DETAILED ACTION
Election/Restrictions
Applicant’s election of species NY-ESO-1, filed August 17, 2026, is acknowledged.
Claims Summary
Claim 1 is directed to a method of treating pediatric brain tumors, specifically Diffuse Intrinsic Pontine Glioma (DIPG) (claim 2), comprising administering to a subject a replication competent oncolytic adenovirus. In claim 4, the subject has one or more of a:
H3.3 K27M mutation
H3.1 K27M mutation
H3.2 K27M mutation
Wild-type H3 mutation
The adenovirus comprises a deletion in part or all of an E1 gene region (claim 9), and an insertion of an integrin binding motif in an H1 loop of a fiber (claim 10), the insertion comprising CDCRGDCFC (SEQ ID NO: 2) (claim 11). The adenovirus is a human adenovirus type 5, or a hybrid comprising a human type 5 component (claim 12). The adenovirus is selected from Delta-24, Delta-24-RGD, DNX-2401 or DNX-2440 (claim 13). The adenovirus comprises one or more heterologous nucleic acid sequence encoding a tumor antigen that is expressed on a surface of an adenovirus-infected cell (claim 15), the tumor antigen being NY-ESO-1 or an immunogenic peptide thereof (claims 16 and 18, elected species), inserted into hyper-variable region 5 of a hexon gene of the adenovirus, or inserted into a HI loop region of a fiber gene of the adenovirus (claims 17 and 18).
The replication competent oncolytic adenovirus is administered systemically, local or region to a tumor, among other routes (claim 22). The tumor growth and/or tumor size is reduced in the treated tumor (claim 27).
The method further comprises:
Administering radiation therapy to the subject (claim 5)
No resection surgery on the subject (claim 6)
Utilization of a neuroventricular catheter to administer the adenovirus (claim 7), wherein the single or multiple administrations are at a dose of 108-1013 pfu
Administering a second anticancer therapy selected from chemotherapy, radiotherapy, immunotherapy, hormonal therapy or toxin therapy
Administering one or more Th1 stimulating agents selected from the list in claim 20
Claim Objections
Claims 2 and 24 are objected to because of the following informalities:
In claim 2, the word “Intrinsic” is misspelled.
In claim 24, Delta-24-RGD and DNX-2401 appear to be redundant because they appear to refer to the same virus. See paragraph [0220] of the published application US 2024/0216492.
Appropriate clarification and/or correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 2, 4-13, 15-20, 22 and 27 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation "said subject". There is insufficient antecedent basis for this limitation in the claim preamble. Claims 2, 4-13, 15-20, 22 and 27 are included in this rejection because they depend from claim 1.
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.
Claim 13 is 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 claim(s) contains 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.
It is apparent that the viruses Delta-24, Delta-24-RGD, DNX-2401 and DNX-2440 are required to practice the claimed invention because they are a necessary limitation for the success of the invention as stated in the claims. The names of the viruses indicate that they are specific viruses, not just terms that describe a generic adenovirus construct. The names of the viruses appear to be laboratory designations, thus the Office’s interpretation is that the viruses are particular viruses, not just terminology for generic virus constructs. The specification describes the viruses Delta-24 (which appears to be the same as DNX-2401) and Delta-24-RGD in terms of some of their structural features and patent publications and non-patent literature references that describe the viruses, but there is no indication that these are readily available to the public.
As required elements they must be known and readily available to the public or obtainable by a repeatable method set forth in the specification, or otherwise readily available to the public. If they are not so obtainable or available, the enablement requirements of 35 U.S.C. § 112, first paragraph, may be satisfied by a deposit of the viruses. See 37 CFR 1.802. One cannot practice the claimed invention without the viruses. Therefore, access is required to practice the invention. The specification does not provide a repeatable method for obtaining the viruses without access to them and they do not appear to be readily available material.
Deposit of viruses Delta-24, Delta-24-RGD, DNX-2401 and DNX-2440 in a recognized deposit facility would satisfy the enablement requirements of 35 U.S.C. 112, because the strains would be readily available to the public to practice the invention claimed, see 37 CFR 1.801- 37 CFR 1.809.
If a deposit is made under the terms of the Budapest Treaty, then an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature, stating that the deposit has been made under the terms of the Budapest Treaty and that all restrictions imposed by the depositor on the availability to the public of the deposited material will be irrevocably removed upon the granting of a patent, would satisfy the deposit requirements. See 37 CFR 1.808.
