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 .
Election/Restrictions
Applicant’s election without traverse of Group I (Claims 1-12 and 18-21; drawn to a recombinant oncolytic virus, a vector, and a nucleic acid) in the reply filed on December 2, 2025, is acknowledged.
Claims 15-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Groups II-IV), there being no allowable generic or linking claim.
DETAILED ACTION
The amended claims filed on May 29, 2026, have been acknowledged. Claims 4 and 14 was cancelled. Claims 1, 7, 9, and 11 were amended. In light of the Applicant’s elected invention, claims 15-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-3, 5-13, and 18-21 are pending and examined on the merits.
Priority
The applicant claims foreign priority from EP20205209.8 filed on November 2, 2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55, received April 27, 2023. Claims 1-3, 5-13, and 18-21 find support in foreign application EP20205209.8.
Withdrawn Claim Rejections - 35 USC § 112
The prior rejection of Claim 11 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in light of Applicant’s amendment to claim 11 to require 90% sequence identity.
New Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 11 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 11 is dependent on claims 1 and 8 which require a high affinity soluble PD-1. However, as identified in the instant specification, SEQ ID NO: 16 comprises s-PD-1 without high affinity modification and without the Fc domain (page 20 of the instant specification). As such, SEQ ID NO: 16 fails to include all the limitations of the claim upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1-3, 5-10, 12-13, and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over World Intellectual Property Organization Patent Application No: 2017198779 (Ebert; referenced in IDS), Wang et al. (Nature Communications 11: 1-14. 2020; Published March 2020), Bartee et al. (Cancer Res 77: 2952-2963. 2017; referenced in IDS), and United States Patent Application No. 20150368316 (Lazar-Molnar). This is a new rejection substantially similar to a previous rejection of record made in response to Applicant’s amendments to claim 1. Any aspect of Applicant’s traversal that is relevant to the new rejection of record is addressed below.
Regarding claims 1-3, 5, and 18-19, Ebert teaches a recombinant oncolytic virus, comprising a vesicular stomatitis virus (VSV), wherein the glycoprotein (G protein) of VSV is deleted, and which comprises a modified fusion protein (F protein) of Newcastle disease virus (NDV); and the hemagglutinin neuraminidase (HN) protein of NDV to treat cancer (claims 1-15).
Ebert does not teach that their oncolytic virus further comprises a soluble PD-1 (sPD-1).
However, Wang teaches that they generated an engineered oncolytic vaccinia virus ((VV)-iPDL1/GM) coexpressing a murine soluble PD-1 extracellular domain fused with IgG1 Fc as a PD-L1 inhibitor (i.e., iPDL1) and murine GM-CSF (VV-iPDL1/GM), in the backbone of a tumor-selective double-deleted oncolytic VV, in which thymidine kinase (TK) and vaccinia growth factor viral genes had been deleted. They found that the oncolytic virus is able to secrete the PD-L1 inhibitor that systemically binds and inhibits PD-L1 on tumor cells and immune cells. Furthermore, this engineered oncolytic virus is capable of activating neoantigen-specific T cell responses by the likely synergistic action of viral replication, GM-CSF stimulation, and PD-L1 inhibition on tumor cells and immune cells, providing a novel oncolytic immunotherapy. Importantly, the intratumoral injection with the oncolytic virus overcomes PD-L1-mediated immunosuppression during both the priming and effector phases, provokes systemic T cell responses against dominant and subdominant neoantigen epitopes derived from mutations, and leads to an effective rejection of both virus-injected and distant tumors. In summary, this engineered oncolytic virus is able to activate tumor neoantigen-specific T cell responses, providing a potent, individual tumor-specific oncolytic immunotherapy for cancer patients, especially those resistant to PD-1/PD-L1 blockade therapy (abstract, page 2, column 1, paragraph 23-column 2, paragraph 1, and Figures 1-3).
Bartee teaches that oncolytic virotherapy represents an attractive option for the treatment of a variety of aggressive or refractory tumors. While this therapy is effective at rapidly debulking directly injected tumor masses, achieving complete eradication of established disease has proven difficult. One method to overcome this challenge is to use oncolytic viruses to induce secondary antitumor immune responses. Unfortunately, while the initial induction of these immune responses is typically robust, their subsequent efficacy is often inhibited through a variety of immunoregulatory mechanisms, including the PD1/PDL1 T-cell checkpoint pathway. Because of the known propensity for OV to induce initially robust antitumor immune responses, and the ability of PD1-blockade to maintain these responses, the combination of oncolytic viruses (OV) and checkpoint blockade is viewed as therapeutically attractive. Unfortunately, preliminary data from clinical trials combining IMLYGIC with PD1-blockade suggests that this combination likely results in the same increases in autoimmune-like toxicity seen with other combination therapies.
