DETAILED ACTION
Disposition of Claims
Claims 1-29 were pending. Claim 2 is cancelled. Amendments to claims 1, 6-7, and 19-23 are acknowledged and entered. Claims 1 and 3-29 will be examined on their merits.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20230372472A1, 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.
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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.
Response to Arguments
Applicant's arguments filed 12/29/2025 regarding the previous Office action dated 10/01/2025 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 If they have been found to be persuasive, the objection/rejection has been withdrawn below. Likewise, if a rejection/objection has not been recited, said rejection/objection has been withdrawn.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arguments have not been found to be persuasive, or if there are arguments presented over art that has been utilized in withdrawn rejections but utilized in new rejections, the arguments will be addressed fully with the objection/rejection below.
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 expanded – necessitated by amendment.) Claim 1 and dependent claims 2-29 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 of claim 2 is withdrawn in light of the cancellation of said claim.
Claim 1 is drawn to a replication-defective oncolytic herpes simplex virus 1 (oHSV-1) recombinant virus, comprising within its genome:
one or more therapeutic gene coding sequences,
wherein the genome comprises at least one alteration in each of a gene encoding infected cell polypeptide (ICP) 4 (ICP4), a gene encoding ICP22, a gene encoding ICP27, and a gene encoding ICP47,
wherein the at least one alteration renders the gene non-functional,
wherein the genome does not encode a functional ICP4, ICP22, ICP27 and ICP47 protein, and
wherein the therapeutic gene coding sequence is inserted in place of open reading frame 1 (ORF1) of the gene encoding ICP27 (UL54 loci).
However, HSV-1 comprises two copies of certain genes encoding certain proteins, namely ICP4, ICP0, ICP22, and ICP47, as these genes are found in the inverted terminal repeat regions of the genome. Therefore, the wording of claim 1 is unclear because from the wording of the claim, it is not clear if only one copy of ICP4, ICP22, and/or ICP47 comprises an alteration, or if both copies comprise the alteration.
Additionally, with the newly added limitation of “wherein the at least one alteration renders the gene non-functional”, the antecedent basis of “the gene” which is rendered “non-functional” is unclear, because before this limitation, four genes are recited, with seven potential open reading frames that could be altered. Further, the wording also makes it unclear if each alteration renders its respective protein encoded by the gene non-functional, or a single alteration renders some unspecified protein non-functional. Additionally, with the inclusion of the limitation stating the therapeutic gene is inserted into UL54 (ICP27), it is unclear if this gene comprises at least one alteration in addition to this insertion, or the “alteration” is this replacement by the therapeutic gene.
Finally, claim 1 states “wherein the therapeutic gene coding sequence is inserted in place of open reading frame 1 (ORF 1) of the gene encoding ICP27 (UL54 loci).” As stated in the previous Office action with respect to the rejection over cancelled claim 2, the use of “ORF1” with respect to a herpes simplex virus type 1 (HSV-1) genome is confusing as there is no official “ORF1” within the HSV-1 genome. 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 “ORF1” in claim 1 is used by the claim to mean “the open reading frame of the UL54 gene which encodes the protein ICP27,” while the accepted meaning is relevant to other viruses, such as coronaviruses, which comprise “ORF1”, while HSV-1 does not. The term is indefinite because the specification does not clearly redefine the term.
One suggestion to help clarify the metes and bounds of the claim is to draft it along the lines of the following:
“1. A replication-defective recombinant oncolytic herpes simplex virus 1 (oHSV-1), comprising within its genome one or more therapeutic gene coding sequences,
wherein the genome comprises at least one alteration in each copy of a gene encoding infected cell polypeptide (ICP) 4 (ICP4), ICP22, and ICP47, wherein the at least one alteration renders the corresponding protein non-functional, and
wherein the therapeutic gene coding sequence is inserted in place of the open reading frame (ORF) for UL54, which is the gene that encodes the ICP27 protein.”
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim 1 is rejected on the grounds of being indefinite. Claims 3-29 are also rejected since they depend from claim 1, but do not remedy these deficiencies of claim 1.
Response to Arguments
Applicant's arguments filed 12/29/2025 have been fully considered but they are not persuasive.
Applicant states that the claims have been amended as suggested to overcome the rejection. However, no suggested claim amendment had been presented by the Office with respect to instant claim 1, and the claims were rendered further unclear by the additional amendments for the reasons set forth supra. Therefore, the arguments are not persuasive, and the claims remain rejection for the reasons set forth supra.
