open reading frames, adjuvants, etc.) would assist in imparting patent eligibility to the methods. Applicant is also free to persuasively argue that their claims are drawn towards non-natural viral elements.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 5, 9, 11, 13, 18, 20, and 23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cui et. al. (US20190367561A1; Pub. 12/05/2019; hereafter “Cui”.)
The Prior Art
Cui teaches immunogenic compositions and uses thereof that include at least two human herpesvirus (HHV) polypeptides involved in mediating HHV binding, fusion, and entry into host cells, such as gp350, gH, gL, and gB, or nucleic acids encoding the polypeptides (entire document; see abstract.) Cui teaches the HHV polypeptides comprise any combination of: a gB polypeptide; an EBV gp350 polypeptide; a gL polypeptide; and a gH polypeptide, and optionally any one or more of the following polypeptides: gp42, gM, gN, gI, gC, gE, gD, ORF68, BMRF-2, BDLF2, UL128, UL130, UL131A, and gpK8.1 (entire document; see abstract.) Cui teaches the HHV may be any known HHV, including HSV-1, HSV-2, VZV, EBV, CMV, HHV-6A, HHV-6B, HHV-7, or KSHV, and the combination of glycoproteins may be from any combination of HHV fusion and host cell entry proteins (¶[0018][0278]; instant claim 13). Cui teaches the formulations may be formulated in sterile containers and would be in sterile form (¶[0255]; instant claims 1, 11, 13). Cui teaches the sequences would be from any known HHV sequences that allow formation of the native structures (¶[0224]; instant claim 2). The use of native sequences inherently comprises Kozak sequences, and Cui teaches that promoters, origins of replication, ribosome-binding sites, and other control elements may be present in the nucleic acid, and the nucleic acid would be either DNA or RNA that would allow for transcription and translation in the target cell (¶[0076-0077][0090][0155][0240-0244][0253]; instant claim 3). Cui teaches nucleic acids which encode the HHV sequences, such as DNA and RNA (¶[0239-0249]; instant claim 5). Cui teaches that the gB protein can be stabilized to maintain its native trimeric formation in vaccines (reference claim 16; ¶[0008-0009][0216-0217]; Figs. 4-5), and SEQ ID NO: 47 of Cui aligns with 99.9% and 99.8% identity, respectively, to instant SEQ ID NOs: 9 and 8 (See ABSS sequence alignments in file wrapper; instant claim 9). Cui teaches that immunomodulatory cytokines may be within the composition, such as IL-1, IFN-alpha, and GM-CSF (¶[0259]). Cui teaches methods of administering the compositions to a person in need thereof to elicit a therapeutic immune response against the HHV (¶[0126][0136][0251-0274]; instant claims 18, 20). Cui teaches methods of making the peptides, such as culturing host cells in vitro to express and then isolate said proteins (¶[0242-0243]) and methods of making the nucleic acid compositions in physiologically acceptable solutions, carriers, or excipients (¶[0251-0255]; instant claim 23).
Cui therefore teaches the limitations of instant claims 1-3, 5, 9, 11, 13, 18, 20, and 23, and anticipates the invention encompassed by said claims.
Claims 1-5, 12-13, 18, 20, 23-24, and 29 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ciaramella et. al. (US20200069793A1; Pub. 03/05/2020; hereafter “Ciaramella”.)
The Prior Art
Ciaramella teaches vaccines that include at least one RNA polynucleotide having an open reading frame encoding at least one varicella zoster virus (VZV) antigen, and teaches methods for preparing and using such vaccines (Entire document; see abstract.) Ciaramella teaches the polynucleotides may encode VZV antigens gE, gI, gB, gH, and gL (reference claim 12) in composition with lipid nanoparticles (reference claims 1, 9-49; ¶[0014-0021]). Additionally, Ciaramella teaches the vaccine may comprise live attenuated VZV, whole inactivated VZV, or VZV virus-like particles (VLPs)(¶[0024]). Ciaramella teaches gI is important in membrane fusion during replication, and gE and gI are found complexed together on the virion surface, wherein gB, which is also important in viral entry, and gH, which has a fusion function, are the most prevalent antigens along with gE on the VZV surface (¶[0132]). Ciaramella teaches the VZV peptides may be in multimolecular complexes and can form dimers, trimers, or tetramers (¶[0150]). Therefore, one could at once envisage a composition which comprises multiple glycoproteins from VZV, such as gE, gI, gH, gB, and gL, and since Ciaramella teaches the compositions may be sterile (¶[0277]), Ciaramella teaches the limitations of instant claims 1, 5, 14-15. Ciaramella teaches the sequences encoding the VZV antigens may or may not be codon optimized (¶[0029]; instant claim 2), and that the mRNA encoding said VZV antigens may comprise 5’ and 3’ untranslated regions (UTRs), poly A tails, and/or a 5’ cap (¶[0174]; instant claims 3-4). Ciaramella teaches the mRNA may encode adjuvanting flagellins from bacteria (¶[0079]; instant claims 12-13). Ciaramella teaches administering the compositions to a patient in need thereof to elicit an immune response against VZV to provide any type of therapeutically effective outcome, such as preventing or treating a VZV infection (¶[0047][0050][0558]; instant claims 18, 20). Ciaramella teaches methods of manufacturing the sterile VZV vaccine with pharmaceutically acceptable carriers or excipients (¶[0049][0089][0277]; instant claim 23.) Ciaramella teaches the mRNAs may be used to express the proteins in vitro, in vivo, in situ, or ex vivo (¶[0173]), and teaches human HeLa cells can express the VZV proteins (¶[0672-0676]), and as Ciaramella teaches the compositions may further comprise VLPs or inactivated VZV virions, and VLPs and VZV virions inherently comprise lipid membranes, this encompasses the method of instant claims 24 and 29.
