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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 7/9/2026 has been entered.
Claims 1-5, 7-8, 10-12, 16, and 18, of record 4/3/2026, are pending and subject to prosecution. Claim 16 is amended.
Declaration under 37 CFR 1.132
A declaration under 37 CFR 1.132, of record 7/9/2026, was filed by co-inventor Hwanjun Choi. Mr. Choi asserts that therapeutic efficacy of an oncolytic virus depends on properties of the viral backbone and interactions with a tumor and its microenvironment, not simply whether encoded transgenes are expressed (Declaration, page 3-6). The anti-tumor efficacy of a vaccinia virus comprising all of the claimed limitations is argued as being unexpectedly superior to vaccinia viruses comprising sub-combinations of limitations, as well as the closest embodiment of the prior art, and this could not have been predicted (Declaration, page 7-8).
The arguments and references presented have been fully considered but are not found persuasive. Arguments directed toward viral backbones, entry mechanisms, and interactions with tumor microenvironments are ultimately spurious and not conducive to advancing prosecution, particularly as each of sPD-1 and IL-12 have been demonstrated to have antitumoral effects outside of the context of virally-encoded transgenes (See He et al., fig. 4-6 and Tugues et al., fig. 2). Any differences between the claimed invention and the prior art may be expected to result in some differences in properties; the issue is whether the properties differ to such an extent that the difference is really unexpected. See MPEP 716.02.
From the results presented by the applicant, the antitumor performance of the three claimed transgenes together in a TK-/VGF-/K3L-deleted vaccinia virus appears to be no more than additive (See fig. 28-29 of the instant application). While a lack of synergism is not necessarily indicative of obviousness, the applicant would have to demonstrate that the effects are greater than the results that would have been expected from the prior art to an unobvious extent. See MPEP 716.02(a)(I). The primary reference used to reject the claims, Thorne et al., discloses an oncolytic vaccinia virus encoding a hyaluronidase gene and having a TK gene deletion (See col. 4, line 51-67). The virus can be further modified to comprise deletions of VGF and K3L (See col. 22, line 47-55). The issue at hand is whether the addition of transgenes encoding sPD-1 and IL-12 to the oncolytic VACV rendered obvious by Thorne et al. yields superior therapeutic results that could not have been expected by one of ordinary skill in the art.
PD-1 blockade is known to prevent T cell exhaustion, and Bartee et al. demonstrate that sPD-1 could be expressed by an oncolytic virus (myxoma virus) for enhancing virotherapy (See Abstract; page 2952, col. 1, ¶2 and col. 2, ¶1-2; and fig. 4-5 and 7). IL-12 is known to boost immune responses, and Meko et al. show that vaccinia virus encoding IL-12 reduces tumor growth in mice (See Abstract; page 4765, col. 1, ¶1-2; and fig. 1 and 3). Further, vaccinia virus had been previously engineered to express a wide variety of transgenes (See Haddad, entire document). From this fact pattern, one of ordinary skill could very reasonably expect that sPD-1 and IL-12 could be expressed from vaccinia virus, such as that rendered obvious by Thorne et al., and that each component would have a positive effect on antitumor therapy. Expected beneficial results are evidence of obviousness. See MPEP 716.02(c)(II). The declaration is thus insufficient to overcome the finding of obviousness.
Status of Prior Rejections
RE: Rejection of claims 16 and 18 under 35 U.S.C. 112(a):
The amendment to claim 16 is effective to obviate the rejection. The rejection is withdrawn.