To overcome this inhibition and increased toxicity, they generated a novel recombinant myxoma virus (vPD1), which inhibits the PD1/PDL1 pathway specifically within the tumor microenvironment by secreting a soluble form of PD1 from infected cells. This virus both induced and maintained antitumor CD8+ T-cell responses within directly treated tumors and proved safer and more effective than combination therapy using unmodified myxoma and systemic aPD1 antibodies. It has been previously reported that, similar to aPD1 antibodies, soluble splice variants of PD1 can also inhibit the PD1/PDL1 checkpoint and improve overall T-cell function. In contrast to aPD1 antibodies, however, these PD1 splice variants are small single-chain polypeptides, which can be easily encoded into the genome of an OV. Furthermore, incorporation of soluble PD1 into MYXV actually enhanced efficacy compared with MYXV combined with systemically administered aPD1 antibody (Fig. 4). Localized vPD1 treatment combined with systemic elimination of regulatory T cells had potent synergistic effects against metastatic disease that was already established in secondary solid organs. These results demonstrate that tumor-localized inhibition of the PD1/PDL1 pathway can significantly improve outcomes during oncolytic virotherapy (abstract, page 2952, column 2, paragraph 1, page 2955, column 1, paragraph 2, page 2960, column 1, paragraph 1).
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 oncolytic virus of Ebert to include a transgene encoding soluble PD-1 fused to an IgG Fc, as identified by Wang, 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 Ebert, Wang, and Bartee are all interested in using oncolytic viruses for treating cancer and Wang and Bartee successfully reduce to practice that expression of soluble PD-1 fused to an Fc and soluble PD-1 without fusion, respectively, improves oncolytic anti-tumor activity. Furthermore, Bartee teaches that incorporating soluble PD-1 into the genome of the oncolytic virus improves the efficacy and safety of the anti-tumor treatment compared to combination treatment with an oncolytic virus and aPD1 antibodies. Although Wang and Bartee do not incorporate soluble PD-1 into a vesicular stomatitis virus, they show that soluble PD-1 improves oncolytic anti-tumor activity for multiple oncolytic viruses (vaccinia virus and myoma virus, respectively). Therefore, it would have been well understood that it can be incorporated into other oncolytic viruses, such as vesicular stomatitis virus, to improve anti-tumor activity and safety. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
The combined teachings of Ebert, Wang, and Bartee do not teach using a high affinity sPD-1.
However, Lazar-Molnar teaches that they developed an A132L mutant human PD-1 receptor fused to IgG1 with over 50- and 30-fold higher affinity to its two ligands, PD-L1 and PD-L2, respectively, compared to wild-type PD-1, When presented in the context of a bivalent Ig fusion protein, this mutant exhibits greater than two orders of magnitude higher avidity for target T cells compared to the wild type PD-1 receptor. In addition to its enhanced binding properties, this mutant Ig-fusion construct elicited a range of potentially desirable cytokine responses distinct from those associated with blocking monoclonal antibodies. By selectively blocking an important T cell inhibitory pathway, the reagent represents a novel strategy to enhance T cell responses to infectious agents and malignancies, with reduced side effects compared to existing biologics.
Since the mutant PD-1 Ig is able to bind the PD-Ligands with high affinity, it will prevent inhibitory signals into tumor infiltrating T cells through the endogenous PD-1 receptor. Removal of these inhibitory signals has dramatic effects on anti-tumor immune responses, the fusion polypeptide can be used in malignancies to activate the tumor-specific T cell response and induce tumor regression (paragraphs 0045-0062).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the soluble PD-1 fused to an IgG1 Fc of the combined oncolytic virus of Ebert, Wang, and Bartee with a high affinity soluble PD-1 fused to an IgG1 Fc, as identified by Lazar-Molnar, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to substitute with a reasonable expectation of success because Lazar-Molnar teaches that their high affinity soluble PD-1 fused to an IgG1 Fc improves binding to PD-L1 and PD-L2 and it will prevent inhibitory signals into tumor infiltrating T cells through the endogenous PD-1 receptor, improving the anti-tumor immune response by activating the tumor-specific T cell response and induce tumor regression. Both Wang and Bartee also identify the importance of inhibiting PD-L1 to improve outcomes during oncolytic virotherapy. Therefore, it would have been obvious to use a high affinity soluble PD-1 fused to an IgG1 Fc as this shows improved binding the PD-L1 and PD-L2 receptors and would improve anti-tumor activity of the oncolytic virus.
