DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/24/2026 has been entered.
Amended claims 1-10 are pending in the present application.
Applicant elected previously without traverse Group I, which is drawn to a heat-controlled replication-competent controlled alpha-herpesvirus whose replication can be transiently activated in infected nonneural cells but that cannot be activated in infected neural cells.
Applicant also elected previously the following species: (i) HSV-1 virus as a species of an alpha-herpesvirus; and (ii) an influenza virus surface antigen or parts thereof.
Claims 9-10 were withdrawn previously from further considerations because they are directed to a non-elected invention. Claims 5 and 7 were also withdrawn previously from further considerations because they are directed to non-elected species.
Accordingly, amended claims 1-4, 6 and 8 are examined on the merits herein with the above elected species.
Priority
This application is a CIP of U.S. Patent Application No. 17,300,287, filed on 05/12/2021, now US Patent No. 12,257,300; which is a 371 of PCT/EP2019/080138, filed on 11/04/2019; which claims the benefit of U.S. Provisional Patent Application No. 62/917,066, filed on 11/19/2018 and the Foreign Application EPO EP18207121.7, filed on 11/19/2018.
Upon reviewing the specifications for the above U.S. Patent Application, Provisional Patent Application and Foreign Application, it is determined that the pending claims have at best the priority date 11/04/2019. This is because none of the Provisional Application and the Foreign Application described at least a heat-controlled replication-competent controlled alpha-herpesvirus whose replication can be transiently activated in infected nonneural cells but that cannot be activated in infected neural cells.
Response to Amendment
The rejection under 35 U.S.C. 102(a)(1) as being anticipated by Voellmy et al (Expert Rev. Vaccines 14:637-649, 2015) was withdrawn in light of currently amended independent claim 1, particularly with the new limitation “and (b) a further heterologous genetic element inserted in the genome of the replication-competent controlled alpha-herpesvirus which element prevents replication of the replication-competent controlled alpha-herpesvirus in infected neural cells”.
Claim Rejections - 35 USC § 112 (Lack of Written Description)
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.
Amended claims 1-4, 6 and 8 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new ground of rejection.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc). Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” Vas-Cath Inc. v. Mahurkar, 19USPQ2d at 1117. The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” Vas-Cath Inc. v. Mahurkar, 19USPQ2d at 1116.
The instant claims encompass a replication-competent controlled alpha-herpesvirus (e.g., HSV-1, HSV-2 or a varicella-zoster virus) whose replication can be transiently activated in infected nonneural cells by application of an activating heat dose but that cannot be activated in infected neural cells by application of an activating heat dose, wherein the replication-competent controlled alpha-herpes virus comprises:
(a) a heterologous promoter that is a nucleic acid sequence that is a heat shock promoter, the heterologous promoter controlling the expression not a replication-essential gene of the replication-competent controlled alpha-herpesvirus, wherein (1) the heterologous promoter is functionally linked to the replication-essential gene of the replication-competent controlled alpha-herpesvirus, or (2) the heterologous promoter is functionally linked to a gene for a heterologous unregulated transactivator that has been inserted in the genome of the replication-competent controlled alpha-herpesvirus and the replication-essential gene is functionally linked to a promoter that is responsive to the transactivator, and
(b) a further heterologous genetic element of any structure as long as it is inserted in the genome of the replication-competent controlled alpha-herpesvirus and it prevents replication of the replication-competent controlled alpha-herpes virus in infected neural cells; and a vaccine composition comprising an effective amount of the same heat-controlled replication-competent controlled alpha-herpesvirus and a pharmaceutically acceptable carrier or excipient.
