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 .
Applicant's submission filed on 20 March 2026 has been entered.
Claims 16-18, 21-24, 27-33, 36, 37 and 39-42 are currently pending.
Claims 24, 27-33 and 39-42 are withdrawn as being drawn to a nonelected invention.
Claims 16-18, 21-23, 36 and 37 are considered here with respect to the elected species (applicable to Group I) of: XVir-N-31, PD0332991 (Palbociclib), Olaparib and JQ1.
Any rejection not reiterated herein has been withdrawn.
Response to Arguments
Applicant’s arguments in the Response of 20 March 2026 have been fully considered but are not persuasive.
Applicant argues that Holm teaches adenoviruses lacking expression of E1A13S only as one out of several possible embodiments. This is not persuasive because Holm specifically teaches Ad-Delo3-RGD (i.e. XVir-N-31), and thus it would be prima facie obvious to make a composition according to Holm wherein the adenovirus is XVir-N-31.
Applicant further argues that cell cycle inhibitors are only taught by Holm as one of a laundry list of potential additional agents. This is not persuasive because Holm teaches that the adenovirus can advantageously be combined with one or more additional agents having different modes of action than the adenovirus, and thus it would have been prima facie obvious to use any known anticancer compound having a different mode of action, including cell cycle inhibitors/cytostatics.
Applicant further argues that Holm only mentions a CDK2 inhibitor (CYC202) as an exemplary CDK inhibitor and does not disclose any CDK4/6 inhibitors, and CDK2 inhibitors have a different mechanism of action than palbociclib (CDK2 inhibitors being G1-to-S phase inhibitors, while palbociclib is early G1). This is not persuasive because one of ordinary skill reading Holm as a whole would recognize that Holm teaches combinations that include any anticancer compound having a different mode of action than the adenovirus, including cell cycle inhibitors/cystostatics generally. Thus, one of ordinary skill would not read Holm as being limited to any particular type of CDK inhibitor. Moreover, O’shea teaches compositions comprising similar oncolytic adenoviruses combined with palbociclib, which would give one a reasonable expectation of success in combining XVir-N-31 and palbociclib.
Applicant further argues that the teachings in Holm relating to cytostatics are distinct from cell cycle inhibitors such as palbociclib. This is not persuasive because Holm defines cytostatics broadly to include compounds that "result in the cell no longer growing and/or no longer dividing or slowing down cell division and/or cell growth" (p. 79, last ¶ to p. 80, 1st ¶), which would encompass cell cycle inhibitors such as palbociclib. One of ordinary skill would regard the groups of exemplary cytostatics at p. 80-81 of Holm as exemplary. Moreover, as an inhibitor of the cell cycle, palbociclib can be considered a mitosis inhibitor.
Applicant further argues that the adenoviruses of O'Shea are functionally different than the claimed adenovirus, and thus one of ordinary skill would not regard the teachings therein to be applicable to XVir-N-31. This is not persuasive because the cited combination as a whole renders the claimed combination obvious - Holm teaches combinations comprising XVir-N-31 and one or more cytostatics/cell cycle inhibitors, and O'Shea teaches that combinations comprising oncolytic adenoviruses and the cytostatic/cell cycle inhibitor palbociclib. Thus, it would have been obvious to combine XVir-N-31 and palbociclib with a reasonable expectation of success. Since Holm teaches that XVir-N-31 can be combined with any type of anticancer agent having a different mechanism of action, one of ordinary skill would have a reasonable expectation of success with any of a wide range of additional compounds (the combination of Holm does not require any specific functional interplay between XVir-N-31 and the additional agent).
Applicant further argues that O'Shea teaches palbociclib as one of a laundry list of potential additional agents without any specific guidance for selecting Palbociclib or any experimental evidence supporting such combinations. This is not persuasive because, while O'Shea mentions several broad categories of anticancer drugs, Palbociclib is specifically recited in a relatively short list of specific drugs useful in such combinations ("Chemotherapeutic agents, include, but are not limited to 5-fluorouracil; mitomycin C; methotrexate; hydroxyurea; cyclophosphamide; dacarbazine; mitoxantrone; anthracyclins (epirubicin and doxurubicin); antibodies to receptors, such as herceptin; etoposide; pregnasome; hormone therapies such as tamoxifen and anti-estrogens; interferons; aromatase inhibitors; progestational agents; and LHRH analogs Suitable CDK inhibitors for use in the provided methods include, but are not limited to, AG-024322, AT7519, AZD5438, flavopiridol, indisulam, P1446A-05, PD-0332991 [Palbociclib], and P276-00" (O'Shea, [0105])). Thus, one of ordinary skill reading O'Shea would not have needed to select Palbociclib from an unduly long or extensive list of potential agents (the above list includes only about two dozen specific agents). Moreover, there is no requirement that a prior art reference provide experimental evidence relating to any particular teaching.
