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 .
Claims 1-3, 5-18 are pending in the application. Claims 8-15 are withdrawn. Claims 1-3, 5-7, 16-18 are currently under examination.
This office action is in response to the amendment filed on 4/27/2026.
All previous rejection not reiterated in this office action are withdrawn.
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.
Claim(s) 1-3, 5-7 and 16-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Durden, Martuza, Parson, and Kaur (US20100272686). This rejection is rewritten to address the amendment.
Durden teaches a nucleic acid encoding a PTEN (Col.13, lines 60-61, and 66, Col.14, lines 21-25). Durden teaches the nucleic acid encodes a PTEN from human origin (Col.14, lines 23-24). Durden teaches a variety of vectors may be used to deliver said PTEN nucleic acid to a target cell, wherein the vectors includes viruses such as SV40, vaccinia virus, herpes viruses HSV and EBV, retroviruses (col.23, liens 15-20). Durden also teach PTEN is a pivotal signaling molecule which modulates a wide variety of cellular processes, and mutations in PTEN have been associated with malignant progression of brain tumors (col.2, lines 26-29). Durden teaches delivering native PTEN encoding nucleic acid to cancer cells to treating cancer associated with PTEN mutation (col.2, lines 34-40). Durden demonstrates glioblastoma U87MG cells engineered to stably express PTEN sensitizes the cells to chemotherapeutic agents (example 5, lines 64).
However, Durden does not teach the PTEN gene is PTEN-long gene, and HSV lacks functional UL56 protein or neurovirulence factor gamma-34.5 expression, said recombinant oncolytic virus being HSVQ (claim 1) or HSV-P10 (16).
Parson teaches a PTEN-long, which is a differentially translated PTEN that contains a N-terminal signal peptide and secreted extracellularly (col.3, lines 23-26). Parson teaches expression vectors comprising nucleic acid encoding PTEN-long (col.4, lines 44-54). Parson teaches injection of PTEN-long to the mouse xenografts U87 model showed inhibition of angiogenesis compared to PTEN, suggesting PTEN-long affects the tumor environment (col.21, lines 20-26). Parson teaches PTEN-long is a novel antitumor compound that is normally present in human serum, which has anti-angiogenic and pro-apoptotic properties (col. 22, lines 49-51).
Martuza et al. teach cancer immunotherapy that comprises oncolytic virus compositions, wherein the preferred oncolytic virus comprises HSV1 that do not express functional ICP34.5, and/or other genes including UL56 (paragraph [0061], lines 1-4, and lines line 17). Martuza et al. teach said oHSV can include exogenous nucleic acid, serving as oncolytic virus vector, preferably encodes an anti-oncogenic or oncolytic gene product, and the gene product inhibits growth or replication of only the cell infected by virus (paragraph [0060]).
Kaur teaches generation of oncolytic virus capable of killing target cells, wherein the oncolytic virus is armed or encodes a therapeutic polypeptide (abstract). Kaur teaches using HSVQuick methodology to produce oncolytic virus expressing a heterologous polypeptide, wherein the entire HSV-1 genome lacking a functional ICP6 gene and deleted in both copies of the gamma 34.5 gene (paragraph [0107]). Kaur teaches such modifications allows the virus to replicate selectively in cancer cells (paragraph [0107]).
It would have been obvious to an ordinary skilled in the art that the PTEN variant, PTEN long has tumor suppressive action in a mouse model of glioblastoma based on the teaching from Parson. The ordinary skilled in the art reading Durden would be motivated to use PTEN-Long to further testing the specific form of PTEN’s ability to treat cancer because Parson teaches PTEN-long is an antitumor compound. It would have been obvious to an ordinary skilled in the art that the oncolytic vectors may be used to deliver PTEN long may be modified to knockout specific genes such as ICP34.5 and/or UL56 to target specific cancer based on combined teaching of Durden, Parson, Martuza and Kaur. The ordinary skilled in the art would be motivated to use the modified HSV-1 to deliver the PTEN-Long rendered obvious by Durden and Parson because Martuza specifically teaches oncolytic vector that encoding anti-oncogenic gene product that inhibits growth or replication of only the cell infected by virus (paragraph [0060]). Similarly, Kaur already demonstrates that HSVQ can target and replicate in tumor cells and expressing heterologous protein that is anti-tumorigenic, and have potent anti-tumor efficacy compared to the parent control oncolytic virus (paragraph [0119). The ordinary skilled in the art would thus be motivated to use said recombinant oncolytic HSVQ to express PTEN-Long. The specification teaches HSV-P10 is a HSV-1 with doubly deleted gamma 34.5 and insertional mutation in viral ICP6, including GFP and PTEN-Long expression vectors. As such, the resultant recombination HSV that comprises PTEN-Long and HSVQ meets the structural limitation of HSV-P10. Therefore, the claimed invention of claims 1 and 16 would have been prima facie obvious to an ordinary skilled in the art at the time of filing in view of combined teaching from Durden, Martuza, Parson and Kaur.