RE: Rejection of claims 1, 10, 12, 16, and 18 under 35 U.S.C. 103 over Thorne (US 11065286 B2) in view of Meko et al. (Cancer Research, 1995) and Bartee et al. (Cancer Research, 2017):
RE: Rejection of claims 1-2, 10, 12, 16, and 18 under 35 U.S.C. 103 over Thorne (US 11065286 B2) in view of Meko et al. (Cancer Research, 1995) and Bartee et al. (Cancer Research, 2017), further in view of Ahmed et al. (US 20100040614 A1):
RE: Rejection of claims 1, 4, 10, 12, 16, and 18 under 35 U.S.C. 103 over Thorne (US 11065286 B2) in view of Meko et al. (Cancer Research, 1995) and Bartee et al. (Cancer Research, 2017), further in view of Frost et al. (US 20120171153 A1):
RE: Rejection of claims 1, 5, 10, 12, 16, and 18 under 35 U.S.C. 103 over Thorne (US 11065286 B2) in view of Meko et al. (Cancer Research, 1995) and Bartee et al. (Cancer Research, 2017), further in view of Carrio et al. (US 20120148535 A1):
RE: Rejection of claims 1, 7, 10, 12, 16, and 18 under 35 U.S.C. 103 over Thorne (US 11065286 B2) in view of Meko et al. (Cancer Research, 1995) and Bartee et al. (Cancer Research, 2017), further in view of Hicklin et al. (US 10232053 B2):
RE: Rejection of claims 1, 8, 10, 12, 16, and 18 under 35 U.S.C. 103 over Thorne (US 11065286 B2) in view of Meko et al. (Cancer Research, 1995) and Bartee et al. (Cancer Research, 2017), further in view of Wähler et al. (US 8067227 B2):
RE: Rejection of claims 1, 10-12, 16, and 18 under 35 U.S.C. 103 over Thorne (US 11065286 B2) in view of Meko et al. (Cancer Research, 1995) and Bartee et al. (Cancer Research, 2017), further in view of Chen et al. (US 8052968 B2):
The arguments directed to unexpected results are addressed above. The rejections are maintained.
Maintained Rejections
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 10, 12, 16, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Thorne (US 11065286 B2), of record, in view of Meko et al. (Cancer Research, 1995), of record, and Bartee et al. (Cancer Research, 2017), of record.
Regarding claims 1, 10, 12, 16, and 18: Thorne teaches oncolytic VACV encoding a variant HMGB1 protein and hyaluronidase and having a TK gene deletion (See col. 4, line 51-67). Thorne teaches the use of the Western Reserve strain having a deletion in TK and expressing the PH-20 hyaluronidase (with and without HMGB1) for treating mice in Example 2 (See col. 46, line 5-25 and fig. 8). The virus can be further modified to have deletions of virulence genes such as VGF and K3L (See col. 22, line 47-55). The virus can be used in a pharmaceutical composition and can be used for treating solid tumors or leukemia or lymphoma (which read on “blood cancer”) (See col. 6, line 27-45; col. 24, line 2-18; and col. 25, line 1-30). Specific cancers that can be treated include lung cancer, prostate cancer, colorectal cancer, breast cancer, head and neck squamous cell carcinoma (which reads on “head and neck cancer”), epithelial carcinoma (which reads on “skin cancer”), gastric cancer, hepatocellular carcinoma (which reads on “liver cancer”), ovarian cancer, bladder cancer, pancreatic cancer, and multiple myeloma (See col. 24, line 2-67 and col. 25, line 1-30). Thorne does not teach the virus as expressing IL-12 or sPD-1.
Meko et al. teach a recombinant VACV encoding IL-12 capable of reducing tumor growth in mice (See Abstract and fig. 1 and 3).
Bartee et al. teach myxoma virus expressing sPD-1 for enhancing oncolytic virotherapy (See Abstract and fig. 4-5 and 7). Bartee et al. mention that an anti-PD-1 antibody had been previously expressed from VACV and that myxoma virus-expressed sPD-1 worked better than myxoma virus in combination with anti-PD-1 antibodies (See page 2959, col. 2, full ¶1 and page 2960, col. 1, ¶1), which suggests that VACV-expressed sPD-1 may be similarly efficacious.
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the recombinant VACV of Thorne to comprise a gene encoding IL-12, as taught by Meko et al. One would be motivated to make this modification because Meko et al. teach that VACV expressing IL-2 has increased anti-tumor activity (See Abstract and fig. 3). There would be a reasonable expectation of success in making this modification because Thorne teaches that the virus can comprise one or more insertions of heterologous nucleic acids (See col. 14, line 32-36).
