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 .
Application Status
Applicant’s remarks, and amendments to the specification, drawings, and claims filed June 12, 2026 are acknowledged. Claims 1-2, 9, 19, 21-22, and 24-25 were amended, and claims 3-4, 7, and 12-15 were cancelled. Claims 1-2, 8-11, and 19-36 are pending.
Notice Regarding Evidence Submitted in the Remarks to Traverse Rejections
Applicant’s remarks include evidence submitted to traverse the § 103 rejections raised in the prior action, where the evidence is not otherwise provided for in the disclosure. See “Figure 1. The trend of average tumor volume changes in each group of animals,” “Figure 2. Weight changes of golden hamster HPD-1NR subcutaneous tumor model,” and associated description on pgs. 19-22 of the remarks.
37 CFR § 1.132 states that “When any claim of an application or a patent under reexamination is rejected or objected to, any evidence submitted to traverse the rejection or objection on a basis not otherwise provided for must be by way of an oath or declaration under this section.” Applicant has not submitted the evidence traversing the rejections through the proper avenue. The evidence currently presented in the remarks, and any additional evidence which Applicant wishes to have considered in an effort to traverse rejections, must be submitted in the form of an affidavit or declaration under 37 CFR § 1.132. See MPEP 716. The evidence above which is presented in the remarks will not be considered, accordingly.
Restriction/Election
Claims 32-36 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-2, 8-11, and 19-31 are under consideration herein.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of prior-filed Application No. 63/006,115 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Specifically, Application No. 63/006,115 does not disclose the limitations of instant claims 19-20. The first disclosure of “gene editing,” and gene editing using “anti-sense RNA, a siRNA, a shRNA and/or a CRISPR/Cas system” is Application No. PCT/IB2021/052898 ([100]; [195]). The effective filing date of claims 19-20 is April 7, 2021, accordingly. The remaining claims under examination find support in Application No. 63/006,115, and have an effective filing date of April 7, 2020.
Withdrawn Rejections
The remarks and amendments have been thoroughly reviewed. The amendments to the claims are sufficient to overcome the § 101 rejection raised in the prior action. The amendments recite several elements which clearly differentiate the modified Ad5 virus from any naturally occurring counterpart, e.g., “the expression and/or activity of a E1ACR2 gene, a E1B19K gene, and/or a E3gp19K gene is downregulated… at least one modification in the fibre region… comprises expression of IL-21… comprises expression of an A20.” The amendments to the claims are also sufficient to overcome the § 102 rejection over Man, and § 103 rejection over Man in view of Baker. Neither Man, nor Man in view of Baker, teach a modified Ad5 virus as recited in instant claim 1. Specifically, Man and Baker fail to teach “expression of IL-21.” The aforementioned rejections are withdrawn, accordingly.
Applicant’s remarks and amendments are not persuasive to place the claims in condition for allowance for the reasons that follow. Any objection or rejection not reiterated herein has been overcome by amendment.
Claim Objections
Claims 1, 9-10, and 21-22 are objected to because of the following informalities:
Claim 1 is missing several conjunctions, and recites redundant phrases. The claim also recites “comprises expression of IL-21” and “comprises expression of an A20.” It is clear that these phrases require that the modified virus Ad5 comprise a gene encoding an IL-21 and a gene encoding an A20 ([7]; [39]-[40]), however the skilled artisan would use the phrase “expresses IL-21,” or “comprises a gene encoding IL-21.” It would be preferable to amend claim 1 to recite the following, accordingly:
“A modified virus Ad5, wherein compared to a wild virus Ad5, the expression and/or activity of a E1ACR2 gene, a E1B19K gene, and/or a E3gp19K gene is downregulated in the modified virus Ad5, wherein the modified virus Ad5 has at least one modification in fibre region, wherein the modification in fibre region comprises an amino acid substitution Y477A, and a deletion of amino acids TAYT at the residues 489-492, wherein the amino acid residue numbering of the fiber region is based on GenBank Accession WEG78228.1, wherein the modified virus Ad5 comprises a gene encodinga gene encoding
Claim 9 recites “a gene encoding the IL-21 and/or the gene encoding the A20….” It would be preferable to amend the claim to recite “the[[a]] gene encoding the IL-21 and/or the gene encoding the A20…,” because it is clear that the phrase “a gene encoding the IL-21” refers to the gene encoding the IL-21 which is required of claim 1 as described above.