Regarding claim 6, Lazar-Molnar teaches that the mutant PD-1 comprises SEQ ID NO: 6 which has 100% sequence similarity to SEQ ID NO: 3 of the instant application.
It would have been obvious that this sequence could have been used as the sequence for the high affinity soluble PD-1 as it was a known sequence for encoding the high affinity soluble PD-1. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 7 and 20, Ebert teaches that their recombinant oncolytic virus of claim 1 can comprise a modified F3aa-modified fusion protein (F protein) of NDV and comprises at least one amino acid substitution in the protease cleavage site in position L289, e.g. L289A (claim 2).
Regarding claim 8, Ebert teaches that the recombinant oncolytic VSV virus can be encoded by a nucleic acid (claim 4).
Regarding claim 9, as stated supra, Wang teaches that they generated an engineered oncolytic vaccinia virus ((VV)-iPDL1/GM) coexpressing a murine soluble PD-1 extracellular domain fused with IgG1 Fc as a PD-L1 inhibitor (i.e., iPDL1) (Figure 1). As can be seen in Figure 1, Wang also shows a nucleic acid encoding the murine soluble PD-1 extracellular domain fused with IgG1 Fc.
Regarding claim 10, Ebert teaches that a vector can comprise the nucleic acid encoding the VSV virus (claim 5).
Regarding claim 12, Ebert teaches a pharmaceutical composition comprising the recombinant oncolytic virus or the nucleic acid encoding the oncolytic virus (claim 7).
Regarding claim 13, Ebert teaches that the pharmaceutical composition is formulated for systemic delivery (claim 9).
Response to Arguments
Applicant's arguments filed May 29, 2026, are acknowledged.
Applicant argues that Ebert does not teach or suggest a sPD-1, let alone a high affinity sPD-1. Neither Wang nor Bartee provide any teachings that would motivate one skilled in the art to replace a wild-type sPD-1 with a high affinity sPD-1. For example, Wang teaches the use of the wild-type sPD-1 extracellular domain fused to an Fc domain and demonstrate that this construct is effective in binding PD-L1 and inhibiting the PD-1/PD-L1 interaction. The focus of Wang is on the effectiveness of the wild-type PD-1-Fc fusion protein. There is no discussion or suggestion in Wang that a higher affinity sPD-1 would be preferable. In fact, Wang states that the wild-type PD-1 is sufficient to achieve comparable results to established anti-PD-L1 therapies and do not raise the need for a high affinity sPD-1.
The mere fact that the purported prior art could have been modified or applied in a manner to yield the Applicants' invention would not have made the modification or application obvious unless the prior art suggested the desirability of the modification. In re Gordon, 221 USPQ 1125, 1127 (Fed. Cir. 1984).
The cited references do not provide any teachings that suggest the desirability of replacing the wild-type sPD-1 with a high affinity sPD-1. A person of ordinary skill in the art would not be motivated to combine the teachings of Ebert, Wang, and Bartee with the teaching of Lazar-Moinar to substitute wild-type sPD-1 with a high affinity variant. Doing so would require impermissible hindsight reasoning.
It is impermissible to use the claimed invention as an instruction manual or "template" to piece together the teachings of the prior art so that the claimed invention is rendered obvious. In re Gorman, 933 F.2d 982, 987, 18 USPQ2d 1885, 1888 (Fed. Cir. 1991). The Court has previously stated that " [ojne cannot use hindsight reconstruction to pick and choose among isolated disclosures in the prior art to deprecate the claimed invention,"In re Fine, 837 F.2d at 1075, 5 USPQ2d at 1600.
The Ebert, Wang et al., Bartee et al. and Lazar-Molnar references, taken either alone or in combination, do not teach or suggest every element of the claimed invention, and thus, do not render obvious the claimed subject matter (page 10, paragraph 1-page 11, paragraph 3).
Applicant's arguments have been fully considered but they are not persuasive.