Applicant further argues that Sathe teaches that the antitumor killing activity of palbociclib depends on a secondary agent (cisplatin), and does not suggest any combination with an adenovirus. This is not persuasive because Sathe is cited only for the teaching that Palbociclib is a cytostatic agent/cell cycle inhibitor, and thus falls within the class of agents that Holm teaches to be combined with XVir-N-31. Applicant further argues that Sathe teaches that the precise mechanism of action of palbociclib is unclear, but this is also not persuasive because Sathe teaches that Palbociclib is a cytostatic agent/cell cycle inhibitor and the precise mechanism by which such inhibition occurs is not relevant to the instant case of prima facie obviousness.
Applicant further argues that Holm teaches away from claim 16 by teaching combinations of XVir-N-31 with multiple additional agents. This is not persuasive because claim 16 uses a 'comprising' transitional phrase and is thus not limited to just XVir-N-31 and palbociclib (as evidenced by the fact that dependent claims 17 and 18 recite additional agents).
Applicant argues that Koll teaches that XVir-N31 has strong oncolytic activity by itself, and thus one of ordinary skill would not have been motivated to augment its activity via a combination and/or would have been taught away from doing so. This is not persuasive because Koll teaches only that XVir-N31 has "strong oncolytic activity in vitro". The teachings of Holm that XVir-N31 can be advantageously combined with additional agents would have led one of ordinary skill to pursue combinations of XVir-N31 with other known anticancer therapeutics such as Palbociclib. There is nothing in Koll that criticizes, discredits, or otherwise discourages combining XVir-N31 with additional therapeutic agents that would amount to teaching away from such combinations (see MPEP 2145).
Applicant further requests that the rejection for obviousness-type double patenting be held in abeyance. The rejection is thus maintained below.
Claim Rejections - 35 USC § 103
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 16, 21-23, 36 and 37 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of WO2012022496 to Holm in view of WO2014153204 to O’shea (cited in IDS of 13 Sept. 2022), as evidenced by Sathe et al., The Journal of urology 195.3 (2016): 771-779 (previously cited).
Holm teaches anticancer compositions comprising a YB-1-dependent oncolytic adenovirus and one or more additional active agents, wherein the adenovirus can be Ad-Delo3-RGD (i.e. XVir-N-31; see Published Spec. US20210038661, [0401]) and the additional anticancer agent can be, e.g. a cytostatic agent/cell cycle inhibitor (e.g., the CDK inhibitor CYC202) (entire doc, including p. 4, 3rd ¶ to p. 18, last ¶; p. 62, first full ¶ to p. 68, 2nd ¶; p. 78, last ¶ to p. 86, last ¶; Examples). The instant specification evidences that Xvir-N31 i) lacks expression of E1A13S; ii) is replication deficient in cells lacking YB-1 in the nucleus, but replication proficient in cells expressing YB-1; iii) lacks expression of E1B 19 kDa protein; and iv) expresses an RGD motif at a fibre (Published Spec. US20210038661, [0401], [0509]). Holm teaches that the anticancer efficacy of the oncolytic adenovirus can be enhanced by combining it with additional anticancer agents, and that it is preferable to combine with agents having different mechanisms/targets (p. 79, 1st full ¶ to p. 81, 4th ¶). Holm further teaches that the adenovirus and additional agent(s) can be combined in a single composition (p. 86, last ¶). Holm teaches that the compositions can be used to treat any type of cancer (p. 20, last ¶ to p. 28, 3rd ¶; Examples).
Claims 16, 21-23, 36 and 37 differ from Holm in that: the additional agent is a CDK4/6 inhibitor which is Palbociclib.
