DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
The amended claims filed 02/17/2026 are acknowledged and entered.
Claims 13-24 were previously presented
Claims 15, 17, 22, and 24 have been amended
Claims 1-14, 16, 18, and 19 are cancelled
Claims 20-23 are withdrawn.
Claims 15, 17, and 24 are pending and examined on their merits.
Response to Amendment
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Claim Rejections - 35 USC § 102 - withdrawn
The rejections of claims 13 and 24, under 35 U.S.C. 102(a)(b) as anticipated by Liao (previously cited) are all withdrawn in view of Applicant’s cancellation of claim 13 and amendments to claim 24.
Double Patenting - withdrawn
The rejections of claims 13-15, 17-18 and 24 on the ground of nonstatutory double patenting as being unpatentable over claims 13-15, 17-18 and 24 of copending Application No. 17/914,882 are withdrawn in view of Applicant’s amendments to claim 15, 17 and 24 and cancellation of claims 13-14 and 18.
Rejections Maintained
Claim Rejections - 35 USC § 112 maintained
1. The rejections for claims 15 and 17 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph (16 and 19 are cancelled), second paragraph, as being indefinite is maintained in view of the amended claims 15 and 17.
Applicant’s Arguments:
The PD-1 is as set forth in SEQ ID NO: 6. SEQ ID NO: 6, which is fully disclosed and defined in the specification. Nucleotides 1-59 of SEQ ID NO: 6 encode an optimized signal peptide, representing a specific technical improvement made by the invention to enhance recombinant viral expression efficiency. Together with the subsequent sequence encoding the mature PD-1 protein, it forms a complete and functional expression construct. A person skilled in the art, reading the specification, will clearly understand the entirety of the sequence and its purpose, with no ambiguity regarding the scope of the claims. The assessment of definiteness must consider the referenced sequence in its entirety. Including the optimized signal peptide within the claimed PD-1 coding sequence accurately captures the molecular entity actually invented and intended to be protected.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive.
Claim 15 and 17 have been amended to recite the limitation "… wherein a DNA corresponding to a genome of the recombinant Newcastle disease virus further comprises an exogenous gene, which is PD 1; the PD1 is as set forth in SEQ ID NO: 6 …..”. SEQ ID NO: 6 is 504 nucleotide long and is defined as PD-1 (see image below). However, SEQ ID NO: 6 does not code for PD-1 exclusively as nucleotides 1 to 59 (out of 504) do not align with the complete PD-1 cDNA sequence as discussed in Claim Rejections - 35 USC § 103).
Applicant argues PD-1 is defined as set forth in SEQ ID NO: 6 [0013] and that SEQ ID NO: 6 is fully disclosed and defined in the specification. However SEQ ID NO: 6 does not match the known PD-1 sequence (see Claim Rejections - 35 USC § 112 Section and in the Office action dated 11/20/2025). Where applicant acts as his or her own lexicographer to specifically define a term of a claim (in this case PD-1) contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term is indefinite because the specification does not clearly redefine the term (MPEP. ¶ 7.34.02 Terminology Used Inconsistent with Accepted Meaning). Applicant argues that PD-1, as set forth in SEQ ID NO: 6, encodes a PD-1 protein variant incorporating an optimized signal peptide, a key aspect of the invention. However, applicant does not cite where the optimized signal peptide is so clearly described in the specification or where SEQ ID NO: 6 is fully defined in the specification. As a matter of fact, searching the specification for the terms “signal” or “signal peptide” or “PD1” or “SEQ ID NO” or “optimized” does not find any such information as part of the invention. Therefore, the rejection for claims 15 and 17 is maintained.
Claim Rejections - 35 USC § 103 - Maintained
Claims 15 and 24 are rejected under 35 U.S.C. 103 (claims 13, 14, 16 are cancelled) as being unpatentable over Liao (previously cited) in view of AY508514.1 (previously cited), U64863.1 (previously cited) and Bartee (previously cited). Applicant’s arguments have been fully considered and are not persuasive. Therefore, the rejections are maintained.
Applicant’s Arguments:
Claims 15 has been amended (underlined) to recite: "A rNDV obtained by replacing an F gene in a genome of the Newcastle disease virus lasota with an F gene of the NDV virulent strain, wherein a DNA corresponding to the F gene of the rNDV is as set forth in SEQ ID NO: 1 at the positions 7274-8935 from the 5'-terminus;
- wherein a DNA corresponding to a genome of the recombinant Newcastle disease virus further comprises an exogenous gene, which is PD 1;
- the PD1 is as set forth in SEQ ID NO: 6; and
- the exogenous gene is located between a P gene and an M gene of the recombinant Newcastle disease virus..".