Apart from disclosing a heat controlled replication-competent controlled alpha-herpesvirus comprising: (a) a first heterologous promoter that replaces the resident promoter of a first replication-essential gene of the alpha-herpesvirus and is a heat shock gene promoter, or the first heterologous promoter is functionally linked to a gene encoding a unregulated transactivator that has been inserted in a suitable intergenic region in the genome of the alpha-herpesvirus and the first replication-essential gene of the alpha-herpesvirus is functionally linked to an inserted promoter that is responsive to the transactivator; and (ii) a further second heterologous promoter that replaces the resident promoter of a second replication-essential gene of the alpha-herpesvirus, wherein the second heterologous promoter is a keratin gene promoter, a MLANA gene promoter or a TYR gene promoter that is active in the epidermis (or the skin and/or an intended inoculation site) but is essentially inactive in nerve ganglia (e.g., dorsal root ganglia) or other nerve tissue of a mammalian subject, or instead of the second heterologous promoter a nerve cell-specific promoter that is functionally linked to a gene encoding a repressor of HSF1 (heat shock transcription factor 1) activity, a gene encoding a repressor for a transactivator function, a gene encoding an antisense RNA or siRNA directed against the transactivator gene or a replication-essential gene of the alpha-herpesvirus, or a gene encoding a ribozyme that targets a LAT (latency-associated transcript) to prevent reactivation/replication of the alpha-herpesvirus (see at least Summary of the Invention; page 11, line 28 continues to line 5 at page 13; page 20, line 9 continues to line 5 at page 21; Examples 1, 3-4, 6 and 12-13; and Table 1); the instant disclosure fails to provide sufficient and complete written description for any other heat-controlled replication-competent controlled alpha-herpes virus with the desired properties, particularly a heat-controlled replication-competent controlled alpha-herpesvirus comprising a further heterologous genetic element of any other structures that prevents replication of the replication-competent controlled alpha-herpesvirus in infected neural cells, as encompassed broadly by the instant claims? For example, apart from the use of a second heterologous promoter to control a second replication-essential gene of the alpha-herpesvirus, wherein the second heterologous promoter is known to be active in cells of the intended inoculation site region of a mammalian subject but is known to be essentially inactive in the cells of the nerve ganglia of the subject, and wherein the second heterologous promoter is a keratin gene promoter, a MLANA gene promoter or a TYR gene promoter; or instead of the second heterologous promoter apart from the use of a nerve cell-specific promoter that is functionally linked to any one of the various specific disclosed genes in the alpha-herpesvirus; which other specific essential or critical elements that other further heterologous genetic elements inserted in the genome of the replication-competent controlled alpha-herpesvirus possess such that they prevent replication of the replication-competent controlled alpha-herpesvirus in infected neural cells as encompassed broadly by the instant claims? The statement “A tissue- or cell-specific or restricted promoter that is appropriate for the intended use in an RCCHV of the present disclosure can be identified by mining available databases and other scientific literature (see, e.g., the BioGPS database or the article of Su et al. (2002)(Proc Natl Acad Sci USA (2002) 99:4465-4470” (lines 28-31) is not deemed to satisfy the required Written Description [Adequate written description requires more than a mere statement that it is part of the invention and reference to a method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991)]. For example, which specific tissue- or cell-specific promoters from the available databases and other scientific literatures that are appropriate for the intended use in an RCCHV of the present application as the second heterologous promoter other than a keratin gene promoter, a MLANA gene promoter or a TYR gene promoter?
Since the prior art before the effective filing date of the present application (11/04/2019) did not provide sufficient description and/or guidance regarding the above issues as evidenced at least by the teachings of Voellmy et al (Expert Rev. Vaccines 14:637-649, 2015), Bloom et al (J. Virol. 89:10668-10679, 2015), Voellmy et al (WO 2016/030392) and Martuza et al (WO 96/39841); it is incumbent upon the present specification to do so. The present application also fails to provide a representative number of species for a broad genus of a heat-controlled replication-competent controlled alpha-herpesvirus whose replication can be transiently activated in infected nonneural cells by application of an activating heat dose but that cannot be activated in infected neural cells by activation of an activating heat dose as claimed broadly.
The claimed invention as a whole is not adequately described if the claims require essential or critical elements which are not adequately described in the specification and which are not conventional in the art as of Applicants’ filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641, 1646 (1998). The skilled artisan cannot envision the complete detailed structure of a representative number of species for a broad genus of a heat-controlled replication-competent controlled alpha-herpesvirus whose replication can be transiently activated in infected nonneural cells by application of an activating heat dose but that cannot be activated in infected neural cells by activation of an activating heat dose as claimed broadly, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method. Adequate written description requires more than a mere statement that it is part of the invention and reference to a method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481, 1483.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Response to Arguments
Applicant’s arguments related in part to the above modified 35 U.S.C. 112(a) rejection for Lack of Written Description in the Amendment filed on 03/24/2026 (pages 5-) have been fully considered, but they are respectfully not found persuasive for the reasons discussed below.
With respect to the new element (b) of currently amended claim 1, Applicant cited Capron which explained “that the written description requirement may be satisfied ‘if in the knowledge of the art the disclosed function is sufficiently correlated to a particular, known structure’”. Additionally, Applicant believed that a heat-controlled replication-competent controlled alpha-herpesvirus comprising a heat shock promoter that controls the expression of a first replication-essential gene and a tissue-selective promoter that drives the expression of a second replication-essential gene has been described in detail throughout the as-filed specification. With respect to additional tissue-selective promoters that could endow heat-controlled replication-competent controlled alpha-herpesviruses with the claimed properties, Applicant cited lines 28-31 at page 11 disclosing that useful tissue-selective promoters can be identified by the mining of appropriate databases mentioning the BioGPS database, and the criteria that such a promoter must satisfy are detailed on page 4, lines 19-36 such as the second heterologous promoter is a promoter that is known to be active in cells in the intended innoculation site region of a mammalian subject but is known to be essentially inactive in cell of the nerve ganglia of the mammalian subject. Additionally, Applicant also argued that nucleotide sequences of useful promoters can be retrieved from the Eucaryotic Promoter Database, and technical details relating to the isolation of suitable tissue-selective promoters and their characterization are provided in Example 1. With respect to the issue of the number of species provided, Applicant cited page 20, lines 27-32 describing a “heat- or heat- and SMR-controlled RCCHV in which the heat shock promoter controls an unregulated or regulated transactivator comprising a GAL4 DNA-binding domain may comprise, instead of the second heterologous promoter, a gene for a repressor of transactivator function which gene is expressed under the control of a nerve cell-specific or selective promoter. Such a repressor may comprise a GAL4 DNA-binding domain and a Kruppel-associated box (KRAB) repressor domain”; with a nerve cell-specific promoter is disclosed at page 20, line 25 and suitable sites for insertion of the repressor gene into the alpha-herpesvirus genome are disclosed at page 11, lines 7-10.