O’shea teaches compositions comprising oncolytic adenoviruses similar to that of Holm (designed for preferential replication in cancer cells) in combination with other anticancer therapeutics, which can include CDK inhibitors including Palbociclib (PD-0332991) in a single composition (p. 46, lines 6-20). The instant specification evidences that Palbociclib is an ATP-competitive CDK4/6 inhibitor (Published Spec. US20210038661, [0406]).
Sathe evidences that Palbociclib is a CDK4/6 inhibitor which has antitumor activity against a variety of cancer types and is FDA-approved for treating breast cancer (p. 772, 2nd full ¶). Palbociclib inhibits the G1-S phase transition (arresting cells in the G1 phase) and targets Rb (i.e. Palbociclib is a cytostatic agent/cell cycle inhibitor) (p. 772, 1st full ¶).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to prepare a composition comprising the oncolytic adenovirus Xvir-N-31 and an additional anticancer agent as taught by Holm wherein the anticancer agent is the CDK4/6 inhibitor Palbociclib as taught by O’Shea because it would have been obvious to combine prior art elements according to known methods to yield predictable results. One of ordinary skill would have been motivated to include Palbociclib in the Xvir-N-31 composition of Holm because Holm teaches that the efficacy of the oncolytic adenovirus can be advantageously enhanced by combination with other cytostatic anticancer agents having different targets/mechanisms of action, and Sathe evidences that Palbociclib is a cytostatic anticancer agent with a distinct target/mechanism from Xvir-N-31. Including Palbociclib in the Xvir-N-31 composition of Holm would have led to predictable results with a reasonable expectation of success because O’shea teaches that similar types of oncolytic adenoviruses can be combined with Palbociclib in anticancer compositions and Sathe evidences that Palbociclib has established anticancer effects and is FDA-approved for treating cancer. Moreover, Holm specifically recites another CDK inhibitor (the CDK2 inhibitor CY202) as an exemplary cytostatic agent for combination with the adenovirus (Holm, p. 78, last ¶).
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over the combination of Holm in view of O’shea, as applied to claims 16, 21-23, 36 and 37, further in view of Koll et al., European Urology Supplements 2.14 (2015): e32 and Rimar et al., Cancer 123.11 (2017): 1912-1924 (each previously cited).
Claim 17 differs from the combination of Holm in view of O’shea, as applied to claims 16, 21-23, 36 and 37, in that: the composition further comprises the PARP inhibitor Olaparib.
Koll teaches that YB-1 is overexpressed in a variety of cancers including bladder cancer (under INTRODUCTION & OBJECTIVES), and that the YB-1-dependent adenovirus Xvir-N-31 (as taught by Holm) efficiently replicates in and lyses a range of bladder cancer cell lines and causes immunogenic cell death (under MATERIALS & METHODS; RESULTS).
Rimar teaches that PARP inhibitors are anticancer agents which inhibit DNA repair enzymes that are necessary for cell function, and that PARP inhibitors are known to be more effective in cancer cells having mutations in certain genes involved in DNA repair processes that can help compensate for loss of PARP function (p. 1912-1916, under INTRODUCTION). Rimar further teaches that bladder cancer is associated with mutations in genes known to confer PARP inhibitor sensitivity (also commonly found in breast cancer), and that a preclinical study has shown a PARP inhibitor as effective against bladder cancer in combination with chemotherapy (p. 1919-1920, under Genetic Characterization of Bladder Cancer and DNA Damage Repair Deficiency; p. 1920, under PARP1 Inhibition in Bladder Cancer). Rimar further teaches that Olaparib is FDA-approved for the treatment of cancer (p. 1914, under PARPs: Early Clinical Results).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to use a composition comprising Xvir-N-31 and Palbociclib as taught by Holm in view of O’shea for treatment of cancer (e.g., bladder cancer) wherein the composition further includes the PARP inhibitor Olaparib as taught by Rimar because it would have been obvious to combine prior art elements according to known methods to yield predictable results. One of ordinary skill would have been motivated to include Olaparib in the composition of Holm in view of O’Shea because Holm teaches that the efficacy of the oncolytic adenovirus can be advantageously enhanced by combination with other cytostatic anticancer agents having different targets/mechanisms of action. Moreover, Koll teaches that Xvir-N31 has efficacy against bladder cancer, and Rimar teaches that PPAR inhibitors are likely to be effective against bladder cancer via a distinct DNA repair mechanism. Including Olaparib in the composition of Holm in view of O’shea would have led to predictable results with a reasonable expectation of success because Holm and O’Shea teach that oncolytic adenoviruses can be combined with a variety of anticancer agents and Rimar teaches that Olaparib is known FDA-approved anticancer agent.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over the combination of Holm in view of O’shea, as applied to claims 16, 21-23, 36 and 37, further in view of Koll et al., European Urology Supplements 2.14 (2015): e32 and Wu et al., Molecular cancer therapeutics 15.5 (2016): 1029-1042 (each previously cited).
