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 .
Election/Restrictions
Applicant’s election without traverse of species, namely, low dose of the virus as a preconditioning agent, and intraventricular administration as the route of administration, in the reply filed on 06/29/2026 is acknowledged.
Claims 5-6, and 16-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/29/2026.
Therefore, claims 1-4,7-15 and 18-23 are under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application provisional application 63273577, filed on 10/29/2021 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) was filed before the mailing date of the non-final first action on the merits. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4,7-15 and 18-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This is because the specification, while being enabling for a limited number of the preconditioning agents, namely, a low dose of oncolytic HSV (G207), and polyinosinic-polycytidylic acid (poly(I:C)), does not reasonably provide enablement for any preconditioning agents. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention, if not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirement, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d at 737, 8 USPQ2d 1400, 1404 (Fed. Cir.1988)).
Furthermore, the USPTO does not have laboratory facilities to test if an invention with function as claimed when working examples are not disclosed in the specification, therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention, therefore skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
Nature of the invention and The breadth of the claim
Claim 1 is directed to a method of treating a central nervous system cancer comprising administering a preconditioning agent to a subject, followed by administering a therapeutic dose of an oncolytic virus wherein both administration are to the cerebrospinal fluid or periependymal region. The recited preconditioning agent is broadly claimed and encompasses any agent capable of performing the claimed preconditioning function. Thus, the claim encompasses a broad genus of preconditioning agents.
The level of one of ordinary skill in the art
The artisan of ordinary skill would be one having an advanced degree in neuroscience, molecular biology and/or significant experience in virology, and cancer therapeutics. One may also have experience in clinical trials, and at least have extended knowledge regarding assaying the effects of administering the preconditioning agents followed by a therapeutic dose of oncolytic virus to a subject.
The working examples and guidance provided
The specification provides enabling disclosure only for a limited number of the preconditioning agents. Specifically, the specification demonstrates preconditioning using a low dose of oncolytic HSV (G207), and polyinosinic-polycytidylic acid (poly(I:C)), and attributes its effect to induction of an interferon-mediated antiviral response but does not provide sufficient guidance demonstrating that other preconditioning agents encompassed by the claim will achieve the claimed therapeutic results. Nor does it disclose the criteria by which an ordinary skill in the art could identify, without undue experimentation, which additional preconditioning agents within the claimed genus would be suitable, or the appropriate dosing, timing, or route of administration for such agents.
State of the prior art
At the time of the filing, immunostimulatory agents and oncolytic viruses were known. However, the specification does not establish that it was well understood which preconditioning agents, if any, would reliably produce the claimed protective effect when administered into the cerebrospinal fluid or periependymal region prior to administration of the oncolytic virus. Furthermore, the art is considered unpredictable because biological responses to immunostimulatory agents and oncolytic viruses depend on the dosing, timing of administration, route of administration, and underlying disease. Consequently, results from one preconditioning agent cannot reasonably be extrapolated to all agents encompassed by the claims.
The amount of experimentation necessary
One skilled in the art before the effective filing date of the claimed invention would need to screen numerous candidate of preconditioning agents to determine whether each agent would provide the claimed protective effect when administered prior to an oncolytic virus, as well as determine appropriate dosage, timing, and administration conditions. It would have required undue experimentation for one with ordinary skill in the art before the effective filing date of the claimed invention to practice over the full scope of the invention claimed. In total, the scope of the claim is beyond what was known/expected based on the prior art, and taught in the instant specification.
Accordingly, the specification does not enable one of ordinary skill in the art to make and use the full scope of the claimed invention without undue experimentation.
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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-4,7-14 and 18-23 are rejected under 35 U.S.C. 103 as being unpatentable over Markert et al (Gene Therapy,2000), in view of Ochiai et al ( Cancer Therapy, 2006), and Pecora et al ( Journal of Clinical Oncology, 2002).
Regarding claims 1-2,4, 7, and 9-10, Markert et al teach the use of genetically engineered, conditionally replicating derivative of an oncolytic herpes simplex virus (HSV) mutant (G207) for the treatment of a central nervous system (CNS) cancer, namely, malignant glioma. Specifically, Markert et al teach administering a therapeutic dose of the oncolytic virus G207 directly into intracerebral tumors. Markert et al show that G207 demonstrates anti-tumor activity and can be safely inoculated into human brain tumors, thereby teaching oncolytic viral therapy for treatment of CNS malignances. ( See abstract).
