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 . 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.
Information Disclosure Statement
The information disclosure statement filed 20 May, 2024 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. No documents were included with this statement, so citations to non-US patent literature documents were not considered.
Specification
The disclosure is objected to because of the following informalities: Applicants have stated that SEQ IDs 1 and 2 are human IL-13, but also mention an E13K mutation (note claims 26 and 27 and applicant’s elected species). However, neither of these sequences have a Glu at position 13.
Appropriate correction is required.
Election/Restrictions
Applicant’s election without traverse of IL-13 with an E13K mutation attached to Pseudomonas exotoxin A, gadolinium as the imaging component, and histology of the detection component in the reply filed on 20 July, 2026 is acknowledged.
The requirement is deemed proper and is therefore made FINAL.
Applicants elected IL13 with an E13K mutation attached to Pseudomonas exotoxin A, gadolinium as the imaging agent, and histology for detection. A search was conducted for this invention, and references rendering it obvious were found. As a result, claims 1, 2, 5, 6, 9-11, 15, 17, 19-24, 26, and 27 were examined and claims 25, 28, and 29 have been withdrawn from consideration. Applicants have stated that they believe claims 26 and 27 do not read on their elected species, but both of those claims discuss IL13 mutations that read on E13K, so it would not be proper to withdraw them.
During examination, references were found that anticipated or rendered obvious one or more non-elected species. These references are discussed below.
Claim Status
Claims 1, 2, 5, 6, 9-11, 15, 17, and 19-29 are pending.
Claims 27 and 28 have been amended.
Claims 25, 28, and 29 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 20 July, 2026.
Claim Rejections - 35 USC § 112(a)
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 22 and 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 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.
The MPEP states “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: 1) the breadth of the claims; 2) the nature of the invention; 3) the state of the prior art; 4) the level of one of ordinary skill; 5) the level of predictability in the art; 6) the amount of direction provided by the inventor; 7) the existence of working examples; and 8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure” (MPEP 2164.01(a).
1 and 2) the breadth of the claims and the nature of the invention: The rejected claims require a statistical analysis of the reduction of volume of a tumor (from claim 21) for a single patient (from claim 1, from which the rejected claims depend).
3) the state of the prior art: Statistics is defined (Merriam Webster online dictionary) as a branch of mathematics dealing with masses of numeric data.
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618
792
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A single data point is not masses of numeric data. The statistics how to web page (downloaded July, 2026) defines the standard deviation (used in both student T and ANOVA) as
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85
179
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. Note with one data point, n=1, and this calculation is meaningless.
4) the level of one of ordinary skill: The level of skill in the art is high.
5) the level of predictability in the art: This is mathematics, which is equations. This leads to a high level of predictability in the art.
6 and 7) the amount of direction provided by the inventor and the existence of working examples: Applicant’s disclosure just copies the language of the claims, but is vague on the number of subjects (note paragraphs 72, 103, and 104).
8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure: Applicants claims require a statistical analysis of a single data point. However, statistics is the analysis of large amounts of data, and the equations do not make sense with a single data point. Thus, it will take undue experimentation to use the invention as claimed.
Claim Rejections - 35 USC § 112(b)
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.
first rejection
Claim 17 is 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 17 requires an increase in survival of the patient compared to a control subject with malignant glioma that is not treated with cmIL13. There are two issues here. First, it is not clear what cmIL13 is; it is not mentioned in claim 1. This is a lack of antecedent support. Second is that the control subject is not defined sufficiently for this to be a reliable test. For example, there is no requirement that the control subject have a similar grade lesion, be treated identically other than the cmIL13, or even be the same species.
second rejection
Claims 19 and 20 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 19 and claims dependent on it discuss the effect on non-glioma cells and tissue, but these cells and tissues are not defined. If the claimed therapy had liver toxicity in a patient, but no toxicity to astrocytes (for example), it is not clear if the claim limitations have been met.
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.
Claim(s) 1, 2, 5, 6, 17, and 19-21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kioi et al (Technol. Canc. Res. Treatments (2006) 5(3) p239-250, cited by applicants) with evidentiary support from the Liv hospital web page on cintredekin besudotox (downloaded July, 2026).
