DETAILED ACTION
Applicant’s amendment and remarks filed July 25, 2025 are acknowledged. Any prior objection or rejection that is not repeated or addressed below is either withdrawn or moot in view of Applicant’s amendment.
The rejection of claims 1-4 and 6-19 on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,738,079, is withdrawn in view of the acceptance of a terminal disclaimer filed July 28, 2025.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 17/262,580, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Claim 1, and dependent claims 2-4, and 6-19, recite, “secreted from a mammalian cell and forms a heptamer or a hexamer”. The embodiment of a hexamer does not appear to be supported in the prior-filed application.
In Applicant’s remarks filed July 25, 2025, Applicant points to paragraph [0108] of the specification, reproduced below:
[0108] Flavivirus NS1 proteins have been shown to occur in vivo in three different forms: (i) ER membrane-associated NS1 homodimer, which has a critical role in viral RNA replication, (ii) a plasma membrane-bound NS1 dimer; and (iii) secreted NS1 which forms a hexamer (trimer of dimers). It is the secreted form that has been shown to elicit protective antibodies in other flaviviruses, such as Dengue Virus (Hilgenfeld, R., supra). However, Zika NS1 has only been demonstrated to show and overall average sequence homology of 55% with dengue virus, and as such extrapolation of NS1 function in dengue virus (and other flaviviruses) should be done with caution (Freire, M.C.L.C et al., ACS Omega, 2(7):3913-3920; Hilgenfeld, R., supra). Indeed the outer surface of Zika secreted NS1 is markedly different from those of other flavivirus members including Dengue Virus type 2 and West Nile virus (Hilgenfeld, R., supra).
Paragraph [0108] of the specification discloses what is already known about flavivirus NS1 forming a hexamer in vivo, but also notes that Zika NS1 only shares about 55% sequence homology with Dengue virus NS1. It does not appear from this portion of the specification that Applicant contemplated hexamers in the context of the inventive subject matter.
Applicant also points to paragraph [0230] of the specification, which describes four separate plasmids that were produced: a control (no NS1 peptide), wild-type (ZIKV NS1), tPA-NS1, and NS1 heptamer. The NS1 heptamer plasmid comprises a tPA signal sequence, NS1 and IMX313P. Applicant notes that only the construct comprising both tPA and IMX313P produced a heptamer, thus the other two NS1 plasmids produced the other secreted forms, such as a hexamer (referencing paragraph [0108]). In response to Applicant’s remarks, it does not follow that the other two plasmids necessarily produced hexamers, since paragraph [0108] indicates that other secreted forms of NS1 are homodimers and dimers in vivo. The disclosure concerning the secreted forms that were produced by Applicant is limited. There is no clear indication that ZIKV NS1 hexamers, specifically, were produced. Therefore, the earliest effective filing date for instant claims 1-4 and 6-19 is the filing date of this application, June 13, 2023.
Claims Summary
Claim 1 and its dependent embodiments are directed to a pharmaceutical composition that induces an immune response when administered to a mammal, comprising a nucleic acid molecule encoding an immunogenic peptide comprising a portion of the NS1 protein of ZIKV. The nucleic acid is RNA (claim 16). The nucleic acid further comprises a heterologous signal peptide operatively linked to the immunogenic peptide. When expressed, the peptide is secreted from a mammalian cell and forms a heptamer or hexamer. The immunogenic peptide has at least 90%, at least 95% or at least 99% sequence identity to SEQ ID NO: 1 (claim 2). SEQ ID NO: 1 is 352 amino acids in length and represents ZIKV NS1. The immunogenic peptide elicits one or more of a T-cell response, a T-helper response, a cytotoxic T-cell response or a B-cell response (claim 3). The immunogenic peptide has at least 90% sequence identity to a portion of NS1, SEQ ID NO: 1, located at position 172-352, 172-278, 204-278, 204-352, 204-218, 204-221, 207-218, 207-221, 261-275, 261-278, 264-275, or 264-278 (claim 4).
The signal peptide directs secretion (claim 6), or is selected from a tissue plasminogen activator (tPA) (claims 7 and 8), among others, or is not an immunoglobulin (Ig) signaling peptide, or is not an IgE signaling peptide (claim 9). The signal peptide has at least 90%, at least 95% or 100% sequence identity to SEQ ID NO: 5 or SEQ ID NO: 12 (claim 10). SEQ ID NO: 5 represents a 23 amino acid tPA signal sequence. SEQ ID NO: 12 represents a 22 amino acid tPA signal sequence. The nucleic acid molecule comprises SEQ ID NO: 6, which is a 69-mer representing an optimized sequence encoding SEQ ID NO: 5 (tPA), or a sequence that is at least 80%, 85%, 90%, 95% or 100% identical to SEQ ID NO: 6 (claim 11). The nucleic acid comprises a promoter which is a constitutive promoter in a mammalian cell (claim 12), such as CMV (claim 13).
