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 .
Continued Examination Under 37 CFR 1.114
1. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 22, 2025 has been entered. Claims 1-8, 11-13, 16, 17, 25, 30, and 32 are now pending. Claim 11 is amended. Claims 5, 8, and 17 remain withdrawn as being draw to non-elected species. Claims 1-4, 6, 7, 11-13, 16, 25, 30, and 32 are being examined.
New Rejections
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
2. Claim(s) 1-4, 6, 7, 11-13, 16, 25, 30, and 32 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by ClinicalTrials.gov, NCT00805376, record history version 19, posted December 22, 2011; as evidenced by Lang et al (J Clinical Oncology, May 10, 2018, 36:1419-1427).
NCT00805376 teaches a method for treating a recurrent glioma or glioma that has failed one or more primary glioma therapies in a human patient comprising:
Identifying a patient having glioma (p. 10-11; p. 17, “Criteria”, “Inclusion Criteria” points 1-2); and
Contacting the glioma with oncolytic adenovirus DNX-2401 (Delta-24-RGD-4C) by intratumoral injection through a catheter into the brain tumor (p. 9-12; p. 15-16, “Arms and Interventions”),
wherein the oncolytic adenovirus is a Δ24 adenovirus characterized as having an E1A polypeptide that cannot bind Rb and comprises a fiber protein with an RGD amino acid sequence inserted into the H1 domain;
wherein the patient is identified as having glioma by tumor imaging with MRI, followed by a tumor biopsy; followed by intratumoral treatment with the adenovirus (p. 10-11; Groups A and B; p. 17, “Criteria”, “Inclusion Criteria” points 2 and 5);
wherein the glioma is resectable and is resected after treatment (Group B patients; p. 11-13; p. 17, point 4);
wherein the post-resection tumor bed is treated with the oncolytic adenovirus by injection through an implanted catheter (Group B patients; p. 13);
wherein the glioma includes glioblastoma (GBM), anaplastic glioma, astrocytoma (p. 17, “Criteria”, “Inclusion Criteria” point 1);
wherein the oncolytic adenovirus is administered stereotactically into more than one site in the glioma (p. 17, points 3 and 5);
wherein the patient failed one or more primary glioma therapies (p. 17, “Criteria”, “Inclusion Criteria” points 2, 7, 11).
With regard to the claimed results of the method, Lang provides evidence that these results are an inherent feature of the method of NCT00805376 (see p. 1419, far left column citing “Clinical trial information: NCT00805376”). Lang teaches in NCT00805376 Group A patients (n = 25), 20% of patients survived 3 years from treatment, and three patients had a ≥95% reduction in the enhancing tumor (12%), with all three of these dramatic responses resulting in > 3 years of progression-free survival from the time of treatment (abstract; p. 1422, col. 2; Figure 1). Treatment also resulted in necrosis (Figures 1-3; p. 1422, col. 2; p. 1423, col. 2; p. 1426, Discussion); and a Th1 response (abstract; p. 1423, col. 2 to p. 1423, col. 1; Figure 3; p. 1426, Discussion). Lang teaches treatment did not result in adverse events sufficient to cause termination of the treatment (p. 1420, Methods; Table 2; p. 1420, col. 1 to p. 1422, col. 1).
Therefore, Lang provides evidence that the method of NCT00805376 inherently results in:
greater than 25% reduction in tumor burden;
six-month progression-free survival;
tumor necrosis,
Th1 response; and
does not produce an adverse event resulting from said oncolytic adenovirus that is sufficient to cause termination of said treatment.
Lang further teaches (p. 1422, col. 2; Figure 1 D and 1E):
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Figure 1:
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Therefore, Lang provides evidence that the method of NCT00805376 inherently results in:
a clinical benefit in 30% of said patients, with clinical benefit defined by complete responders + partial responders plus stable disease;
a 25% six-month progression-free survival; and/or
a 12 month median survival for responders, with responders defined by complete responders + partial responders.