Claim 10 recites “a gene encoding the A20….” It would be preferable to amend the claim to recite “the[[a]] gene encoding the A20…,” because it is clear that the phrase “a gene encoding the A20” refers to the gene encoding the A20 required of claim 1 as described above.
Claims 21 and 22 recite gene names, which would preferable be italicized, such as in claim 1.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 1-2, 8-11, 19-20, and 22-31 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. The rejections that follow are maintained from the prior action, or are new and necessitated by Applicant’s amendments to the claims
Claim 1 recites “compared to a wild virus Ad5, the expression and/or activity of a E1ACR2 gene, a E1B19K gene, and/or a E3gp19K gene is downregulated in the modified virus Ad5.” The specification provides that the downregulation may be achieved by “gene editing and/or gene recombination,” wherein gene editing encompasses “anti-sense RNA, a siRNA, a shRNA, and/or a CRISPR/Cas system” ([49]-[51]).. While functional limitations, such as the downregulation function recited in claim 1, are not per se indefinite, they can be indefinite if it is unclear how the functional limitations limit the structure of the product, or what structural characteristics of the product are necessary to achieve the function.
The skilled artisan would understand that means encompassed by the claim to achieve the downregulation function, e.g., gene recombination and CRISPR-Cas system gene editing, can be used to delete the recited genes in the modified virus Ad5 genome. However, it is not clear how an anti-sense RNA, siRNA, or shRNA would modify the structure of the modified virus Ad5, because these would be understood to function on the RNA products produced from the modified virus Ad5 genome, rather than the modified virus Ad5 genome itself. Because the means of achieving the downregulation function are not limited, and the claim appears to encompass means which would not be understood to result in a structural difference in the modified virus Ad5, the structure required of the modified Ad5 virus by the functional limitations is unclear. For example, it is not clear whether the modified virus Ad5 must comprise a structure which confers the downregulation (e.g., a deletion of at least a portion of one or more of the recited genes), or whether the modified virus Ad5 must merely be amenable of downregulation (e.g., by introduction of an antisense RNA, siRNA, shRNA, or other agent which downregulates the expression/activity of one or more of the recited genes).
Claims 2, 8-11, 19-20, and 22-31 are rejected for depending from claim 1 and failing to remedy the indefiniteness. In the interest of compact prosecution, the claims will be interpreted hereinafter as requiring deletion of at least a portion of one or more of the recited genes.
Claim 23 recites that the modified virus Ad5 is “capable of expressing a gene and/or a ligand targeting a T cell, a gene and/or a ligand targeting a tumor cell, and/or a therapeutic gene.” Neither the claim nor specification clearly define what makes an Ad5 “capable of” expressing a gene and/or a ligand targeting a T cell, a gene and/or a ligand targeting a tumor cell, and/or a therapeutic gene. It is not clear whether “capable of” implies an unrecited structural element, e.g., a promoter sequence, a sequence encoding one or more of the elements recited in claim 23, machinery for protein expression, and/or machinery which enables the Ad5 to infect a host cell which comprises machinery for protein expression, or, alternatively, whether any Ad5 is “capable” owing to gene editing and gene recombination techniques described in the specification. It is not clear what, if any, structure(s) the modified virus Ad5 must have to be “capable of” expressing one or more of the elements recited in claim 23, which renders the claim indefinite.
Claims 24-27 are rejected for depending from claim 23 and failing to remedy the indefiniteness.
In view of the indefiniteness described above, hereinafter, the phrase “capable of” will not be interpreted as implying unrecited structural elements; any Ad5 (i.e., adenovirus species C serotype 5, [94]) will be understood as “capable of” expressing a protein encompassed by the claims 23-27 owing to gene editing and gene recombination techniques described in the specification.
Response to Remarks - 35 USC § 112(b)
The remarks regarding the § 112(b) rejections raised in the prior action have been reviewed. Applicant’s remarks do not specifically address the new or maintained rejections above, and claim 23 has not been amended to overcome the issues raised in the prior action as described above.
Claim Rejections - 35 USC § 112(a) – Written Description
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 1-2, 8-11, and 19-31 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The rejections that follow are new matter rejections necessitated by Applicant’s amendments to the claims.
Claim 1 has been amended to recite “wherein the amino acid numbering of the fiber region is based on GenBank Accession WEG78228.1.” Applicant’s remarks do not specifically point out where the support for the amendments to the claims may be found in the original disclosure. A thorough search of the original disclosure failed to uncover any explicit or implicit support for GenBank Accession WEG78228.1 as recited in claim 1. The newly introduced limitation fails to comply with the written description requirement.
