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 .
DETAILED ACTION
Applicant’s amendments and remarks filed on April 28, 2026 are acknowledged. Claims 1-35, 37-42, 45, 47-55, 57-63, 65, 67, 69, 71-73, 75-78, and 80-82 have been canceled. Claims 36, 44, 46, 66, 68, 70, 74, and 79 were amended. Claims 36, 43, 44, 46, 56, 64, 66, 68, 70, 74, 79, and 83-98 are pending.
Election/Restrictions
Applicant’s election of Group II (claims 36, 37, 43, 44, 46, 56, 58, 59, and 64) and the following species: (SEQ ID NO: 44 recited in claim 46 and Newcastle Disease Virus (NDV) recited in claim 15) in the reply filed on October 7, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 36, 43, 44, 46, 56, 64, 66, 68, 70, 74, 79, and 83-98 are examined on the merits herein.
Priority
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Withdrawn Objections
In view of Applicant’s amendments and response, the objections to the abstract, specification, and claims are withdrawn.
Withdrawn Rejections
In view of Applicant’s amendments and response, the 35 U.S.C 112(b) rejection is withdrawn.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on April 28, 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
New Grounds of Rejections Necessitated by Amendment
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.
Claims 36 and 44 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 36 and 44 recite the broad recitation vascular endothelial growth factor, and the claims also recite VEGF-C which is the narrower statement of the range/limitation. The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
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.
Claims 36, 43, 44, 46, 56, 64, 66, 68, 70, 74, 79, and 83-98 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for treating melanoma comprising administering intratumorally a pharmaceutical composition wherein the pharmaceutical composition comprises a recombinant Newcastle Disease Virus (NDV) or a recombinant avian paramyxovirus serotype 4 (APMV-4) in a pharmaceutically acceptable carrier or excipient wherein the recombinant NDV or recombinant APMV-4 comprises a genome that comprises a transgene and wherein the transgene comprises a nucleotide sequence encoding VEGF-C, does not reasonably provide enablement for a method for treating melanoma comprising administering a pharmaceutical composition wherein the pharmaceutical composition comprises a recombinant Newcastle Disease Virus (NDV) or a recombinant avian paramyxovirus serotype 4 (APMV-4) in a pharmaceutically acceptable carrier or excipient wherein the recombinant NDV or recombinant APMV-4 comprises a genome that comprises a transgene and wherein the transgene comprises a nucleotide sequence encoding any other vascular endothelial growth factor. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue". These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Breadth of claims and nature of the invention:
Claims 36, 43, 66, 68, 70, 74, 83, 85, 87, 90, 92, 94, and 97 are drawn to a method for treating melanoma, comprising administering a pharmaceutical composition to a subject in need thereof, wherein the pharmaceutical composition comprises a recombinant Newcastle Disease Virus or a recombinant avian paramyxovirus serotype 4 (APMV-4) in a pharmaceutically acceptable carrier or excipient, wherein the recombinant NDV or recombinant APMV-4 comprises a genome that comprises a transgene, and wherein the transgene comprises a nucleotide sequence encoding vascular endothelial growth factor (VEGF-C). The broadest reasonable interpretation of claim 36 is that the method encompasses treating melanoma, comprising administering a pharmaceutical composition to a subject in need thereof, wherein the pharmaceutical composition comprises a recombinant Newcastle Disease Virus or a recombinant avian paramyxovirus serotype 4 (APMV-4) in a pharmaceutically acceptable carrier or excipient, wherein the recombinant NDV or recombinant APMV-4 comprises a genome that comprises a transgene, and wherein the transgene comprises a nucleotide sequence encoding any vascular endothelial growth factor including VEGF-C.