Regarding claim 2, Kaur teaches the recombinant HSVQ targets the glioma cells (paragraph [0118]).
Regarding claim 3, Martuza teaches the main transcriptional unit of an HSV may be placed under transcriptional control of tumor growth factor-beta promoter, because it is known that certain tumor cells overexpress TGF-beta, relative to non-tumor cells of the same type (paragraph [00063]), which meets the limitation of tumor specific promoter.
Regarding claim 5, it would have been obvious to an ordinary skilled in the art to use tissue specific promoter to direct the expression of PTEN-Long depending on the type of tissue the cancer cells originates from so that only PTEN-Long is expressed in said cancer cells.
Regarding claim 6, Durden teaches the expression of PTEN is under inducible promoter that respond to muristirone (col.6, lines 62-65).
Regarding claim 7, Durden discloses the U87MG cells are transfected with PTEN gene under constitutive or muristirone induced conditions (col. 40, lines 45-49), which meets the limitation of PTEN gene operably linked to constitutive or inducible promoter.
Regarding claims 17 and 18, the PTEN-L gene taught by Parson comprises nucleic acid sequence having 99.9% identical to SEQ ID NO: 1 (alignment provided in previous office action). Since the specification does not disclose any amino acid sequence that is encoded by SEQ ID NO:1, nor does the specification teach any modification to PTEN-L gene, the PTEN-L gene taught by Parson meets the claimed limitation of both claims.
Response to Arguments
Applicant argues that the oncolytic virus of claim 1 results in surprising and unexpected results which act in 3 major ways to elicit tumor cell killing: 1) the virus is able to selectively replicate in and destroy infected tumor cells; 2) HSV-P10 induces secretion of the tumor suppressor PTEN-Long, which can act to locally slow the growth of uninfected tumor cells and recruit the 5 innate immune system to the site of infection; 3) HSV-P10 acts as “cancer vaccine” that provoking an adaptive immune response against the tumor cells. Applicant asserts that these functional advantages are achieved by combining oncolytic viral replication and restoration of PTEN function within the infected cells, which are not achievable by either strategy alone. Applicant argues that the prior art fails to appreciate that restoring PTEN prior to oncolytic lysis fundamentally reprograms tumor cells to become more susceptible to immunogenic cell death and more effectively triggers anti-tumor immunity. Applicant alleges that combining a tumor suppressor gene with a lytic virus would inherently pose toxicity risks to normal cells. Applicant argues that the recombinant HSV, which selectively replicates and kills cancer cells, whereas normal cells inherently possess intact antiviral responses and functional PTEN that limit viral replication and expression of the PTEN gene. Applicant argues that experimental evidence from the instant application demonstrates that combining PTEN expression with oncolytic viral therapy yields unexpectedly superior anti-tumor activity compared to either modality alone. Applicant asserts that tumors treated with recombinant oncolytic virus with PTEN-long gene exhibited enhanced immunogenic cell death markers and improved immune infiltration, whereas surrounding tissue are spared due to selective viral replication and the physiological compatibility of PTEN restoration in non-malignant cells. Applicant cites Russell et al. for teaching the faster kinetics implied that cells infected with HSV-P10 would burst faster than control HSVQ-infected cells, and such teaching indicates the consequence of tumor cells were more sensitive to HSV-P10 induced killing at lower MOI than control infected cells. Applicant asserts that the presently claimed HSV-PTEN-long virus had an additional surprising result which is reduced PDL1 surface expression on cancer cells. Applicant argues that none of Durden, Parson, Martuza and Kaur cannot account for all the feature of the claims. Applicant argues that since Durden and Parsons are similarly useful in treating cancer, an ordinary skilled in the art would find no motivation to choose the vector-mediated expression of PTEN-Long versus purified recombinant PTEN-Long for the treatment of cancer. Applicant argues that Parson teaches PTEN-Long does not require an expression vector to be useful in treating cancer, thus an ordinary skilled in the art would not generate of a recombinant viral expression vector for simplicity, precise control of dosing and the ability to provide repeated systemic dosing. Applicant argues that the teaching from Parson suggests utilizing PTEN-Long to generate a viral therapy vector would forgo all of these advantages conferred by PTEN-Long as taught in Parson.