It is noted that NCT00805376 does not need to recognize or disclose the inherent feature of results or clinical endpoints from practicing the method at the relevant time to anticipate the claims. MPEP 2112, section II, states (bold emphasis added):
There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003) (rejecting the contention that inherent anticipation requires recognition by a person of ordinary skill in the art before the critical date and allowing expert testimony with respect to post-critical date clinical trials to show inherency); see also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004) ("[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention."); Abbott Labs v. Geneva Pharms., Inc., 182 F.3d 1315, 1319, 51 USPQ2d 1307, 1310 (Fed. Cir. 1999) ("If a product that is offered for sale inherently possesses each of the limitations of the claims, then the invention is on sale, whether or not the parties to the transaction recognize that the product possesses the claimed characteristics."); Atlas Powder Co. v. IRECO, Inc., 190 F.3d 1342, 1348-49, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999) ("Because ‘sufficient aeration’ was inherent in the prior art, it is irrelevant that the prior art did not recognize the key aspect of [the] invention.... An inherent structure, composition, or function is not necessarily known."); SmithKline Beecham Corp. v. Apotex Corp., 403 F.3d 1331, 1343-44, 74 USPQ2d 1398, 1406-07 (Fed. Cir. 2005) (holding that a prior art patent to an anhydrous form of a compound "inherently" anticipated the claimed hemihydrate form of the compound because practicing the process in the prior art to manufacture the anhydrous compound "inherently results in at least trace amounts of" the claimed hemihydrate even if the prior art did not discuss or recognize the hemihydrate); In re Omeprazole Patent Litigation, 483 F.3d 1364, 1373, 82 USPQ2d 1643, 1650 (Fed. Cir. 2007) (The court noted that although the inventors may not have recognized that a characteristic of the ingredients in the prior art method resulted in an in situ formation of a separating layer, the in situ formation was nevertheless inherent. "The record shows formation of the in situ separating layer in the prior art even though that process was not recognized at the time. The new realization alone does not render that necessary [sic] prior art patentable.").
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 §§ 706.02(l)(1) - 706.02(l)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
3. Claims 1-4, 6, 7, 11-13, 16, 25, 30, and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 9,061,055, in view of ClinicalTrials.gov, NCT00805376, record history version 19, posted December 22, 2011; US Patent Application Publication 2003/0138405, Fueyo et al, published 2003; Lamfers et al (Cancer Research, 2002, 62:5736-5742); Jiang et al (Curr. Gene Ther. 2009, 9:422-427).
Although the claims at issue are not identical, they are not patentably distinct from each other because the US Patent claims:
1. A method for treating a brain tumor in a patient comprising contacting the brain tumor with (i) an oncolytic adenovirus that encodes an E1A polypeptide with a deletion of amino acids corresponding to amino acids 122-129 (LeuThrCysHisGluAlaCysPhe SEQ ID NO:22) and (ii) temozolomide or CPT-11, in an amount sufficient to treat the brain tumor.
2. The method of claim 1, wherein contacting is by intracranial administration.
3. The method of claim 2, wherein intracranial administration is by perfusion.
4. The method of claim 2, wherein intracranial administration is by injection.
5. The method of claim 1, wherein the composition is directly injected into the tumor.
6. The method of claim 1, wherein a cell of the tumor is a metastasis.
7. The method of claim 6, wherein the metastasis is derived from a lung, breast, ovary, cervix, pancreas, stomach, colon, skin, larynx, bladder, or kidney cancer.
8. The method of claim 1, wherein the tumor is a neurocytoma, neutroblastoma, primitive.neuroectodermic tumor (PNET), medulloblastoma, glioma, sarcoma, astrocytoma, oligodendroglioma, anaplastic glioma, ependymonas, meningiomas, pineal region tumor, choroid plexus tumor, or neuroepithelial tumor.
9. The method of claim 8, wherein the tumor is a glioma.
10. The method of claim 1, wherein the adenovirus encodes a fiber protein comprising a RGD motif.
U.S. Patent No. 9,061,055 does not claim the glioma is recurrent and/or refractory to primary glioma therapies, the results of the treatment method, the glioma is GBM, is resectable, and is treated by catheter delivery before and after resection, or that the glioma exhibits Th1 response.
ClinicalTrials.gov NCT00805376 teach and anticipate the instant claims, as set forth above.