Claims 44, 46, 56, 64, 79, 84, 86, 88, 89, 91, 93, 95, 96, and 98 are drawn to a method for treating melanoma, comprising administering intratumorally to a subject in need thereof a first pharmaceutical composition comprising a recombinant NDV or a recombinant APMV-4 and administering intratumorally to the subject a second pharmaceutical composition comprising vascular endothelial growth factor (VEGF-C), or a nucleotide sequence encoding VEGF-C; or administering intratumorally to a subject in need thereof a pharmaceutical composition comprising a recombinant NDV or a recombinant APMV-4, and VEGF-C or a nucleotide sequence encoding VEGF-C. The broadest reasonable interpretation of claim 44 is that the method encompasses treating melanoma, comprising administering intratumorally to a subject in need thereof a first pharmaceutical composition comprising a recombinant NDV or a recombinant APMV-4 and administering intratumorally to the subject a second pharmaceutical composition comprising any vascular endothelial growth factor including VEGF-C, or a nucleotide sequence encoding VEGF-C; or administering intratumorally to a subject in need thereof a pharmaceutical composition comprising a recombinant NDV or a recombinant APMV-4, and VEGF-C or a nucleotide sequence encoding VEGF-C.
State of the prior art, level of predictability in the art, and level of one of
ordinary skill:
Zheng et al. (Molecular Therapy Oncolytics 2019; reference previously cited by the Examiner) discloses that oncolytic viruses (OVs) are powerful new therapeutic agents in cancer therapy; however, despite extensive research, oncolytic virotherapy has shown limited efficacy against solid tumors [abstract] because of physical barriers, tumor heterogeneity, and an immunosuppressive tumor microenvironment [page 234, right column, first full paragraph]. Zheng et al. also discloses that limitations and challenges include issues with manufacturing OVs, immunological barriers to viral delivery, and limitations to the success of oncolysis [page 234, right column, first full paragraph].
Although post-filing, Lonberg (Cancer Immunology Research 2025; reference previously cited by the Examiner) discloses that syngeneic mouse tumor models do not faithfully recapitulate the interactions between cancer cells and the immune systems of human patients who have solid tumors. Further, Lonberg discloses that the lack of translatability of syngeneic models is probably responsible for many failed clinical trials conducted at considerable expense, involving far too many patients with cancer who received no benefit [abstract]. Lonberg compares alternatives to syngeneic models but discloses that the alternatives also fail to fully recapitulate the dynamics between the tumor and the immune system and are cumbersome and expensive. Although it may be possible to optimize the syngeneic models, the improvement is likely to be only incremental. Thus, in the absence of breakthroughs in model development, the best way forward is to properly interpret experimental results, recognizing the underlying differences and considering them in vivo assays rather than true disease models [page 460, right column].
Although post-filing, Serrati et al. (Cancer Biology & Medicine 2025) discloses that melanoma, the most aggressive form of skin cancer, remains a significant clinical challenge due to the high metastatic potential and drug resistance [abstract]. Serrati et al. also discloses that VEGF is a multifunctional peptide critical for endothelial cell proliferation, migration, and survival in both physiologic and pathologic conditions. Further, the VEGF family includes VEGF-A, placental growth factor (PlGF), VEGF-B, VEGF-C, and VEGF-D [page 1328, right column, second paragraph].
As evidenced by Zheng et al., challenges and limitations exist using oncolytic viruses as therapeutic agents in cancer therapy. Furthermore, as evidenced by Lonberg and Serrati et al., there is a lack of translatability of syngeneic models to humans and melanoma is the most aggressive form of skin cancer and remains a significant clinical challenge, respectively. Serrati et al. also disclosed that the VEGF family includes not only VEGF-C but also VEGF-A, PIGF, VEGF-B, and VEGF-D. Thus, one would not expect to treat melanoma comprising administering a pharmaceutical composition comprising a recombinant NDV or a recombinant APMV-4 in a pharmaceutically acceptable carrier or excipient wherein the recombinant NDV or recombinant APMV-4 comprises a genome that comprises a transgene wherein the transgene comprises a nucleotide sequence encoding any vascular endothelial growth factor as instantly claimed.