- (a) Liao fails to teach the positions 7274-8935 from a 5' terminus of SEQ ID NO: 1 in which the F protein is replaced (instant claims 15) or that the exogenous gene to be inserted is PD-1 (as required by instant claim 15). Liao reveals that it teaches mutating the cleavage site (residues 112-117) of the LaSota strain F protein to that of a virulent strain (112-RRQRRF-117), rather than teaching the replacement of the entire F protein. There is no suggestion in Liao that completely replacing the F protein, as required by the instant claims, would be an obvious or effective method to enhance oncolytic activity.
Liao teaches enhancing oncolytic activity by mutating residues 112-117 of the F protein to the 112-RRQRRF-117 sequence of virulent strains and improving clinical effect by inserting a gene encoding a PD-L1 antibody. The core concept is enhancing direct oncolysis (via F protein amino acid mutation) and introducing immune modulation via a PDL-1 targeting antibody. Herein, the F protein of the LaSota strain is replaced with that of a virulent strain for controlling viral virulence within a desired range and enhancing its anti-tumor effect. This design is based on the fact that regions of the F protein other than residues 112-117 are also capable of affecting viral virulence and oncolytic activity, and the cited reference provides no guidance for the aforesaid design. The proposed combination improperly treats the complete protein replacement in the instant invention as an obvious equivalent to the site-directed mutagenesis taught by Liao, which is not supported by the art.
Moreover, existing studies have shown that protein replacement between different strains does not always achieve the expected results. Even if genetic replacement is performed with the protein function of the donor strain known, the constructed chimeric strain does not necessarily possess the functions of the donor strain.
(b) Bartee teaches expressing the PD-1 ectodomain as a soluble decoy receptor for the PD- 1/PD-L1 pathway in a completely different viral backbone (Myxoma virus, a poxvirus), with a mechanism distinct from antibody blockade. A person of ordinary skill in the art would have no motivation to substitute the specific teaching of Bartee (using a PD-1 ectodomain as a decoy in a poxvirus) for the already disclosed and suggested "PDL-1 antibody" approach in Liao, given their differing mechanisms (receptor decoy vs. antibody blockade), structures (truncated receptor vs. full antibody), and viral vectors (poxvirus vs. paramyxovirus). This proposed combination is not a logical design path driven by a recognized problem or teaching.
The prior art, including Bartee, provides no teaching or suggestion for successfully inserting and stably expressing a functional PD-1 (particularly the optimized sequence shown as SEQ ID NO: 6) at the P/M site of an NDV. Combining elements from disparate sources (different viral backbones, different genes, different insertion sites) to achieve synergistic functionality requires inventive effort and carries no predictable expectation of success.
The Action's interpretation of SEQ ID NO: 6 as a "truncated PD-1 sequence" and the assertion that nucleotides 1-59 are "not relevant for the function of PD-1" is inaccurate and overlooks a key aspect of the invention.
SEQ ID NO: 6 is the definite, complete DNA sequence claimed by the present invention. It encodes a PD-1 protein variant incorporating an optimized signal peptide. This optimized design (including the signal peptide) is crucial for ensuring high-efficiency expression and correct secretion/localization of this exogenous gene within the recombinant NDV vector, addressing the technical problem of low expression efficiency of foreign genes in viral vectors. U64863.1 merely discloses the native PD-1 genomic/cDNA sequence and does not teach how to optimize its coding sequence for high-level expression in a viral vector, particularly an NDV. SEQ ID NO:6 of the present invention represents the inventive solution to this specific technical problem. Therefore, the cited prior art does not render the claimed invention obvious..
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive.
