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 Application/Amendments/Claims
Applicant’s response filed on 2/24/2026 has been considered. The terminal disclaimer submitted on 2/18/2026 was received and approved. Claims 14-16 are canceled. Claims 13 and 17-24 are pending. Claims 20-23 are currently withdrawn with traverse from further consideration pursuant to 37 CFR 1.142 (b) as being drawn to a nonelected invention, there being no allowable generic or linking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 13, 17-19 and 24 are the subject of the present Official action. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Priority
Applicant’s claim for the benefit of a prior-filed application CN202010238162.4 and PCT/CN2021/09200 filed on 3/30/2020 and 5/21/2021 respectively, under 35 U.S.C 119(e) or under 35 U.S.C 120, 121 or 365(c) is acknowledged.
Accordingly, the effective priority date of the instant application is granted as 3/30/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 9/27/2022 and 1/9/2023 was received. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement was considered by the examiner.
Withdrawn Rejections
The provisional nonstatutory double patenting rejection of claims 13-15, 17-18 and 24 over copending Application No: 17/914,868 has been withdrawn in light of applicant’s submission of a terminal disclaimer on 2/18/2026.
The 35 U.S.C. 103 rejection of claims 13 and 24 as obvious over Liao in view of Estevez has been withdrawn in light of applicants claim amendments which move the limitations from canceled claims 14-16 into independent claim 13.
Claim Interpretation
Claim 13 describes a recombinant Newcastle disease virus which has an F protein replaced from a lasota strain to an Anhinga strain. However, the claims do not specify the serotype or strain of the rest of the template recombinant Newcastle disease virus. Taking the broadest reasonable interpretation, the rest of the template recombinant Newcastle disease virus could be from the lasota strain or any velogenic, mesogenic or lentogenic strains.
Claim 24 describes a drug comprising the recombinant Newcastle disease virus according to claim 13 “and/or” a recombinant plasmid. Although claim 13 has been amended, the alternative interpretation remains unamended and reads on the limitations of claim 17.
Maintained 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 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.
Claims 17, 18 and 24 stand rejected under 35 U.S.C. 103 as being unpatentable over Liao et al, CN109627336A, machine generated translation, published 4/16/2019 (hereinafter Liao, reference of record) in view of Estevez et al. "Evaluation of Newcastle disease virus chimeras expressing the Hemagglutinin-Neuraminidase protein of velogenic strains in the context of a mesogenic recombinant virus backbone." Virus Research 129.2 (2007): 182-190 (hereinafter Estevez, reference of record), Li et al. CN104357409, machine generated translation, published 2/18/2015 (hereinafter Li, reference of record) and Bai et al. "Genetically engineered Newcastle disease virus expressing interleukin 2 is a potential drug candidate for cancer immunotherapy." Immunology Letters 159.1-2 (2014): 36-46 (hereinafter Bai, reference of record). This rejection is maintained and a response to applicant’s traversal follows the rejection below.
Claims 17 and 24: Liao describes a recombinant Newcastle disease virus (NDV) in which an F (fusion) protein from a lasota strain has been replaced with an F protein from a “strong strain” at the F protein cleavage site 112R-R-Q-K-R-F117 (Liao, para 19). Liao presents this as a strategy to modulate the oncolytic abilities of the virus, thereby increasing the clinical effects of the virus in treating tumors (Liao, para 19). It is noted that this is a machine translation. “Strong strain” appears to indicate that a velogenic (highly virulent) NDV strain was used rather than the claimed mesogenic (moderately virulent) strain.
Claims 17 and 24: Estevez provides a description of the three main NDV strains (velogenic, mesogenic and lentogenic) and how they share the exact same virulent sequence of the F protein cleavage site 112R-R-Q-K-R-F117 (Estevez, Intro). Estevez describes how the F (fusion) protein is one of six viral envelope proteins and is the main determinant of virulence (Estevez, intro para 1). Estevez discloses a mesogenic NVD strain (anhinga) and methods for generating recombinant NDVs and full-length cDNA clones of mesogenic NDV strains (Estevez, 2.2 and Fig 1).