First, please refer to the above modified 112(a) rejection for details.
Second, the element (b) of currently amended claims recites the limitation “a further heterologous genetic element inserted in the genome of the replication-competent controlled alpha-herpesvirus which element prevents replication of the replication-competent controlled alpha-herpesvirus in infected neural cells”. It is noted that the further heterologous genetic element does not have any recited structure element, and yet the genetic element has the desired property of preventing replication of the replication-competent controlled alpha-herpesvirus in infected neural cells. There is no recited structure in the further heterologous genetic element to correlate with the recited property.
Third, apart from the use of a second heterologous promoter to control a second replication-essential gene of the alpha-herpesvirus, wherein the second heterologous promoter is known to be active in cells of the intended inoculation site region of a mammalian subject but is known to be essentially inactive in the cells of the nerve ganglia of the subject, and wherein the second heterologous promoter is a keratin gene promoter, a MLANA gene promoter or a TYR gene promoter; or instead of the second heterologous promoter apart from the use of a nerve cell-specific promoter that is functionally linked to any one of the various specific disclosed genes in the alpha-herpesvirus; which other specific essential or critical elements that other further heterologous genetic elements inserted in the genome of the replication-competent controlled alpha-herpesvirus possess such that they prevent replication of the replication-competent controlled alpha-herpesvirus in infected neural cells as encompassed broadly by the instant claims? The statement “A tissue- or cell-specific or restricted promoter that is appropriate for the intended use in an RCCHV of the present disclosure can be identified by mining available databases and other scientific literature (see, e.g., the BioGPS database or the article of Su et al. (2002)(Proc Natl Acad Sci USA (2002) 99:4465-4470” (lines 28-31) is not deemed to satisfy the required Written Description [Adequate written description requires more than a mere statement that it is part of the invention and reference to a method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991)]. For example, which specific tissue- or cell-specific promoters from the available databases and other scientific literatures that are appropriate for the intended use in an RCCHV of the present application as the second heterologous promoter other than a keratin gene promoter, a MLANA gene promoter or a TYR gene promoter?
Fourth, the present application fails to provide a representative number of species for a broad genus of a heat-controlled replication-competent controlled alpha-herpesvirus as claimed, particularly with any further heterologous genetic element of any structure as long as it is inserted in the genome of the replication-competent controlled alpha-herpesvirus and which element prevents replication of the replication-competent controlled alpha-herpesvirus in infected neural cells.
Claim Rejections - 35 USC § 103
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.
Amended claims 1-4, 6 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Voellmy et al (Expert Rev. Vaccines 14:637-649, 2015) in view of Martuza et al (WO 96/39841). This is a new ground of rejection.
The instant claims encompass a replication-competent controlled alpha-herpesvirus (e.g., HSV-1, HSV-2 or a varicella-zoster virus) whose replication can be transiently activated in infected nonneural cells by application of an activating heat dose but that cannot be activated in infected neural cells by application of an activating heat dose, wherein the replication-competent controlled alpha-herpes virus comprises:
(a) a heterologous promoter that is a nucleic acid sequence that is a heat shock promoter, the heterologous promoter controlling the expression not a replication-essential gene of the replication-competent controlled alpha-herpesvirus, wherein (1) the heterologous promoter is functionally linked to the replication-essential gene of the replication-competent controlled alpha-herpesvirus, or (2) the heterologous promoter is functionally linked to a gene for a heterologous unregulated transactivator that has been inserted in the genome of the replication-competent controlled alpha-herpesvirus and the replication-essential gene is functionally linked to a promoter that is responsive to the transactivator, and
(b) a further heterologous genetic element inserted in the genome of the replication-competent controlled alpha-herpesvirus which element prevents replication of the replication-competent controlled alpha-herpes virus in infected neural cells; and a vaccine composition comprising an effective amount of the same heat-controlled replication-competent controlled alpha-herpesvirus and a pharmaceutically acceptable carrier or excipient.
