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Claims 15-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Groups II-IV), there being no allowable generic or linking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 April 27, 2023, have been acknowledged. Claim 14 was cancelled. Claims 2-12 and 15-16 were amended. Claims 17-21 are new. In light of the Applicant’s elected invention, claims 15-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 1-13 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 1-13 and 18-21 find support in foreign application EP20205209.8.
Information Disclosure Statement
The information disclosure statement (IDS) filed on April 28, 2023, has been considered.
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.
Claim 11 is 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.
Claim 11 encompass a genus of nucleic acids encoding oncolytic vaccinia virus vectors (see Specification pages 19-20) with at least 60% sequence identity to SEQ ID NOs: 9, 15, or 16. Furthermore, the recited sequence is recited with the functionality of being an oncolytic virus that comprises a modified fusion protein (F protein) of Newcastle disease virus (NDV), and the hemagglutinin neuraminidase (HN) protein of NDV, further comprising soluble PD-1 (sPD-1) and therefore the claim requires these functional limitations associated with the recited structure. Applicant has shown limited examples of nucleic acids that would fall within this broad genus that retain the required functional properties
Regarding the genus of nucleic acids of claim 11, under the new Written Description Guidelines for antigen binding proteins molecules, the Examiner is directed to determine whether one skilled in the art would recognize that the applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination: on 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guidelines for claims drawn to antibodies, which can be found at www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen. Accordingly, the instant claims have been re-evaluated in view of that guidance.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
Actual Reduction to Practice
In regard to the genus of nucleic acids of claim 11, the specification only embodies three species of the genus in SEQ ID NO:s 9, 15, and 16. SEQ ID NO: 9 is 81.2% and 92% similar to SEQ ID NOs: 15 and 16, respectively, and SEQ ID NO: 15 is 90.1% similar to SEQ ID NO: 16. The specification discloses that SEQ ID NO: 9 represents the nucleic acid sequence of an exemplary vector of the present invention comprising a construct VSV-NDV-HA-sPD-1-Fc with non-coding regions, SEQ ID NO. 15 represents the nucleic acid sequence of the construct VSV-NDV-HA-sPD-1-Fc. SEQ ID NO. 16 represents the total nucleic acid sequence of rVSV-NDV-sPD-1, wherein said sPD-1 is normal sPD-1 without high-affinity modification, and wherein said sequence does not comprise a Fc-encoding sequence (page 10, paragraph 1 and pages 19-20). Although Applicant shows examples of VSV-NDV-HA-sPD-1-Fc and rVSV-NDV-sPD-1 vaccinia viruses having an oncolytic effect, the nucleic acid encoding these vectors was not identified. Therefore, it is not clear that SEQ ID NOs: 9 and 15-16 have the required oncolytic function.
Sufficient relevant identifying characteristics
As mentioned above, the complete nucleic acid sequence of the three claimed SEQ ID NOs (9 and 15-16) is provided. Although there is some variation in the three sequences identifies, these are specific changes, as identified by the Applicant. For example, SEQ ID NO: 9 and SEQ ID NO: 15 have a single difference that accounts for the 18.8% change between the two sequences, SEQ ID NO: 9 retains non-coding regions while SEQ ID NO: 15 does not. Similarly, the change between SEQ ID NOs: 9 and 15 SEQ ID NO: 16 is that SEQ ID NO: 16 comprises s-PD-1 without high affinity modification and without the Fc domain. As such, these represent specific changes to the nucleic acid structures that do not confer understanding of what other changes could be made to the nucleic acid sequence while retaining the required oncolytic function and maintaining expression of the fusion protein. For example, SEQ ID NO: 9 has a lowest similarity with SEQ ID NO: 15 at 81.2% and SEQ ID NO: 16 has a lowest similarity with SEQ ID NO: 15 at 90.1%. This is far from the lower limit of 60% similarity. Furthermore, Applicant, as stated supra, has not identified the sequences of any of the vectors used in the example. As such, it is unclear whether the sequences of SEQ ID NOs: 9 and 15-16 have the required oncolytic activity. As a result, this leads to uncertainty about which sequences could be modified to reach 60% similarity while retaining the required functions. There are many possible sequences that could be generated that fall within the limitation of at least 60% sequence identity to SEQ ID NOs: 9, 15, or 16. However, there is no guarantee that these multitude of possible sequences have the recited function.