It also would have been obvious to modify the recombinant VACV of Thorne to comprise a sPD-1 gene, such as is taught by Bartee et al. One would be motivated to make this modification because Bartee et al. teach that sPD1 can be expressed from an oncolytic virus for improved outcomes in cancer (See Abstract and fig. 4-5 and 7). There would be a reasonable expectation of success in doing so because Thorne teaches that the virus can comprise one or more insertions of heterologous nucleic acids (See col. 14, line 32-36) and because Bartee et al. suggest that the expression of sPD-1 by other oncolytic viruses could be feasible and efficacious (See page 2959, col. 2, full ¶1 and page 2960, col. 1, ¶1).
Claims 1-2, 10, 12, 16, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Thorne (US 11065286 B2), of record, in view of Meko et al. (Cancer Research, 1995), of record, and Bartee et al. (Cancer Research, 2017), of record, further in view of Ahmed et al. (US 20100040614 A1), of record.
The teachings of Thorne, Meko et al., and Bartee et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 2: Following the discussion of claims 1, 10, 12, 16, and 18, Thorne, modified by Meko et al. and Bartee et al., render obvious a recombinant VACV encoding genes for sPD-1, hyaluronidase, and IL-12 but do not teach the sequence of sPD-1 as comprising instant SEQ ID NO 131 or 133.
Ahmed et al. teach PD-1 antagonists for enhancing specific anti-tumor immune responses that can be delivered by vectors such as vaccinia virus (See ¶0010, 0206, and 0245-0246). Ahmed et al. teach a PD-1 sequence comprising the sequence of instant SEQ ID NO 131 (See ¶0047, SEQ ID NO 2, and alignment below (first 120 aa displayed)).
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It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the recombinant vaccinia virus of Thorne, modified by Meko et al. and Bartee et al., to substitute the PD-1 sequence taught by Ahmed et al. Simple substitution of one known element for another known element is considered to be prima facie obvious, absent a showing that the result of the substitution yields more than predictable results.
Claims 1, 4, 10, 12, 16, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Thorne (US 11065286 B2), of record, in view of Meko et al. (Cancer Research, 1995), of record, and Bartee et al. (Cancer Research, 2017), of record, further in view of Frost et al. (US 20120171153 A1), of record.
The teachings of Thorne, Meko et al., and Bartee et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 4: Following the discussion of claims 1, 10, 12, 16, and 18, Thorne, modified by Meko et al. and Bartee et al., render obvious a recombinant VACV encoding genes for sPD-1, hyaluronidase, and IL-12 but do not teach the hyaluronidase as comprising the amino acid sequence of instant SEQ ID NO 135.
Frost et al. teach a hyaluronidase sequence comprising the sequence of instant SEQ ID NO 135 for administration to tumors (See table 2, SEQ ID NO 111, and alignment below (first 120 aa displayed)).
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It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the virus of Thorne, modified by Meko et al. and Bartee et al., to substitute the hyaluronidase sequence taught by Frost et al. Simple substitution of one known element for another known element is considered to be prima facie obvious, absent a showing that the result of the substitution yields more than predictable results.
Claims 1, 5, 10, 12, 16, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Thorne (US 11065286 B2), of record, in view of Meko et al. (Cancer Research, 1995), of record, and Bartee et al. (Cancer Research, 2017), of record, further in view of Carrio et al. (US 20120148535 A1), of record.
The teachings of Thorne, Meko et al., and Bartee et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 5: Following the discussion of claims 1, 10, 12, 16, and 18, Thorne, modified by Meko et al. and Bartee et al., render obvious a recombinant VACV encoding genes for sPD-1, hyaluronidase, and IL-12 but do not teach the hyaluronidase as comprising the nucleotide sequence of instant SEQ ID NO 136.
Carrio et al. teach a genetically modified oncolytic virus comprising a hyaluronidase gene for use as an anticancer agent (See Abstract). Carrio et al. teach a nucleotide sequence matching nucleotides 1-1467 of instant SEQ ID NO 136 (See ¶0059, SEQ ID NO 2, and alignment below (first 120 bp displayed)).