Claims 2, 8-11, and 19-31 are rejected for encompassing the new matter introduced to claim 1, and failing to remedy the written description issues therein.
Claim 24 has been amended to recite “a gene encoding a cytotoxin.” Applicant’s remarks do not specifically point out where the support for the amendments to the claims may be found in the original disclosure. A thorough search of the original disclosure failed to uncover any explicit or implicit support for a gene encoding a cytotoxin as recited in claim 24. The specification does recite a “cytotoxic gene” ([149]), but the skilled artisan would not interpret a cytotoxic gene to be equivalent to a gene encoding a “cytotoxin.” The newly introduced limitation fails to comply with the written description requirement.
Claims 25-27 are rejected for encompassing the new matter introduced to claim 24, and failing to remedy the written description issues therein.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 9 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. This is a new rejection necessitated by Applicant’s amendments to the claims.
Claim 9 recites that “a gene encoding the IL-21 and/or the gene encoding the A20 is incorporated in to the genome of the modified virus Ad5.” As described in paragraph 8 above, the phrases “comprises expression of IL-21” and “comprises expression of an A20” are interpreted as requiring that the modified virus Ad5 of claim 1 comprise a gene encoding the IL-21 and a gene encoding the A20. Claim 9, therefore, does not further limit the subject matter of the claim upon which it depends, because the modified virus Ad5 of claim 1 already comprises a gene encoding an IL-21 and a gene encoding an A20 in its genome.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Notice to Joint Inventors
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.
Claim Rejections - 35 USC § 103 – Man in view of Baker, Wang, and Ugai
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 1, 9-11, and 19-31 are rejected under 35 U.S.C. 103 as being unpatentable over Man (Man et al., February 2018, Molecular Cancer Therapeutics, 17(2), pg. OF1-OF13; of record) in view of Baker (Baker et al., 2018, Cancers, 10, 201, pg. 1-39; of record), Wang (Wang et al., WO 2014/063601 A1, published 1 May 2014, and machine translation), and Ugai (Ugai et al., 2003, Cancer Gene Therapy, 10, pg. 771-778). The rejections that follow are new and necessitated by Applicant’s amendments to the claims.
The phrase “wherein the amino acid residue numbering of the fiber region is based on GenBank Accession WEG78228.1” is interpreted as a reference sequence for the residue numbering recited in the claim. The claims are not interpreted as requiring the sequence set forth in GenBank Accession WEG78228.1. Accordingly, a teaching of the same modifications with the same residues and numbering set forth in the claims is interpreted hereinafter as meeting the limitations with respect to the fibre region modifications.
Regarding claims 1, 9, and 21-22, Man teaches a modified Ad5 virus (“Ad5-3∆-A20T”) which comprises a modification in the fibre region relative to a reference Ad5, wherein the modification comprises an amino acid substitution Y477A and a deletion of the amino acids TAYT (“Ad5-3∆-A20477dlTAYT (Ad5-3∆-A20T,” pg. OF2, right col.; “Y477A/∆TAYT,” “Fibre,” Fig. 5A). Man teaches that the E1ACR2 gene, E1B19K gene, and E3gp19K gene are deleted in the modified Ad5 virus (pg. OF1, right col.; “Viruses and infections,” pg. OF2, right col.; Fig. 5A; pg. OF8, left col.).
Man teaches that the modified Ad5 virus is “highly selective for αvβ6 integrin-expressing pancreatic cancer cells” by virtue of comprising a gene encoding an A20 originated from foot-and-mouth disease virus (“A20FMDV2”) which selectively binds to αvβ6 (Abstract; pg. OF2, left col.). Man teaches that the virus exhibits “enhanced infectivity and cell killing in PDAC cells,” and is “an excellent candidate for targeting pancreatic cancer” (pg. OF11, right col.). Man states that the virus will “guide further optimization of oncolytic adenoviruses for systemic delivery to improve on therapeutic efficacy in patients with pancreatic cancer…” (pg. OF2, left col.).
Man does not teach that the modified Ad5 virus comprises a gene encoding an IL-21 in the E1ACR2 gene, the E1B19K gene, or the E3gp19K gene as encompassed by claims 1, 9, and 21-22.