Amount of direction provided by the inventor and existence of working
examples:
The instant specification as filed envisions the following:
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[0013]. In addition, Section 5.7.4 of the specification (paragraphs [00260] through [00272] envisions a laundry list of cancers being treated in accordance with the methods of the instant application.
Working example 2 of the specification evaluated the oncolytic activity of APMVS in B16-F10 and B16-VEGF-C+ syngeneic murine melanoma tumor models wherein B16-F10 or B16-VEGF-C+ cells were implanted in the flank of the right posterior leg of C57BL/6 mice [00315]. The specification further discloses that the data demonstrates that the administration of NDV or APMV-4 to VEGF-C positive tumors increases the survival of animals and decreases the size of the tumors. The data also demonstrates that re-challenge of animals that were administered NDV or APMV-4 and display complete remission of the primary tumors post-administration have reduced tumor volume and increased survival [00322].
Working example 3 of the specification discloses that B16F10 or B16F10/VEGF-C+ cells were injected intradermally into C57BL6/J mice. 50ug of Poly(I:C) was injected intratumorally and tumor growth upon stimulation in B16F10 with Poly(I:C) with or without VEGF-C, or with a combination of both VEGF-C and Poly(I:C) was evaluated.
Working example 4 of the specification demonstrates that recombinant NDV-VEGF-C constructs expressing the full length VEGF-C are able to reduce tumor growth and extend survival of mice implanted with B16F10 tumors. B16F10 tumors were treated by intra-tumoral injections of NDV-VEGF-C and monitored for tumor growth and survival. Specifically, the data demonstrates that the NDV-VEGF-C wild type full length construct effectively reduces tumor growth and extends survival, whereas NDV-VEGF-C dNdC-WT variant does not. Further, the anti-tumor effects of VEGF-C are likely mediated through VEGFR-3 and not through VEGFR-2.
Working example 5 of the specification evaluated the in vivo effects of NDV/VEGF-C. Specifically, mouse melanomas were treated with intra-tumoral injections of NDV to examine the effects of NDV oncolytic viral therapy on tumors expressing VEGF-C, B16F10, or B16F10/VEGF-C. The data demonstrates that combination of NDV and VEGF-C in tumors has potent anti-tumor effect leading to long-term survival after tumor eradication in majority of the animals.
Quantity of experimentation:
In view of the state and level of predictability in the art and the failure to provide adequate guidance to overcome the state and level of predictability of the art, one of skill would have to perform undue experimentation in order to practice the invention commensurate in scope with the claims.
Response to Arguments
Applicant's arguments filed April 28, 2026 have been fully considered but they are not persuasive.
Applicant asserts that amending the independent claims to recite a method for treating melanoma overcomes the 35 U.S.C. 112(a) enablement rejection.
This argument is not found persuasive. As discussed in the 35 U.S.C. 112(a) enablement rejection, the claims are enabled for a method for treating melanoma comprising administering intratumorally a pharmaceutical composition wherein the pharmaceutical composition comprises a recombinant Newcastle Disease Virus (NDV) or a recombinant avian paramyxovirus serotype 4 (APMV-4) in a pharmaceutically acceptable carrier or excipient wherein the recombinant NDV or recombinant APMV-4 comprises a genome that comprises a transgene and wherein the transgene comprises a nucleotide sequence encoding VEGF-C and does not reasonably provide enablement for a method for treating melanoma comprising administering a pharmaceutical composition wherein the pharmaceutical composition comprises a recombinant Newcastle Disease Virus (NDV) or a recombinant avian paramyxovirus serotype 4 (APMV-4) in a pharmaceutically acceptable carrier or excipient wherein the recombinant NDV or recombinant APMV-4 comprises a genome that comprises a transgene and wherein the transgene comprises a nucleotide sequence encoding any other vascular endothelial growth factor.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 36, 43, 66, 68, 70, 74, 90, and 97 are rejected under 35 U.S.C. 103 as being unpatentable over Beier et al. (US 2009/0208495; reference cited by Applicant) in view of Hubbell et al. (US 2021/0094995; reference previously cited by the Examiner).