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Carrio et al. also teach that the sequence was appended with the stop codon TAA, yielding a sequence identical to instant SEQ ID NO 136 (See ¶0059).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the recombinant virus of Thorne, modified by Meko et al. and Bartee et al., to substitute the hyaluronidase sequence taught by Carrio et al. Simple substitution of one known element for another known element is considered to be prima facie obvious, absent a showing that the result of the substitution yields more than predictable results.
Claims 1, 7, 10, 12, 16, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Thorne (US 11065286 B2), of record, in view of Meko et al. (Cancer Research, 1995), of record, and Bartee et al. (Cancer Research, 2017), of record, further in view of Hicklin et al. (US 10232053 B2), of record.
The teachings of Thorne, Meko et al., and Bartee et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 7: Following the discussion of claims 1, 10, 12, 16, and 18, Thorne, modified by Meko et al. and Bartee et al., render obvious a recombinant VACV encoding genes for sPD-1, hyaluronidase, and IL-12 but do not teach the hyaluronidase as comprising the amino acid sequence of instant SEQ ID NO 137.
Hicklin et al. teach an immunomodulatory oncolytic virus comprising an IL-12 transgene with a polypeptide sequence identical to instant SEQ ID NO 137 (See table 1, SEQ ID NO 20, and alignment below (first 120 aa displayed)).
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It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the recombinant virus of Thorne, modified by Meko et al. and Bartee et al., to substitute the IL-12 sequence taught by Hicklin et al. Simple substitution of one known element for another known element is considered to be prima facie obvious, absent a showing that the result of the substitution yields more than predictable results.
Claims 1, 8, 10, 12, 16, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Thorne (US 11065286 B2), of record, in view of Meko et al. (Cancer Research, 1995), of record, and Bartee et al. (Cancer Research, 2017), of record, further in view of Wähler et al. (US 8067227 B2), of record.
The teachings of Thorne, Meko et al., and Bartee et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 8: Following the discussion of claims 1, 10, 12, 16, and 18, Thorne, modified by Meko et al. and Bartee et al., render obvious a recombinant VACV encoding genes for sPD-1, hyaluronidase, and IL-12 but do not teach the IL-12 gene as comprising the nucleotide sequence of any of instant SEQ ID NO 138-140.
Wähler et al. teach viral vectors comprising nucleic acid sequences coding for IL-12 for the treatment of tumors (See Abstract). Wähler et al. teach the IL-12 gene comprising a sequence identical to instant SEQ ID NO 139 (See fig. 1, SEQ ID NO 1, and alignment below (first 120 bp displayed)).
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It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the recombinant virus of Thorne, modified by Meko et al. and Bartee et al., to substitute the IL-12 sequence taught by Wähler et al. Simple substitution of one known element for another known element is considered to be prima facie obvious, absent a showing that the result of the substitution yields more than predictable results.
Claims 1, 10-12, 16, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Thorne (US 11065286 B2), of record, in view of Meko et al. (Cancer Research, 1995), of record, and Bartee et al. (Cancer Research, 2017), of record, further in view of Chen et al. (US 8052968 B2), of record.
The teachings of Thorne, Meko et al., and Bartee et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 11: Following the discussion of claims 1, 10, 12, 16, and 18, Thorne, modified by Meko et al. and Bartee et al., render obvious a recombinant VACV encoding genes for sPD-1, hyaluronidase, and IL-12 but do not teach the VACV strain as IHD-W.
Chen et al. teach genetically modified vaccinia virus comprising therapeutic heterologous genes for use as antitumor agents (See col. 3, lines 59-66 and col. 6, lines 6-12). Chen et al. teach that the IHD-W strain can be modified for therapeutic use (See col. 31, lines 18-23).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the recombinant vaccinia virus of Thorne, modified by Meko et al. and Bartee et al., to substitute the IHD-W strain, as taught by Chen et al., for use in cancer treatment. Simple substitution of one known element for another known element is considered to be prima facie obvious, absent a showing that the result of the substitution yields more than predictable results.
Allowable Subject Matter
Claim 3 is objected to as being dependent upon a rejected base claim but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. SEQ ID NOs 132 and 134 appear to be free of the prior art.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER S SPENCE, whose telephone number is 571-272-8590. The examiner can
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normally be reached M-F 8:30-5:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher M Babic, can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.S.S./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
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