Accordingly, if the skilled artisan sought to generate the claimed genus of nucleic acids, they would first need to know which sequences can be altered while still being able to predictably produce a functional oncolytic virus. Hence, based on the new written description guidelines, the Examiner should conclude that the applicant was not in possession of the claimed genus of nucleic acids beyond the sequences described in the specification (i.e. the oncolytic viruses encompassed in SEQ ID NOs: 9 and 15-16).
Thus, the ordinary artisan would be required to undergo a trial-and-error selection process to identify sequences that fall within the sequence limitations of claim 11 and that retain oncolytic activity and expression of the fusion protein. It would be unpredictable to determine which sequences perform this function a priori.
Furthermore, claim 11 is claiming a genus of sequences based on the function of the sequences. This claim would encompass novel sequences not yet described in the literature.
Without a correlation between structure (possible sequences) and function (oncolytic acitivity and expression of the fusion protein), the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Therefore, conception is not achieved until reduction to practice has occurred. See Fiers v. Revel, 25 USPQ2d 1602 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481, 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
As such, there is a wide variety of sequences encompassed by the scope of claim 11. Accordingly, given that the specification recites limited species that fall within the limitations of the broadly-defined genera as recited in claim 11, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the required starting materials, that is a sequences comprising SEQ ID NOs: 9, 15, 0r 16 with at least 60% sequence identity and that has the function of oncolytic activity and expression of the fusion protein, at the time the application was filed. Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
Applicant is reminded that MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
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, 7-13, and 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), and Bartee et al. (Cancer Res 77: 2952-2963. 2017; referenced in IDS).
Regarding claims 1-3, 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.
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 11, Ebert teaches a nucleic acid sequence (SEQ ID NO: 13) encoding the VSV virus that is 67.8% similar with 91.3% local similarity (as the sequences are over 13000 nucleotides in length, the results are not shown) to SEQ ID NO: 9 of the instant application.
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).
Claims 1-2, 4-6, and 18-19 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), and Bartee et al. (Cancer Res 77: 2952-2963. 2017) as applied to claims 1-2 above, and further in view of United States Patent Application No. 20150368316 (Lazar-Molnar).
Regarding claims 4-5 and 18-19, the teachings of Ebert, Wang, and Bartee are as discussed above.
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.
Claims 1, 8, 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), and Bartee et al. (Cancer Res 77: 2952-2963. 2017) as applied to claims 1 and 8 above, and further in view of United States Patent No. 8022186 (Sheffer), United States Patent Application No. 20150368316 (Lazar-Molnar), United States Patent Application No. 20190055297 (Zhao).
The teachings of Ebert, Wang, and Bartee are as discussed above.
Wang is silent regarding the sequences encoding the Fc domain and the sPD-1.
However, regarding the sequence encoding the Fc domain, 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 Fe 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.
Regarding the sequence encoding the sPD-1, this sequence corresponds to a high affinity sPD-1 molecule.
The teachings of Ebert, Wang, and Bartee are as discussed above.
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 the sequence for 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.
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, 7-13, and 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), and Bartee et al. (Cancer Res 77: 2952-2963. 2017).
Regarding claims 1-3, ‘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.
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 11, ‘942 teaches a nucleic acid sequence (SEQ ID NO: 13) encoding the VSV virus that is 67.8% similar with 91.3% local similarity (as the sequences are over 13000 nucleotides in length, the results are not shown) to SEQ ID NO: 9 of the instant application (claim 18).
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 1-2, 4-6, and 18-19 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), and Bartee et al. (Cancer Res 77: 2952-2963. 2017) as applied to claims 1-2 above, and further in view of United States Patent Application No. 20150368316 (Lazar-Molnar).
Regarding claims 4-5 and 18-19, the teachings of ‘942, Wang, and Bartee are as discussed above.
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.
Claims 1, 8, 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), and Bartee et al. (Cancer Res 77: 2952-2963. 2017) as applied to claims 1 and 8 above, and further in view of United States Patent No. 8022186 (Sheffer), United States Patent Application No. 20150368316 (Lazar-Molnar), United States Patent Application No. 20190055297 (Zhao).
Regarding the sequence encoding the Fc domain, the teachings of ‘942, Wang, and Bartee are as discussed above.
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 Fe 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 sPD-1, this sequence corresponds to a high affinity sPD-1 molecule.
The teachings of ‘942, Wang, and Bartee are as discussed above.
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.
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.
Conclusion
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/KEENAN A BATES/Examiner, Art Unit 1631