Voellmy et al already disclosed at least a replication-competent controlled HSV-1 virus, in which genome the promoter of at least one replication-essential viral gene would be replaced with an HSP70B promoter, and for safety reasons, it may be prudent to subject at least two replication-essential genes to HSP promoter control (see section titled “Immunization by means of a replication-competent controlled virus” on pages 641-644; particularly at page 642, left column, middle two complete paragraphs at page 642; and Fig. 1A). Figure 1A is reproduced below.
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Voellmy et al taught that the resulting recombinant HSV-1 should be capable of infecting host cells and, subsequent to a transient activating heat treatment of the host cells, undergo a single round of replication; and further rounds of virus replication may be induced by further activating heat treatments. Voellmy et al also disclosed that replication-essential genes include immediate early (RL1 [ICP0], RS1 [ICP4]), early (UL9, UL29) as well as late (UL38, UL48) genes (left column, last complete paragraph at page 642). Voellmy et al stated “Inoculation of a subject with such a replication-competent controlled virus in a location in which viral replication will not cause illness or undue distress followed by localized activation of one or more rounds of controlled virus replication would be expected to induce a similarly potent immune response as infection with wild-type virus, but without the negative consequences of illness, malaise and enablement of secondary infection” (page 641, right column, bottom of first paragraph); and “The inoculation site may be, for example, an area skin of an upper extremity or a mucosal surface” (page 641, right column, top of first full paragraph). Voellmy et al also disclosed that the replication-competent controlled virus can be used as an immunization platform, with an inserted gene encoding a heterologous antigen (e.g., influenza virus antigen) that may be subjected to the same control as vector replication or may be driven by a constitutively active promoter (right column, second last paragraph at page 645); and hemagglutinin (HA) is the major surface antigen (an influenza virus spike protein) against which a host antibody response is directed (left column, last paragraph at page 638) and present vaccines rely largely on the induction of HA antibodies (right column, last full paragraph at page 639). Voellmy et al further disclosed that additional modifications of the HSV backbone could be envisioned to further enhance the immune response, including deletion of the ICP47 gene (right column, last sentence of third full paragraph at page 645). Moreover, Voellmy et al also stated “To attain a high margin of safety, replication of a controlled virus ought to be subject to dual regulation. Our preferred solution would be to subject one or, better, two replication-essential genes to the control of both an HSP promoter and a small-molecule regulator (SMR)-activated gene switch (FIGURE 1B). Alternatively, one may place one replication-essential gene under the control of an HP promoter and another under the control of a SMR-activated gene switch (FIGURE 1C)” (page642, right column, top of first full paragraph).
Voellmy et al did not teach explicitly at least a heat-controlled replication-competent controlled alpha-herpesvirus with a dual regulation comprising: (a) a heat shock promoter that is functionally linked to a replication-essential gene of the replication-competent controlled alpha-herpesvirus, and (b) a further heterologous genetic element inserted in the genome of the replication-competent controlled alpha-herpesvirus which element prevents replication of the replication-competent controlled alpha-herpesvirus in infected neural cells; and a vaccine composition comprising an effective amount of the heat-controlled replication-competent controlled HSV-1 and a pharmaceutically acceptable carrier or excipient.
Before the effective filing date of the present application (11/04/2019), Martuza et al already taught at least a replication competent herpes simplex virus vector with an essential herpes simplex virus gene (e.g., an HSV gene encodes a protein which is essential to viral replication such as the immediately-early genes ICP4 and ICP27) is driven by a cell-specific or tissue-specific promoter, including a keratin promoter which is a skin-specific promoter, to ablate the specific target cell (e.g., keratinocytes/epithelial cells responsible for wart) via cell-specific viral replication; and a pharmaceutical composition comprising the same replication competent herpes simplex virus vector and a pharmaceutically acceptable vehicle (e.g., aqueous solutions, non-toxic excipients such as salts, preservatives, buffers and the like) for the vector (at least Abstract; Summary of the Invention; particularly page 9, line 35 continues to line 6 at page 10; page 16, lines 14-18, lines 27-29; page 17, lines 18-34; page 48, lines 23-35; page 49, lines 8-22; and Table 1). Martuza et al stated “[t]he HSV immediate-early genes are the preferred HSV genes to be placed under the control of the cell-, tissue- or tumor-specific promoter in the HSV of the invention. The immediate-early HSV genes ICP4 and ICP27 are preferred because they are transcriptional regulatory genes. For example, ICP4 must be turned on before the other genes essential to HSV replication” (lines 28-34 at page 17). Martuza et al also taught that the tissue specific recombinant HSV vectors may further include other coding sequences, such as for immune modulatory products, which can be placed under control of viral early and late promoters (page 34, lines 26-30); and they may be additionally engineered to disrupt expression of the endogenous γ34.5 gene and/or the ribonucleotide reductase gene (page 40, lines 17-33). Martuza et al also taught that a replication-competent HSV that is incapable of expressing one or both of (i) a functional γ34.5 gene product and (ii) a ribonucleotide reductase can be used as a vaccine to protect an animal against HSV infection (page 9, lines 15-21; and Examples 6 and 8)
Accordingly, it would have been obvious for an ordinary skilled artisan before the effective filing date of the present application to modify the teachings of Voellmy et al by also at least replacing the endogenous promoter of the immediate-early HSV ICP4 gene with a heterologous keratin promoter (a skin-specific promoter) to be operably linked to the replication-essential ICP 4 gene, in addition to an HSP70B promoter operably linked to another replication-essential gene of HSV to have a dual regulation for the replication of a heat-controlled replication-competent controlled HSV virus to increase a margin of safety, particularly to prevent the replication or reactivation of the heat-controlled replication-competent controlled alpha-herpesvirus in infected neural cells with accidental application of an activating heat dose (e.g., a high fever); as well as formulating a vaccine composition comprising an effective amount of the heat-controlled replication-competent controlled recombinant HSV-1 virus with a pharmaceutically acceptable carrier or excipient, in light of the teachings of Martuza et al as presented above.
