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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 6/27/2025 has been entered.
Applicant's arguments filed 6/27/2025 have been fully considered but they are not persuasive.
Claims 1-2 and 4 have been cancelled.
As stated in the final rejection mailed 1/6/2025, the rejection of claims 3 and 5-12 under 35 U.S.C. 103 as being unpatentable over Agus (U.S. Patent Application Publication 2006/0034840, of record) in view of Beidler et al. (U.S. Patent No. 8,613,921, of record), Kersten (U.S. Patent Application Publication 2015/0320861, of record), Martin et al. (2017, of record), Verma et al. (May 2020), and Roepstorff et al. (2009) was withdrawn in favor of the enablement rejection of record. While it is maintained that the prior art as whole suggests the claimed method for reasons of record, the clinical trial evidence documenting that the claimed method of treatment was ineffective as compared to placebo documents that the expectation of success provided by the prior art was incorrect. That is, it was surprising that administration of the claimed antibody didn’t work in treating chronic diabetic peripheral neuropathy pain to reduce pain. This art could be reapplied is the claims are amended and/or if additional evidence regarding operability of the method is made of record. No claim amendments were made in the 6/27/2026 response.
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 3 and 5-13 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.
Example 8 describes a randomized, placebo-controlled, phase 2 clinical trial to evaluate Antibody I for the treatment of diabetic peripheral neuropathic pain. It is prophetic and no results are provided.
The examiner previously made of record the 14 November 2023 results for NCT04476108. This clinical trial (Chronic Pain Master Protocol (CPMP): A study of LY3016859 in Participants with Diabetic Peripheral Neuropathic Pain) did not demonstrate statistically signific effects for administration of antibodies encompassed by the instant claims (LY3016859) when compared to a placebo. See outcome measurements on pages 7-14. See also Sloan-Lancaster et al. (January 2018, of record) for a description of LY3016859, particularly page 760, left column, second full paragraph, as a high-affinity humanized IgG4 monoclonal antibody that binds to the C-terminal regions of TGF-α and epiregulin, preventing their binding to the EGFR. “Engagement of the 2 targets by LY results in internalization of the transmembrane precursors and neutralization of the activity of the mature ligands in vitro.” See also page 2, lines 21-26, of the instant specification, with respect to Antibody I.
Moisset (2024) references the NCT04476108 clinical trial and further confirms that administration of LY3016859 (the antibody of the instant claims) provided negative results in treating diabetic neuropathic pain. Administration of the antibody failed to demonstrate superiority over placebo. See at least page 3, left column, second full paragraph. Baudaceau et al. (2024) is also cited to document that current and proposed treatments for diabetic neuropathic pain do not include antibodies against epiregulin and TGF-α. See at least abstract and section 7.3 (reviewing symptomatic treatment) starting at page 3.
The claimed methods to reduce neuropathic pain in subjects with chronic diabetic peripheral neuropathy pain are not enabled.
Applicant’s response references a post-filing date article by James et. al. (Clinical Pharmacokinetics (2025) 64:757-767). The abstract indicates that fepixnebart (LY3016859) is being developed as an analgesic to treat chronic pain and that the phase 2 dose regimen is adequate to test the analgesic effect of fepixnebart in patients with osteoarthritis, diabetic peripheral neuropathic pain (DPNP), and chronic low back pain (CLBP). Fepixnebart is a humanized immunoglobulin G4 monoclonal antibody with high binding affinity to epiregulin and TGF-α. Target engagement reflects the ability of the drug to interact with the intended biological target. The strong engagement in the “Key Points” on page 757 does not speak to therapeutic effectiveness. This paper indicates that Fepixnebart would be suitable to study but does not establish enablement of the claimed methods or that the proposed treatment is effective.
With regard to clinical trial NCT04476108, applicant notes that the primary endpoint was change from baseline in average pain intensity as measured by the Numeric Rating Scale (NRS) from baseline, up to Week 8, (outcome measure 1 at pages 6-7). Applicant argues that LY3016859 demonstrated 0.42 treatment difference of the primary endpoint at 8 weeks, and asserts that this difference yields a probability that LY3016859 is better than placebo of greater than 70%. This is not agreed with or persuasive. The treatment arm mean was -1.98 with a confidence interval of (-2.42 to -1.56) and the placebo arm mean was -1.56 with a confidence interval of (-2.17 to -0.96). The treatment arm and placebo arm mean values are not statistically significantly different.
Applicant also points to secondary endpoints in the clinical trial without providing any comment or discussion. This is not persuasive.
Change from baseline in the Brief Pain Inventory-Short Form (BPI-SF) (outcome measure 2 at page 7) was not statistically significantly different.
Total Interference Score, Change from baseline for Overall Improvement as Measured by Patient's Global Impression of Change (outcome measure 3 at page 8) was not statistically significantly different.
Change From Baseline for Worst Pain Intensity as Measured by NRS (outcome measure 4 at page 9) was not statistically significantly different.
Change From Baseline on the Visual Analog Scale (VAS) for Pain (outcome measure 5 at page 10) was not statistically significantly different.
Change From Baseline Assessment to Endpoint on the Sleep Scale From the Medical Outcomes Study (MOS Sleep Scale) (outcome measure 6 at page 11) was not statistically significantly different. Furthermore, this sleep scale does not speak to reducing chronic diabetic peripheral neuropathy pain.
Total Amount of Rescue Medication Use as Measured by Average Dosage Per Week (outcome measure 7 at page 12) was not statistically significantly different.
Change From Baseline on the EuroQol-5D 5 Level Questionnaire (EQ-5D-5L) (United States) (outcome measure 8 at page 13) was not statistically significantly different. Furthermore, this quality of life scale does not speak to reducing chronic diabetic peripheral neuropathy pain.
Applicant’s arguments do not point to evidence that administration of the claimed antibody reduced chronic diabetic peripheral neuropathy pain in subjects in need thereof.
It is noted that instant claims 3, 5-9, and 11-13 are not limited to Fepixnebart. See page 16 for antibody I. Only claim 12 is limited to the dosages in NCT04476108. The clinical trial document does not indicate that the subjects were refractory to two or more prior monotherapy and/or dual therapy treatment regimens as in claim 13.
The art made of record and not relied upon is considered pertinent to applicant's disclosure.
Newton et al. (Blood, https://doi.org/10.1182/blood.2025029836, published online 17 September 2025) states that four phase 2 clinical trials of fepixnebart/LY3016859 to treat chronic pain were ineffective (citing Sloan-Lancaster et al., of record). See lines 300-304 on page 11.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE P ALLEN whose telephone number is (571)272-0712. The examiner can normally be reached 7:00-3:30 EST Monday-Friday.
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/Marianne P Allen/Primary Examiner, Art Unit 1647
mpa