Baker teaches a modified Ad5 virus comprising a gene encoding a cytokine (i.e., IL-12), which is “currently in Phase I clinical trials for patients with metastatic pancreatic cancer in combination with cytotoxic drugs” (pg. 8). Baker teaches that the gene coding the cytokine is incorporated into the site of the E3gp19K gene (“by replacing the E3gp19k gene, pg. 8). Baker teaches that the resulting virus showed promising efficacy in models of pancreatic cancer (pg. 8). As evidenced by Baker, the “Ad∆∆ mutant” which was modified to comprise a gene encoding a cytokine is identical to the Ad∆∆ mutant used to generate the modified Ad5 virus of Man (“We previously generated an E1ACR2-deleted mutant… deleting… E1B19K (Ad∆∆)… we further increased the selectivity and efficacy of Ad∆∆ by… inserting… (A20FMDV) generating Ad5-3∆-A20T,” pg. 5).
Baker does not teach the cytokine is IL-21.
However, Wang teaches a substantially identical modified adenovirus to Man and Baker, which comprises a gene encoding IL-21 (“The oncolytic adenovirus… can enhance the vaccine effect by expressing a tumor-associated antigen, an immunomodulatory gene and/or an immunoregulatory protein antibody… The immunomodulatory gene is.. IL21,” pg. 2 of machine translation, “Ad5,” pg. 4, as well as the machine translation of the claims). Wang’s modified adenovirus is used for the same purpose as Man and Baker, and may be used in pancreatic cancer therapy (“An application of the vaccine or the cell vaccine in the preparation of a drug for treating tumors… The vaccine composed of adenovirus… can induce tumor-induced specific immunity, and the generated anti-tumor effect is studied in the HPD-1 NR model of the pancreatic cancer,” see pg. 2 of machine translation).
Ugai provides motivation for the skilled artisan to select IL-21 from the cytokines recited by Wang. Ugai teaches that “expression of IL-21… in human pancreatic tumors produced antitumor effects in the inoculated immunocompromised mice” (pg. 776, right col.). Ugai teaches that “expression of IL-21… could be a therapeutic strategy for pancreatic cancer patients, who may be suffering from immune tolerance to the tumors” (pg. 777, left col.).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the Ad5 virus of Man such that it comprised a gene encoding an IL-21 in the E3gp19K gene. It would have amounted to a simple combination of a known modified Ad5 virus, with a known gene encoding a cytokine compatible with a modified Ad5 virus, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success in inserting a gene encoding IL-21 into the E3gp19K gene, because Baker teaches that a substantially identical Ad5 virus used in clinical trials has already been successfully modified in this way (i.e., by insertion of a gene encoding a cytokine into the E3gp19K gene). The skilled artisan would have been motivated to further modify the virus of Man, and, would have chosen IL-21, with a reasonable expectation that that the resulting modified Ad5 virus would be of use in models of pancreatic cancer as described by Man given I) Man’s suggestion to further optimization the virus ("guide further optimization of oncolytic adenoviruses for systemic delivery to improve on therapeutic efficacy in patients with pancreatic cancer ... ," pg. OF2, left col.), and II) the substantially identical modified Ad5 virus encoding IL-21 described by Wang, coupled with the evidence of Ugai for the use of overexpressing IL-21 in pancreatic cancer therapy.
Regarding claim 10, Man teaches the gene encoding the A20 (“A20FMDV2 peptide”) is incorporated into the HI-loop of the virus’ genome (“the A20FMDV2 peptide was inserted and CAR binding was ablated in the fiber knob (HI-loop) of the Ad∆∆ mutant, to generate Ad5-3∆-A20T,” pg. OF8, left col.; Fig. 5A).
Regarding claim 11, the claim is interpreted as product-by-process, which is limited by the structures implied by the process step (“wherein the incorporation uses a method of gene editing and/or gene recombination”). See MPEP 2113 (I). The structure implied by the process steps is a modified Ad5 virus comprising a gene encoding an A20 in its genome. This is obvious for the reasons described above.
Regarding claims 19-20, the claims are interpreted as products-by-process, which are limited by the structures implied by the process step (“wherein the downregulation uses a method of gene editing and/or gene recombination,” wherein “the gene editing uses an anti-sense RNA, a siRNA, a shRNA and/or a CRISPR/Cas system”). See MPEP 2113 (I). The structure implied by the process steps is a modified Ad5 virus, which when compared to a wildtype Ad5 virus, displays downregulated expression and/or activity of a E1ACR2 gene, E1B19K gene, and/or E3gp19K gene. This is obvious for the reasons described above.