An ordinary skilled artisan would have been motivated to carry out the above modifications because Martuza et al already taught the use of a keratin promoter (a skin-specific promoter) that is functionally linked to an essential herpes simplex virus gene (e.g., the immediate-early ICP4 gene which must be turned on before the other genes essential to HSV replication) to control replication of a replication competent herpes simplex virus vector to ablate target keratinocytes/epithelial cells that are responsible for wart; and a pharmaceutical composition comprising the same replication competent herpes simplex virus vector and a pharmaceutically acceptable vehicle (e.g., aqueous solutions, non-toxic excipients such as salts, preservatives, buffers and the like). Please note that the primary Voellmy reference already stated explicitly “To attain a high margin of safety, replication of a controlled virus ought to be subject to dual regulation”.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Voellmy et al and Martuza et al as set forth above; coupled with a high level of skill of an ordinary skilled artisan in the relevant art.
The modified compositions resulting from the combined teachings of Voellmy et al and Martuza et al are indistinguishable and encompassed by the presently claimed invention. The modified heat-controlled replication-competent controlled alpha-herpesvirus with at least the additional replication-essential viral ICP4 gene under the control of a skin cell-specific keratin promoter in infected neural cells cannot be activated and/or replicated by application of an activating heat dose alone.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments related to the above modified 103 rejection in the Amendment filed on 03/24/2026 (pages 16-20) have been fully considered, but they are respectfully not found persuasive for the reasons discussed below.
A. Applicant argued basically that the Office fails to explain why an ordinary skilled artisan would have been motivated to generate a replication-competent controlled alpha herpesvirus comprising an HSP70B promoter-controlled first replication-essential viral gene and a keratin promoter-controlled second replication-essential viral gene, and all it conveys is that it might be technically possible to construct such a recombinant based on the combination of the cited references. Particularly, Voellmy et al teach replication-competent alpha-herpesviruses for vaccination and expression of heterologous antigens and Martuza et al teach replication-competent herpesviruses for ablation of particular cell types or tissues. Applicant also argued that since Voellmy et al teach in the section entitled “Safety” that a heat-and small regulator-controlled replication-competent controlled alpha-herpesvirus could be further engineered by introducing a block to reactivation of the virus in the nervous system, Voellmy et al do not teach or suggest that such a block could substitute for the small regulator control of the recombinant virus, nor do Voellmy et al disclose the possibility of blocking reactivation by replacing the promoter of a replication-essential viral gene with a tissue-selective promoter that is inactive in cells of the nervous system. Accordingly, an ordinary skill in the art would not be motivated to consult Martuza et al to identify a suitable tissue-selective promoter for insertion into a heat- and small regulator-controlled replication-competent controlled alpha-herpesvirus, even less a heat-controlled replication-competent controlled alpha-herpesvirus. With respect to the Martuza reference, Applicant argued that the reference focused on tumor virotherapy and the experimental ablation of particular cell types or tissues using replication-competent herpesviruses whose replication is controlled by tumor- or tissue-selective promoters; and although keratin gene promoters for skin tissue ablation are listed, but no information is provided about the activity of these promoters in nerve cells. Additionally, the claims recite transient activation of replication of replication-competent controlled alpha-herpesvirus in infected nonneural cells and not cell destruction as taught by Martuza et al. Thus, an ordinary skill in the art would not have known to achieve the transient activation of virus replication in infected nonneural cells. Moreover, Applicant argued that when discussing vaccine uses, Martuza et al do not teach or suggest using a tissue-selective promoter to prevent neurotoxicity of replication-competent herpesvirus vectors, and instead they propose to reduce neurotoxicity by inactivating the γ34.5 and ribonucleotide reductase genes. Applicant further argued that an ordinary skill in the art would not have had a reasonable expectation of success in arriving at the claimed replication-competent controlled alpha-herpesvirus whose replication can be transiently activated in infected nonneural cells but not in infected neural cells and which virus was heat-controlled but not heat- and SMR-controlled.