As an initial matter, regarding Applicant’s argument regarding impermissible hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
As stated in the rejection above, It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the soluble PD-1 fused to an IgG1 Fc of the combined oncolytic virus of Ebert, Wang, and Bartee with a high affinity soluble PD-1 fused to an IgG1 Fc, as identified by Lazar-Molnar, with a reasonable expectation of success because Lazar-Molnar teaches that their high affinity soluble PD-1 fused to an IgG1 Fc improves binding to PD-L1 and PD-L2 and it will prevent inhibitory signals into tumor infiltrating T cells through the endogenous PD-1 receptor, improving the anti-tumor immune response by activating the tumor-specific T cell response and induce tumor regression. Both Wang and Bartee also identify the importance of inhibiting PD-L1 to improve outcomes during oncolytic virotherapy. Therefore, it would have been obvious to use a high affinity soluble PD-1 fused to an IgG1 Fc as this shows improved binding the PD-L1 and PD-L2 receptors and would improve anti-tumor activity of the oncolytic virus.
Therefore, the prior art provides a distinct reason why one of ordinary skill in the art would want to make the modification to the high affinity soluble PD-1. Although Ebert, Wang, and Bartee do not discuss the possibility of using the high affinity soluble PD-1, they are all related to using oncolytic viruses to treat cancer and Lazar-Molnar teaches that the high affinity soluble PD-1 would improve the anti-tumor response. Thus, it would have been obvious to make the modification as improved anti-tumor response is well understood to be desirable for any method of treating cancer.
Claims 1, 8, 11, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over World Intellectual Property Organization Patent Application No: 2017198779 (Ebert), Wang et al. (Nature Communications 11: 1-14. 2020; Published March 2020), Bartee et al. (Cancer Res 77: 2952-2963. 2017), and United States Patent Application No. 20150368316 (Lazar-Molnar) as applied to claims 1 and 8 above, and further in view of United States Patent No. 8022186 (Sheffer) and United States Patent Application No. 20190055297 (Zhao). This is a new rejection substantially similar to a previous rejection of record made in response to Applicant’s amendments to claim 1. Applicant’s traversal has been addressed above.
The teachings of Ebert, Wang, Bartee, and Lazar-Molnar are as discussed above.
Wang is silent regarding the sequences encoding the Fc domain.
However, Sheffer teaches SEQ ID NO: 23 which corresponds to the wild type sequence of the human IgG1-Fc lacking the signal sequence and SEQ ID NO: 20 which corresponds to the wild-type Fc polynucleotide sequence, both of which have 100% sequence similarity to SEQ ID NO: 7 of the instant application (column 155).
It would have been obvious that the IgG1 Fc sequence identified by Sheffer could have been used to encode the Fc domain of oncolytic virus of the combined teachings of Ebert, Wang, and Bartee as Wang teaches that their Fc domain is also from IgG1 and Sheffer teaches their sequence corresponds to the wild type sequence of IgG1 Fc. It is well understood that the wild type sequence can be used as it is known to generate a functioning protein. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Lazar-Molnar is silent regarding the nucleic acid sequence encoding the high affinity soluble PD-1.
However, Zhao teaches SEQ ID NO: 133 encodes for a high affinity soluble PD-1 molecule comprising a A132L mutation, the same as used in Lazar-Molnar, and SEQ ID NO: 133 has 100% sequence similarity to SEQ ID NO: 6 of the instant application (paragraphs 0253-0254).
It would have been obvious that this sequence could have been used as the sequence for the high affinity soluble PD-1 as it was a known sequence for encoding the high affinity soluble PD-1. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 11, specifically, Ebert teaches a nucleic acid sequence (SEQ ID NO: 13) encoding the VSV virus that is 82.3% similar to SEQ ID NO: 15 of the instant application. SEQ ID NO: 13 of Ebert does not have the Fc domain nor the HA sPD-1 sequences within the sequence. However, as identified above, Sheffer and Zhao teach sequences that are 100% similar to SEQ ID NOs: 6-7 of the instant application. Incorporation of these sequences into SEQ ID NO: 13 of Ebert would result in a sequence that is 90.7% similar to SEQ ID NO: 15 of the instant application. Regarding placement of the sequences of Sheffer and Zhao, it would have been well understood to one of ordinary skill in the art that these sequences could be placed in the same region of modification of the VSV genome as was used to insert the F and HN genes, either upstream of both F and HN genes, downstream of both F and HN genes, or between the F and HN genes. Downstream modification, one of three options would have been readily envisioned by one of ordinary skill in the art and would lead to the 90.7% sequence similarity.