If a deposit is not made under the terms of the Budapest Treaty, then an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature, stating that the deposit has been made at an acceptable depository and that the following criteria have been met:
(a) during the pendency of this application, access to the invention will be afforded to one determined by the Commissioner to be entitled thereto;
(b) all restrictions imposed by the depositor on the availability to the public of the deposited material will be irrevocably removed upon granting of the patent;
(c) the deposit will be maintained for a term of at least thirty (30) years and at least five (5) years after the most recent request for the furnishing of a sample of the deposited material;
(d) a viability statement in accordance with the provisions of 37 CFR 1.807; and
(e) the deposit will be replaced should it become necessary due to inviability, contamination or loss of capability to function in the manner described in the specification.
In addition the identifying information set forth in 37 CFR 1.809(d) should be added to the specification. See 37 CFR 1.803 - 37 CFR 1.809 for additional explanation of these requirements.
Claims 1, 2, 4-13, 15-20, 22 and 27 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.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to 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 the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The breadth of the claims encompasses the treatment of pediatric brain tumors, encompassing DIPG, by administering a replication competent oncolytic adenovirus. In some embodiments, the adenovirus has a deletion in part or all of an E1 gene region, an insertion of an integrin binding motif in an H1 loop of a fiber, is a type 5 human adenovirus, or more specifically, is one of Delta-24, Delta-24-RGD, DNX-2401 and DNX-2440. The claims also encompass the administration of other therapies, such as radiation and Th1 stimulating agents.
The nature of the invention is the use of oncolytic adenoviruses to induce cell death in brain tumors, specifically pediatric brain tumors such as DIPG.
The specification teaches, as background information, that there are no effective treatments for DIPG, and surgical resection is not feasible due to its location and diffuse nature, with radiotherapy being the main palliative treatment (see paragraphs [0027], [0046] and [0047]). The exemplified virus is DNX-2401 which is administered to a subject, followed by radiation and chemotherapy (see prophetic Example 1). Other particular viruses mentioned in prophetic Example 1 are Delta-24, Delta-24-RGD and DNX-2440.
The art recognizes the potential of DNX-2401 in combination with radiation. Martinez-Velez et al. (Acta Neuropathologica Communications, published April 29, 2019, Vol. 7, Article Number 64, 12 pages) proposes a combination therapy for children with DIPG comprising administration of Delta-24-RGD (which appears to be DNX-2401) combined with radiotherapy (see abstract). Applicant’s own work confirms that DNX-2401 in combination with radiotherapy resulted in a reduction in or stabilization of tumor size in some pediatric patients with DIPG (see page 2471 of Gállego Pérez-Larraya et al. (N Engl J Med, 2022, 386:2471-2481)). Of a total of 12 patients that received DNX-2401, 11 received subsequent radiotherapy. During the follow-up period, nine patients had a reduction in tumor size, three had a partial response, and eight had stable disease (see Figure 2B). Gállego Pérez-Larraya et al. conclude that their study is valuable as a rationale for a larger clinical trial, however, the results are not conclusive as regards treatment (see page 2480, Discussion section).
In view of the breadth of the claims, the nature of the invention, the limited teachings in the specification, no working examples, the state of the art and unpredictability surrounding the treatment of DIPG, it would require undue experimentation to practice the claimed methods.
If Applicant were to resolve the enablement issue surrounding the availability of Delta-24-RGD and DNX-2401, and if the claims were amended to a method of intratumoral administration in combination with radiotherapy, instead of a method of treatment, then this rejection would be withdrawn.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure. Martinez-Velez et al. (Acta Neuropathologica Communications, published April 29, 2019, Vol. 7, Article Number 64, 12 pages, cited in the IDS filed 12/22/2023) proposes a combination therapy for children with DIPG comprising administration of Delta-24-RGD (which appears to be DNX-2401) combined with radiotherapy (see abstract). This reference is not applied as prior art because it is not enabling for the reason that the Delta-24-RGD virus does not appear to be readily available material (see enablement rejection above). MPEP 2121.02 states that the disclosure in an assertedly anticipating reference must provide an enabling disclosure of the desired subject matter; mere naming or description of the subject matter is insufficient, if it cannot be produced without undue experimentation. In this instance, the Delta-24-RGD virus cannot be produced without undue experimentation. Please note that should Applicant resolve the enablement issue concerning the availability of the Delta-24-RGD virus (and the others in claim 13), the Martinez-Velez et al. may be applied in a prior art rejection.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to Stacy B. Chen whose telephone number is 571-272-0896. The examiner can normally be reached on M-F (7:00-4:30). If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas Visone, can be reached on 571-270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
/STACY B CHEN/Primary Examiner, Art Unit 1672
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