Claim 18 differs from the combination of Holm in view of O’shea, as applied to claims 16, 21-23, 36 and 37, in that: the composition further comprises the bromodomain inhibitor JQ1.
Koll teaches that YB-1 is overexpressed in a variety of cancers including bladder cancer (under INTRODUCTION & OBJECTIVES), and that the YB-1-dependent adenovirus Xvir-N-31 (as taught by Holm) efficiently replicates in and lyses a range of bladder cancer cell lines and causes immunogenic cell death (under MATERIALS & METHODS; RESULTS).
Wu teaches that bromodomain proteins (including BRD4) are key transcriptional regulators that are overexpressed in bladder cancer tissues and that its inhibition using the bromodomain inhibitor JQ1 exerts a range of anticancer effects on bladder cancer in vitro and in vivo (under INTRODUCTION; RESULTS). Wu concludes that “JQ1 may be an innovative therapeutic approach for treatment of bladder cancer” and that “[w] Whether treatment with JQ1 combined with other chemotherapeutics simultaneously exert the synergistic effect in bladder cancer therapy needs to be answered in the future” (under DISCUSSION, 2nd full ¶).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to use a composition comprising Xvir-N-31 and Palbociclib as taught by Holm in view of O’shea for treatment of cancer (e.g., bladder cancer) wherein the composition further includes the bromodomain inhibitor JQ1 as taught by Wu because it would have been obvious to combine prior art elements according to known methods to yield predictable results. One of ordinary skill would have been motivated to include JQ1 in the composition of Holm in view of O’shea because Holm teaches that the efficacy of the oncolytic adenovirus can be advantageously enhanced by combination with other cytostatic anticancer agents having different targets/mechanisms of action. Moreover, Koll teaches that Xvir-N31 has efficacy against bladder cancer, and Wu teaches that JQ1 is effective against bladder cancer via a distinct transcriptional regulatory mechanism. Including JQ1 in the composition of Holm in view of O’shea would have led to predictable results with a reasonable expectation of success because Holm and O’Shea teach that oncolytic adenoviruses can be combined with a variety of anticancer agents and Wu teaches that JQ1 is effective against bladder cancer (the same type of cancer Koll teaches Xvir-N31 as being effective against) in vitro and in vivo.
While the instant specification has various results that could potentially amount to unexpected results sufficient to overcome the above prima facie case of obviousness, Applicant is reminded that Applicant bears the burden of producing objective evidence establishing that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance (MPEP 716.02(b)). Such evidence must be factually supported by an appropriate affidavit or declaration to be of probative value (MPEP 716.01 (a)). The arguments of counsel cannot take the place of evidence in the record (MPEP 716.01 (a)). Moreover, any unexpected results must be commensurate in scope with the claims the evidence is offered to support (MPEP 716.02(d)).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 16-18, 21-23, 36 and 37 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 4 and 19-37 of copending Application No. 17640720, in view of Rimar (in the case of claim 17) and Wu (in the case of claim 18). The claims of the ‘720 App teach a composition comprising XVir-N-31 and Palbociclib (‘720, claims 1 and 19). Thus, the ‘720 claims anticipate instant claims 16, 19-23 and 34-37. The claims of the ‘720 further teach that the composition includes an additional agent that can be a PARP inhibitor or a bromodomain inhibitor, and Rimar and Wu teach and make obvious the elected species of Olaparib and JQ1 in the context of the claimed composition (see 103 rejection, above).
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT J YAMASAKI whose telephone number is (571)270-5467. The examiner can normally be reached M-F 930-6 PST.
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/ROBERT J YAMASAKI/Primary Examiner, Art Unit 1657
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