Fueyo et al teach a method of identifying a human patient having a glioma and contacting the glioma with an oncolytic Δ24-RGD adenovirus (an adenovirus having a 24 nucleotide deletion in the Rb binding domain region of the E1A gene and having an RGD insertion into the fiber knob to improve infection of primary glioma cells); wherein the tumor is identified by imaging, wherein a biopsy is obtained after glioma diagnosis ([14]; [173-178]; [237-241]; [314]); wherein the tumor is resectable and resected after treatment ([114]); wherein a post-resection tumor bed is treated with said oncolytic virus or the adenovirus is delivered by catheter (106]; [114]; [115]; [315]; Example 2); wherein the adenovirus is delivered intracranially and by intratumoral injection ([9]; [41]; [112-113]; [145]; [332]; [335]; [337]; Examples 2, 8, 9); wherein multiple injections are performed ([24]; [78]; [113]; [115]; [155]; [333]; [339]; Examples 8 and 9); wherein the glioma is glioblastoma ([8]; [15]; [93]; Example 18); wherein virus administration is via infusion by a needle over a period of over 10 minutes ([315, Example 2; [24]); wherein the virus is administered stereotactically into more than one site in the glioma patient ([87]; [107]; [335]; Example 9); wherein from about 105 to about 1012 viral particles are administered to the patient ([29]; [105]; [315]; Example 2; claims 45-47). Utilizing a human glioblastoma xenograft mouse model, Fueyo et al demonstrate successful reduction in tumors, including complete elimination of tumors in some mice which would be a greater than 25% reduction of tumor burden, as well as enhanced survival out to at least 140 or 170 days (5.5 months). Fueyo et al demonstrate successful tumor necrosis in vivo using the oncolytic virus (Figure 6; Example 9). Fueyo et al do not teach there were any adverse events resulting from the virus for mice treated and surviving 140 or 170 days and did not terminate treatment based on any adverse events, therefore it is reasonably expected there were no adverse events to cause termination of treatment.
Lamfers et al teach successful treatment of gliomas by administering Δ24-RGD adenovirus, and teach this virus is receiving widespread attention for the treatment of gliomas, particularly for treatment of glioblastomas refractory to current treatments (abstract). Lamfers demonstrate successful treatment of gliomas with Δ24-RGD adenovirus (Figure 3).
Jiang et al teach human patients with recurrent malignant gliomas are now being treated with Δ24-RGD, and this is based on success of treatment of xenografts in mice with the Δ24-RGD that resulted in extended survival time, wherein more than half of the mice survived more than 4 months, and treatment resulted in complete suppression of the tumors (section 4).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer Δ24-RGD adenovirus to recurrent and/or refractory gliomas including GBM in the claimed method of U.S. Patent No. 9,061,055 and result in greater than 25% reduction in tumor burden, six-month progression-free survival (PFS), greater than 25% six-month PFS for a population, tumor necrosis, and not produce an adverse event requiring termination of treatment. One would have been motivated to because ClinicalTrials.gov NCT00805376, Fueyo, Lamfers and Jiang specifically suggest and teach these types of gliomas are to be treated with the Δ24-RGD adenovirus. One of ordinary skill in the art would have a reasonable expectation of success to treat gliomas including recurrent and refractory glioblastomas and to result in greater than 25% reduction in tumor burden, six-month PFS, greater than 25% six-month PFS for a population, tumor necrosis, and without adverse events given Fueyo, Jiang, and Lamfers et al demonstrate successful reduction or eradication of glioma tumors through administration of the same claimed Δ24-RGD adenovirus, successful extension of survival tested out to 5.5 months, induction of tumor necrosis, and without adverse events sufficient to end treatment.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to further resect the tumor and treat the tumor bed by catheter delivery of oncolytic adenovirus in the method of the US Patent. One would have been motivated to and have a reasonable expectation of success to because: (1) ClinicalTrials.gov NCT00805376 recognizes glioma tumors can be resectable and accessible for surgery, and teaches treating the tumors in Group B patients with MRI image, tumor biopsy, adenovirus treatment, tumor resection, followed by treating the tumor bed with adenovirus; (2) Fueyo et al suggests further resecting the resectable tumor and treating the tumor bed by catheter delivery of oncolytic adenovirus; (3) Fueyo et al, Lamfers et al, and Jiang et al all demonstrate and/ or recognize the success of administering oncolytic adenovirus for the in vivo treatment of glioma.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for the glioma to exhibit Th1 response in the patented method. One would have been motivated to and have a reasonable expectation of success to because: (1) the US patent claims treatment of glioma patients and Waziri et al teach these patients commonly exhibit a Th1 response; and (2) the US patent claims treatment of glioma patients with oncolytic adenovirus and Endo et al teach that such treatment results in exhibition of a Th1 response.