It would have been prima facie obvious to one of ordinary skill in the art to replace an F protein from a lasota strain with an F protein from a mesogenic strain as described by Estevez rather than the strong velogenic strain described by Liao. It would have been a matter of simple substitution of one known element for another to obtain predictable results since all F protein genes are known to contribute differently to virulency. One would be motivated to substitute a mesogenic NDV F protein rather than a velogenic NDV F protein in order to modulate the recombinant NDV virulency as an oncolytic therapy. One would have a reasonable expectation of success given that all three NDV strains share the same F protein cleavage site 112R-R-Q-K-R-F117 and there exists predictable methods for substituting viral fusion proteins (Estevez, Intro).
Neither Liao nor Estevez expressly disclose a recombinant pBrLosata plasmid as set forth in SEQ ID NO: 1 or positions 7274-8935 from a 5’ terminus of SEQ ID NO: 1 in which the F protein is replaced.
Claims 17, 18 and 24: It is noted that SEQ ID NO: 1 encodes for the recombinant chimeric plasmid pBrLosata, wherein positions 7274-8935 set forth the replaced F gene sequence. 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. With respect to positions 7274-8935 from a 5’ terminus of SEQ ID NO: 1 indicating the replaced F protein, this corresponds to the known F protein cleavage site 112R-R-Q-K-R-F117 described by Estevez (Estevez, Intro). Furthermore, it is noted that the disclosure of Li is a machine translation. The same inventors have published an article which provides greater detail into the recombinant NDV and pBrLosata plasmid (Bai, abstract and 2.3).
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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 genome was known in the art as shown by Li and there exists predictable means for generating recombinant plasmids following the methods outlined in the disclosure of Bai. One would be motivated to make this combination given that substituting in a anhinga mesogenic 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. One would have a reasonable expectation of success given that positions 7274-8935 from a 5’ terminus of SEQ ID NO: 1 correspond to the known F protein cleavage site 112R-R-Q-K-R-F117. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered Claims 17, 18 and 24 to have been prima facie obvious to at the time the invention was made.
Response to Traversal
Applicant traverses the rejection by arguing that improper hindsight reconstruction of the invention was used to dissect the invention into discrete known parts and assert their combination would be obvious. Applicant argues that the rejection treats the claimed recombinant plasmid pBrLosata as a mere assembly of known genetic elements and overlooks the fact that SEQ ID NO: 1 is the tangible embodiment of the complete and non-obvious technical scheme previously described. Applicant states that the high sequence matching with a prior art plasmid does not render the claimed invention obvious as the significance lies in the specific modifications made and their functional purpose and unexpected properties of the final viral product.
Although applicant has argued that the Examiner’s conclusion of obviousness is based on improper hindsight reasoning. However, any judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper, see MPEP 2145. The examiner argues that 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 genome was known in the art as shown by Li and there exists predictable means for generating recombinant plasmids following the methods outlined in the disclosure of Bai. One would be motivated to make this combination given that substituting in an anhinga mesogenic 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.
Claims 13, 17-19 and 24 stand rejected under 35 U.S.C. 103 as being unpatentable over Liao (supra), Estevez (supra), Li (supra) and Bai (supra) as applied to claims 17, 18 and 24 above in further view of Gieseke et al. US 2020/0147176, published 5/14/2020 (hereinafter Gieseke, reference of record). This rejection is maintained in modified form and a response to applicant’s traversal follows the rejection below.
A description of Liao, Estevez, Li and Bai can be found above with respect to claims 17, 18 and 24.
Claim 13: Estevez provides a description of the three main NDV strains (velogenic, mesogenic and lentogenic) and how they share the exact same virulent sequence of the F protein cleavage site 112R-R-Q-K-R-F117 (Estevez, Intro). Estevez discloses a mesogenic NVD strain (anhinga) and methods for generating recombinant NDVs and full-length cDNA clones of mesogenic NDV strains (Estevez, 2.2 and Fig 1).