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.
Claims 1-3, 5-10, 12-13, and 18-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 and 14-18 of U.S. Patent No. 10906942 in view of Wang et al. (Nature Communications 11: 1-14. 2020; Published March 2020), Bartee et al. (Cancer Res 77: 2952-2963. 2017), and United States Patent Application No. 20150368316 (Lazar-Molnar). This is a new rejection substantially similar to a previous rejection of record made in response to Applicant’s amendments to claim 1. Applicant’s traversal has been addressed above.
Regarding claims 1-3, 5, and 18-19, ‘942 claims a recombinant oncolytic virus, comprising a vesicular stomatitis virus (VSV), wherein the glycoprotein (G protein) of VSV is deleted, and which comprises a modified fusion protein (F protein) of Newcastle disease virus (NDV); and the hemagglutinin neuraminidase (HN) protein of NDV to treat cancer (claim 1).
‘942 does not teach that their oncolytic virus further comprises a soluble PD-1 (sPD-1).
However, Wang teaches that they generated an engineered oncolytic vaccinia virus ((VV)-iPDL1/GM) coexpressing a murine soluble PD-1 extracellular domain fused with IgG1 Fc as a PD-L1 inhibitor (i.e., iPDL1) and murine GM-CSF (VV-iPDL1/GM), in the backbone of a tumor-selective double-deleted oncolytic VV, in which thymidine kinase (TK) and vaccinia growth factor viral genes had been deleted. They found that the oncolytic virus is able to secrete the PD-L1 inhibitor that systemically binds and inhibits PD-L1 on tumor cells and immune cells. Furthermore, this engineered oncolytic virus is capable of activating neoantigen-specific T cell responses by the likely synergistic action of viral replication, GM-CSF stimulation, and PD-L1 inhibition on tumor cells and immune cells, providing a novel oncolytic immunotherapy. Importantly, the intratumoral injection with the oncolytic virus overcomes PD-L1-mediated immunosuppression during both the priming and effector phases, provokes systemic T cell responses against dominant and subdominant neoantigen epitopes derived from mutations, and leads to an effective rejection of both virus-injected and distant tumors. In summary, this engineered oncolytic virus is able to activate tumor neoantigen-specific T cell responses, providing a potent, individual tumor-specific oncolytic immunotherapy for cancer patients, especially those resistant to PD-1/PD-L1 blockade therapy (abstract, page 2, column 1, paragraph 23-column 2, paragraph 1, and Figures 1-3).
Bartee teaches that oncolytic virotherapy represents an attractive option for the treatment of a variety of aggressive or refractory tumors. While this therapy is effective at rapidly debulking directly injected tumor masses, achieving complete eradication of established disease has proven difficult. One method to overcome this challenge is to use oncolytic viruses to induce secondary antitumor immune responses. Unfortunately, while the initial induction of these immune responses is typically robust, their subsequent efficacy is often inhibited through a variety of immunoregulatory mechanisms, including the PD1/PDL1 T-cell checkpoint pathway. Because of the known propensity for OV to induce initially robust antitumor immune responses, and the ability of PD1-blockade to maintain these responses, the combination of oncolytic viruses (OV) and checkpoint blockade is viewed as therapeutically attractive. Unfortunately, preliminary data from clinical trials combining IMLYGIC with PD1-blockade suggests that this combination likely results in the same increases in autoimmune-like toxicity seen with other combination therapies.
To overcome this inhibition and increased toxicity, they generated a novel recombinant myxoma virus (vPD1), which inhibits the PD1/PDL1 pathway specifically within the tumor microenvironment by secreting a soluble form of PD1 from infected cells. This virus both induced and maintained antitumor CD8+ T-cell responses within directly treated tumors and proved safer and more effective than combination therapy using unmodified myxoma and systemic aPD1 antibodies. It has been previously reported that, similar to aPD1 antibodies, soluble splice variants of PD1 can also inhibit the PD1/PDL1 checkpoint and improve overall T-cell function. In contrast to aPD1 antibodies, however, these PD1 splice variants are small single-chain polypeptides, which can be easily encoded into the genome of an OV. Furthermore, incorporation of soluble PD1 into MYXV actually enhanced efficacy compared with MYXV combined with systemically administered aPD1 antibody (Fig. 4). Localized vPD1 treatment combined with systemic elimination of regulatory T cells had potent synergistic effects against metastatic disease that was already established in secondary solid organs. These results demonstrate that tumor-localized inhibition of the PD1/PDL1 pathway can significantly improve outcomes during oncolytic virotherapy (abstract, page 2952, column 2, paragraph 1, page 2955, column 1, paragraph 2, page 2960, column 1, paragraph 1).