(a) Liao teaches a recombinant LaSota Newcastle disease virus (NDV) wherein the F (fusion) protein from the LaSota strain has been replaced with an F protein from a “strong strain” NDV (rNDV) ([0020], the “strong strain” language has been interpreted as a more virulent strain that the LaSota strain) as required by instant claim 15. Liao also teaches that the (wild-type) LaSota strain NDV does not have oncolytic ability but the rNDV, created by the replacement of the LaSota F protein by an F protein from a virulent strain, has oncolytic activity [0020]. Therefore, the increase of oncolytic activity of the rNDV can function as (a) treating a tumor; (b) inhibiting tumor cell proliferation; and/or (c) killing tumor cells as required by instant claim 24. Liao teaches the insertion of an exogenous gene (in this case, a gene encoding a PDL-1 antibody) between the P and M protein genes of the rNDV thereby increasing the clinical effect of the virus in treating tumors [0020] as required in instant claim 15. AY508514.1 teaches the sequence of the F protein from the more virulent NDV strain F48E9. as required by instant claim 15. The sequence submitted to GenBank is 100% identical to the SEQ ID NO: 1 of the instant application at positions 7274-8935 from a 5’ terminus. See sequence alignment in the Office Action dated 11/20/2025. Since positions 7274-8935 from a 5’ terminus of NDV is where the F gene is located, it would be obvious to exchange the F protein from the LaSota strain with the F protein from a more virulent strain in the position where the F protein is in the genome, as taught by Liao. Additional information taught by Liao, including mutagenesis to modify the F protein, that it is not a limitation of the instant claims is not relevant to the obviousness analysis, in particular because Liao does teach the swapping of the F proteins (F protein from the LaSota strain has been replaced with an F protein from a more virulent strain). Applicant has not provided any citations for the existing studies showing that protein replacement between different strains does not always achieve the expected results. In this case, the rNDV, created by the replacement of the LaSota F protein by an F protein from a virulent strain, has oncolytic activity which is the expected result (as taught by Liao) Applicant’s argues that constructing a chimeric strain may or may not generate rNDVs with the functions of the donor strain. In this case, however, chimeric strains having the same functions of the donor strain is not the desired outcome because the goal is to create a rNDV with oncolytic activity to treat tumors. Moreover, it is well known in the art that any NDV strain or rNDV has to maintain the “rule of six” for efficient viral replication, as the nucleocapsid (NP) binds to exactly 6 nucleotides at a time. If the genome length is off (e.g. not a multiple of 6), the viral polymerase cannot properly initiate or sustain efficient replication. Replacement of an entire ORF with another ORF of the same length would be further obvious (and the easiest way) to a skilled artisan in NDV recombineering because of the need to adhere to the “rule of six”, so it would make sense to do a 1-for-1 switch of the nucleotides. In addition, the art also shows that other NDV genes, or even entire sections have been replaced successfully as long as the “rule of six” is followed.
(b) applicant arguments regarding PD-1 as set forth in SEQ ID NO: 6 have been discussed above in Claim Rejections - 35 USC § 112 Section and in the Office action dated 11/20/2025.
Applicant also argues that combining elements from disparate sources (different viral backbones, different genes, different insertion sites) to achieve synergistic functionality requires inventive effort and carries no predictable expectation of success. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, all prior art share common elements such as teaching a recombinant oncolytic virus vector carrying an insert involved in the PDL-PD-1 pathway. The prior art also shows that the combination has a reasonable expectation of success as discussed in the Office action dated 11/20/2025. In addition, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Whereas Liao teaches that the replacement of the F protein from one strain by another F protein from a more virulent strain can generate a more potent oncolytic virus capable of treating tumors, AY508514.1 teaches the sequence of the NDV strain F48E9F protein and the insertion at positions 7274-8935 from a 5’ terminus, U64863.1 teaches the complete human PD-1 cDNA sequence and Bartee teaches that PD-1, in the context of a recombinant virus is capable of inhibiting the PD1/PDL1 pathway specifically within the tumor microenvironment. Applicant has not sufficiently described why there is no prima facie case for obviousness for the combination of the cited prior art and the motivation to combine. See discussion in Claim Rejections - 35 USC § 103 Section in the Office Action dated 11/20/2025.
Claim 17 is rejected under 35 U.S.C. 103 (claims 18 and 19 are cancelled) as being unpatentable over Liao in view of AY508514.1, U64863.1, Bartee, Palese (previously cited) and pBR322 (previously cited).
Applicant’s Arguments:
Claim 17 has been amended (underlined) to introduce the additional limitations also recited in claim 15. Now claim 17 recites: “A recombinant plasmid obtained by replacing an F gene in a pBrlasota plasmid, wherein the F gene of the recombinant plasmid is as set forth in SEQ ID NO: 1 at positions 7274-8935 from a 5'-terminus;
- wherein the recombinant plasmid is a DNA molecule plasmid as set forth in SEQ ID NO:1
- further comprising an exogenous gene, which is PD1, wherein
- the PD1 is as set forth in SEQ ID NO: 6;
- and the exogenous gene is located between a P gene and an M gene of a genome of the recombinant Newcastle disease virus.