The pharmaceutical composition comprises a DNA vector including the nucleic acid molecule encoding the immunogenic peptide and the operatively linked heterologous signal peptide, or a viral vector comprising such (claim 14). The DNA vector is the pVax 1 vector (claim 15).
Also claimed is a method for eliciting an immune response in a subject by administering the pharmaceutical composition (claim 17). The immune response elicited is a T cell response (claim 18). Also claimed is a method of viral titer in a subject with a ZIKV infection by administering the pharmaceutical composition (claim 19).
Specification
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required:
The claims recite the formation of hexamers, however, the specification does not appear to contemplate this embodiment. The embodiment of a hexamer does not appear outside of paragraph [0108] of the specification which discloses that Flavivirus NS1 proteins occur in vivo in three different forms, including a secreted NS1 that forms a hexamer. This portion of the specification is disclosing what is already known about NS1 forming a hexamer, but does not appear to be particular to the claimed invention.
Applicant’s remarks filed July 25, 2025 regarding this matter have been addressed above. The specification remains objected to.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4 and 6-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a pharmaceutical composition comprising a nucleic acid molecule that expresses a ZIKV NS1 heptamer in secreted form wherein the nucleic acid molecule comprises a tPA sequence and IMX313P sequence, does not reasonably provide enablement for a heptamer in the absence of tPA and IMX313P. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
The breadth of the claims encompasses a nucleic acid molecule comprising ZIKV NS1 and any heterologous signal sequence operatively linked thereto that results in a secreted heptamer form from a mammalian cell. The nature of the invention is the expression of certain secreted forms engineered from the nucleic acid molecule construct for ZIKV NS1. The specification discloses that the NS1 heptamer is produced when the nucleic acid vector comprises tPA and IMX313P (see paragraph [0230), in combination with Applicant’s remarks filed July 25, 2025, page 6, indicating that this particular embodiment comprising both tPA and IMX313P resulted in heptamer secretion. This is in contrast with the other construct that was made with tPA but not IMX313P, which is not indicated as having produced heptamers (see paragraph [0230]) and Applicant’s remarks filed July 25, 2025, page 6.
In view of breadth of the claims, the nature of the invention, the teachings of the specification in the working example, and low level of predictability (i.e., only constructs with tPA and IMX313P produced heptamers), it would have required undue experimentation to arrive at the claimed invention as it regards heptamer secretion.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-4 and 6-19 are rejected under 35 U.S.C. 102(a)(1) as being Gowans et al. (US 2021/0228704 A1, published 7/29/2021, “Gowans”). It is acknowledged that Gowans is published application of USSN 17/262,580, the parent application of the instant application. It qualifies as prior art because the instantly claimed embodiment of “hexamer” does not appear to find support in the parent application, as explained above. Since the earliest effective filing date for the instant claims is 6/13/2023, Gowans is prior art. While Gowans does not disclose the embodiment of a hexamer, all other limitations are disclosed with regard to the embodiment of heptamers (see Gowans, paragraph [0069], [0074], and [0077], for example). Therefore, the claims are anticipated by Applicant’s own work (see also the patented claims). Applicant’s remarks filed July 25, 2025 are addressed above with regard to priority.
Claims 1-4, 6, 7, 9, 14 and 16-19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Petsch et al. (WO 2017/140905 A1, published August 24, 2017, cited in the IDS filed 6/13/2023, “Petsch”). The claims are summarized above and correlated with the teachings of the prior art in bold font below.
Petsch discloses an artificial nucleic acid comprising a coding region for ZIKV NS1, or a fragment thereof, along with a heterologous secretory signal peptide, that is expressed from a mammalian cell and induces an immune response in a subject (see page 21, lines 13-24, and page 89, lines 11-27) (addresses aspects of claims 1 and 6). Petsch discloses an NS1 sequence, SEQ ID NO: 26, which is an exact match for Applicant’s SEQ ID NO: 1 (addresses claims 2 and 4). Secretory signal peptides include calreticulin, which is not an Ig signaling nor an IgE signaling peptide (addresses claims 7 and 9).
Although T-cell responses to Petsch’s NS1 construct are not disclosed, they are expected because Petsch uses the same construct as claimed (i.e., nucleic acid comprising ZIKV NS1 with a secretory signal sequence for mammalian cell expression) (addresses claims 3, 18 and 19). Although Petsch does not disclose the formation of hexamers or heptamers, those forms are expected outcomes of doing what the prior art teaches with the same construct (addresses claim 1, hexamer).