Regarding claims 36, 66, 70, 74, and 90, Beier et al. teaches a method for treatment of cancer comprising administration to a subject in need thereof a pharmaceutically effective amount of the pharmaceutical composition of the present invention. A pharmaceutically effective amount is a titer of the virus of the present invention which cures or suppresses the disease [0039]. Further, Beier et al. teaches a method for tumor treatment comprising administering paramyxovirus, APMV4, wherein the virus is recombinant and the genetic modification results in a higher selectivity of the virus to infect tumor cells compared to non-transformed normal cells [claims 1, 3, and 10]. Beier et al. also teaches that a tumor with low proliferation rate such as melanoma can be treated [0027] and [0028]. Further, transgenes are inserted that encode for proteins that have an anti-tumor activity like toxins, prodrug-converting enzymes, proteases, antibodies etc. Examples are TRAIL and mutants thereof, MDA-7, IL2, TNF-a, IGF-BP-7 [0064].
Regarding claim 43, Beier et al. teaches that modification results in a higher oncolytic potency as measured by the antitumor-effect when administered to tumor-bearing human [0034].
Regarding claim 68, Beier et al. teaches that the inventive virus may further be recombinant and may further be modified to express one or more additional genes that originates from APMV1-9, preferably it may be modified to express one or more additional gene(s) that originates from APMV1 (Newcastle disease virus) [0031].
Regarding claim 97, Beier et al. teaches that the pharmaceutical carrier and diluents may comprise an emulsion of the inventive virus and may be administered by intratumoral injection [0038].
However, Beier et al. does not teach that the transgene comprises a nucleotide sequence encoding VEGF-C. Beier et al. also does not teach that the VEGF-C comprises the amino acid sequence set forth in SEQ ID NO: 44.
Hubbell et al. teaches compositions and methods for treating cancer wherein the cancer is melanoma [0122]. Specifically, Hubbell et al. teaches compositions and methods for targeting or localizing a therapy in areas having vascular leak or permeability by providing a cytokine that is specifically targeted to and/or retained by collagen limiting systemic exposure and reducing side-effects associated with the cytokine [0005]. Hubbell et al. teaches recombinant polynucleotides encoding proteins, polypeptides, and peptides such as extracellular matrix-affinity peptide operatively linked to cytokines or chemokines [0069]. Further, Hubbell et al. teaches a cytokine peptide such as SEQ ID NO: 32 [0011] which is a human VEGF-C amino acid sequence [0054]. Hubbell et al. SEQ ID NO: 32 (designated as Db) has a 100% match to instant SEQ ID NO: 44 (designated as Qy) as shown in the alignment below.
Query Match 100.0%; Score 635; DB 1; Length 116;
Best Local Similarity 100.0%;
Matches 116; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AHYNTEILKSIDNEWRKTQCMPREVCIDVGKEFGVATNTFFKPPCVSVYRCGGCCNSEGL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 AHYNTEILKSIDNEWRKTQCMPREVCIDVGKEFGVATNTFFKPPCVSVYRCGGCCNSEGL 60
Qy 61 QCMNTSTSYLSKTLFEITVPLSQGPKPVTISFANHTSCRCMSKLDVYRQVHSIIRR 116
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 QCMNTSTSYLSKTLFEITVPLSQGPKPVTISFANHTSCRCMSKLDVYRQVHSIIRR 116
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to substitute a nucleotide sequence encoding IL2 with a nucleotide sequence encoding VEGF-C with a reasonable expectation of success. One would have made such a substitution in order to achieve the predictable result of providing a composition comprising a recombinant oncolytic virus for treating melanoma.
Claims 85 and 92 are rejected under 35 U.S.C. 103 as being unpatentable over Beier et al. (US 2009/0208495; reference cited by Applicant) in view of Hubbell et al. (US 2021/0094995; reference previously cited by the Examiner) as applied to claims 36, 43, 66, 68, 70, 74, 90, and 97 above, and further in view of Vijayakumar et al. (EBioMedicine 2019).