The rejection is predicated on an ex post facto combination and speculation involving up to six prior art documents (Liao, AY508514.1, U64863.1, Bartee, Palese, and pBR322). Asserting that combining teachings from these diverse references - each with its own context, problem addressed, and technical details - would inevitably lead to the specific, complete recombinant plasmid SEQ ID NO: 1 and its variant containing the specific optimized PD1 sequence (SEQ ID NO: 6) lacks a genuine technical motivation or teaching that would have guided a person of ordinary skill in the art to make such a specific combination at the time the invention was made. The inventive plasmid of the present application represents an integrated whole, the product of deliberate and specific design choices.
The Action's proposed path - "replace the F protein in the Palese sequence with that from AY508514.1, then clone into pBR322" – is a theoretical route designed to arrive at a sequence that is "functionally the same" as SEQ ID NO: 1. However, the prior art does not present the specific technical problem of needing to construct a plasmid identical or highly similar in sequence to SEQ ID NO: 1. Liao teaches using a pBR322 backbone and F protein replacement but does not disclose the full-length sequence of its final plasmid, nor does it teach that using this specific F gene fragment from the F48E9 strain (positions 7274-8935 of SEQ ID NO: 1) is necessary to achieve a particular, predictable oncolytic effect. The precise combination of Palese's specific NDV sequence, AY508514.1's specific F gene fragment, and a specific pBR322 variant requires creative screening and experimental verification, not an obvious routine attempt.
The invention inserts a specific, optimized PD1 sequence (SEQ ID NO: 6) designed for high-efficiency expression of functional PD-1 protein in the NDV system. U64863.1 discloses the native cDNA, and Bartee uses a truncated ectodomain, neither of which is SEQ ID NO: 6. Liao inserts a PD-L1 single-chain antibody gene, whose mechanism (antibody blockade) and molecular structure are fundamentally different from a PD-1 receptor gene. Applying Liao's "insertion site" teaching directly to a PD1 gene with completely different functional, structural, and expression requirements is not an obvious direct substitution. Bartee's teaching is limited to a poxvirus (Myxoma virus) vector, whose gene regulation and genomic structure are fundamentally distinct from a paramyxovirus (NDV) vector. There is no reason to expect that a strategy workable for a PD-1 (ectodomain) in a poxvirus would be directly and obviously successful for a full- length/optimized PD1 gene in an NDV vector.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive.
In response to applicant's argument that Liao, AY508514.1, U64863.1, Bartee, Palese, and pBR322 are nonanalogous art, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, Liao, AY508514.1, U64863.1, Bartee, are needed for the rejection of the independent claim 15 and Palese, and pBR322 are needed for the rejection of claim 17 which depends on claim 15. All the prior art is related to the field of invention: a recombinant viral vector, optimized for its oncolytic activity and carrying an insert. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, all prior art share common elements such as teaching a recombinant virus vector carrying an insert involved in the PDL-PD-1 pathway, or the construction of a plasmid carrying an oncolytic rNDV. The prior art also shows that the combination has a reasonable expectation of success. The construction of this plasmid with a rNDV with an F protein from a more virulent NDV strain and a PD-1 gene is obvious based not only on the prior art but also because DNA recombination technologies have been used in labs for decades. Applicant has not provided a clear reasoning as to why the precise combination of Palese's specific NDV sequence, AY508514.1's specific F gene fragment, and a specific pBR322 variant requires creative screening and experimental verification, when these are standard molecular biology techniques and nothing seems to be novel about the generation of the this rNDV inserted into pBR322. Regarding the PD-1 sequence, see Claim Rejections - 35 USC § 112 and arguments above.
Applicant argues as set forth above. Thus, for the reasons set forth above and the reasons of record, the rejection is maintained.
New Rejections Based on Amendments
Drawings
The drawings filed on 09/27/2022 are acceptable subject to correction of the informalities indicated below. The “LaSota” term is misspelled (Losata) in Fig.2, 3A-E, 4-25. In order to avoid abandonment of this application, correction is required in reply to the Office action. The correction will not be held in abeyance.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 15 and 17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 15 recites the limitation “"A rNDV obtained by replacing an F gene in a genome of the Newcastle disease virus lasota with an F gene of the NDV virulent strain, wherein a DNA corresponding to the F gene of the rNDV is as set forth in SEQ ID NO: 1 at the positions 7274-8935 from the 5'-terminus;
- wherein a DNA corresponding to a genome of the recombinant Newcastle disease virus further comprises an exogenous gene, which is PD 1;
- the PD1 is as set forth in SEQ ID NO: 6; and
- the exogenous gene is located between a P gene and an M gene of the recombinant Newcastle disease virus.."