Regarding claims 23-27, the “gene and/or ligand targeting a T cell…” is not required of claims 23-27, and any Ad5, including the Ad5 rendered obvious above, is understood to be “capable of” expressing these proteins in view of the indefiniteness described above. These claims are also obvious for the reasons described above.
Regarding claim 28, the interpretation of claim 28 is described in paragraph 23 of the prior action and applied here. Man teaches an isolated nucleic acid encoding the modified Ad5 virus (““Viruses and infections,” pg. OF2, right col.).
Regarding claim 29, for the reasons described in paragraph 23 of the prior action, the claim is interpreted as encompassing a virus comprising the isolated nucleic acid, which is interpreted as encompassing a viral genome. The modified Ad5 virus rendered obvious above meets these limitations.
Regarding claim 30, Man teaches cells comprising the modified Ad5 virus (“Panc04.03,” and “Suit-2,” pg. OF8-OF9; Figs. 5-6).
Regarding claim 31, the interpretation of claim 31 is described in paragraph 23 of the prior action and applied here. Man teaches pharmaceutical compositions comprising the modified Ad5 virus and a pharmaceutically accepted adjuvant (“All infections were performed in serum-free DMEM,” pg. OF2, right col.; “Treatments were initiated… by intratumoral administration of adenoviral mutants at doses ranging from…,” pg. OF3, right col.; “Cells were infected with Ad5-3∆-A20T… and virus collected from media,” Fig. 5 and description; “Adenoviral mutants or PBS (mock controls) were administrated intratumorally…,” Fig. 6 and description).
Claim Rejections - 35 USC § 103 – Man in view of Baker, Wang, and Ugai, in further view of GenBank
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Man (Man et al., February 2018, Molecular Cancer Therapeutics, 17(2), pg. OF1-OF13; of record) in view of Baker (Baker et al., 2018, Cancers, 10, 201, pg. 1-39; of record), Wang (Wang et al., WO 2014/063601 A1, published 1 May 2014, and machine translation), and Ugai (Ugai et al., 2003, Cancer Gene Therapy, 10, pg. 771-778) as applied as to claims 1, 9-11, and 19-31, in further view of GenBank (Homo sapiens interleukin 21 (IL21), RefSeqGene (LRG_1263) on chromosome 4, NCBI Reference Sequence: NG_031966.2, available 31 July 2018). The rejection that follows is new and necessitated by Applicant’s amendments to the claims.
The teachings of Man, Baker, Wang, and Ugai are described above and applied as to claims 1, 9-11, and 19-31 therein. Wang also teaches genes encoding cytokines originated from human (“hIL-12,” see pg. 5 of machine translation).
None of Man, Baker, Wang, or Ugai teach a gene encoding an IL-21 which is originated from human.
However, GenBank teaches a gene encoding an IL-21 which is originated from human.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have incorporated an IL-21 gene originated from human into the modified Ad5 virus rendered obvious above. It would have amounted to a simple substitution of a gene encoding a generic IL-21 taught by the prior art, for a gene encoding a human IL-21, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success of incorporating a gene encoding a human IL-21 gene because such a gene was readily available in the prior art as evidenced by GenBank, and means to incorporate genes into modified Ad5 virus were well known as evidenced by the prior art cited herein. The skilled artisan would have been motivated to incorporate a gene encoding a human IL-21 because the teachings of the prior art cited herein are related to treatments of human subjects, e.g., subjects with pancreatic cancer, and because the use of a human cytokine would be relevant to such methods as evidenced by Wang.
Claim Rejections - 35 USC § 103 – Man in view of Baker, Wang, and Ugai, in further view of Uusi-Kerttula
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Man (Man et al., February 2018, Molecular Cancer Therapeutics, 17(2), pg. OF1-OF13; of record) in view of Baker (Baker et al., 2018, Cancers, 10, 201, pg. 1-39; of record), Wang (Wang et al., WO 2014/063601 A1, published 1 May 2014, and machine translation), and Ugai (Ugai et al., 2003, Cancer Gene Therapy, 10, pg. 771-778), as applied as to claims 1, 9-11, and 19-31, in further view of Uusi-Kerttula (Uusi-Kerttula, “Development of ovarian cancer-targeted adenoviral vectors,” 2 May 2017, https://orca.cardiff.ac.uk/id/eprint/100129). The rejection that follows is new and necessitated by Applicant’s amendments to the claims.
The phrase “a nucleic acid sequence as set forth in SEQ ID NO. 4” is interpreted as any two or more consecutive nucleotides of SEQ ID NO: 4 (“a nucleic acid sequence”).