4. Claims 1-4, 6, 7, 11-13, 16, 25, 30, and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 10,238,698, in view of ClinicalTrials.gov, NCT00805376, record history version 19, posted December 22, 2011; US Patent Application Publication 2003/0138405, Fueyo et al, published 2003; Lamfers et al (Cancer Research, 2002, 62:5736-5742); Jiang et al (Curr. Gene Ther. 2009, 9:422-427).
Although the claims at issue are not identical, they are not patentably distinct from each other because the US Patent claims:
1. A method for treating cancer in a patient having or suspected of having cancer comprising (a) administering a Delta-24 oncolytic adenovirus for a treatment period, (b) measuring the level of one or more Th1 biomarkers at a first time point and at a subsequent second time point, and (c) comparing the level of one or more Th1 biomarkers at the first time point and the second time point, wherein a decrease in one or more Th1 biomarkers at the second time point compared to the first time point indicates that the patient is non-responsive to treatment with the Delta-24 oncolytic adenovirus.
2. The method of claim 1, further comprising administering a Th1 stimulating agent to the patient with the Delta-24 oncolytic adenovirus if the patient is determined to be non-responsive.
3. The method of claim 1, wherein said Delta-24 oncolytic adenovirus is a Delta-24-RGD oncolytic adenovirus.
4. The method of claim 1, wherein the cancer is selected from the group consisting of primary brain cancer, metastatic brain cancer, lung cancer, breast cancer and prostate cancer.
5. The method of claim 4, wherein the cancer is low-grade or high-grade glioma.
6. The method of claim 5, wherein the cancer is high-grade glioma.
The U.S. Patent does not claim the glioma is recurrent and/or refractory to primary glioma therapies, the results of the treatment method, the glioma is GBM, is resectable, and is treated by catheter delivery before and after resection
ClinicalTrials.gov NCT00805376, Fueyo, Lamfers, and Jiang teach as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer Δ24-RGD adenovirus to recurrent and/or refractory gliomas including GBM in the claimed method of the U.S. Patent and result in greater than 25% reduction in tumor burden, six-month progression-free survival (PFS), greater than 25% six-month PFS for a population, tumor necrosis, and not produce an adverse event requiring termination of treatment. One would have been motivated to because ClinicalTrials.gov NCT00805376, Fueyo, Lamfers and Jiang specifically suggest and teach these types of gliomas are to be treated with the Δ24-RGD adenovirus. One of ordinary skill in the art would have a reasonable expectation of success to treat gliomas including recurrent and refractory glioblastomas and to result in greater than 25% reduction in tumor burden, six-month PFS, greater than 25% six-month PFS for a population, tumor necrosis, and without adverse events given Fueyo, Jiang, and Lamfers et al demonstrate successful reduction or eradication of glioma tumors through administration of the same claimed Δ24-RGD adenovirus, successful extension of survival tested out to 5.5 months, induction of tumor necrosis, and without adverse events sufficient to end treatment.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to further resect the tumor and treat the tumor bed by catheter delivery of oncolytic adenovirus in the method of the US Patent. One would have been motivated to and have a reasonable expectation of success to because: (1) ClinicalTrials.gov NCT00805376 recognizes glioma tumors treated encompass resectable tumors accessible for surgery, and teaches treating the tumors in Group B patients with MRI image, tumor biopsy, adenovirus treatment, tumor resection, followed by treating the tumor bed with adenovirus; (2) Fueyo et al suggests further resecting the resectable tumor and treating the tumor bed by catheter delivery of oncolytic adenovirus; (3) Fueyo et al, Lamfers et al, and Jiang et al all demonstrate and/ or recognize the success of administering oncolytic adenovirus for the in vivo treatment of glioma.
5. Claims 1-4, 6, 7, 11-13, 16, 25, 30, and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,065,285, in view of ClinicalTrials.gov, NCT00805376, record history version 19, posted December 22, 2011; US Patent Application Publication 2003/0138405, Fueyo et al, published 2003; Lamfers et al (Cancer Research, 2002, 62:5736-5742); Jiang et al (Curr. Gene Ther. 2009, 9:422-427).