(Rejection withdrawn.) The rejection of Claim 2 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 6-7 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 withdrawn.) The rejection of Claims 19-20 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 said claims.
(Rejection withdrawn.) The rejection of Claim 21 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 claim.
(Rejection withdrawn.) The rejection of Claims 22-23 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.
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 replication-defective oncolytic herpes simplex virus 1 (oHSV-1) recombinant virus, comprising within its genome one or more therapeutic gene coding sequences,
wherein the genome comprises at least one alteration in each of a gene encoding infected cell polypeptide (ICP) 4 (ICP4), a gene encoding ICP22, a gene encoding ICP27 and a gene encoding ICP47, and wherein the genome does not encode a functional ICP4, ICP22, ICP27 and ICP47 protein, and
wherein the therapeutic gene coding sequence is inserted in place of the open reading frame (ORF) for UL54, which is the gene that encodes the ICP27 protein.
Further limitations on the recombinant virus of claim 1 is wherein the genome further comprises at least one alteration in an S component repeated sequence in a promoter between a gene encoding ICP4 and a gene encoding ICP22 or in a promoter between a gene encoding ICP4 and a gene encoding ICP47 (claim 3); wherein the genome lacks at least one Oct-1 site present in wild-type HSV-1 genome (claim 4); wherein the genome lacks at least one Oct-1 site present in a promoter of a gene encoding ICP22 or a gene encoding ICP47 (claim 5); wherein the genome lacks at least one SP1 binding site present in wild-type HSV-1 genome (claim 6), wherein the genome lacks at least one SP1 binding site present in a promoter of a gene encoding ICP22 or a gene encoding ICP47 (claim 7); wherein the therapeutic gene coding sequence is a codon optimized sequence (claim 8); wherein the therapeutic gene coding sequence does not comprise an internal ribosome entry site (IRES)(claim 9); wherein the virus comprises two or more therapeutic gene coding sequences within its genome (claim 10), wherein the virus comprises two or more therapeutic gene coding sequences within its genome and wherein at least two of the therapeutic gene coding sequences are different (claim 11); wherein the therapeutic gene coding sequence encodes a cytokine (claim 12); wherein the therapeutic gene coding sequence encodes a heterodimeric cytokine (claim 13); wherein the therapeutic gene coding sequence encodes interleukin 12 (IL-12), IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10,IL-12, IL-15, IL-17, IL-18, interferon (IFN)-7, or any combinations thereof (claim 14); wherein the therapeutic gene coding sequence encodes a non-fusion protein (claim 15); wherein the therapeutic gene coding sequence encodes a fusion protein (claim 16); wherein the therapeutic gene coding sequence encodes a fusion protein comprising a first domain and a second domain linked via a linker, wherein the nucleotide sequence encoding the linker does not comprise an IRES (claim 17); wherein the therapeutic gene coding sequence encodes a fusion protein comprising a first domain and a second domain linked via a linker, wherein one of the first and second domain is a p40 subunit of IL-12 and the other domain is a p35 subunit of IL-12 (claim 18); wherein the therapeutic gene coding sequence comprises a nucleotide sequence selected from the group consisting of SEQ ID NO:14-18, 20, and 22-24 and any combinations thereof (claim 19); wherein the therapeutic gene coding sequence comprises a nucleic acid sequence encoding an amino acid sequence selected from the group consisting of SEQ ID NO: 19, SEQ ID NO: 21, and any combinations thereof (claim 20); wherein the recombinant virus has increased sensitivity to acyclovir (ACV) relative to the corresponding wild-type HSV-1 or the parent HSV-1 from which the recombinant virus was derived (claim 21); a composition comprising the recombinant virus of claim 1 (claim 22); a vaccine and/or immunomodulatory virus comprising the recombinant virus of claim 1 (claim 23).
Claim 24 is drawn to a method of eliciting and/or modifying an immune response in a subject, the method comprising administering to said subject the recombinant virus of claim 1.
Further limitations on the method of claim 24 are wherein the subject is diagnosed or has been diagnosed as having cancer (claim 25).
Claim 26 is drawn to a method of treating cancer, the method comprising: administering to the subject in need thereof the recombinant virus of claim 1.
Further limitations on the method of claim 26 are wherein the cancer is a solid tumor, a benign tumor, or a malignant tumor (claim 27); wherein the cancer is selected from the group consisting of a carcinoma, a melanoma, a sarcoma, a germ cell tumor, and a blastoma (claim 28); and wherein the cancer is metastatic (claim 29).
