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 .
Response to Amendment
The rejections of claims 2 and 3 are moot in view of the cancellation of the claims.
The rejection of claim 9 under 35 U.S.C. 112(b) is withdrawn in view of the amendment to the claim indicating there is a “further therapy”.
The rejections of claims 1-4, 7 and 9 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as lacking enablement is withdrawn in view of the amendment specifying administration is in an individual that has neuroblastoma and further specifying the TNF inhibitors and cancellation of claims 2-3.
The rejections of claims 1-4, 7 and 9-11 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in view of the amendment to the claims removing the genus of inhibitors which are i) nucleic acids or nucleic acid derivatives, ii) small molecules or iii) immunotherapies, cell therapies and/or antibodies which do not directly bind and antagonize or neutralize TNFα, TNFR1 or TNFR2, and specifying the TNF inhibitors are direct TNFα or TNFR2 inhibitors and cancellation of claims 2-3. Note a new rejection appears below due to amendment of the claims.
The rejections of claims 1-5, 7 and 9-11 under 35 U.S.C. 102(a)(1) as being anticipated by Gesundheit et al., J. Clin. Oncol. 25(33): 5321-5124, 2007 (cited in the PTO-892 mailed 7/2/25) is withdrawn in view of the amendment specifying the TNF inhibitor directly binds TNFα or TNFR2 and cancellation of claims 2-3.
The rejections of claims 1-5, 7 and 9-11 under 35 U.S.C. 103 as being unpatentable over Brown 2008 (cited in the IDS filed 9/26/2022), Golliot et al. (Canc. Res., 52(11): 3194-200, 1992), US 20190255050 A1 (Habib, cited in the IDS filed 04/29/2024) in view of Cheung et al.(Nat. Rev. Cancer, 13:397-411, June 2013) is withdrawn in view of the amendment requiring treatment with CAR-T or CAR-NKT cells and cancellation of claims 2-3.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See paragraph [0155], line 4.
TITLE
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested: TREATING NEUROBLASTOMA BY TNFa SIGNALING TRIGGERING TUMOR-PROMOTING INFLAMMATION AND CAR-T CELLS
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 1 and 4-11 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims as amended are drawn to a method for treating neuroblastoma by administering to an individual with neuroblastoma one or more TNF inhibitors that directly bind TNFα or TNFR2, wherein the inhibitor is an immunotherapy, cell therapy or fusion protein., and chimeric antigen receptor- (CAR-) T or NKT cells. There are two issues related to lack of written description for the claims. One relates to cell therapy and the other to the genus of fusion proteins, in combination with the limitation that the inhibitor must directly bind TNFα or TNFR2 as the claim has been amended.
The specification does not teach any specific cell therapies and merely mentions CAR-T or CAR-NKT cells ([0176]). The prior art does not teach cell therapies that act as a TNF inhibitor and can be used to treat neuroblastoma. A simple definition of cell therapy consistent with the art is provided by Am. Soc. Gene + Cell Ther., Patient Ed., “What is Cell Therapy?” (https://patienteducation.asgct.org/understanding-cell-gene-therapy/what-is-cell-therapy, 06/15/2026) as, “Cell therapy is the transfer of a specific cell type(s) into a person to treat or prevent a disease.” Neither the specification nor prior art disclose a cell therapy that inhibits TNF activity and directly binds TNFα or TNFR2. A cell therapy as set forth in section (a) of claim 1 does not meet the requirements of written description under 35 USC 112(a).
Neither the specification nor the prior art teaches a TNF inhibitor which is a fusion protein that directly binds TNFα or TNFR2 other than a TNFR2-Fc fusion protein that binds TNFα (e.g., etanercept). No TNFα-Fc is disclosed in the specification or taught, nor would one skilled in the art expect such a fusion to be inhibitory. While an anti-TNFα antibody-drug conjugate (ADC) might be expected to function as a TNF inhibitor by killing TNFR2-expressing cells, no such ADCs are disclosed nor does the prior art teach the use of one for treatment of a cancer. Further, an anti-TNFα ADC could be considered an “immunotherapy” because the ADC construct by definition comprises an antibody.
A TNF inhibitor meeting the limitations of the claims and the written description provision of 35 USC 112(a) is an immunotherapy (see claim 5) or a fusion protein which is a TNFR2-Fc fusion protein (e.g., etanercept). However, the claims are directed to or encompass cell therapies and fusion proteins other than a TNFR2-Fc. None of these inhibitors meets the written description provision of 35 USC 112(a).