Although the claims at issue are not identical, they are not patentably distinct from each other because the US Patent claims:
1. A method for treating a brain tumor in a patient having or suspected of having a primary or metastatic brain tumor comprising administering to said patient (a) an oncolytic virus selected from the group consisting of Delta-24 and Delta-24 RGD; and (b) a PD-1/PD-L1 receptor antagonist.
2. The method of claim 1, wherein said PD-1/PD-L1 receptor antagonist is selected from the group consisting of MDX-1106, MK-3475, AMP-224, Pidilizumab, and MDX-1105.
3. The method of claim 1, wherein the virus is administered intratumorally.
4. The method of claim 3, wherein the virus is administered intratumorally by injection into multiple tumor sites.
5. The method of claim 1, wherein the virus is administered intravascularly.
6. The method of claim 1, wherein said brain tumor is a glioma.
7. The method of claim 6, wherein the glioma is low-grade glioma.
8. The method of claim 6, wherein the glioma is high-grade glioma.
9. The method of claim 1, wherein the oncolytic virus is administered to the patient prior to the patient receiving a Th1 stimulating agent.
10. The method of claim 1, wherein the oncolytic virus is administered to the patient after the patient receives a Th1 stimulating agent.
11. The method of claim 1, where the brain tumor is primary brain tumor.
12. The method of claim 1, where the brain tumor is metastatic brain tumor.
13. The method of claim 1, wherein the virus is administered intravenously.
14. The method of claim 1, wherein the virus is administered intraarterially.
The U.S. Patent does not claim the glioma is recurrent and/or refractory to primary glioma therapies, the results of the treatment method, the glioma is GBM, is resectable, and is treated by catheter delivery before and after resection
ClinicalTrials.gov NCT00805376, Fueyo, Lamfers, and Jiang teach as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer Δ24-RGD adenovirus to recurrent and/or refractory gliomas including GBM in the claimed method of the U.S. Patent and result in greater than 25% reduction in tumor burden, six-month progression-free survival (PFS), greater than 25% six-month PFS for a population, tumor necrosis, and not produce an adverse event requiring termination of treatment. One would have been motivated to because ClinicalTrials.gov NCT00805376, Fueyo, Lamfers and Jiang specifically suggest and teach these types of gliomas are to be treated with the Δ24-RGD adenovirus. One of ordinary skill in the art would have a reasonable expectation of success to treat gliomas including recurrent and refractory glioblastomas and to result in greater than 25% reduction in tumor burden, six-month PFS, greater than 25% six-month PFS for a population, tumor necrosis, and without adverse events given Fueyo, Jiang, and Lamfers et al demonstrate successful reduction or eradication of glioma tumors through administration of the same claimed Δ24-RGD adenovirus, successful extension of survival tested out to 5.5 months, induction of tumor necrosis, and without adverse events sufficient to end treatment.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to further resect the tumor and treat the tumor bed by catheter delivery of oncolytic adenovirus in the method of the US Patent. One would have been motivated to and have a reasonable expectation of success to because: (1) the US Patent claims treating the tumor by intratumoral delivery of Delta-24 RGD virus; (2); ClinicalTrials.gov NCT00805376 recognizes glioma tumors treated encompass resectable tumors accessible for surgery, and teaches treating the tumors in Group B patients with MRI image, tumor biopsy, adenovirus treatment, tumor resection, followed by treating the tumor bed with adenovirus; (3) Fueyo et al suggests further resecting the resectable tumor and treating the tumor bed by catheter delivery of oncolytic adenovirus; (4) Fueyo et al, Lamfers et al, and Jiang et al all demonstrate and/ or recognize the success of administering oncolytic adenovirus for the in vivo treatment of glioma.
6. Claims 1-4, 6, 7, 11-13, 16, 25, 30, and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,090,344, in view of ClinicalTrials.gov, NCT00805376, record history version 19, posted December 22, 2011; US Patent Application Publication 2003/0138405, Fueyo et al, published 2003; Lamfers et al (Cancer Research, 2002, 62:5736-5742); Jiang et al (Curr. Gene Ther. 2009, 9:422-427).
Although the claims at issue are not identical, they are not patentably distinct from each other because the US Patent claims:
1. A method for treating and/or preventing a glioma in a mammal in need thereof, comprising administering to the mammal an effective amount of a combination comprising (a) a Delta24-RGD nucleic acid backbone, and a heterologous nucleic acid sequence encoding an OX40 agonist inserted in a nonessential region of the adenovirus genome, wherein the inserted heterologous nucleic acid sequence is under the control of a sequence permitting expression of the OX40 agonist and (b) one or more immune checkpoint inhibitors, wherein said one or more immune checkpoint inhibitor inhibits a checkpoint protein selected from the group consisting of PD-L1, programmed cell death protein 1 (PD-1), and PD-L2.