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, 3-7, 9-15, and 22-27 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Glorioso et. al. (US20190276845A1; Pub. 09/12/2019; hereafter “Glorioso”) is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The rejection of Claims 1-2, 8-11, 15, and 22 under 35 U.S.C. 102(a)(2) as being anticipated by Pechan et. al. (US20220307052A1; Priority 05/30/2019; hereafter “Pechan”) is withdrawn in light of the amendments to the claims.
(New rejection – necessitated by amendment.) Claims 1, 3-11, 15-17, and 22-24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Watanabe et. al. (Watanabe D, et. al. Virology. 2007 Jan 20;357(2):186-98. Epub 2006 Sep 22.; hereafter “Watanabe”) as evidenced by Rosati et. al. (Rosati M, et. al. J Virol. 2005 Jul;79(13):8480-92.; hereafter “Rosati”.)
The Prior Art
Watanabe teaches an HSV vaccine vector, namely an HSV-1 multiple immediate-early (IE) gene deletion mutant virus, d106, which contains deletions in the ICP4, ICP27, ICP22, and ICP47 genes (entire document; see abstract.) Watanabe teaches generating d106 recombinants wherein the virus expresses a heterologous gene, such as Escherichia coli beta-galactosidase or simian immunodeficiency virus (SIV) gag, env, or a rev-tat-nef fusion protein (entire document; see abstract; Figs. 3-9.) Watanabe teaches the SIV proteins were inserted into the UL54 ORF (Fig. 8). Watanabe therefore teaches every limitation of instant claims 1 and 22.
Watanabe teaches the d106 virus contains deletions of the ICP4 and ICP27 ORFs and contains deletions of the promoter/enhancers of the ICP22 and ICP47 genes, wherein said alterations inherently delete Oct-1 and SP1 binding sites present in the native promoters of ICP22 or ICP47 (p. 187, rt. Col., ¶2; instant claims 3-7). Watanabe teaches the insertion of the SIV gag ORF reading frame, which, as evidenced by Rosati, is codon-optimized (p. 195, “Construction of the d106-SIV.gag recombinant virus”; instant claims 8, 15). As Watanabe does not teach the use of IRES in the therapeutic gene constructs, Watanabe teaches the limitations of instant claim 9. Watanabe teaches the generation of a d106 SIV-ref-tat-nef recombinant virus, and as noted by the specification at ¶[0068], a “linker” may be any molecular entity that can directly or indirectly connect two parts of a composition, such as a single peptide bond (p. 195, “Construction of the d106-SIV.RTN recombinant virus”; instant claims 10-11, 16-17). Watanabe teaches the d106 recombinant constructs can be used as vaccines, such as AIDS vaccines (p. 193, “Discussion”; instant claims 23-24).
For at least these reasons, Watanabe, as evidenced by Rosati, teaches every limitation of instant claims 1, 3-11, 15-17, and 22-24, and anticipates the invention encompassed by said 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 16-20 and 28-29 under 35 U.S.C. 103 as being unpatentable over Glorioso as applied to claims 1, 3-7, 9-15, and 22-27 above, and further in view of McFadden et. al. (US20210061864A1, Priority 09/02/2019; hereafter “McFadden”) is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The rejection of Claim 21 under 35 U.S.C. 103 as being unpatentable over Glorioso as applied to claims 1, 3-7, 9-15, and 22-27 above, and further in view of Cassady et. al. (US20080206199A1, Pub. 08/28/2008; hereafter “Cassady”) is withdrawn in light of the amendments to the claims.
(New rejection – necessitated by amendment.) Claims 12-15 and 25-27 are rejected under 35 U.S.C. 103 as being unpatentable over Watanabe as applied to claims 1, 3-11, 15-17, and 22-24 above, and further in view of Glorioso et. al. (US20190276845A1; Pub. 09/12/2019; CITED ART OF RECORD; hereafter “Glorioso”).
The Prior Art
The teachings of Watanabe have been set forth supra. While Watanabe teaches the majority of the instant claims, and teaches a d106 recombinant HSV that comprises the claimed deletions and a gene of interest (GOI) or transgene inserted into the UL54 ORF, Watanabe fails to teach said GOI would be a cytokine, such as IL-4. However, such optimization wherein one GOI is substituted for another would be obvious to a skilled artisan, as evidenced by the teachings of Glorioso.