First, as set forth in the above modified 103 rejection it would have been obvious for an ordinary skilled artisan before the effective filing date of the present application to modify the teachings of Voellmy et al by also at least replacing the endogenous promoter of the immediate-early HSV ICP4 gene with a heterologous keratin promoter (a skin-specific promoter) to be operably linked to the replication-essential ICP 4 gene, in addition to an HSP70B promoter operably linked to another replication-essential gene of HSV to have a dual regulation for the replication of a heat-controlled replication-competent controlled HSV virus to increase a margin of safety, particularly to prevent the replication or reactivation of the heat-controlled replication-competent controlled alpha-herpesvirus in infected neural cells with accidental application of an activating heat dose (e.g., a high fever) because Martuza et al already taught the use of a keratin promoter (a skin-specific promoter) that is functionally linked to an essential herpes simplex virus gene (e.g., the immediate-early ICP4 gene which must be turned on before the other genes essential to HSV replication) to control replication of a replication competent herpes simplex virus vector to ablate target keratinocytes/epithelial cells that are responsible for wart.
Second, please note that Voellmy et al does teach to engineer replication-competent alpha-herpesviruses to replicate like wild-type virus, and in effect lyse cells at the inoculation site such as an area of skin on an upper extremity to be a superior immunization agent when compared with either a corresponding attenuated virus with a diminished replication or a non-replicating virus (the paragraph bridging left and right columns at page 641). Voellmy et al also stated “Based on the above-discussed results, one may reasonably argue that if an attenuated virus capable of some degree of replication induces a more potent and complete immune response in a subject than a corresponding non-replication virus, an even more potent and complete immune response would be elicited by a virus that replicates more efficiently than the latter attenuated virus” (left column, second last full paragraph at page 641). Similarly, Martuza et al teach the use of a keratin promoter (a skin-specific promoter) that is functionally linked to an essential herpes simplex virus gene (e.g., the immediate-early ICP4 gene which must be turned on before the other genes essential to HSV replication) to control replication of a replication competent herpes simplex virus vector to ablate target keratinocytes/epithelial cells that are responsible for wart. Please note that the primary Voellmy reference already stated explicitly “To attain a high margin of safety, replication of a controlled virus ought to be subject to dual regulation”. Accordingly, an ordinary skill in the art would readily recognize that the use of a heat shock promoter and a skin-specific promoter such as a keratin promoter, wherein each of which is functionally linked to an essential herpes simplex virus gene would constitute a dual regulation for a controlled replication of a replication-competent virus.
Third, please note that the heat- and SMR-controlled RCCHV is only a preferred vaccine construct with a high margin of safety that is disclosed in the Voellmy reference as evidenced by the following statements “To attain a high margin of safety, replication of a controlled virus ought to be subject to dual regulation. Our preferred solution would be to subject one or, better, two replication-essential genes to the control of both an HSP promoter and a small-molecule regulator (SMR)-activated gene switch (FIGURE 1B). Alternatively, one may place one replication-essential gene under the control of an HP promoter and another under the control of a SMR-activated gene switch (FIGURE 1C)” (page642, right column, top of first full paragraph). However, Voellmy et al also disclosed at least a replication-competent controlled HSV-1 virus, in which genome the promoter of at least one replication-essential viral gene would be replaced with an HSP70B promoter, and for safety reasons, it may be prudent to subject at least two replication-essential genes to HSP promoter control (see section titled “Immunization by means of a replication-competent controlled virus” on pages 641-644; particularly at page 642, left column, middle two complete paragraphs at page 642; and Fig. 1A). Figure 1A is reproduced below.
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Voellmy et al taught that the resulting recombinant HSV-1 should be capable of infecting host cells and, subsequent to a transient activating heat treatment of the host cells, undergo a single round of replication; and further rounds of virus replication may be induced by further activating heat treatments. Voellmy et al also disclosed that replication-essential genes include immediate early (RL1 [ICP0], RS1 [ICP4]), early (UL9, UL29) as well as late (UL38, UL48) genes (left column, last complete paragraph at page 642). It is noted that an ordinary skill in the art would readily recognize that any safety feature that is useful for a heat- and SMR-controlled RCCHV is also useful for a heat-controlled replication-competent controlled RCCHV.
Fourth, since the above rejection was made under 35 U.S.C. 103 none of the cited references have to teach every limitation of the instant claims. For example, the Voellmy reference does not have to disclose the use of any tissue-selective promoter for any reason, let alone one that is inactive in cells of the nervous system. Similarly, the Martuza reference does not have to teach a transient activation of virus replication in infected nonneural cells. It is also apparent that Applicant considered each of the cited references in total isolation one from the other, without considering the specific combination of Voellmy et al and Martuza et al. Please refer to the above modified 103 rejection for details along with the provided motivation for combining the cited references.