2. The replication competent oncolytic adenovirus of claim 1, wherein the OX40 agonist is an OX40 ligand polypeptide.
3. The method of claim 1, wherein the sequence permitting expression of the OX40 agonist is a CMV or RSV promoter.
4. The method of claim 1, wherein the adenovirus genome further comprises a heterologous nucleic acid sequence encoding a tumor antigen.
5. The method of claim 1, wherein the replication competent oncolytic adenovirus and the checkpoint inhibitor are administered simultaneously.
6. The method of claim 1, wherein the replication competent oncolytic adenovirus and the checkpoint inhibitor are administered sequentially and wherein a first administration of oncolytic adenovirus occurs prior to a first administration of checkpoint inhibitor and preferably occurs within 30 days of a first administration of checkpoint inhibitor.
7. The method of claim 1, wherein the checkpoint inhibitor is an antibody or fusion protein and is administered as one or more doses of 0.01-10 mg/kg, 0.1-10 mg/kg, 1-10 mg/kg, 2-8 mg/kg, 3-7 mg/kg, 4-5 mg/kg or at least 10 mg/kg.
8. The method of claim 1, wherein the adenovirus is administered intratumorally, intravascularly, intratumorally and intravascularly or in a neuronal or mesenchymal stem cell carrier.
9. The method of claim 1, wherein the adenovirus is administered once or multiple times at a dose of 108-1014 plaque forming units (pfu).
10. The method of claim 1, wherein the mammal is a human.
11. The method of claim 10, wherein the human has failed one or more treatments with an immune checkpoint inhibitor.
12. A method for treating and/or preventing cancer and/or treating and/or preventing a metastasis in a human subject in need thereof, comprising administering to the subject an effective amount of a replication competent oncolytic adenovirus according to claim 1, wherein the immune checkpoint inhibitor and optionally the immune cell co-stimulatory receptor agonist is expressed in a cancer cell of the subject.
13. The method according to claim 1 wherein said wherein said one or more immune checkpoint inhibitor inhibits PD-1.
14. The method according to claim 13, wherein said inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, and Pidilizumab.
It is noted that anti-PD-1 antibodies/inhibitors promote Th1 immune response.
The U.S. Patent does not claim the glioma is recurrent and/or refractory to primary glioma therapies, the results of the treatment method, the glioma is GBM, is resectable, and is treated by catheter delivery before and after resection
ClinicalTrials.gov NCT00805376, Fueyo, Lamfers, and Jiang teach as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer Δ24-RGD adenovirus to recurrent and/or refractory gliomas including GBM in the claimed method of the U.S. Patent and result in greater than 25% reduction in tumor burden, six-month progression-free survival (PFS), greater than 25% six-month PFS for a population, tumor necrosis, and not produce an adverse event requiring termination of treatment. One would have been motivated to because ClinicalTrials.gov NCT00805376, Fueyo, Lamfers and Jiang specifically suggest and teach these types of gliomas are to be treated with the Δ24-RGD adenovirus. One of ordinary skill in the art would have a reasonable expectation of success to treat gliomas including recurrent and refractory glioblastomas and to result in greater than 25% reduction in tumor burden, six-month PFS, greater than 25% six-month PFS for a population, tumor necrosis, and without adverse events given Fueyo, Jiang, and Lamfers et al demonstrate successful reduction or eradication of glioma tumors through administration of the same claimed Δ24-RGD adenovirus, successful extension of survival tested out to 5.5 months, induction of tumor necrosis, and without adverse events sufficient to end treatment.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to further resect the tumor and treat the tumor bed by catheter delivery of oncolytic adenovirus in the method of the US Patent. One would have been motivated to and have a reasonable expectation of success to because: (1) the US Patent claims treating the tumor by intratumoral delivery of oncolytic adenovirus Delta-24 RGD; (2); ClinicalTrials.gov NCT00805376 recognizes glioma tumors treated encompass resectable tumors accessible for surgery, and teaches treating the tumors in Group B patients with MRI image, tumor biopsy, adenovirus treatment, tumor resection, followed by treating the tumor bed with adenovirus; (3) Fueyo et al suggests further resecting the resectable tumor and treating the tumor bed by catheter delivery of oncolytic adenovirus; (4) Fueyo et al, Lamfers et al, and Jiang et al all demonstrate and/ or recognize the success of administering oncolytic adenovirus for the in vivo treatment of glioma.
