Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
The amended claims filed on December 17, 2025, have been acknowledged. Claims 1-5, 7, and 12 were cancelled. Claims 6, 8-11, and 13 were amended. Claims 6, 8-11, and 13 are pending and examined on the merits.
Priority
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d).The applicant claims foreign priority from JP2020-166661 filed on October 1, 2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55, received March 24, 2023, and English translations filed on December 17, 2025. Claims 6, 8-11, and 13 find support in foreign application JP2020-166661 filed on October 1, 2020.
Withdrawn Claim Rejections - 35 USC § 112
The prior rejection of claims 1-13 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in light of Applicant’s cancellation of claim 1.
New Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 6, 8-11, and 13 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The limitation “deficient in the following regions in the genome sequence of a vaccinia virus strain” in claim 6 is unclear. First, Applicant has not defined deficiency. It is unclear whether the deficiency can be a mutation, a deletion, or an insertion that leads to a deficiency in a gene or genes within the region. Second, it is unclear whether the deficiency must be across the entire nucleotide regions, as defined in claim 6 or if any deficiency within the region is sufficient. Of particular issue is that a region in the genome sequence of a vaccinia virus which corresponds to a region consisting of nucleotides from the nucleotide at position 23767 to the nucleotide at position 32499 in the nucleotide sequence shown in SEQ ID NO: 17 would require a deficiency in the C1L, N1L, and N2L genes (Morikawa evidences that nucleotide positions 23739-25416 correspond to these genes) if the whole identified region is required to be deleted as is shown in Applicant’s examples (Examples 1-4).Third, it is unclear what is meant by the consisting of language. A region is a location. As such, it is unclear whether the consisting of language requires the deficiency (mutation, deletion, or insertion) must encompass the whole region. As an example, it is unclear whether a single point mutation that creates a stop codon in a gene or an insertion that disrupts a gene function within the identified regions would fall within the limitation of claim 6 as this would lead to a deficiency in a gene that is within the region but would not occur over the full region. As identified above, this issue is amplified because of the incongruency between the deficiency in the second identified region (nucleotides 23767 to 32499) and the requirement that the C1L, N1L, and N2L genes are not deficient. A full deletion of the identified region would not be possible without deleting C1L, N1L, and N2L genes. Either a deletion of at least one of the genes, excluding the C1L, N1L, and N2L genes, in the region or deletion of the whole region and reinsertion of the C1L, N1L, and N2L genes as transgenes would allow for both limitations to not be incongruous. Therefore, claim 6 is indefinite.
Claims 8-11 and 13 are also rejected because of their dependency on claim 6.
Claim 11 recites that the exogenous DNA can be “a DNA encoding an antigen, wherein the antigen is a cancer, a virus, a bacterium, or a protozoan.” However, none of a cancer, a virus, a bacterium, or a protozoan are antigens. Although they produce antigens, they are not antigens themselves. It is recommended Applicant amends the claims to recite that the antigen is derived from a cancer cell, a virus, a bacterium, or a protozoan.
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 6, 8-11, and 13 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 rejection is made solely for the interpretation that deficiency is defined as deletion of the entire region as identified in claim 6. Applicant’s examples use full deletions of a ~8000 kb region (Examples 1-4), which supports interpreting deficiency to be defined as deletion of the entire region.
Claim 6, amended on December 17, 2025, recites:
An oncolytic vaccinia virus which is deficient in the following regions in the genome sequence of a vaccinia virus strain, does not grow in normal cells, grows in cancer cells and damages cancer cells:
a region in the genome sequence of a vaccinia virus which corresponds to a region consisting of nucleotides from the nucleotide at position 26240 to the nucleotide at position 34314 in the nucleotide sequence shown in SEQ ID NO: 17; or
a region in the genome sequence of a vaccinia virus which corresponds to a region consisting of nucleotides from the nucleotide at position 23767 to the nucleotide at position 32499 in the nucleotide sequence shown in SEQ ID NO: 17,
wherein the vaccinia virus is not deficient in the C2L, C1L, NIL, or N2L gene or genes homologous to the genes.
Of particular issue is that a region in the genome sequence of a vaccinia virus which corresponds to a region consisting of nucleotides from the nucleotide at position 23767 to the nucleotide at position 32499 in the nucleotide sequence shown in SEQ ID NO: 17 would require a deficiency in the C1L, N1L, and N2L genes (Morikawa evidences that nucleotide positions 23739-25416 correspond to these genes). Thus, for the C1L, N1L, and N2L genes to still be a part of the vaccinia virus, they would need to be reintroduced as transgene. Clear support for reintroduction of these genes cannot be found in the instant application or priority documents
Clear support for the new limitation cannot be found in the instant application or priority documents.