Kioi et al discuss an IL-13 cytotoxin, which is a fusion protein of IL-13 and Pseudomonas exotoxin as a cytotoxic moiety (p241, 1st column, 2nd paragraph, continues to 2nd column, 1st paragraph). Note that, as evidenced by the Liv hospital web page, this is Pseudomonas exotoxin A (2nd page “payload”). In glioma cell lines, toxicity is mediated by the IL13Rα2 receptor, and is non-toxic to astrocytes (p241, 2nd column, 2nd paragraph, continues to p242, 1st column, 1st paragraph). A clinical trial of patients with malignant glioma using convection enhanced delivery with this compound is discussed (p243, 2nd column, 4th paragraph). The material was dosed via two catheters at 400 µL/h per catheter for 96 hrs (p243, 2nd column, 4th paragraph), anticipating claims 1, 5, and 6. Dosing was at 0.125, 0.25, 0.5, 1, 2, and 4 µg/mL (p244, 1st column, 1st paragraph), anticipating claim 2. While the reference does not directly discuss survival compared to a control, or effects on the tumor, this is the same therapeutic administered to the same patient population, so it will necessarily have the same effects, anticipating claims 17 and 19-21. In a different experiment MR imaging was conducted preoperatively and at regular intervals postinfusion to look at tumor changes (p244, 2nd column, 2nd paragraph).
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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
first rejection
Claim(s) 1, 2, 5, 6, 9, 17, and 19-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kioi et al (Technol. Canc. Res. Treatments (2006) 5(3) p239-250, cited by applicants) in view of Li et al (Sci. Rep. (2013) 3:1623).
Kioi et al discuss an IL-13 cytotoxin, which is a fusion protein of IL-13 and Pseudomonas exotoxin as a cytotoxic moiety (p241, 1st column, 2nd paragraph, continues to 2nd column, 1st paragraph). In glioma cell lines, toxicity is mediated by the IL13Rα2 receptor, and is non-toxic to astrocytes (p241, 2nd column, 2nd paragraph, continues to p242, 1st column, 1st paragraph). A clinical trial of patients with malignant glioma using convection enhanced delivery with this compound is discussed (p243, 2nd column, 4th paragraph). The material was dosed via two catheters at 400 µL/h per catheter for 96 hrs (p243, 2nd column, 4th paragraph). Dosing was at 0.125, 0.25, 0.5, 1, 2, and 4 µg/mL (p244, 1st column, 1st paragraph). While the reference does not directly discuss survival compared to a control, or effects on the tumor, this is the same therapeutic administered to the same patient population, so it will necessarily have the same effects. In a different experiment MR imaging was conducted preoperatively and at regular intervals postinfusion to look at tumor changes (p244, 2nd column, 2nd paragraph).
As noted above, this reference anticipates claims 1, 2, 5, 6, 17, and 19-21.
The difference between this reference and the remaining claim is that this reference does not discuss an imaging agent.
Li et al discuss a choline nanoprobe for glioma imaging via MRI (title). Gd chelate contrast enhanced MRI is the preferred choice for tumor localization, and has been approved for this purpose (p1, 3d paragraph). This reference teaches gadolinium chelates for MR imaging of gliomas.
Therefore, it would be obvious to image the gliomas of Kioi et al with Gd MRI imaging, to view the tumor and to monitor the efficacy of the therapy. As Kioi et al use MR imaging (with no mention of a contrast agent) for the same purpose, an artisan in this field would attempt this modification with a reasonable expectation of success.
second rejection
Claim(s) 1, 2, 5, 6, 10, 11, 15, 17, 19-21, 26, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Debinski et al (PloS one (2013) 8(10) e77719, cited by applicants) in view of Kioi et al (Technol. Canc. Res. Treatments (2006) 5(3) p239-250, cited by applicants).
Debinski et al discuss targeting IL13Rα2 receptor in human and canine brain tumors (title). This used an IL13 E13K fused to a Pseudomonas exotoxin A, which lacked the growth induction of tumor cells with this receptor of the native IL-13 (p8, 2nd column, 1st paragraph). Note this is identical to applicant’s elected therapeutic. These were successfully tested in cell lines (p8, 2nd column, 2nd paragraph, continues to p9, 1st column, 1st paragraph). Examination of a number of canine and human brain cancers showed high expression of the receptor in some tumors, but not all (p9, 2nd column, 2nd paragraph, continues to p10, 1st column, 1st paragraph). This was shown by western blots (p9, 2nd column, 1st paragraph) and histology (p10, 1st column, 2nd paragraph).
The difference between this reference and the examined claims is that this reference does not discuss administering the therapeutic to patients.