7. Claims 1-4, 6, 7, 11-13, 16, 25, 30, and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of U.S. Patent No. 11,110,137, in view of ClinicalTrials.gov, NCT00805376, record history version 19, posted December 22, 2011; US Patent Application Publication 2003/0138405, Fueyo et al, published 2003; Lamfers et al (Cancer Research, 2002, 62:5736-5742); Jiang et al (Curr. Gene Ther. 2009, 9:422-427).
Although the claims at issue are not identical, they are not patentably distinct from each other because the US Patent claims:
1. A method of treating a subject having brain tumor comprising:
(a) administering an oncolytic adenovirus to said subject;
(b) administering an anti-PD-1 antibody to said subject; and
(c) assessing tumor response by measuring tumor size;
wherein the oncolytic adenovirus is an adenovirus serotype 5 strain, is selectively replication competent in cells defective in the Rb/p16 tumor suppressor pathway, contains a deletion of the 24 nucleotides encoding amino acids 122 to 129 of the adenoviral E1A protein, and/or contains an integrin binding RGD-4C motif; and
wherein the anti-PD-1 antibody is pembrolizumab administered at 200 mg per dose; and
wherein the tumor exhibits reduced growth, no growth, a 10% reduction in tumor mass, a 20% reduction in tumor mass, a 30% reduction in tumor mass, a 40% reduction in tumor mass, a 50% reduction in tumor mass, a 60% reduction in tumor mass, a 70% reduction in tumor mass, an 80% reduction in tumor mass, a 90% reduction in tumor mass, or a 100% reduction in tumor mass following initiation of treatment.
2. The method of claim 1, wherein the oncolytic adenovirus is DNX-2401.
3. The method of claim 1, wherein the oncolytic adenovirus is delivered intratumorally.
4. The method of claim 3, wherein the oncolytic adenovirus is delivered via cannula or needle.
5. The method of claim 1, wherein the oncolytic adenovirus is delivered at 5×108 viral particles per dose, 5×109 viral particles per dose, or 5×1010 viral particles per dose.
6. The method of claim 1, wherein the anti-PD1 antibody is delivered by intravenous infusion.
7. The method of claim 1, wherein the anti-PD1 antibody dose is administered over 30 minutes.
8. The method of claim 1, wherein a single dose of the oncolytic adenovirus is provided prior to three consecutive doses of the anti-PD1 antibody.
9. The method of claim 8, wherein the time between oncolytic adenovirus administration and the first administration of the anti-PD1 antibody is about 7-9 days.
10. The method of claim 8, wherein the time between sequential administrations of the anti-PD1 antibody is about three weeks.
11. The method of claim 1, further comprising administering to the subject one or more of a steroid, an anticonvulsant or an antibody that inhibits vascular endothelial growth factor A.
12. The method of claim 8, wherein treating further comprises additional administrations of the anti-PD1 antibody for up to 105 weeks or 24 months from the date of oncolytic adenovirus administration.
13. The method of claim 1, wherein said subject is further evaluated for one of more of overall survival, clinical benefit rate, Karnofsky performance status, neurologic status, cytokine levels, lymphocyte levels, or a biomarker.
14. The method of claim 13, wherein said biomarker is PD-1 level or PDL-1 level.
15. The method of claim 1, wherein tumor size is measured by MRI.
16. The method of claim 1, further comprising stereotactically-guided biopsy of the brain tumor.
17. The method of claim 1, wherein the brain tumor is glioblastoma multiforme.
18. The method of claim 1, wherein the brain tumor is gliosarcoma.
19. The method of claim 1, wherein the subject exhibits an overall survival of at least 9 months, 12 months, 15 months, 18 months, 24 months, 36 months or 48 months, any interval therebetween.
20. The method of claim 1, wherein the subject exhibits an increase in overall survival, as compared to an untreated control subject, of at least 6 months, 9 months, 12 months, 15 months, 18 months, 24 months, 36 months or 48 months, any interval therebetween.