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
With the exception of the TNF inhibitors referred to above, the skilled artisan cannot envision the detailed chemical structure of the encompassed inhibitors; and, therefore, conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation of a TNF inhibitor. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
Additionally, claim 7 lists disparate routes of administration of the TNF inhibitor, including transdermally, intranasally, topically, orally, by inhalation or by a lavage. The inhibitor must reach the neuroblastoma cells in the brain or be able to sufficiently reduce TNFα activity in the brain. ClinicalTrial.gov ID NCT03294954 described in the previous Office action (p. 17) taught administration of CAR-NKT cells for treatment of neuroblastoma by infusion. Brown et al. (2008) also discussed in the previous Office action (p. 15), taught administration of anti-TNFα antibody infliximab by intravenous (IV) infusion. FDA prescribing information for etanercept (https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/103795s5582lbl.pdf, 08/2020) limits administration to injection (p. 1, right side, first section, including subcutaneously (SC), p. 25, middle, “Once Weekly Dosing”). FDA prescribing information for anti-TNFα antibody groliumuab (https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125433s024lbl.pdf, 02/2018) limits administration to intravenous injection (p. 1, second paragraph, and p. 28), These limited known routes of administration are in contrast to the laundry list of routes by which the antibody may be administered as set forth in claims (claim 7) and the specification (e.g., [0062]). The considerations for administration other than IV or SC are important and the specification does not support the genus of routes contemplated for either the TNF inhibitors encompassed or the chimeric antigen receptor cells of claim 1. Not only does the specification not support administration by other routes for the claimed method, the art does not either. For example, Pitiot et al. (Antibodies, 11(3):56, 2022) reviewed antibody literature published before April 1, 2022, to describe the state of the art of antibody (Ab) administration. While the advantages of and advancements related to subcutaneous (SC) administration of antibodies are discussed, it is also stated that bioavailability of SC delivered antibodies is difficult to predict. “Advances in preclinical models would be necessary to investigate the fate of Abs at the SC injection site and their diffusion into the blood/lymphatic compartment.... Nevertheless, as no in vitro model is yet accurate enough, the pharmacokinetics of Abs still relies on in vivo studies.... ⁋ Formulating Abs for the SC route remains challenging...” (p. 7/25, section 2.1.4) Note that etanercept is not an antibody but a protein-Fc region fusion protein. Pitiot et al. discusses (p. 7/25, section 2.2.1) that intramuscular (IM) injection is often used for vaccines but rarely considered for Abs. IM injection requires a more concentrated product than IV administration. While a small number of IM administered antibodies are in phase 3 clinical trials, none have yet been approved by the FDA and/or EMA (Table 3). As to pulmonary administration, it was determined (end of p. 12/25), “Abs administration through systemic routes led to a low bioavailability in the airway compartment [84,85]. This may limit the efficacy of Abs to treat respiratory diseases, if their target antigen primarily acts within the respiratory organ, while exposing the rest of the body to potential side effects [86].” Issues for antibody administration by inhalation include (p. 13/25, first paragraph), “Abs aerosolization is generally difficult since they are highly sensitive to mechanical, thermal, and physical stresses occurring during aerosol generation.” Also, only a single antibody is being developed for nasal inhalation and is not yet approved (p. 13/25, last sentence). The antibody and agents of the instant claims must treat a cancer in the brain. Also, oral administration of antibodies has challenges, including harsh pH conditions and presence of proteases, such that less than 20% of orally administered antibodies have been found to be immunologically active after passage through the gastrointestinal tract, requiring large amounts (p. 18/25, last paragraph, and p. 19/25, first paragraph). Topical administration of Abs has shown low skin penetration, thereby requiring a high dose. “Several strategies using cell-penetrating peptides, physical penetration enhancer, or injection with microneedles have been tested, but none of them has entered clinical trials.” (p. 19/25, last paragraph) It does not appear the inventor was in possession of the method as it currently encompasses a genus of administration routes which are not supported by the specification or art, other than the species of IV and/or SC administration. Note the instant specification has no in vivo working examples, with the exception of etanercept administration to mice by injection ([0138]). It reasonably appears in view of the art and highly limited instant disclosure that the inventors were in possession only of administration which is IV or SC for the immunotherapy and fusion protein and IV only for the CAR cells.
Therefore, only a TNF inhibitor that directly binds TNFα or TNFR2 and is an immunotherapy or is a fusion protein which is a TNFR2-Fc fusion protein, and which TNF inhibitor is administered IV or SC and wherein the CAR-T or CAR-NKT cells are administered IV, but not the full breadth of the claim meets the written description provision of 35 U.S.C. § 112(a). Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Allowable Subject Matter
Claims 25 and 26 are allowed.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 Claire Kaufman, whose telephone number is (571) 272-0873. Examiner Kaufman can generally be reached Monday through Friday 7am-3:30pm, Eastern Time.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa Ford, can be reached at (571) 272-0857.
Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600.
Official papers filed by fax should be directed to (571) 273-8300. NOTE: If applicant does submit a paper by fax, the original signed copy should be retained by the applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice .
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
June 23, 2026
Prosecution Insights