Glorioso teaches replication-defective herpes simplex virus (HSV) vectors that do not express toxic HSV genes in non-complementing cells and comprises a genome comprising one or more transgenes, wherein the vector is capable of expression of the one or more transgenes for at least 28 days in non-complementing cells (entire document; see abstract, ¶[0003][0043][0063][0091].) Glorioso teaches the vector does not express ICP0, ICP4, ICP22, ICP27, and ICP47 as immediate early (IE) genes, either from an inactivating deletion in one or more of the loci of these genes, or a complete deletion of the coding sequences of said genes (reference claims 60-65; ¶[0043][0060][0084-0086][0105]). Glorioso teaches the HSV to be HSV-1 (¶[0087][0102][0104-0109][0119]) and to comprise transgenes, microRNAs, or the like for preferential expression in malignant cells vs. non-malignant cells (¶[0056]). As per the definition provided in the instant specification ¶[0146], the recombinant HSV-1 of Glorioso are replication-defective oncolytic HSV-1 which comprise at least one therapeutic transgene and functional deletions of ICP4, ICP22, ICP27, and ICP47.
Glorioso teaches that the preference is for the transgene to have insulator/boundary elements flanking said transgene (e.g. CTRL1 and CTRL2, ¶[0049]), and if the transgene is not inserted into the region of the HSV genome where these naturally occur (e.g. LAT region; ¶[0048-0051]) or that the gene may be inserted within the ICP4 gene loci (¶[0053]). Glorioso teaches the promoters for ICP0, ICP4, ICP22, ICP27, and ICP47 may be mutated or altered so that they are absent or are replaced with different promoter elements, the latter of which would inherently delete Oct-1 sites present in the native promoters of ICP22 or ICP47 (¶[0043-0044]; instant claims 3-5). Glorioso teaches deletion of the promoters for ICP22 and ICP47, which deletes at least one SP1 binding site present in a wild-type HSV-1 genome (¶[0043][0060]; instant claims 6-7). Glorioso does not teach that the therapeutic gene sequence encodes IRES elements anywhere in their disclosure, thus meeting the negative limitations of instant claim 9. Glorioso teaches the transgenes may be one or more sequences, such as the cytokines IL-4, TNF-alpha, and nerve growth factor (NGF) (¶[0058]; instant claims 10-15). Glorioso teaches the oHSV-1 may be within compositions (entire document; see abstract; ¶[0071]; instant claim 22), such as compositions that are administered in methods to prophylactically upregulate a subject’s natural defenses against disease (e.g. vaccination; ¶[0073][0076][0079]; instant claims 23-24). Glorioso teaches the vector can be used to treat cancer in a host (¶[0056]; instant claims 25-26) wherein the cancerous cells are or are not in tumors (¶[0075-0076]; instant claim 27).
Given the teachings of Watanabe, one of skill in the art would be apprised as to a recombinant HSV lacking the functional genes ICP4, ICP22, ICP27, and ICP47 that also encoded a transgene from the ICP27 loci. Given the teachings of Glorioso, one of skill in the art would be apprised as to the knowledge in the art of these recombinant HSV, and the usefulness of said viral vectors in vaccine delivery in order to treat pathogens or cancers. Given the related teachings of Watanabe and Glorioso, it would be obvious to a skilled artisan to amend the teachings of Watanabe to arrive at the limitations of instant claims 12-15 and 25-27.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Watanabe in order to deliver cancer antigens or cytokines using the recombinant HSV, thereby generating an oncolytic HSV vector that could be used in cancer therapeutics. One would have been motivated to do so, given the suggestion by Glorioso that the methods and compositions comprising the recombinant, attenuated HSV vectors would be useful in treatment of cancers due to the oncolytic capabilities of HSV. There would have been a reasonable expectation of success, given the knowledge that HSV could encode a variety of transgenes from the UL54 ORF, as taught by Watanabe, and also given the knowledge that oHSV vectors could encode transgenes that would be useful therapeutically in treatment of tumors and cancers, as taught by Glorioso. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
(New rejection – necessitated by amendment.) Claims 18-20 and 28-29 are rejected under 35 U.S.C. 103 as being unpatentable over Watanabe and Glorioso as applied to claims 1, 3-17, and 22-27 above, and further in view of McFadden et. al. (US20210061864A1, Priority 09/02/2019; hereafter “McFadden”) and Ghouse et. al. (Ghouse SM, et. al. Front Oncol. 2020 Mar 24;10:384.; hereafter “Ghouse”.)