However, Markert et al do not expressly teach administration of the oncolytic virus through cerebrospinal fluid (CSF) or periependymal region, nor does Markert expressly teach administering a preconditioning agent prior to administration of the therapeutic dose of the oncolytic virus.
Ochiai et al supplement Markert by teaching a method of treating a CNS malignancies using intrathecal delivery of an oncolytic recombinant poliovirus (PVS-RIPO). Specifically, Ochiai et al teach intrathecal administration of oncolytic virus for the treatment of glioblastoma multiforme neoplastic meningitis and show that regional intrathecal administration is an effective route for treating CNS tumors. It should be noted that the intrathecal route of administration involves administration into the cerebrospinal fluid (CSF). ( See abstract). Ochiai et al further state that “ Intrathecal delivery may be even more advantageous in the context of oncolytic virus therapy because it shields the virus from host immunity, allowing the virus to infect and spread more”. ( See the 1st pargraph od the Discussion on page 1352). Accordingly, it would have been prima facie obvious for one with ordinary skill in the art at the time the invention was filed to modify the method of Markert by administering the oncolytic virus through the CSF, as taught by Ochiai et al, because Ochiai et al teach that intrathecal delivery provides effective regional route for delivering oncolytic virus to CNS. Such modification merely substitutes one known route of administration for another known route for obtaining the predictable result of delivering the oncolytic virus to a CNS malignancy. In other words, instant claims are combining prior art elements according to known methods to yield predictable results.
It is submitted that neither Markert nor Ochiai et al expressly teach administering a preconditioning agent prior to administration of the therapeutic dose of the oncolytic virus.
Pecora et al supplement Markert and Ochiai by teaching administration of an oncolytic virus, namely, Newcastle disease virus (PV701) using a desensitization regimen comprising administration of an initial lower dose of the oncolytic virus followed by administration of subsequent higher therapeutic doses. Pecora et al further teach that the initial lower dose desensitizes the patient to toxicity associated with subsequent administrations, permitting administration of higher therapeutic doses while reducing the incidence and severity of adverse events. ( See abstract, and 1st column-1st paragraph-on page 2252). It should be noted that Applicant elected administering a low dose of oncolytic virus as a preconditioning agent, thereby Pecora et al teach the claimed preconditioning agent administration in the form of an initial low-dose administration of the same oncolytic virus prior to administration of subsequent therapeutic doses. Therefore, it would have been prima facie obvious to one with ordinary skill in the art at the time the invention was filed to further modify the combined teachings of Markert and Ochiai by administering an initial dose of the oncolytic virus of Markert prior to administration of the therapeutic dose, as taught by Pecora, in order to reduce toxicity, improve tolerability, and permit administration of therapeutically effective doses of oncolytic virus. Accordingly, the combined teachings of Marker, Ochiai and Pecora render obvious the method of instant claims.
Regarding claim 3, following the discussion of claim 1 above. Markert in view of Ochiai and Pecora render obvious the administration of initial low dose of the oncolytic virus as a preconditioning agent prior to administration of subsequent higher therapeutic dose. Pecora et al further teach that following administration of the initial dose, levels of type I interferon (IFN), IFN-γ, TNF-α, and IL-6 are elevated, with INF levels first detected approximately 6 hours after administration and peaking at approximately 6 hours, thereby demonstrating a transient INF response. Pecora also teach that the reduction in adverse events observed following the subsequent dose parallels the reduction in serum cytokine levels associated with the desensitization phenomena, thereby Pecora et al teach that the initial low dose of PV701 induces transient antiviral response and/or upregulate IFN response as recited in claim 3. ( See Pecora et al 2nd column on page 2263).
Regarding claim 8, following the discussion of claim 1, Pecora et al teach administering an initial low dose of the oncolytic virus PV701, followed by higher therapeutic dose of the same oncolytic virus. Specifically Pecora et al teach administration of 3*108 PFU followed by the subsequent administration of 1*1010 PFU. ( See Pecora et al 2nd column-2nd paragraph- on page 2263).