Regarding claims 85 and 92, the teachings of Beier et al. and Hubbell et al. are discussed above.
However, Beier et al. and Hubbell et al. do not teach that the recombinant NDV is the LaSota strain as recited in claims 85 and 92.
Vijayakumar et al. teaches the use of recombinant lentogenic (low pathogenicity) NDV LaSota L289A strain [page 98, left column, Section 2.2] and also teaches that the NDV strain LaSota is of low pathogenicity and induces little tumour cell lysis as a single agent in vitro [page 98, right column, Section 3.1].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Beier et al. and Hubbell et al. wherein the recombinant NDV is the LaSota strain as recited in the instant claims because Beier et al. and Hubbell et al. taught a method for treating melanoma and Vijayakumar et al. taught the use of recombinant lentogenic (low pathogenicity) NDV LaSota L289A strain and taught that the NDV strain LaSota is of low pathogenicity. One of ordinary skill in the art would have made such a modification because it would have amounted to combining known prior art elements to yield predictable results.
Claims 87 and 94 are rejected under 35 U.S.C. 103 as being unpatentable over Beier et al. (US 2009/0208495; reference cited by Applicant) in view of Hubbell et al. (US 2021/0094995; reference previously cited by the Examiner) as applied to claims 36, 43, 66, 68, 70, 74, 90, and 97 above, and further in view of GenBank (Avian paramyxovirus 4 strain APMV-4/duck/Hongkong/D3/75, complete genome, NCBI Reference Sequence: FJ177514.1, available November 4, 2008).
Regarding claims 87 and 94, the teachings of Beier et al. and Hubbell et al. are discussed above.
However, Beier et al. and Hubbell et al. do not teach that the recombinant APMV-4 is a recombinant APMV-4 Duck/Hong Kong/D3/1975 strain.
GenBank teaches the complete genome sequence of the APMV-4 Duck/Hong Kong/D3/1975 strain (GenBank FJ177514.1).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Beier et al. and Hubbell et al. wherein the recombinant APMV-4 is a recombinant APMV-4 Duck/Hong Kong/D3/1975 strain because Beier et al. and Hubbell et al. taught a method for treating melanoma and GenBank specifically taught the APMV-4 Duck/Hong Kong/D3/1975 strain. One of ordinary skill in the art would have made such a modification because it would have amounted to combining known prior art elements to yield predictable results.
Claims 44, 46, 56, 64, 79, 91, and 98 are rejected under 35 U.S.C. 103 as being unpatentable over Beier et al. (US 2009/0208495; reference cited by Applicant) in view of Hubbell et al. (US 2021/0094995; reference previously cited by the Examiner).
Regarding claims 44, 46, 56, 79, and 91 Beier et al. teaches a method for treatment of cancer comprising administration to a subject in need thereof a pharmaceutically effective amount of the pharmaceutical composition of the present invention. A pharmaceutically effective amount is a titer of the virus of the present invention which cures or suppresses the disease [0039]. Further, Beier et al. teaches a method for tumor treatment comprising administering paramyxovirus, APMV4, wherein the virus is recombinant and the genetic modification results in a higher selectivity of the virus to infect tumor cells compared to non-transformed normal cells [claims 1, 3, and 10]. Beier et al. also teaches that a tumor with low proliferation rate such as melanoma can be treated [0027] and [0028]. Further, transgenes are inserted that encode for proteins that have an anti-tumor activity [0064]. Beier et al. also teaches that the pharmaceutical carrier and diluents may comprise an emulsion of the inventive virus, and may be administered by intratumoral injection [0038].
Regarding claims 64 and 98, Beier et al. teaches that modification results in a higher oncolytic potency as measured by the antitumor-effect when administered to tumor-bearing human [0034].
However, Beier et al. does not teach administering a dose of a second pharmaceutical composition comprising VEGF-C or a nucleotide sequence encoding VEGF-C. Beier et al. also does not teach that the VEGF-C comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 44 or comprises the amino acid sequence of SEQ ID NO: 44. Beier et al. also does not teach that the subject is not administered an antigen.