Applicant states that the claimed system uses G207 viral backbone, which is an F-strain HSV-1 doubly deleted for the neurovirulence factor 34.5 and viral ribonucleotide reductase ICP6, which conditionally replicates in tumor cells that are not neuronally derived, are deficient in protein kinase signaling and produce their own ribonucleotide reductase during division. Applicant further states that being an oncolytic virus means that virus is a recombinant virus that derives most of its therapeutic effect in cancer by preferentially replicating in and killing of cancer cells in vivo by this replication. Applicant argues that it is different from a mere viral gene transfer vector as those disclosed in Durden for expression of PTEN. Applicant argues that the oncolytic virus is not a lytic agent, but also has to determine whether the payload to be delivered by HSV would impair the ability of the oncolytic virus to infect and replicate in a subject. Applicant asserts that PTEN impacts antiviral immunity and inhibits viral replication citing Mateeva. Applicant repeats previous arguments that PTEN expression restored in cancer cells would work against oncolytic viral replication. Applicant argues that the prior art reference must be considered in its entirety and is improper to combine references where the references teaches away from their combination because scientific evidence against of the viral suppressive ability of PTEN, and the art teaches away from the combination of Durden, Parson, Martuza to arrive at the presently claimed invention.
Applicant argues that Martuza uses oHSV-infected tumor material as an antigen source for preparing a dendritic cell vaccine, but the current invention is not directed to a dendritic cell vaccine, but a recombinant virus that express PTEN-Long to tumor cells and produce therapeutic effects through mechanisms including reduction of Akt phosphorylation, reduction of PD-L1 expression, and increased immune cell infiltration. Applicant argues that Martuza does not teach expressing PTEN-Long, or suggesting a virus to reduce Akt phosphorylation or PD-L1 expression. Applicant argues that Martuza provides no teaching that an oHSV expressing PTEN-Long would produce functional PTEN-Long, retain suitable viral activity, downregulate Akt signaling, reduce PD-L1 mediated immune suppression, or increase antitumor immune infiltration.
The above arguments have been fully considered but deemed unpersuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As discussed in the previous rejection, the claimed invention of claim 1 is drawn to a recombinant oncolytic HSV comprising a HSV1 backbone and a gene encoding PTEN-Long. The structure limitation of said virus is that it lacks either functional UL56 protein, or neurovirulence factor gamma-34.5 expression. In latter case, the recombinant oncolytic virus is HSVQ. The recitation of “wherein the oncolytic virus infects and kills cancer cells preferentially” does not further limit the claimed recombinant virus to a particular structure, but is an inherent feature to all oncolytic virus, including HSV1 virus the recombinant virus that is derived from. The amended claim 1 is limiting the recombinant virus to HSVQ, which was taught by Kaur to be methodology to produce oncolytic virus expressing a heterologous polypeptide, wherein the entire HSV-1 genome lacking a functional ICP6 gene and deleted in both copies of the gamma 34.5 gene (paragraph [0107]). Kaur teaches such modifications allows the virus to replicate selectively in cancer cells (paragraph [0107]). Kaur teaches various embodiments that the oncolytic virus encodes a therapeutic polypeptide, wherein a recombinant oncolytic virus has been engineered that can specifically replicate in cancer cells leading to their destruction and at the same time secrete robust amounts of a therapeutic polypeptide (abstract). As such, the recombinant HSVQ taught by Kaur comprises all recited structural limitation besides PTEN-Long being the therapeutic polypeptide. Similarly, the oHSV taught by Martuza comprises all structural limitation of a HSV (lacks functional UL56 protein) besides PTEN-Long. As discussed in the previous rejection and above, Parson teaches PTEN-Long as a therapeutic agent for treating tumors. Contrary to Applicant’s assertion, Parson not only teaches treating PTEN-Long as polypeptide, but also treating solid tumor by administering to the subject an amount of expression vector which encodes human PTEN-Long in cells of solid tumor (col. 11, lines 9-17). Even if Parson demonstrates by example that PTEN-Long is provided to mouse with xenografted tumor in polypeptide form, treating tumor by using expression vector encoding PTEN-Long is not mutually exclusive. Kaur teaches angiogenesis is critical for the development and maintenance of glioblastomas, and combining oncolysis with anti-angiogenesis may produce a synergistic effect since the anti-cancer mechanisms are different but complimentary (paragraph [0051]). Kaur teaches a preferred embodiment allows an anti-angiogenic nucleic acid or polypeptide to be produced and delivered to the extracellular compartment (paragraph [0051]). Although Kaur gives an example of the anti-angiogenic compound being vasculostatin protein, the fact that PTEN-Long has anti-angiogenic and is a secreted protein (Parson col.20, lines 41-50, and lines 19-21), would motivate an ordinary skilled in the art to combine PTEN-Long with an oncolytic virus for delivering said transgene to tumor cells as taught by combined teaching from Parson and Kaur.