Claim 17 recites “A recombinant plasmid obtained by replacing an F gene in a pBrlasota plasmid, wherein the F gene of the recombinant plasmid is as set forth in SEQ ID NO: 1 at positions 7274-8935 from a 5'-terminus;
- wherein the recombinant plasmid is a DNA molecule plasmid as set forth in SEQ ID NO:1
- further comprising an exogenous gene, which is PD1, wherein
- the PD1 is as set forth in SEQ ID NO: 6;
- and the exogenous gene is located between a P gene and an M gene of a genome of the recombinant Newcastle disease virus.”
It is unclear what SEQ ID NO: 1 actually is. SEQ ID NO: 1 is about 18,931 nucleotides long, but NDV has a non-segmented, negative-sense RNA genome that is either approximately 15,186, 15,192, or 15,198 nucleotides in length, PD-1 has about 504 base pairs in length, therefore additional sequences must be found in SEQ ID NO: 1 that are not viral genome sequences or PD-1 sequences.
It appears that the additional sequence is the pBR322 plasmid because claim 17 recites SEQ ID NO: 1 as a recombinant plasmid and not as a rNDV. and therefore SEQ ID: 1 needs to be clearly defined because claims 15 and 17 recite the same SEQ ID NO: 1 giving it different descriptions. A better description of the limitation in claim 15 would be “A recombinant pBR322 plasmid comprising a recombinant Newcastle disease virus genome…as set forth in SEQ ID NO: 1.” defining for SEQ ID NO: 1 the following: the NDV genome strain, the starting and ending nucleotide positions of the viral genome, the starting and ending of nucleotide positions of the PD-1 insert and if the F protein has been replaced, the starting and ending nucleotide positions of the F protein and the strain it belongs to.
Another alternate possible interpretation is that Applicant is attempting to describe the F gene as found in the plasmid of SEQ ID NO:1. If this alternate interpretation is correct, it should be clearly drafted so that the artisan is aware that the F gene in the LaSota genome is being replaced with a heterologous F gene, wherein said heterologous F gene is 7274-8935 of SEQ ID NO:1.”. The SEQ ID NO: 1 still needs to be defined by the NDV genome strain, the starting and ending nucleotide positions of the viral genome, the starting and ending of nucleotide positions of the PD-1 insert and if the F protein has been replaced and the strain it belongs to.
Appropriate correction is required.
Double Patenting
Claims 15, 17 and 24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13, 17-19 and 24 of copending Application No. 17/914,882 over Liao, in view of Li (CN104357409, machine generated translation, published 2/18/2015), EF065682.1 (GenBank: EF065682.1, Newcastle disease virus isolate rAnhinga, complete genome VRL: Oct 2009, 2007 https://www.ncbi.nlm.nih.gov/nuccore/EF065682), AB451325 (GenBank AB451325: Homo sapiens IL2 mRNA for interleukin 2 precursor, complete cds, PRI 02-SEP-2008, https://www.ncbi.nlm.nih.gov/nuccore/AB451325), Vijayakumar (J. Virology February 2020 Volume 94 Issue 3, 1-14) and pBR322.
The claims of 17/914,868 are drawn to the rNDV vector with the LaSota F protein being replaced by the F protein of a more virulent strain and with PD-1 inserted into the vector as required by instant claim 15. The 17/914,882 claims are drawn to the rNDV vector with the LaSota F protein being replaced by the F protein of the Anhinga strain which in is more virulent than the LaSota and with hIL-2 inserted into the vector (claim 13).
Li discloses a NDV strain and methods for generating a recombinant pBrLosata plasmid (Li, para 1-14). Li discloses SEQ ID NO: 3, which is a pBrLosata plasmid that contains an exogenous gene (chicken IL2) between a P and M gene of the recombinant NDV genome (Li, claim 2). As shown in the sequence search results below, there is a 95.2% query match between instant SEQ ID NO: 1 and SEQ ID NO: 3 of Li, wherein the discrepancy can be attributed to both the inclusion of the chicken IL-2 gene in the plasmid in addition to codon degeneracy.