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 oncolytic virus of ‘942 to include a transgene encoding soluble PD-1 fused to an IgG Fc, as identified by Wang, 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 ‘942, Wang, and Bartee are all interested in using oncolytic viruses for treating cancer and Wang and Bartee successfully reduce to practice that expression of soluble PD-1 fused to an Fc and soluble PD-1 without fusion, respectively, improves oncolytic anti-tumor activity. Furthermore, Bartee teaches that incorporating soluble PD-1 into the genome of the oncolytic virus improves the efficacy and safety of the anti-tumor treatment compared to combination treatment with an oncolytic virus and aPD1 antibodies. Although Wang and Bartee do not incorporate soluble PD-1 into a vesicular stomatitis virus, they show that soluble PD-1 improves oncolytic anti-tumor activity for multiple oncolytic viruses (vaccinia virus and myoma virus, respectively). Therefore, it would have been well understood that it can be incorporated into other oncolytic viruses, such as vesicular stomatitis virus, to improve anti-tumor activity and safety. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
The combined teachings of ‘942, Wang, and Bartee do not teach using a high affinity sPD-1.
However, Lazar-Molnar teaches that they developed an A132L mutant human PD-1 receptor fused to IgG1 with over 50- and 30-fold higher affinity to its two ligands, PD-L1 and PD-L2, respectively, compared to wild-type PD-1, When presented in the context of a bivalent Ig fusion protein, this mutant exhibits greater than two orders of magnitude higher avidity for target T cells compared to the wild type PD-1 receptor. In addition to its enhanced binding properties, this mutant Ig-fusion construct elicited a range of potentially desirable cytokine responses distinct from those associated with blocking monoclonal antibodies. By selectively blocking an important T cell inhibitory pathway, the reagent represents a novel strategy to enhance T cell responses to infectious agents and malignancies, with reduced side effects compared to existing biologics.
Since the mutant PD-1 Ig is able to bind the PD-Ligands with high affinity, it will prevent inhibitory signals into tumor infiltrating T cells through the endogenous PD-1 receptor. Removal of these inhibitory signals has dramatic effects on anti-tumor immune responses, the fusion polypeptide can be used in malignancies to activate the tumor-specific T cell response and induce tumor regression (paragraphs 0045-0062).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the soluble PD-1 fused to an IgG1 Fc of the combined oncolytic virus of ‘942, Wang, and Bartee with a high affinity soluble PD-1 fused to an IgG1 Fc, as identified by Lazar-Molnar, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to substitute with a reasonable expectation of success because Lazar-Molnar teaches that their high affinity soluble PD-1 fused to an IgG1 Fc improves binding to PD-L1 and PD-L2 and it will prevent inhibitory signals into tumor infiltrating T cells through the endogenous PD-1 receptor, improving the anti-tumor immune response by activating the tumor-specific T cell response and induce tumor regression. Both Wang and Bartee also identify the importance of inhibiting PD-L1 to improve outcomes during oncolytic virotherapy. Therefore, it would have been obvious to use a high affinity soluble PD-1 fused to an IgG1 Fc as this shows improved binding the PD-L1 and PD-L2 receptors and would improve anti-tumor activity of the oncolytic virus.
Regarding claim 6, Lazar-Molnar teaches that the mutant PD-1 comprises SEQ ID NO: 6 which has 100% sequence similarity to SEQ ID NO: 3 of the instant application.
It would have been obvious that this sequence could have been used as the sequence for the high affinity soluble PD-1 as it was a known sequence for encoding the high affinity soluble PD-1. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claims 7 and 20, ‘942 teaches that their recombinant oncolytic virus of claim 1 can comprise a modified F3aa-modified fusion protein (F protein) of NDV and comprises at least one amino acid substitution in the protease cleavage site in position L289, such as. L289A (claims 2 and 16-17).
Regarding claim 8, ‘942 teaches that the recombinant oncolytic VSV virus can be encoded by a nucleic acid (claim 4).