The Prior Art
The teachings of Watanabe and Glorioso have been set forth supra. While Watanabe and Glorioso teaches recombinant oHSV-1 which lack ICP4, ICP22, ICP27, and ICP47 and encode at least one therapeutic transgene, and teaches that said transgene may be an interleukin for treatment of cancer, neither Watanabe nor Glorioso explicitly teach IL-12, namely IL-12 with both the alpha (p35) and beta (p40) subunits fused together via a flexible linker. However, such treatment options for cancer were known in the art, as was delivery of said interleukin using a viral vector, as evidenced by McFadden and Ghouse.
McFadden teaches recombinant viruses which encode one or more transgenes, namely IL-12, and methods for using said viruses in treatment of subjects in need thereof (entire document; see abstract; ¶[0063].) McFadden teaches the IL-12 may comprise an IL-12alpha (p35) and an IL-12beta (p40) subunit, wherein said subunits may be covalently linked with a peptide linker (¶[0110]). While McFadden teaches in some embodiments, expression of the p35 and/ or p40 subunit is driven by an IRES, the language of McFadden also allows the opposite to be true, wherein an IRES is lacking (¶[0013][0108-0109][0128]). McFadden teaches SEQ ID NOs: 47-48, which are 100% identical to instant SEQ ID NOs: 22 and 20, respectively. McFadden teaches the recombinant oncolytic virus may be used to treat metastatic cancers, or to treat solid tumors, such as osteosarcoma, triple negative breast cancer, or melanoma (¶[0012]).
Ghouse teaches an oncolytic HSV (oHSV) engineered to express interleukin 12 (IL-12), wherein said oHSV selectively kills cancer cells while inducing anti-tumor immunity (entire document; see abstract.) Ghouse teaches that the IL-12 is a fusion protein of the p35 and p40 units joined by two bovine elastin motifs (“Materials and Methods: Cells and Viruses”, p. 2). Ghouse teaches said oHSV is useful to inhibit both cancer growth and metastasis (entire document; see abstract; p.2, ¶ bridging cols.; p. 4, “G47delta-mIL12 Treatment Controls TNBC Growth and Inhibits Metastasis”.)
While McFadden teaches the oncolytic virus is a myxoma virus (MYXV), work in this similar field of oncolytic viruses would prompt variations of it in other similar oncolytic viruses, such as oHSV-1. As evidenced by the teachings of Ghouse, one of skill would find it obvious to engineer an oHSV to express IL-12 to treat tumors and prevent metastases. One would easily be able to take the prior art disclosed by McFadden, Ghouse, Watanabe, and Glorioso and combine these elements to yield predictable results, as Glorioso teaches the oHSV-1 may encode transgenes such as interleukins for treatment of cancer, and McFadden and Ghouse teach that oncolytic viruses can express a fusion protein of IL-12 subunits for therapeutic treatment of cancer. Therefore, it would be obvious to a skilled artisan to modify the teachings of Watanabe and Glorioso with the teachings of McFadden and Ghouse to arrive at the limitations of instant claims 18-20 and 28-29.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Watanabe and Glorioso in order to have the oHSV-1 encode specific interleukin transgenes, thereby generating an oncolytic virus expressing a known transgene which had therapeutic usefulness for treatment of cancers. One would have been motivated to do so, given the suggestion by McFadden and Ghouse that oncolytic viruses, such as oHSV, could be engineered to express the heterodimer IL-12 as a fusion protein, wherein the two subunits were joined by a flexible linker. There would have been a reasonable expectation of success, given the knowledge that IL-12 was useful in the treatment of cancers when expressed from an double-stranded DNA oncolytic virus, as taught by McFadden and Ghouse. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
(New rejection – necessitated by amendment.) Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Watanabe as applied to claims 1, 3-11, 15-17, and 22-24 above, and further in view of Cassady et. al. (US20080206199A1, Pub. 08/28/2008; hereafter “Cassady”).
The Prior Art
The teachings of Watanabe have been set forth supra. While Watanabe teaches mutations that may be present in the oHSV-1, and that the oHSV-1 would be attenuated compared to the wild-type version of the oHSV-1, Watanabe fails to explicitly teach that the oHSV-1 would be more sensitive to antivirals, such as acyclovir (ACV) as compared to the wild-type or parent virus. However, motivation was present in the art for oHSV-1 to remain sensitive to ACV therapeutic treatment as a potential safety net in case of unrestricted infections, as evidenced by the teachings of Cassady.