SEQ ID NO: 1 (instant application) compared to SEQ ID NO: 3 (Li)
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100
512
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Greyscale
SEQ ID NO: 1 of 17/914,882 encodes for the recombinant chimeric plasmid pBrLosata, wherein positions 7274-8935 set forth the replaced F gene sequence of the Anhinga strain. EF065682.1 teaches the sequence of the Anhinga F protein at the positions about 7274-8935 nucleotides, wherein the discrepancy can be attributed to both the inclusion of the hIL-2 gene (AB451325) in the rNDV vector, the presence of pBR322 and to codon degeneracy.
SEQ ID NO: 1 at positions 7274-8935 compared to EF065682.1
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79
630
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Greyscale
SEQ ID NO:4 compared to AB451325
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87
643
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Greyscale
It would have been prima facie obvious to one of ordinary skill in the art to generate a NDV virus or recombinant plasmid thereof by replacing a F gene in a pBrLosata plasmid as set forth in SEQ ID NO: 1, wherein the F gene is located at positions 7274-8935 from a 5’ terminus of SEQ ID NO: 1. It would have been a matter of combining prior art elements according to known methods to yield predictable results since the sequence of the NDV LaSota strain, the anhinga F protein, the sequence of hIL-2 and the sequence of pBR3422 were known in the art and Liao teaches the engineering of the viral vector with the F protein from LaSota being swapped by a more virulent F protein from a more virulent strain to increase the oncolytic properties as discussed above. In addition, there are predictable means for generating recombinant plasmids following standard recombinant DNA methods known for decades and commonly used in labs all over the world. One would be motivated to make this combination given that substituting in a anhinga NDV F protein would allow for more control over the virulency of the NDV vector as an oncolytic therapy. Furthermore, generating a pBrLosata plasmid of the NDV vector would allow for further cloning, amplification and storage.
In addition, Vijayakumar teaches that Newcastle disease virus (NDV) is an attractive candidate for oncolytic immunotherapy due to its ability to replicate in tumor cells and potentially to overcome the inherently immunosuppressive nature of the tumor microenvironment (Abstract). Several different recombinant viruses: NDVs expressing checkpoint inhibitors (rNDV–anti-PD1 and rNDV–anti-PDL1 and immunocytokines, where the antibodies are fused to an immunostimulatory cytokine, such as IL-12. These engineered viruses induced tumor control and survival benefits (Abstract). Since IL-2 and IL-12 are potent pro-inflammatory cytokines that act synergistically to drive anti-tumor immunity, it would be obvious for a person of ordinary skill in the art to insert IL-2 in the rNDV for its used as anti-cancer agents. There would be a reasonable expectation of success because a rNDV-IL-2 can be easily engineered and Il-2 is known as a potent cytokine for cancer immunotherapy.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant’s Arguments: The "virulent strain" of the present Application is fundamentally different from the "mesogenic strain" of 17/914,882.
In the virological classification of Newcastle Disease Virus (NDV), "mesogenic strain" and "virulent strain" are two distinct, well-defined categories.
Mesogenic strains possess intermediate virulence and typically do not cause high mortality in chickens, having been used in some live vaccines historically. In contrast, virulent/velogenic strains are highly virulent pathogens causing severe disease and death, characterized by specific polybasic amino acid motifs at the cleavage site of F protein, a key molecular determinant of their high pathogenicity.
"Mesogenic strain" and "virulent strain" differ significantly in biosafety levels and intended use (research, vaccine preparation, etc.). Utilizing genetic elements from a "virulent strain" for constructing a therapeutic viral vector presents fundamentally different safety considerations, technical hurdles, and regulatory requirements compared to using a "mesogenic strain.". Therefore, the scopes of these claims are clearly distinguishable and are patentably distinct.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive.
Instant claim 15 clearly recites the limitation “….by replacing an F gene in a genome of the Newcastle disease virus LaSota with an F gene of the Newcastle disease virus virulent strain…”. That is, the LaSota F protein can be replaced by any strain that is more virulent than the LaSota strain. The instant claim 15 does not define how much more virulent, the more virulent strain needs to be in comparison to the LaSota strain, or if the strain causes death, and the limitation does not recite a velogenic strain. NDV classification is based on virulence but it does not exclusively apply to velogenic strains. Mesogenic strains are virulent as well, even if to a lesser degree and the Anhinga strain is more virulent than LaSota strain.
Conclusion
No claims are allowed.
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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/IMMA BARRERA/
Examiner, Art Unit 1671
/RACHEL B GILL/Primary Examiner, Art Unit 1671