Although Li and Bai describe the inclusion of exogenous therapeutic genes like chicken IL2, the cited prior art des not describe the inclusion of human IL2 (hIL2) as set forth in SEQ ID NO: 4.
Claims 13 and 19: Gieseke describes therapeutic proteins and synthetic DNA fragments which can be incorporated into gene therapy vectors (Gieseke, para 868, 870). Gieseke discloses SEQ ID NO: 465 which shares 99.8% sequence similarity to instant SEQ ID NO: 4 (Sequence search results below). The single nucleotide difference can be attributed to codon degeneracy.
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It would have been prima facie obvious to one of ordinary skill in the art to use hIL2 as set forth in SEQ ID NO: 4 as described by Gieseke rather than chicken IL2 as described by Li in the recombinant NDV virus or plasmid. It would have been a matter of simple substitution of one known exogenous gene for another to obtain predictable results. One would be motivated to make such a substitution given that the oncolytic recombinant NDV could be use to deliver IL2 to humans as a gene therapy. One would have a reasonable expectation of success given that Bai conducts similar experiments and expressed human IL2 using the LaSota NDV strain and plasmid (Bai, pg 37 col 2, sec 2.6 and fig 2). Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the claimed invention to have been prima facie obvious to at the time the invention was made.
Response to Traversal
Applicant traverses the rejection by pointing to amendments to claim 13 which import the limitations of canceled claims 14-16. Applicant argues that Estevez teaches away from predictable and simple substitution from homotypic F genes from the parental velogenic viruses. Applicant argues that Estevez data shows that even within a defined mesogenic backbone, swapping single or two genes does not reliably or predictably alter the viral phenotype and is a multigenic and complex process. Therefore, a person skilled in the art would not conclude that simple gene substitution is a predictable outcome.
This argument has been fully considered, but is not found persuasive since teaching away requires the prior art to criticize, discredit, or otherwise discourage the claimed solution, see MPEP § 2141.02(VI): “the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed.” Since the prior art clearly does not do this, this argument is unconvincing. Since Estevez discloses a mesogenic NVD strain (anhinga) and methods for generating recombinant NDVs and full-length cDNA clones of mesogenic NDV strains it would have been prima facie obvious to one of ordinary skill in the art to replace an F protein from a lasota strain with an F protein from a mesogenic anhinga strain as described by Estevez rather than the strong velogenic strain described by Liao. One would be motivated to substitute a mesogenic NDV F protein rather than a velogenic NDV F protein in order to modulate the recombinant NDV virulency as an oncolytic therapy.
Applicant further argues that the success of Bai to generate a safe and effective LaSota backbone would motivate one of ordinary skill to simply express the human IL-2 as a treatment for human cancer therapy rather than undertake the risky and uncertain step of replacing the core F protein gene. Applicant argues that the present invention involves screening for functional and structural proteins and insertion of an exogenous gene via a specific strategy. Applicant points to the P/M insertion site as one that was experimentally determined and optimized.
This argument has been fully considered, but is not found persuasive since 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). Thus, the P/M insertion site was well known in the prior art and 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. One would be motivated to make this combination given that substituting in a mesogenic NDV F protein would allow for more control over the virulency of the NDV vector as an oncolytic therapy. With respect to selecting hIL2 as the transgene, it would have been a matter of simple substitution of one known exogenous gene for another to obtain predictable results. One would be motivated to make such a substitution given that the oncolytic recombinant NDV could be use to deliver IL2 to humans as a gene therapy. One would have a reasonable expectation of success given that Bai conducts similar experiments and expressed human IL2 using the LaSota NDV strain and plasmid (Bai, pg 37 col 2, sec 2.6 and fig 2).
Conclusion
No claims 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 extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dr. ALEXANDER NICOL whose telephone number is (571)272-6383. The examiner can normally be reached on M-F 8-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria Leavitt can be reached on (571)272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Alexander Nicol
Patent Examiner
Art Unit 1634
/ALEXANDER W NICOL/Examiner, Art Unit 1634
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
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