Regarding claim 11-13, following the discussion of claim 1 above, Markert et al disclose that G207 is a “ conditionally replicating derivative of herpes simplex virus (HSV) type-1 strain F engineered with deletions of both γ134.5 loci and a lacZ insertion disabling the UL39 gene”. ( See the abstract). It should be noted that UL39 gene encodes the HSV-1 ICP6 protein (the large subunit of viral ribonucleotide reductase). Thus, Markert et al teach that HSV-1 comprises both mutation of γ134.5 loci and the UL39 gene encoding the ICP6 protein. Moreover, Markert et al expressly states that the UL39 (ICP6) mutation comprises insertion of lacZ gene, thereby teaching the limitation of claim 13 that the mutation in the UL39 gene encoding the ICP6 protein comprises of the E.coli LacZ gene.
Regarding claim 18, following the discussion of claims 1 and 8, Pecora et al further teach repeated administration of the oncolytic virus PV701 following the initial low dose administration. Specifically, Pecora et al teach that the efficacy increased with repeat dosing and reports. (See section “Desensitizing regimen” on page 2253 of Pecora et al).
Regarding claim 19, Markert et al repeatedly performs serial MRI examination to evaluate tumor size and progression. For example, figure.1 plots MRI tumor volumes overtime, and the text discusses progression and regression. This constitutes screening/monitoring for tumor growth.
Regarding claims 20-21, Markert et al further teach that the method further comprises administering one or more therapeutic agents wherein the therapeutic agent is chemotherapy, as evidenced by the disclosure that patients received chemotherapy following G207 inoculation and tumor progression. ( See section “Progression and survival” on page 869).
Regarding claim 22, following the discussion of claim 1 above, Ochiai et al teach the intrathecal administration of the oncolytic virus for the treatment of glioblastoma multiforme neoplastic meningitis. It should be noted that neoplastic meningitis is synonymous with leptomeningeal disease, thus, Ochiai et al satisfy the limitation leptomeningeal disease limitation.
Regarding claim 23, recites a functional limitation, e.g. wherein the preconditioning agent protects ependymal cells, this functional limitation is considered to be met because it naturally flows from the combined teachings of the cited prior arts. In other words, the recited functional limitation is considered to be the natural result of administering the preconditioning agent taught by Pecora in the combined method of Markert and Ochiai. Therefore, this limitation does not patentably distinguish the claimed method.
Claim15 is rejected under 35 U.S.C. 103 as being unpatentable over Markert, Ochiai, and Pecora as applied to claims 1-4,7-14 and 18-23 above, and further in view of France et al ( Journal of General Virology, 2011).
Regarding claim 15, following the discussion of claim 1, Markert et al teach administering the oncolytic virus G207 for treating malignant glioma (i.e. CNS cancer), Ochiai et al supplement Markert et al by teaching the administration of an oncolytic virus into the cerebrospinal fluid by intrathecal administration for the treatment of glioblastoma multiforme neoplastic meningitis, thereby demonstrating the use of CSF delivery routes for treatment of CNS cancers. Pecora et al teach administration of a preconditioning agent in conjunction with oncolytic virus therapy. It is submitted that none of the cited prior arts teach an intraventricular route of administration.
France et al supplement the cited prior arts by teaching administering an oncolytic virus by intraventricular injection. Specifically, France et al teach injection into the lateral ventricle of the brain, and demonstrate that intraventricular administration is a feasible and well-tolerated route for the delivery of an oncolytic virus. France et al further evaluate the safety of the intraventricular administration by examining viral expression, ependymal cell integrity, and histopathological changes following intraventricular administration. ( See abstract).
Therefore, it would have been prima facie obvious to one with ordinary skill in the art at the time the invention was filed to modify the obvious oncolytic viral therapy and adopt the intraventricular route of delivery for step (a), step (b), or for both as taught by France et al because France et al demonstrate that intraventricular administration is a recognized, feasible, and safe route for delivering an oncolytic virus within the central nervous system. A Person of ordinary skill in the art would have a reasonable expectation of success that delivering an oncolytic virus via intraventricular route would have the predictable results of delivering the oncolytic virus into the cerebrospinal fluid for treatment of CNS malignancies.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FATIMAH KHALAF MATALKAH whose telephone number is (703)756-5652. The examiner can normally be reached Monday-Friday,7:30 am-4:30 pm EST.
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/FATIMAH KHALAF MATALKAH/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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