Accordingly, the amendments to Claim 6 are considered to constitute new matter.
MPEP 2163.06 notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph - written description requirement. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981).” MPEP 2163.02 teaches that “Whenever the issue arises, the fundamental factual inquiry is whether a claim defines an invention that is clearly conveyed to those skilled in the art at the time the application was filed...If a claim is amended to include subject matter, limitations, or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application”. MPEP 2163.06 further notes “When an amendment is filed in reply to an objection or rejection based on 35 U.S.C. 112, first paragraph, a study of the entire application is often necessary to determine whether or not “new matter” is involved. Applicant should therefore specifically point out the support for any amendments made to the disclosure” (emphasis added).
In the remarks filed on December 17, 2025, Applicant identifies that the amendments find support in in the claims and specification, as originally filed. The oncolytic vaccinia virus of claim 6 is d8k vaccinia virus which is explained in paragraphs [0015] to [0027] of the specification of the present application. As described in paragraph [0027], d8k vaccinia virus is not deficient in the C2L, C1L, N1L, or N2L gene or any of genes homologous to these genes. However, these paragraphs (nor any part of the specification) do not reference reintroducing the C1L, N1L, or N2L following deletion of nucleotide positions 26240-34314.
If Applicant believes that support for the new limitations, as now recited in Claim 6, is present and clearly envisaged in the instant application or earlier filed priority documents, applicant must, in responding to this Office Action, point out with particularity, where such support may be found.
Declarations and new references cannot demonstrate possession of a concept after the fact.
Claims 8-11 and 13 are also rejected because of their dependency on claim 6.
As a result of the new matter issue, the term “deficiency” is interpreted to mean that a single mutation that results in a deleted gene within the identified region, as long as none of C1L, C2L, N1L, and N2L are deleted, is sufficient to fall within the limitations of claim 6.
Withdrawn Claim Rejections - 35 USC § 102
The prior rejection of claims 1-13 are rejected under 35 U.S.C. 102(a)(1) and 102 (a)(2) as being anticipated by World Intellectual Property Organization Patent Application No. 2020/124274 (Bell), as evidenced by Morikawa et al. (Journal of Virology 79: 11873-11891. 2005; referenced in specification) is withdrawn in light of Applicant’s cancellation of claims 1-5, 7, and 12 and amendments to claim 6 to require that the vaccinia virus is not deficient in the C2L, C1L, N1L, and N2L genes.
The prior rejections of claims 1 and 9-13 under 35 U.S.C. 102(a)(1) and 102 (a)(2) as being anticipated by Mejias-Perez et al. (Molecular Therapy: Oncolytics 8: 27-40. 2018) in light of Applicant’s cancellation of claims 1 and 12 and amendments to claims 9-11 to make these claims dependent on claim 6.
New Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 6, 8-11, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over World Intellectual Property Organization Patent Application No. 2020/124274 (Bell), Meijas-Perez et al. (Molecular Therapy: Oncolytics 8: 27-40. 2018), and Turner et al. (Virology 380: 226–233. 2008), as evidenced by Morikawa et al. (Journal of Virology 79: 11873-11891. 2005). This a new rejection made in response to Applicant’s amendments to claim 6. Applicant’s traversal has been considered but is moot in response to the new rejection.
As an initial matter, as per the 112 issues identified above, the deficiency of claim 6 is not interpreted to require full deletion of the identified regions. Therefore, deletion of any gene within the identified region, excluding the C2L, C1L, N1L, or N2L genes, is considered to fall within a deficiency in the region.
Regarding claim 6, Bell teaches genetically modified vaccinia viruses from the LC16mO strain modified to contain deletion of the K2L gene (a gene that encodes a serine protease inhibitor that prevents cell fusion) and expression of at least one of three transgenes: IL-12-TM, FLT3-L and anti-CLTA4 to treat cancer. Bell teaches that genetic modification of the vaccinia viruses can enhance oncolytic activity and spread of infection (paragraphs 0006, 00210, 00281, and 00447).
Bell does not teach wherein deletion of the K2L gene causes the vaccinia virus to not grow in normal cells but still grow in cancerous cells.
However, Mejias-Perez teaches that they deleted the A48R, B18R, C11R, and J2R genes in a vaccinia virus (WR-Δ4) (Introduction and Figure 1).