21. The method of claim 1, wherein the tumor exhibits reduced growth or no growth following initiation of treatment.
22. The method of claim 1, wherein the Karnofsky performance status improves or remains unchanged following step (b).
23. The method of claim 1, wherein there is a statistically measurable clinical benefit.
24. The method of claim 1, wherein the subject exhibits recurrent or progressive brain tumor following previous treatment.
25. The method of claim 1, wherein the previous treatment was chemotherapy, radiotherapy, or antibody therapy.
26. The method of claim 1, wherein the subject is a human.
27. The method of claim 1, wherein the tumor exhibits a 10% reduction in tumor mass, a 20% reduction in tumor mass, a 30% reduction in tumor mass, a 40% reduction in tumor mass, a 50% reduction in tumor mass, a 60% reduction in tumor mass, a 70% reduction in tumor mass, an 80% reduction in tumor mass, a 90% reduction in tumor mass, or a 100% reduction in tumor mass following initiation of treatment.
28. The method of claim 1, wherein the tumor exhibits a 10% reduction in tumor mass following initiation of treatment.
29. The method of claim 1, wherein the tumor exhibits a 20% reduction in tumor mass following initiation of treatment.
30. The method of claim 1, wherein the tumor exhibits a 50% reduction in tumor mass following initiation of treatment.
31. The method of claim 1, wherein the tumor exhibits a 50%, 60%, 70%, 80% or 90% reduction in tumor mass following initiation of treatment.
It is noted that anti-PD-1 antibodies/inhibitors promote Th1 immune response.
The U.S. Patent does not claim the glioma or glioblastoma is recurrent and/or refractory to primary glioma therapies, does not result in adverse events sufficient to cause termination of treatment, or that the glioma is resectable, and is treated by catheter delivery before and after resection
ClinicalTrials.gov NCT00805376, Fueyo, Lamfers, and Jiang teach as set forth above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer DNX-2401 oncolytic adenovirus to recurrent and/or refractory gliomas in the claimed method of the U.S. Patent, and not produce an adverse event requiring termination of treatment. One would have been motivated to because ClinicalTrials.gov NCT00805376, Fueyo, Lamfers and Jiang specifically suggest and teach these types of gliomas are to be treated with the DNX-2401 or Δ24-RGD adenovirus. One of ordinary skill in the art would have a reasonable expectation of success to treat gliomas, including recurrent and refractory glioblastomas, and to result without adverse events sufficient to end therapy given Fueyo, Jiang, and Lamfers et al demonstrate successful reduction or eradication of glioma tumors through administration of the Δ24-RGD oncolytic adenovirus, successful extension of survival tested out to 5.5 months, induction of tumor necrosis, and without adverse events sufficient to end treatment.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to further resect the tumor and treat the tumor bed by catheter delivery of oncolytic adenovirus in the method of the US Patent. One would have been motivated to and have a reasonable expectation of success to because: (1) the US Patent claims treating the tumor by intratumoral delivery of oncolytic adenovirus DNX-2401; (2); ClinicalTrials.gov NCT00805376 recognizes glioma tumors treated encompass resectable tumors accessible for surgery, and teaches treating the tumors in Group B patients with MRI image, tumor biopsy, adenovirus treatment, tumor resection, followed by treating the tumor bed with DNX-2401 adenovirus; (3) Fueyo et al suggests further resecting the resectable tumor and treating the tumor bed by catheter delivery of oncolytic adenovirus; (4) Fueyo et al, Lamfers et al, and Jiang et al all demonstrate and/ or recognize the success of administering oncolytic adenovirus for the in vivo treatment of glioma.
8. Conclusion: No claim is allowed. The rejection of claims under 35 U.S.C. 102(a)(1) as being anticipated by ClinicalTrials.gov NCT01582516, Record History posted April 22, 2012, is withdrawn because it appears there were no publications on the results of this clinical trial to provide evidence of inherent results/features of practicing the method. Therefore, Examiner could not provide evidence of inherent features for the method of ClinicalTrials.gov NCT01582516. The rejection of claims under 35 USC 103 as being obvious over ClinicalTrials.gov NCT01582516 was withdrawn for similar reasoning and in view of ClinicalTrials.gov NCT00805376, now applied as prior art that has published results that serve as evidence of inherent features.
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/Laura B Goddard/Primary Examiner, Art Unit 1642