Cassady teaches recombinant oHSV-1 (entire document; see abstract), wherein said oHSV-1 were useful in methods of treating tumors, such as neuroblastomas (¶[0017-0018][0043][0070]). Cassady teaches the oHSV are still sensitive to ACV treatment (¶[0018]) as compared to the parental virus, which lacked thymidine kinase (TK)(¶[0142]).
Work in this field of oncolytic HSV would prompt variations of it in other similar oHSV-1. One would easily be able to take the prior art disclosed by both Cassady and Watanabe and combine these elements to yield predictable results, as Watanabe and Cassady teach oHSV-1 which may encode transgenes such as interleukins for treatment of cancer, and Cassady teaches that oHSV can be repaired for TK which allows them to be sensitive to known HSV antivirals, such as acyclovir, as a safety mechanism. The recombinant HSV of Watanabe do not appear to have mutations/deletions in TK, and should remain sensitive to ACV treatment. Therefore, it would be obvious to a skilled artisan to modify the teachings of Watanabe with the teachings of Cassady to arrive at the limitations of instant claim 21.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Watanabe in order to have the recombinant HSV-1 have inherent safety mechanisms, thereby generating an HSV vector which would have additional safety features for use in therapeutic treatments. One would have been motivated to do so, given the suggestion by Cassady that oHSV could be repaired for TK which allowed them to be sensitive to ACV treatment. There would have been a reasonable expectation of success, given the knowledge that oHSV could be engineered to be more sensitive than their parental counterpart against antivirals, as taught by Cassady. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Response to Arguments
Applicant’s arguments, see “Remarks”, filed 12/29/2025, with respect to the rejections of the claims as Glorioso anticipating and rendering obvious the claims in further view of Cassady or McFadden have been fully considered and are persuasive. Therefore, the rejections have been withdrawn. However, upon further consideration, new grounds of rejection using these references are made in view of Watanabe.
Applicant argues that Glorioso fails to teach the transgene being inserted into the UL54 ORF, and that neither McFadden nor Cassady cure this deficiency. This argument was considered persuasive. However, the art teaches the HSV of instant claim 1, as evidenced by the teachings of Watanabe (detailed supra), and the teachings of Glorioso, McFadden, and Cassady remain relevant as they are in the same or similar fields as that of Watanabe and render obvious claimed elements which are not directly taught by Watanabe for the reasons set forth supra. No further arguments regarding the teachings of Glorioso, McFadden, or Cassady were presented.
For at least these reasons, the teachings of Glorioso, McFadden, and Cassady are still determined to render obvious aspects of the instant claims.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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(New rejection – necessitated by filing of new application.) Claims 1 and 3-29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of copending Application No. 19/502,308 (reference application) in view of Glorioso, Watanabe, McFadden, and Ghouse (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to HSV which comprise alterations in ICP0, ICP4, ICP22, ICP27, and ICP47 and also wherein said virus encodes a transgene. The main difference is that the insertion site of the instant claims is UL54, while the insertion site in the dependent claims of ‘308 is a LAT (latency associated transcript) site. Additional differences in dependent claims include that the ‘308 claims fail to teach the therapeutic transgene delivered is IL-12. However, these differences, such as the insertion sites and HSV encoding IL-12, are known in the HSV art, as evidenced by the teachings of Glorioso, Watanabe, McFadden, and Ghouse. Watanabe teaches the d106 virus, which is a virus that fails to encode functional ICP0, ICP4, ICP22, ICP27, and ICP47, and wherein said virus comprises an insertion in the UL54 loci (see detailed analysis supra.) Glorioso teaches similar HSV with similar deletions/mutations, and that HSV can comprise an insertion in the LAT loci (¶[0011][0020]; Figs. 4, 13). McFadden teaches the delivery of IL-12 by a viral DNA vector, and Ghouse teaches recombinant HSV engineered to deliver IL-12. Therefore, these are known elements in the HSV art where insertions of heterologous payloads (such as IL-12) may be made in the HSV vector, and the differences between the ‘308 and instant claims would be obvious to a skilled artisan in light of the teachings of Glorioso, Watanabe, McFadden, and Ghouse.
Further claimed limitations that are the same between the applications include the therapeutic gene comprising a codon-optimized sequence, compositions comprising the HSV, and methods of delivering said HSV to a subject in need thereof for therapeutic purposes.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671