Hubbell et al. teaches compositions and methods for treating cancer wherein the cancer is melanoma [0122]. Specifically, Hubbell et al. teaches compositions and methods for targeting or localizing a therapy in areas having vascular leak or permeability by providing a cytokine that is specifically targeted to and/or retained by collagen limiting systemic exposure and reducing side-effects associated with the cytokine [0005]. Hubbell et al. teaches recombinant polynucleotides encoding proteins, polypeptides, and peptides such as extracellular matrix-affinity peptide operatively linked to cytokines or chemokines [0069]. Further, Hubbell et al. teaches a cytokine peptide such as SEQ ID NO: 32 [0011] which is a human VEGF-C amino acid sequence [0054]. Hubbell et al. SEQ ID NO: 32 (designated as Db) has a 100% match to instant SEQ ID NO: 44 (designated as Qy) as shown in the alignment below.
Query Match 100.0%; Score 635; DB 1; Length 116;
Best Local Similarity 100.0%;
Matches 116; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AHYNTEILKSIDNEWRKTQCMPREVCIDVGKEFGVATNTFFKPPCVSVYRCGGCCNSEGL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 AHYNTEILKSIDNEWRKTQCMPREVCIDVGKEFGVATNTFFKPPCVSVYRCGGCCNSEGL 60
Qy 61 QCMNTSTSYLSKTLFEITVPLSQGPKPVTISFANHTSCRCMSKLDVYRQVHSIIRR 116
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 QCMNTSTSYLSKTLFEITVPLSQGPKPVTISFANHTSCRCMSKLDVYRQVHSIIRR 116
Hubbell et al. also teaches that the method further comprises administration of an additional agent such as an immunostimulatory. The term “immunostimulator" refers to a compound that can stimulate an immune response in a subject, and may include an adjuvant. In some embodiments, an immunostimulator is an agent that does not constitute a specific antigen, but can boost the strength and longevity of an immune response to an antigen [0117].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to substitute a nucleotide sequence encoding IL2 with a nucleotide sequence encoding VEGF-C with a reasonable expectation of success. One would have made such a substitution in order to achieve the predictable result of providing a composition comprising a recombinant oncolytic virus for treating melanoma.
Claims 88, 89, 95, and 96 are rejected under 35 U.S.C. 103 as being unpatentable over Beier et al. (US 2009/0208495; reference cited by Applicant) in view of Hubbell et al. (US 2021/0094995; reference previously cited by the Examiner) as applied to claims 44, 46, 56, 64, 79, 91, and 98 above, and further in view of GenBank (Avian paramyxovirus 4 strain APMV-4/duck/Hongkong/D3/75, complete genome, NCBI Reference Sequence: FJ177514.1, available November 4, 2008).
Regarding claims 88, 89, 95, and 96, the teachings of Beier et al. and Hubbell et al. are discussed above.
However, Beier et al. and Hubbell et al. do not teach that the recombinant APMV-4 is a recombinant APMV-4 Duck/Hong Kong/D3/1975 strain.
GenBank teaches the complete genome sequence of the APMV-4 Duck/Hong Kong/D3/1975 strain (GenBank FJ177514.1). According to the sequence listing, instant SEQ ID NO: 78 is the complete genome of avian paramyxovirus 4 APMV-4/duck/Hongkong/D3/75 (GenBank: FJ177514.1).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Beier et al. and Hubbell et al. wherein the recombinant APMV-4 is a recombinant APMV-4 Duck/Hong Kong/D3/1975 strain because Beier et al. and Hubbell et al. taught a method for treating melanoma and GenBank specifically taught the APMV-4 Duck/Hong Kong/D3/1975 strain. One of ordinary skill in the art would have made such a modification because it would have amounted to combining known prior art elements to yield predictable results.
