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 preliminary amendment filed on October 7, 2025 is acknowledged. Claims 1-35, 37-42, 45, 47-55, 57, and 60-63 have been canceled. Claims 36, 46, 58, and 59 were amended. Claims 36, 43, 44, 46, 56, 58, 59, and 64-82 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)).
Claim 76 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 36, 43, 44, 46, 56, 58, 59, 64-75, and 77-82 are examined on the merits herein.
Priority
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Information Disclosure Statement
The information disclosure statement (IDS) submitted on April 25, 2023 and October 7, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings were received on August 26, 2022. These drawings are found acceptable by the examiner.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because of the use of legal phraseology ("e.g." stands for "exempli gratia", and should be removed or replaced with a non-Latin version, such as "for example"). A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The disclosure is objected to because of the following informalities:
The second line in paragraph [0003] reads in part “(AMPV)” and should read “(APMV)”.
Paragraph [0052]: there are two (2) instances of the recitation of “Effects of NDV treatment and VEGF-C on the distribution of immune cells in tumors.”.
Paragraph [0052] reads “(K)” and should read “(FIG. 17K)” for consistency purposes.
Paragraph [00298] reads in part “well stablished protocol” and should read “established” (emphasis added).
Paragraph [00316] reads in part “FIGS. 7D an 7E” and should read “FIGS. 7D and 7E” (emphasis added).
Paragraph [00317] refers to FIG. 8D; however, there is no FIG. 8D in the drawings.
Paragraph [00346] reads in part “Two overlapping PCR productss…” and should read “Two overlapping PCR products…” (emphasis added).
Appropriate correction is required.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See paragraph [0007].
Claim Objections
Claims 46, 59, 65, and 71 are objected to because of the following informalities:
Claim 46 part (c): the first recitation of “encodes” should recite “encoding”.
Claim 59 recites “The method of claims 58” and should recite “The method of claim 58”.
Claim 65 recites “reovirus” in part (a) and part (b).
There are two (2) instances of the word “in” in claim 71.
Appropriate correction is required.
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 58 is 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 58 recites the limitation "the recombinant oncolytic virus". There is insufficient antecedent basis for this limitation in the claim. Claim 58 depends on claim 44 and claim 44 only recites an oncolytic virus. It would be remedial to amend claim 44 to recite “comprising a recombinant oncolytic virus” (emphasis added).
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, 58, 59, 64-75, and 77-82 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 in a mouse model comprising administering intratumorally a dose of a pharmaceutical composition wherein the pharmaceutical composition comprises a recombinant oncolytic virus in a pharmaceutically acceptable carrier or excipient wherein the recombinant oncolytic virus 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 any other type of cancer. 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, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, and 77 are drawn to a method for treating cancer, comprising administering a dose of a pharmaceutical composition to a subject in need thereof, wherein the pharmaceutical composition comprises a recombinant oncolytic virus in a pharmaceutically acceptable carrier or excipient, wherein the recombinant oncolytic virus comprises a genome that comprises a transgene, and wherein the transgene comprises a nucleotide sequence encoding VEGF-C or VEGF-D. The broadest reasonable interpretation of claim 36 is that the method encompasses treating any type of cancer.
Claims 44, 46, 56, 58, 59, 64, 78, 79, 80, 81, and 82 are drawn to a method for treating cancer, comprising administering intratumorally to a subject in need thereof a dose of a first pharmaceutical composition comprising an oncolytic virus and administering to the subject a dose of a second pharmaceutical composition comprising VEGF-C or VEGF-D, or a nucleotide sequence encoding VEGF-C or VEGF-D. The broadest reasonable interpretation of claim 44 is that the method encompasses treating any type of cancer.
State of the prior art, level of predictability in the art, and level of one of
ordinary skill:
A review of the prior art shows that the state of the art of administering a pharmaceutical composition comprising a recombinant oncolytic virus and VEGF-C or VEGF-D to treat cancer is immature and nascent.
Zheng et al. (Molecular Therapy Oncolytics 2019) 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) 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].
As evidenced by Zheng et al., challenges and limitations exist using oncolytic viruses as therapeutic agents in cancer therapy. Furthermore, as evidenced by Lonberg, there is a lack of translatability of syngeneic models to humans. Thus, one would not expect to treat any type of cancer comprising administering a dose of a pharmaceutical composition comprising a recombinant oncolytic virus in a pharmaceutically acceptable carrier or excipient wherein the recombinant oncolytic virus comprises a genome that comprises a transgene wherein the transgene comprises a nucleotide sequence encoding VEGF-C or VEGF-D 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 breadth of the claims which embrace treating any type of cancer, 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.
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, 65, 66, 67, 68, 69, 70, 71, 73, 74, 75, and 77 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).
Regarding claims 36, 65, 66, 68, 70, 71, 73, 74, 75, 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 claims 43 and 77, 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 claims 67 and 69, Beier et al. teaches that the inventive virus may further encode the gene(s) for the F and/or the HN protein of another paramyxovirus, whereby the F protein may have a multibasic cleavage site, and the virus may be modified in such a way that one gene is replaced by the homologous gene of a virus from the group APMV1-9 [0035].
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 44, 46, 56, 58, 59, 64, 78, 79, 80, 81, and 82 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).
Regarding claims 44, 46, 56, 58, 59, 78, 79, 80, and 82, 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 81, 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. 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.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA TRAN whose telephone number is (571)270-0550. The examiner can normally be reached M-F 7:30 - 5:00pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/C.T./
Examiner, Art Unit 1637
/CELINE X QIAN/Primary Examiner, Art Unit 1637