Kioi et al discuss an IL-13 cytotoxin, which is a fusion protein of IL-13 and Pseudomonas exotoxin as a cytotoxic moiety (p241, 1st column, 2nd paragraph, continues to 2nd column, 1st paragraph). In glioma cell lines, toxicity is mediated by the IL13Rα2 receptor, and is non-toxic to astrocytes (p241, 2nd column, 2nd paragraph, continues to p242, 1st column, 1st paragraph). A clinical trial of patients with malignant glioma using convection enhanced delivery with this compound is discussed (p243, 2nd column, 4th paragraph). The material was dosed via two catheters at 400 µL/h per catheter for 96 hrs (p243, 2nd column, 4th paragraph). Dosing was at 0.125, 0.25, 0.5, 1, 2, and 4 µg/mL (p244, 1st column, 1st paragraph). While the reference does not directly discuss survival compared to a control, or effects on the tumor, this is the same therapeutic administered to the same patient population, so it will necessarily have the same effects. In a different experiment MR imaging was conducted preoperatively and at regular intervals postinfusion to look at tumor changes (p244, 2nd column, 2nd paragraph).
Therefore, it would be obvious to administer the fusion protein of Debinski et al to the patients of Debinski et al, to treat their cancers. As Kioi et al describe experiments in humans with very similar compounds, an artisan in this field would attempt this therapy with a reasonable expectation of success.
Kioi et al describes IL13-Pseudomonas exotoxin A administered by CED for 96 hrs at 800 µL/hr, rendering obvious claims 1, 2, 5, and 6.
Debinski et al discuss histology of tumor samples for the IL13Rα2 receptor, which is the target of the constructs, rendering obvious claims 10, 11, and 15.
This is the same therapy for the same patients, so will necessarily have the same effects, rendering obvious claims 17 and 19-21.
The material of Debinski et al has an E13K mutation of the IL-13 moiety, rendering obvious claims 26 and 27.
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, 2, 5, 6, 10, 11, 17, 19-21, 24, 26, and 27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 15, 16, 18, 19, 24, 27, and 30 of copending Application No. 18/993,145 (US 20260021163) in view of Kioi et al (Technol. Canc. Res. Treatments (2006) 5(3) p239-250, cited by applicants).
Competing claim 1 describes a method of treating cancer, comprising administering a mutagenized IL 13 moiety. Competing claim 5 required convection enhanced delivery, while competing claim 15 requires 0.03-1 µg/mL of the material. Competing claim 16 specifies detection of the IL13Rα2 receptor as indicative of responsiveness to therapy. Competing claims 18 and 19 specify attachment of a toxin, specifically, a bacterial toxin. Competing claim 24 specifies that the IL13 mutant has one or more mutations selected from a group comprising E13K. Competing claim 27 specifies malignant glioma as the patient population, while competing claim 30 requires that the patient have increased survival compared to a control subject not so treated.
The difference between this reference and the examined claims is that this reference does not discuss some therapeutic parameters.
Kioi et al discuss an IL-13 cytotoxin, which is a fusion protein of IL-13 and Pseudomonas exotoxin as a cytotoxic moiety (p241, 1st column, 2nd paragraph, continues to 2nd column, 1st paragraph). In glioma cell lines, toxicity is mediated by the IL13Rα2 receptor, and is non-toxic to astrocytes (p241, 2nd column, 2nd paragraph, continues to p242, 1st column, 1st paragraph). A clinical trial of patients with malignant glioma using convection enhanced delivery with this compound is discussed (p243, 2nd column, 4th paragraph). The material was dosed via two catheters at 400 µL/h per catheter for 96 hrs (p243, 2nd column, 4th paragraph). Dosing was at 0.125, 0.25, 0.5, 1, 2, and 4 µg/mL (p244, 1st column, 1st paragraph). While the reference does not directly discuss survival compared to a control, or effects on the tumor, this is the same therapeutic administered to the same patient population, so it will necessarily have the same effects. In a different experiment MR imaging was conducted preoperatively and at regular intervals postinfusion to look at tumor changes (p244, 2nd column, 2nd paragraph).
Therefore, it would be obvious to use the dosing methodology of Kioi et al, as a substitution of one element (the unspecified dosing methodology of the competing claims) for another (the dosing methodology of Kioi et al) yielding expected results (treatment of tumor).
This is a provisional nonstatutory double patenting rejection.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658
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