Ciaramella therefore teaches the limitations of instant claims 1-5, 12-13, 18, 20, 23-24, and 29, and anticipates the invention encompassed by said claims.
Claims 1-5, 12-13, 18, 20, 23-24, and 29 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by John et. al. (US20200069793A1; Pub. 03/05/2020; hereafter “John”.)
The Prior Art
John teaches vaccines that include at least one RNA polynucleotide having an open reading frame encoding at least one Herpes simplex virus (HSV) antigen, and teaches methods for preparing and using such vaccines (Entire document; see abstract.) John teaches the polynucleotides may encode HSV antigens gD, gB, gH, and gL (¶[0153-0154]) in composition with lipid nanoparticles (reference claims 1-90; ¶[0028]). John teaches gB is important in membrane fusion during replication (¶[0154]), and gD interacts with a gH/gL heterodimer to form a profusion complex (¶[0153]). John teaches the VZV peptides may be in multimolecular complexes and can form homo- or hetero-dimers, trimers, or tetramers (¶[0153-0155][0190]). John teaches prime/boost vaccination regimens, wherein the priming vaccine and booster vaccine may be any of the mRNA-lipid nanoparticle (LNP) vaccines, or other vaccines (e.g. live, attenuated, subunit, VLP, etc.) (¶[0046][0052-0053][0259][0585]). Therefore, one could at once envisage a composition which comprises multiple glycoproteins from HSV, such as gD, gH, gB, and gL, and since John teaches the compositions may be sterile (¶[0308]), John teaches the limitations of instant claims 1, 5, 14-15. John teaches the sequences encoding the HSV antigens may or may not be codon optimized (¶[0170-0172]; instant claim 2), and that the mRNA encoding said HSV antigens may comprise 5’ and 3’ untranslated regions (UTRs), poly A tails, and/or a 5’ cap (¶[0179-0180]; instant claims 3-4). John teaches sequences for the HSV proteins, which include SEQ ID NO: 39 for gD, which is 100% identical to instant SEQ ID NO: 10. John teaches SEQ ID NOs: 42 and 66, which are 99.2% and 99.3% identical, respectively, to instant SEQ ID NOs: 8 and 9 for gB. John teaches the mRNA may encode adjuvanting flagellins from bacteria (¶[0287-0294]; instant claims 12-13). John teaches administering the compositions to a patient in need thereof to elicit an immune response against HSV to provide any type of therapeutically effective outcome, such as preventing or treating a HSV infection (¶[0005][0256-0257]; instant claims 18, 20). John teaches methods of manufacturing the sterile VZV vaccine with pharmaceutically acceptable carriers or excipients (¶[0286][0308][0564]; instant claim 23.) John teaches the mRNAs may be used to express the proteins in vitro, in vivo, in situ, or ex vivo (¶[0167][0297-0299][0312]), and teaches mammalian cells, such as human HEK293T cells, can express the HSV proteins (¶[0174][0216][0224][0297-0298][0565-0566][0709]).
John therefore teaches the limitations of instant claims 1-5, 12-13, 18, 20, and 23, and anticipates the invention encompassed by said claims.
Claims 1-2, 5, 11-15, 18, 20, 23, and 29 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fairman et. al. (US20130171234A1, Pub. 07/04/2013; hereafter “Fairman”.)