Regarding applicant’s argument directed to the entirety of the teaching from prior art, Applicant is reminded teaching from Matveeva was not part of the cited art that formulates the obviousness rejection. None of the cited reference, Durden, Parson, Martuza and Kaur, teaches against the combination of an oncolytic virus with heterologous PTEN-Long. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the advantage of combining a transgene that encodes an antiangiogenic and anti-antitumor polypeptide PTEN-Long is taught in cited prior art, because Kaur teaches angiogenesis is critical for the development and maintenance of glioblastomas, and combining oncolysis with anti-angiogenesis may produce a synergistic effect since the anti-cancer mechanisms are different but complimentary (paragraph [0051]).
In response to applicant's argument that the references fail to show some superior results of the invention, 1) the virus is able to selectively replicate in and destroy infected tumor cells; 2) HSV-P10 induces secretion of the tumor suppressor PTEN-Long, which can act to locally slow the growth of uninfected tumor cells and recruit the 5 innate immune system to the site of infection; 3) HSV-P10 acts as “cancer vaccine” that provoking an adaptive immune response against the tumor cells. It is noted that 1) is a feature inherent to oncolytic virus as demonstrated by Kaur and Mazuza, whereas 2) is also inherent to PTEN-Long because Parson has shown that it is a secreted polypeptide. Regarding 3), it is noted that the claimed invention is directed to a product, not a method of using the recombinant HSV as a “cancer vaccine.” As such, this feature (cancer vaccine) cannot be relied on because it is not part of the claim limitation.
Therefore, for reason discussed in the previous rejection and set forth above, this rejection is still considered proper and thus maintained.
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 1-3, 5-7, 16-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 16, 21-24, 35 and 36 of copending Application No. 18151,195, in view of Kaur.
Claims 16, 21-24, 35 and 36 of ‘195 application recites a recombinant HSV comprising an expression cassette encoding PTEN-Long, which overlaps in scope with the currently claimed HSV in claims 1-3, 5-7, 16-18 (target tumor cells, tissue specific, constitutive and inducible promoter), except that the HSV comprises HSV-1 backbone, HSVQ, HSV-P10.
Kaur teaches generation of oncolytic virus capable of killing target cells, wherein the oncolytic virus is armed or encodes a therapeutic polypeptide (abstract). Kaur teaches using HSVQuick methodology to produce oncolytic virus expressing a heterologous polypeptide, wherein the entire HSV-1 genome lacking a functional ICP6 gene and deleted in both copies of the gamma 34.5 gene (paragraph [0107]). Kaur teaches such modifications allows the virus to replicate selectively in cancer cells (paragraph [0107]).
It would have been obvious to an ordinary skilled in the art to use HSVQ as oncolytic virus to express PTEN-Long gene because Kaur already demonstrates that HSVQ (which comprises HSV-1 backbone) can target and replicate in tumor cells and expressing heterologous protein. The ordinary skilled in the art would thus be motivated to use said recombinant oncolytic HSV to express PTEN-Long. The specification teaches HSV-P10 is a HSV-1 with doubly deleted gamma 34.5 and insertional mutation in viral ICP6, including GFP and PTEN-Long expression vectors. As such, the resultant recombination HSV that comprises PTEN-Long and HSVQ meets the structural limitation of HSV-P10.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant states that claim 1 is amended and requests reconsideration of the provisional nonstatutory double patenting rejection.
This rejection is maintained for same reason discussed above because while the amendment adds the limitation of the recombinant oncolytic HSV is HSVQ, the teaching from Kaur and claims from ‘195 application renders them obvious (see rejection above).
Conclusion
THIS ACTION IS MADE FINAL. 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 CELINE X QIAN whose telephone number is (571)272-0777. The examiner can normally be reached M-F (8-4:00).
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/CELINE X QIAN/ Primary Examiner, Art Unit 1637
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