Fifth, in the vaccine context although Martuza et al propose to reduce neurotoxicity by inactivating the γ34.5 and/or ribonucleotide reductase genes, this proposal does not mean that the inactivation of any one of these genes is the only means to reduce neurotoxicity. Additionally, it also does not exclude the use of a keratin promoter (a skin-specific promoter) that is functionally linked to an essential herpes simplex virus gene to control replication of a replication competent herpes simplex virus vector as a level of regulation, and an ordinary skill in the art would readily recognize such use in the context of the combined teachings of Voellmy et al and Martuza et al as set forth in the above 103 rejection would also be useful in reducing neurotoxicity. An ordinary skill in the art would readily recognize that a skin-specific promoter such as a keratin promoter is inactive in neural cells due to the absence of any reported neurotoxicity by Martuza et al apart from the ablation of target keratinocytes/epithelial cells that are responsible for wart, and there is no evidence of record indicating that a skin-specific promoter is also active in neural cells (otherwise it would not be called a skin-specific promoter).
Sixth, please note that the standard under 35 U.S.C. 103 is a “reasonable” expectation of success.
B. With respect to the Advisory Action dated March 06, 2026, Applicant argued that the Voellmy refence relates exclusively to heat- and SMR-controlled replication-competent controlled herpesviruses but not heat-controlled replication-competent controlled herpesviruses, and once again referred to the section entitled “Safety” that teaches that heat- and SMR-controlled replication-competent controlled herpesviruses could be further engineered to prevent their reactivation in nerve cells. Applicant also argued that the Advisory Action does not provide a reasoned statement how the further engineering of a replication-competent controlled herpesvirus teaches or suggests modifying a heat- and SMR-controlled replication-competent controlled herpesviruses into a heat only controlled replication-competent controlled herpesviruses as claimed. Applicant further argued that without the benefit of the teachings of the as-filed application of the keratin gene promoter as a skin-specific promoter that is inactive in neural cells, one skill in the art would not have known that use of this promoter could reduce the neurotoxicity of a heat-controlled replication-competent controlled herpesvirus; and that Martuza et al did not even believe in their tissue-selective promoters as they advocated disabling two viral genes to reduce toxicity. Finally, Applicant argued that none of the cited references alone or in combination teach or suggest for the concept of a replication-competent controlled herpesvirus that is dually controlled by a heat shock promoter and a drug-independent mechanism that prevents replication in neural cells; and none of the statements and/or Fig. 1A in the Voellmy reference provide the required motivation for an ordinary skill in the art to modify the viral genome of the prior art by including a second heterologous element into the viral genomes such that application of an activating heat dose to infected neural cells does not activate viral replication.
First, once again the heat- and SMR-controlled RCCHV is only a preferred vaccine construct with a high margin of safety that is disclosed in the Voellmy reference as evidenced by the following statements “To attain a high margin of safety, replication of a controlled virus ought to be subject to dual regulation. Our preferred solution would be to subject one or, better, two replication-essential genes to the control of both an HSP promoter and a small-molecule regulator (SMR)-activated gene switch (FIGURE 1B). Alternatively, one may place one replication-essential gene under the control of an HP promoter and another under the control of a SMR-activated gene switch (FIGURE 1C)” (page642, right column, top of first full paragraph). However, Voellmy et al also disclosed at least a replication-competent controlled HSV-1 virus, in which genome the promoter of at least one replication-essential viral gene would be replaced with an HSP70B promoter, and for safety reasons, it may be prudent to subject at least two replication-essential genes to HSP promoter control (see section titled “Immunization by means of a replication-competent controlled virus” on pages 641-644; particularly at page 642, left column, middle two complete paragraphs at page 642; and Fig. 1A).
Second, since Martuza et al already taught the use of a keratin promoter (a skin-specific promoter) that is functionally linked to an essential herpes simplex virus gene to control replication of a replication competent herpes simplex virus vector to ablate target keratinocytes/epithelial cells that are responsible for wart, an ordinary skill in the art would readily recognize that such replication-competent herpes simplex virus vector would not be able to replicate in a neural cell as evidenced at least by the absence of any reported neurotoxicity apart from the ablation of target keratinocytes/epithelial cells that are responsible for wart. Additionally, although Martuza et al propose to reduce neurotoxicity by inactivating the γ34.5 and/or ribonucleotide reductase genes, this proposal does not mean they did not believe in their tissue-selective promoters in any context as Applicant argued.
Third, please refer to the above modified 103 rejection for details along with the provided motivation for combining the cited references. Additionally, please also refer to the Examiner’s responses in Section A above.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Amended claims 1-4, 6 and 8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 12,257,300 (IDS).