Figure 4 of Mejias-Perez shows that the WR-Δ4 virus does not replicate in normal cells (ovaries, peritoneal exudates, and brain) as the viral titer fell between 24 hours and 120 after administration with no detectable virus by 120 hours, at the latest, in two of the three tissues, peritoneal exudates and brain, while Figure 2 shows the titer increasing in cancerous cells. It is worth noting Example 3 of the instant specification used a luciferase assay to assess their expression levels in the tumor versus normal cells with their 8k-Luc and 12k-Luc vaccinia viruses. Expression of the virus Fluc in the mouse peritoneal cavity was confirmed in all virus administration groups at three days after administration. The signal of the virus Fluc had disappeared almost completely in the peritoneal cavity region seven days later, that is, at 10 days after administration. The results of Mejias-Perez and the instant application are similar as in both, viral expression was identified at 72 hours post-administration but no longer seen at 5 days or 10 days post-infection, respectively, in peritoneal tissue. Therefore, the vaccinia virus of Mejias-Perez is also considered to not grow in normal cells. Figure 6 teaches that the virus has anti-tumor activity (i.e. damages cancer cells).
Meijas-Perez teaches that the WR-Δ4 virus showed the most potent oncolytic activity in vitro and in vivo and a greater reduction in virulence as mice injected with the WR-Δ4 virus exhibited 100% survival rate and none of the mice showed negative effects on state of health as a result of the tumor or the virus treatment (page 31, column 2, paragraph 1-page 37, column 1, paragraph 1).
Turner teaches that the K2L (also known as SPI-3) and HA (also known as A56) proteins interact and together prevent cell–cell fusion. The K2L/HA protein complex prevents the superinfection of previously infected cells by reducing virus–cell fusion. When K2L and HA are deleted, superinfection can occur, leading to increased viral loads within cells (abstract and Figure 4).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the K2L deleted vaccinia virus of Bell by further deleting the A48R, B18R, C11R, J2R, and HA genes, as identified by Mejias-Perez and Turner to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Bell and Meijas-Perez are using their vaccinia viruses to treat cancer and Meijas-Perez that deletion of these 4 genes led to significant anti-tumor activity while limiting the negative effects on the state of health. Furthermore, Turner teaches that deletion of the K2L and HA genes allows for superinfection of cells already infected with the vaccinia virus, increasing the viral load in the superinfected cells. Therefore, it would have been obvious to generate a vaccinia virus with deletion of the K2L, A48R, B18R, C11R, J2R, and HA genes as this would lead to a highly anti-tumor oncolytic virus that has improved safety and allows for increased viral load within tumor cells, both of which are stated goals of Bell (paragraph 0006) and Meijas-Perez (page 32, column 2, paragraph 3-page 37, column 1, paragraph 1 and Figure 8). Thus, the combined modifications would improve the efficacy of the vaccinia virus for treating cancer. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding the region of the deletion, as identified above, only a single gene must be deficient within the identified region under the current interpretation of claim 6. Morikawa (Table 1) evidences that the K2L gene (also known as SPI-3) corresponds to positions 28727-29836 of SEQ ID NO: 17 and would be deficient as it has been deleted in the combined vaccinia virus of Bell, Meijas-Perez, and Turner.
Regarding claim 8, as stated supra, Bell teaches that the genetically modified vaccinia virus can be from LC16M0 vaccinia virus strain (paragraph 0006). Bell teaches that the B5R gene is not deleted (paragraph 00535).
Regarding claim 9, Bell teaches that the virus can be included in a pharmaceutical composition for cancer treatment (paragraphs 00652-00662) and Mejias-Perez teaches that they administered the virus to mice with tumors and that the control was PBS alone (Figure 6). Therefore, the virus was delivered in a PBS solution (i.e. a pharmaceutical composition).
Regarding claims 10-11, Bell teaches genetically modified vaccinia viruses can comprise at least one of three transgenes: IL-12-TM, FLT3-L and anti-CLTA4 to treat cancer (paragraphs 0006, 00210, 00281, and 00447). Similarly, Mejias-Perez teaches that the WR-Δ4 virus deletion mutant could be improved by including transgene insertion to boost the antitumor response (TAAs, cytokines, suicide genes, stimulatory molecules), or the combination with anti-PD1/CTLA-4 antibodies used in immunotherapy and/or with co-stimulatory molecules (page 34, column 2, paragraph 3-page 36, column 1, paragraph 1).
Regarding claim 13, Bell teaches treating a cancer patient by administering their vaccinia virus (paragraphs 0006, 00612-00631, and 00652-00680) and Mejias-Perez teaches that they administered the WR-Δ4 virus to mice comprising tumors to treat cancer (Figure 6).
Conclusion
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 KEENAN A BATES whose telephone number is (571)270-0727. The examiner can normally be reached M-F 7:30-5:00.
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/KEENAN A BATES/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631