The Prior Art
Fairman teaches vaccine compositions and methods of delivery thereof for Herpes Simplex Viruses (HSV) types 1 and/or 2, wherein the vaccines comprise isolated antigens or glycoprotein subunits of the viruses, optionally with an adjuvant, such as a cationic liposome DNA complex (CLDC)(entire document; see abstract.) Fairman teaches viral envelope glycoproteins, gC, gB, gD, gH, and gL participate in viral-cell binding and entry (¶[0007]) and teaches the vaccine would comprise gB, gH, gL, and gD (¶[0010]). Said vaccine composition may be a subunit composition, wherein the proteins are complexed with adjuvants which comprise lipid vesicles such as DOTMA and cholesterol (¶[0019][0097]). Fairman also teaches compositions which comprise nucleic acids, such as DNA, which encode the HSV glycoproteins gB, gD, gH, and gL (reference claims 37-42.) Said compositions may be sterile (¶[0095]). Fairman therefore teaches the limitations of instant claims 1, 5, 11, and 14-15. Fairman teaches the nucleic acid may or may not be codon optimized (¶[0066]; instant claim 2). Fairman teaches that human T cell antigenic HSV proteins may also be further included in the compositions, such as ICP27, ICP4, or VP22 (¶[0086]; instant claims 12-13). Fairman teaches that gB, similarly to vesicular stomatitis virus (VSV) G, is a fusion protein that is structurally similar to VSV G. It is known in the art that VSV G has a pre- and post-fusion form of the protein (¶[0074-0076]). Fairman teaches subunit vaccines for HSV and methods of use (entire document; see abstract.) Fairman teaches SEQ ID NO: 5 (gH), which aligns with 100% identity to instant SEQ ID NO: 6, and teaches SEQ ID NO: 7 (gL), which aligns with 100% identity to instant SEQ ID NO: 7. Fairman teaches the compositions may be used therapeutically or prophylactically to raise an immune response against HSV (¶[0010][0054][0093]; instant claims 18, 20, 29). Fairman teaches methods of making the HSV nucleic acids and proteins in pharmaceutically acceptable carriers and excipients (¶[0088][0093-0094][0140]; reference claims 1, 46; instant claim 23).
Fairman therefore teaches the limitations of instant claims 1-2, 5, 11-15, 18, 20, 23, and 29, and anticipates the invention encompassed by said claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 7-8, 10, and 24 are rejected 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”.)
The Prior Art
The teachings of Cui, Fairman, and John have been set forth supra. While Cui, Fairman, and John teach sequences for some of the HHV proteins, especially HSV proteins, neither alone teach every sequence of instant claim 10, namely SEQ ID NOs: 6-10. Fairman teaches subunit vaccines for HSV and methods of use (entire document; see abstract.) Fairman teaches SEQ ID NO: 5 (gH), which aligns with 100% identity to instant SEQ ID NO: 6, and teaches SEQ ID NO: 7 (gL), which aligns with 100% identity to instant SEQ ID NO: 7. While John teaches SEQ ID NO: 39 (gD) which aligns with 100% identity to instant SEQ ID NO: 10 and teaches SEQ ID NOs: 42 and 66 which both align with 99.2% and 99.3% identity, respectively, to instant SEQ ID NOs: 8-9 (gB), none of the references alone or in combination teach each of SEQ ID NOs: 6-10 at 100% identity. However, sequences for HSV gB were known in the art, as further evidenced by Stuve. Additionally, while Fairman notes that gB is likely in a post-fusion conformation similar to VSV G, and may need to be stabilized in a prefusion form to target different epitopes unavailable in the postfusion conformation, Fairman taught at the time of their disclosure that the prefusion form of gB was not known. However, at the time of the instant invention, the prefusion form of HSV gB was known in the art, as well as mutations that could alter its stability, as evidenced by the teachings of Vollmer.
Stuve teaches a sequence for HSV gB that is 100% identical to instant SEQ ID NO:9 (see attached NCBI BLAST for alignment.)
Vollmer teaches that cell entry of enveloped viruses, such as HSV, requires specialized viral proteins that mediate fusion with the host membrane by substantial structural rearrangements from a metastable pre- to a stable postfusion conformation. This metastability renders the herpes simplex virus 1 (HSV-1) fusion glycoprotein B (gB) highly unstable such that it readily converts into the postfusion form, thereby precluding structural elucidation of the pharmacologically relevant prefusion conformation. Vollmer teaches that by identification of conserved sequence signatures and molecular dynamics simulations, they devised a mutation that stabilized this prefusion form (entire document; see abstract.) Fig. 1 of Vollmer shows the do