Although the claims at issue are not identical, they are not patentably distinct from each other because a heat-controlled or heat- and small-molecule regulators-controlled replication-competent controlled alpha-herpesvirus whose replication can be transiently activated in nonneural cells infected with said replication-competent controlled alpha-herpesvirus but that cannot be transiently in neural cells infected with said replication-competent controlled alpha-herpevirus, wherein the replication-competent controlled alpha-herpesvirus is a recombinant alpha-herpesvirus derived from a virus of the group consisting of a herpes simplex virus type 1 (HSV-1), a herpes simplex virus type 2 (HSV-2) and a varicella-zoster virus, said replication-competent controlled alpha-herpesvirus comprising the recited elements (a)-(b); and a vaccine composition comprising an effective amount of the same replication-competent controlled alpha-herpesvirus and a pharmaceutically acceptable carrier or excipient in claims 1-10 of U.S. Patent No. 11,565,001 anticipate a heat-controlled replication-competent controlled alpha-herpesvirus whose replication can be transiently activated in infected nonneural cells but that cannot be activated in infected neural cells in the application being examined and, therefore, a patent to the genus would, necessarily, extend the rights of the species or sub- should the genus issue as a patent after the species of sub-genus.
Response to Argument
Applicant’s argument related to the above nonstatutory double patenting rejection in the Amendment filed on 03/24/2026 (middle of page 20) has been fully considered, but it is respectfully not found persuasive for the reason discussed below.
Applicant argued simply that currently amended claims are not obvious over the claims of the cited patent. Additionally, Applicant stated that Applicant would consider filing a terminal disclaimer should an allowable subject matter is indicated in the present application.
The claims of the cited patent anticipate a heat-controlled replication-competent controlled alpha-herpesvirus of the present application as claimed, particularly claim 1 of US Patent No. 12,257,300 recites the limitation “wherein (1) the first heterologous promoter is functionally linked to the first replication-essential gene of the replication-competent controlled alpha-herpesvirus……and (b) a second heterologous promoter that is known to be active in nonneural cells of a mammalian subject to which the replication-competent controlled alpha-herpesvirus is to be administered but is also known to be essentially inactive in neural cells of the mammalian subject, the second heterologous promoter being functionally linked to a second replication-essential gene of the replication-competent controlled alpha-herpesvirus”. Additionally, there is no terminal disclaimer being filed.
Amended claims 1-3, 6 and 8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 7-10 of copending Application No. 17/803,699 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because a replication-competent controlled herpesvirus capable of delivering an antigen of a SARS-CoV-2 virus, comprising inserted in the genome of an alpha-herpesvirus: (a) a first exogenous promoter that is a nucleic acid sequence that acts as a heat shock promoter, the first promoter controlling expression of a first replication-essential gene of the alpha-herpesvirus, (b) a second exogenous promoter and a functionally linked exogenous gene for an antigen of a SARS-CoV-2 virus, and further comprising (c) a third exogenous promoter that is active in cells in a selected inoculation site of a mammalian subject to which site the replication-competent controlled herpesvirus is administered but is essentially inactive in cells of nerve ganglia of the mammalian subject, the third exogenous promoter being functionally linked to a second replication essential gene of the replication-competent controlled herpesvirus (dependent claim 2); and a vaccine composition comprising an effective amount of the replication-competent controlled herpesvirus encompassed in claims 1-2 and 7-10 of copending Application No. 17/803,699 anticipate/encompass a heat-controlled replication-competent controlled alpha-herpesvirus whose replication can be transiently activated in infected nonneural cells by application of an activating heat dose but that cannot be activated in infected neural cells by application of an activating heat dose in the application being examined and, therefore, a patent to the genus would, necessarily, extend the rights of the species or sub- should the genus issue as a patent after the species of sub-genus.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Argument
Applicant’s argument related to the above provisional nonstatutory double patenting rejection in the Amendment filed on 03/24/2026 (pages 20-21) has been fully considered, but it is respectfully not found persuasive for the reason discussed below.
Applicant argued basically that currently amended claims are not obvious over claims 1-2 and 7-10 of the co-pending application 17/0803,699. Additionally, Applicant also noted that the current application has a priority date of 11/04/2019 while the co-pending application 17/803,699 has a priority date of April 24, 2020; and Applicant requested that the rejection be withdrawn according to MPEP 804(I)(B)(1(b)(i).
Claims 1-2 and 7-10 of the co-pending application 17/0803,699 still anticipate/encompass a heat-controlled replication-competent controlled alpha-herpesvirus of the present application as claimed. Additionally, it is noted that the above provisional nonstatutory double patenting rejection is not the only rejection remaining in the present application.
Conclusions
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Quang Nguyen, Ph.D., at (571) 272-0776.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s acting SPE, James Douglas (Doug) Schultz, Ph.D., may be reached at (571) 272-0763.
To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Group Art Unit 1631; Central Fax No. (571) 273-8300.
Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to (571) 272-0547.
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/QUANG NGUYEN/Primary Examiner, Art Unit 1631
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