Regarding claim 9, as stated supra, Wang teaches that they generated an engineered oncolytic vaccinia virus ((VV)-iPDL1/GM) coexpressing a murine soluble PD-1 extracellular domain fused with IgG1 Fc as a PD-L1 inhibitor (i.e., iPDL1) (Figure 1). As can be seen in Figure 1, Wang also shows a nucleic acid encoding the murine soluble PD-1 extracellular domain fused with IgG1 Fc.
Regarding claim 10, ‘942 teaches that a vector can comprise the nucleic acid encoding the VSV virus (claim 5).
Regarding claim 12, ‘942 teaches a pharmaceutical composition comprising the recombinant oncolytic virus or the nucleic acid encoding the oncolytic virus (claim 7).
Regarding claim 13, ‘942 teaches that the pharmaceutical composition is formulated for intravenous delivery (claim 9).
Claims 1, 8, 11, and 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 and 14-18 of U.S. Patent No. 10906942 in view of Wang et al. (Nature Communications 11: 1-14. 2020; Published March 2020), Bartee et al. (Cancer Res 77: 2952-2963. 2017), and United States Patent Application No. 20150368316 (Lazar-Molnar) as applied to claims 1 and 8 above, and further in view of United States Patent No. 8022186 (Sheffer) and United States Patent Application No. 20190055297 (Zhao). This is a new rejection substantially similar to a previous rejection of record made in response to Applicant’s amendments to claim 1. Applicant’s traversal has been addressed above.
The teachings of ‘942, Wang, Bartee, and Lazar-Molnar are as discussed above.
Regarding the sequence encoding the Fc domain, Wang is silent regarding the sequences encoding the Fc domain and the sPD-1.
However, Sheffer teaches SEQ ID NO: 23 which corresponds to the wild type sequence of the human IgG1-Fc lacking the signal sequence and SEQ ID NO: 20 which corresponds to the wild-type Fc polynucleotide sequence, both of which have 100% sequence similarity to SEQ ID NO: 7 of the instant application (column 155).
It would have been obvious that the IgG1 Fc sequence identified by Sheffer could have been used to encode the Fc domain of oncolytic virus of the combined teachings of ‘942, Wang, and Bartee as Wang teaches that their Fc domain is also from IgG1 and Sheffer teaches their sequence corresponds to the wild type sequence of IgG1 Fc. It is well understood that the wild type sequence can be used as it is known to generate a functioning protein. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding the sequence encoding the high affinity sPD-1, Lazar-Molnar is silent regarding the nucleic acid sequence encoding the high affinity soluble PD-1.
Zhao teaches SEQ ID NO: 133 encodes for a high affinity soluble PD-1 molecule comprising a A132L mutation, the same as used in Lazar-Molnar, and SEQ ID NO: 133 has 100% sequence similarity to SEQ ID NO: 6 of the instant application (paragraphs 0253-0254).
It would have been obvious that this sequence could have been used as the sequence for the high affinity soluble PD-1 as it was a known sequence for encoding the high affinity soluble PD-1. Furthermore, the successful cloning and sequencing of a DNA encoding a known gene and making an amino acid sequence is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the DNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. Ex parte Kubin, 83 U.S.P.Q.2d (BNA) 1410 (B.P.A.I. 2007), aff'd, 561 F.3d 1351 (Fed. Cir. 2009). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 11, specifically, ‘942 claims a nucleic acid sequence (SEQ ID NO: 13) encoding the VSV virus that is 82.3% similar to SEQ ID NO: 15 of the instant application. SEQ ID NO: 13 of ‘942 does not have the Fc domain nor the HA sPD-1 sequences within the sequence. However, as identified above, Sheffer and Zhao teach sequences that are 100% similar to SEQ ID NOs: 6-7 of the instant application. Incorporation of these sequences into SEQ ID NO: 13 of ‘942 would result in a sequence that is 90.7% similar to SEQ ID NO: 15 of the instant application. Regarding placement of the sequences of Sheffer and Zhao, it would have been well understood to one of ordinary skill in the art that these sequences could be placed in the same region of modification of the VSV genome as was used to insert the F and HN genes, either upstream of both F and HN genes, downstream of both F and HN genes, or between the F and HN genes. Downstream modification, one of three options would have been readily envisioned by one of ordinary skill in the art and would lead to the 90.7% sequence similarity.
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.
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/KEENAN A BATES/Examiner, Art Unit 1631
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