Claims 86 and 93 is rejected under 35 U.S.C. 103 as being unpatentable over Beier et al. (US 2009/0208495; reference cited by Applicant) in view of Hubbell et al. (US 2021/0094995; reference previously cited by the Examiner) as applied to claims 44, 46, 56, 64, 79, 91, and 98 above, and further in view of Vijayakumar et al. (EBioMedicine 2019).
Regarding claims 86 and 93, the teachings of Beier et al. and Hubbell et al. are discussed above.
However, Beier et al. and Hubbell et al. do not teach that the recombinant NDV is the LaSota strain as recited in claims 86 and 93.
Vijayakumar et al. teaches the use of recombinant lentogenic (low pathogenicity) NDV LaSota L289A strain [page 98, left column, Section 2.2] and also teaches that the NDV strain LaSota is of low pathogenicity and induces little tumour cell lysis as a single agent in vitro [page 98, right column, Section 3.1].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Beier et al. and Hubbell et al. wherein the recombinant NDV is the LaSota strain as recited in the instant claims because Beier et al. and Hubbell et al. taught a method for treating melanoma and Vijayakumar et al. taught the use of recombinant lentogenic (low pathogenicity) NDV LaSota L289A strain and taught that the NDV strain LaSota is of low pathogenicity. One of ordinary skill in the art would have made such a modification because it would have amounted to combining known prior art elements to yield predictable results.
Response to Arguments
Applicant's arguments filed April 28, 2026 have been fully considered to the extent that they might apply to the new ground of rejection set forth above but they are not persuasive.
Applicant asserts that Beier et al. relates to the use of a group of paramyxoviruses for the production of a medicament for the treatment of tumors. Applicant further asserts that Beier et al. only discloses prophetic examples about how the group of paramyxoviruses may be made and used. Applicant also asserts that Beier et al. and Hubbell et al. alone or in combination do not teach or suggest a method for treating melanoma as recited in the instant claims. Specifically, the instant specification teaches that recombinant NDV and recombinant APMV-4 replicate preferentially in tumor cells thus one of ordinary skill in the art would not look to Hubbell et al.’s teachings regarding a cytokine operably linked to an ECM affinity peptide to achieve localized delivery of VEGF-C to the tumor vasculature.
These arguments are not found persuasive. Beier et al. teaches a method for treatment of cancer comprising administration to a subject in need thereof a pharmaceutically effective amount of the pharmaceutical composition. Beier et al. also teaches a method for tumor treatment comprising administering paramyxovirus, APMV4, wherein the virus is recombinant and the genetic modification results in a higher selectivity of the virus to infect tumor cells compared to non-transformed normal cells. However, Beier et al. does not teach that the transgene comprises a nucleotide sequence encoding VEGF-C. Hubbell et al. teaches compositions and methods for treating cancer wherein the cancer is melanoma [0122]. Hubbell et al. teaches recombinant polynucleotides encoding proteins, polypeptides, and peptides such as extracellular matrix-affinity peptide operatively linked to cytokines or chemokines [0069]. Further, Hubbell et al. teaches a cytokine peptide such as SEQ ID NO: 32 [0011] which is a human VEGF-C amino acid sequence [0054]. It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to substitute a nucleotide sequence encoding IL2 with a nucleotide sequence encoding VEGF-C with a reasonable expectation of success. One would have made such a substitution in order to achieve the predictable result of providing a composition comprising a recombinant oncolytic virus for treating melanoma.
Applicant asserts the following:
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These arguments are not found persuasive. Beier et al. teaches that in order to increase the therapeutic potency, transgenes are inserted that encode for proteins that have an anti-tumor activity [0064] and Hubbell et al. teaches that cytokines such as VEGF-C has anti-tumor properties [0054] and induces lymphangiogenesis leading to increased immune cells infiltration [0175]. Therefore, one of ordinary skill in the art would have a reasonable expectation that the combination of NDV and VEGF-C or APMV-4 and VEGF-C has an anti-tumor effect on melanoma.
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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/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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