Plasmid vectors (DNA) are disclosed (see page 17, line 25), RNA vectors, as well as pharmaceutical compositions comprising DNA (see claims 83 and 105) (addresses claim 1, aspect of pharmaceutical composition, and claims 14 and 16). Also disclosed are methods of inducing an immune response against ZIKV infection are disclosed, as well as prophylactic administration (see abstract, page 200, lines 19-24, page 204, lines 34-35) (addresses claims 17-19). Therefore, the claimed embodiments are anticipated by the prior art.
Applicant’s arguments filed July 25,2025 have been carefully considered but fail to persuade. Applicant points out that ZIKV NS1 protein production was not exemplified in Petsch’s disclosure. Applicant argues that Petsch’s peptides are bound to membranes as part of VLPs, not secreted forms that are able to form hexamers or heptamers.
In response, Petsch’s exemplified or preferred embodiments regarding, for example, VLPs, are not limiting. All of Petsch’s teachings are available as prior art. Petsch is not required to show an actual reduction to practice in the form of secreted ZIKV NS1 hexamers and heptamers. Petsch discloses an artificial nucleic acid comprising a coding region for ZIKV NS1, or a fragment thereof, along with a heterologous secretory signal peptide, that is expressed from a mammalian cell and induces an immune response in a subject (see page 21, lines 13-24, and page 89, lines 11-27). Petsch discloses secretory signal sequences, such as calreticulin (see page 89, line 24). Calreticulin is a secretory signal sequence that Applicant indicates as capable of enabling secretion of ZIKV NS1 as a hexamer or heptamer (see instant claim 7). Thus, all the elements required for secreted hexamers and heptamers (according to the claim limitations) are disclosed by Petsch. Therefore, the rejection is maintained for reasons of record.
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.
Claims 8, 10 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Petsch et al. (WO 2017/140905 A1, published August 24, 2017, cited in the IDS filed 6/13/2023, “Petsch”) as applied to claim 1 above, and further in view of Hooper et al. (US Patent 8,513,005, “Hooper”). Claims 8, 10 and 11 are directed to embodiments wherein the signal sequence is tPA, specifically SEQ ID NO: 5, encoded by SEQ ID NO: 6, respectively.
The teachings of Petsch are outlined above. Petsch discloses secretory signal peptides that allow transport of the peptide to the endoplasmic reticulum, for example (see page 89, lines 11-27). Petsch does not name tPA, nor does Petsch disclose SEQ ID NO: 5 and 6. However, it would have been obvious to have selected tPA as the secretory signal peptide, along with the associated amino acid and nucleic acid sequences, SEQ ID NO: 5 and 6. Hooper discloses DNA constructs comprising a tPA signal sequence to aid with secretion, noting that the tPA sequence is well known in the art for this purpose (see col. 17, lines 26-30) (addresses claim 8). Hooper’s SEQ ID NO: 1 is an exact match for Applicant’s SEQ ID NO: 6 (addresses claim 10), which means that it encodes SEQ ID NO: 5 (see instant specification, Table 1) (addresses claim 11). Given Petsch’s teaching to select a secretory signal peptide that targets the ER, and Hooper’s teaching that tPA is known to have that function, one would have been motivated to use Hooper’s tPA in Petsch’s construct with a reasonable expectation of success. Therefore, the claimed embodiments would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Applicant’s arguments filed July 25, 2025 have been addressed above as they pertain to the teachings of Petsch.
Claims 12, 13 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Petsch et al. (WO 2017/140905 A1, published August 24, 2017, cited in the IDS filed 6/13/2023, “Petsch”) as applied to claim 1 above, and further in view of Muthumani et al. (WO 2017/147458 A1, cited in the IDS filed 6/13/2023, “Muthumani”). Claims 12, 13 and 15 are directed to embodiments wherein the nucleic acid molecule includes a constitutive promoter in mammalian cells, CMV, and wherein the DNA vector is the pVax 1 vector, respectively.
The teachings of Petsch are outlined above. Petsch discloses the use of promoters in nucleic acid constructs, but does not name CMV (a constitutive promoter in mammalian cells), nor the particular plasmid vector pVax 1. However, it would have been obvious to have used pVax 1 with the CMV promoter with predictable results to express Petsch’s ZIKV NS1. Muthumani discloses ZIKV prM/E plasmid constructs using pVax 1 with CMV for expression in mammalian cells (see page 4, description of Figure 16) (addresses claims 12, 13 and 15). One would have been motivated to use pVax 1 with CMV for expression of Petsch’s ZIKV NS1 since Petsch’s disclosure is not limited to any particular plasmid, and Muthumani had success with the plasmid for expressing other ZIKV sequences. Therefore, the claimed embodiments would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Applicant’s arguments filed July 25, 2025 have been addressed above as they pertain to the teachings of Petsch.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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.
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/STACY B CHEN/Primary Examiner, Art Unit 1671