The teachings of Man, Baker, Wang, and Ugai are described above and applied as to claims 1, 9-11, and 19-31 therein.
None of Man, Baker, Wang, or Ugai teach a gene encoding the A20 which has a nucleic acid sequence as set forth in SEQ ID NO: 4.
Uusi-Kerttula teaches a gene encoding an A20 which has a nucleic acid sequence as set forth in SEQ ID NO: 4 (Table 2-6, pg. 94). See attached alignment in Appendix I.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have incorporated the gene encoding an A20 taught by Uusi-Kerttula into the modified Ad5 virus rendered obvious above. It would have amounted to a simple substitution of a generic A20 taught by the prior art, for a known gene encoding an A20, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success of incorporating the gene encoding an A20 of Uusi-Kerttula because the gene sequence was readily available in the prior art and usable in modified adenoviral vectors as evidenced by Uusi-Kerttula. Man and Baker are silent as to the sequence of the A20 gene incorporated into the modified Ad5 virus. The skilled artisan seeking to make the modified Ad5 virus would have been motivated, therefore, to incorporate the gene encoding an A20 taught by Uusi-Kerttula, which was known in the art and usable in modified adenoviral vectors.
Response to Remarks - 35 USC § 103
The remarks regarding the prior art rejections raised in the prior action have been reviewed. As described above, the prior art rejections raised in the previous action have been withdrawn in view of Applicant’s amendments to the claims. The remarks regarding the deficiencies of Man, and Man and Baker, are moot, accordingly.
Applicant’s remarks also allege that the claimed modified virus Ad5 exhibits unexpectedly superior results compared to prior art viruses. Specifically, Applicant states that “the modified virus Ad5 can achieve enhanced targeting of tumor cells and the ability to kill tumor cells… [and] can significantly reduce the toxicity to subjects treated with the virus Ad5.” Applicant indicates that “the results of the crystal violet staining experiment” in Fig. 20 support that “the modified Ad5 of this application can specifically bind to and/or kill αvβ6 integrin-positive tumor cells.” This feature, conferred by incorporation of a gene encoding an A20, is not unexpected based on the prior art cited herein (see Man, “The αvβ6 integrin is highly expressed in many solid tumors but not in normal cells… mutants were engineered to express… A20FMDV2 derived from… []FMDV[] that selectively binds… to αvβ6,” pg. 575, left col.; “The resultant mutant, Ad5-3∆-A20T, infected and killed αvβ6 integrin-expressing cells more effectively,” Abstract). As stated above in paragraph 3, the evidence submitted on pgs. 19-22 is not being considered. There is no other evidence in the specification to support Applicant’s allegations of enhanced targeting/killing of tumor cells, or reduced toxicity. Accordingly, there is insufficient evidence at present that the claimed modified virus Ad5 exhibits unexpectedly superior results compared to prior art viruses.
Applicant alleges that “the technical effects of different cytokines were unpredictable.” However, it was well known in the art that different cytokines may have different effects across different contexts (see, for example, Baker et al., of record, “transgenes that promote local cytokine release and tumor infiltration of lymphocytes are often included in the oncolytic adenoviral genome such as… GM-CSF… (IL)-12 and -18,” “GM-CSF is an immune-modulatory cytokine that induces activation of monocytes and macrophages… tested in patients with metastatic solid cancers… IL-12 is a proinflammatory cytokine… activates both innate and adaptive immune systems… for patients with metastatic pancreatic cancer…,” pgs. 7-8). There are examples in the art of viruses expressing different cytokines, including those cited in this action and the prior action. It does not appear that the diverse effects of different cytokines was a significant barrier to their incorporation in viral genomes, or their use in various therapeutic applications. Furthermore, the obviousness rejections describe why the skilled artisan would have chosen to include an IL-21 gene in a modified Ad5 virus, and, why the skilled artisan could have prepared and used the resulting modified Ad5 virus with a reasonable expectation of success. There is no evidence cited by Applicant, or evidence found in the prior art during the course of examination, that “it is not possible to determine which cytokine is suitable for clinical use, has good tumor-killing efficacy, and is safe when administered to subjects.” Furthermore, the claims are not directed to a method, they are directed to a modified virus Ad5 (i.e., a product), and the specific uses/outcomes described by Applicant are not required of the instant claims.
Taken together, Applicant’s remarks are insufficient to overcome the prior art rejections above, which are new, and necessitated by Applicant’s amendments to the claims.
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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/JENNA L PERSONS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600
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