CTNF 18/561,506 CTNF 98344 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Claim Status Claims 1-15 are pending and under examination. Nucleotide and/or Amino Acid Sequence Disclosures REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES Items 1) and 2) provide general guidance related to requirements for sequence disclosures. 37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted: In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying: the name of the ASCII text file; ii) the date of creation; and iii) the size of the ASCII text file in bytes; In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying: the name of the ASCII text file; the date of creation; and the size of the ASCII text file in bytes; In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended). When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824. If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical. If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical. Specific deficiencies and the required response to this Office Action are as follows: Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above. Required response – Applicant must provide: A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of: A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version); A copy of the amended specification without markings (clean version); and A statement that the substitute specification contains no new matter. Information Disclosure Statement 06-49-07 The information disclosure statement filed 11/16/2023 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. The information disclosure statement has been placed in the application file, but the information referred to as Non-Patent Literature Documents 2-5 have not been considered. Claim Objections Claim 1 is objected to for not defining the abbreviation “Fcab” at first mention. Claim 15 is objected to because of the following informality: “an effective amount of comprising at least one EGFR” should read --comprising an effective amount of at least one--. Appropriate correction is required. Claim Rejections - 35 USC § 112(b) 07-30-02 AIA 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. 07-34-01 Claim 14 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 14 is directed to a Markush grouping of alternatives which should be written as a closed grouping of alternatives with the format "a material selected from the group consisting of A, B, and C" (MPEP2173.05(h)). The “or” in line 4 should be corrected to –and--. Claim Rejections - 35 USC § 112(a) 07-30-01 AIA 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. 07-31-03 AIA Claim s 9-14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, because the specification, while being enabling for treating a cancer expressing EGFR in a subject by administration of the instant EGFR Fcab drug conjugate , does not reasonably provide enablement for : (1) treatment or prophylaxis of every physiological or pathophysiological state or (2) prophylaxis of any hyperproliferative disease or disorder . 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. The factors to be considered in determining whether a disclosure would require undue experimentation include: A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01. The breadth of the claims and the nature of the invention With respect to claim breadth, the standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. As such, the broadest reasonable interpretation of the claimed method is that: (1) prophylactic and therapeutic administration of the EGFR Fcab drug conjugate of the invention can prevent and treat any physiological or pathophysiological state and (2) prophylactic administration of the EGFR Fcab drug conjugate can treat or prevent any hyperproliferative disease or disorder. The state of the relevant art and level of predictability in the art Pertaining to EGFR-targeted therapies: The prior art teaches that EGFR is frequently amplified, overexpressed, and mutated in multiple cancers. In normal cell physiology, EGFR signaling controls cellular differentiation, proliferation, growth, and survival (Halder, Expert Opin Ther Targets. 2023 Apr-May;27(4-5):305-324, Abstract). Halder further teaches EGFR signaling participates in cell survival, proliferation, invasion, and metastasis in several cancers including lung cancer, head and neck cancer, glioma, colorectal cancer, breast cancer, ovarian cancer, pancreatic cancer and cholangiocarcinoma (Fig. 1). Uribe ( Cancers (Basel). 2021 Jun 1;13(11):2748) teaches the use of EGFR-targeting therapies including tyrosine kinase inhibitors and monoclonal antibodies (Pg. 6, Table 1). Pertaining specifically to EGFR-targeting immunoconjugates, Wong ( Oncotarget . 2018 Sep 11;9(71):33446-33458) teaches a low-affinity EGFR ADC comprising an anti-mitotic agent for treatment in a pancreatic cancer model, colorectal cancer model, and NSCLC model (Pg. 33447, Left column, Full paragraph 1, Lines 14-16 and Fig. 4). Hu ( Mol Oncol . 2019 Feb;13(2):246-263) teaches EGFR-targeting ADC, LR004-VC-MMAE for treatment of in preclinical models of esophageal squamous cell carcinoma (Fig. 5) and epidermoid carcinoma (Fig. 6). In all, the art teaches EGFR is overexpressed in many cancers and the art has provided enabling guidance in treating EGFR-expressing cancers with EGFR-targeted immunotherapy. Pertaining to prophylactic/preventative cancer treatment : The art does not provide compensatory teachings regarding the prophylactic treatment or prevention of cancer. Cancer has a wide variety of causes, from environmental and/or developmental exposure to ionizing radiation and/or chemical exposure in addition to some types viral and bacterial exposure (Lichtman MA et al. The Oncologist 2017 ; 22(5); 542–548). Even though cancer is characterized by the infinite cell proliferation, its pathogenesis is extremely complex and related to many mechanisms. In general, the hallmarks of cancer consist of ten biological capabilities during the development of cancers, namely sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, tumor-promoting inflammation, genome instability and mutation, evading immune destruction and reprogramming energy metabolism (Hanahan D et al. Cell 2011 144(5) p646-674, Figures 1 and 3). More than 100 types of cancer have been identified which are typically termed for the organs or tissues where they occur. Hanahan taught over the past decade, tumors have increasingly been recognized as organs whose complexity approaches and may even exceed that of normal healthy tissues (page 661, right column second to last paragraph). Hanahan taught many human tumors are histopathologically diverse, containing regions demarcated by various degrees of differentiation, proliferation, vascularity, inflammation, and/or invasiveness (page 662, left column, first paragraph). The art pertaining to the prevention of cancer focuses mostly on health promoting primary prevention methods that mitigate known risk factors through behavior modification such as reducing of tobacco usage, reducing exposure to occupational carcinogens and managing obesity (Vineis, P. Lancet . 2014 Feb 8;383(9916):549-57). There is no evidence of the use of prophylactic immunotherapy as described in the instant claims in undiagnosed individuals. Clinical trials aimed at proving preventative cancer activity attributable to a specific intervention are largely infeasible, due to the impossibly large number of subjects and an equally impossible long timeframe. Although cancer is a common disease, specific types of cancer are still relatively infrequent events in an otherwise healthy population. Therefore, trials with cancer incidence as endpoints would necessarily involve several thousands of subjects followed for several decades. Such logistic difficulties have precluded trials with cancer incidence prevention as an endpoint. The specification as filed does not provide enabling guidance that overcomes this unpredictability within the art. The amount of direction provided by the inventor and the existence of working examples What is enabled by the working examples is narrow in comparison to the breadth of the claims. The specification teaches that the Fcab-drug conjugates of the instant invention showed inhibitory activity against EGFR-expressing cell lines in an in vitro cell proliferation assay (Example 6, Pg. 71). This in vitro study does not provide enablement for: (1) prophylactic and therapeutic administration of the EGFR Fcab drug conjugate of the invention for preventing and treating any physiological or pathophysiological state and (2) prophylactic administration of the EGFR Fcab drug conjugate for preventing any hyperproliferative disease or disorder. The quantity of experimentation needed to make or use the invention The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. Given that the nature of the invention is in vivo prevention and treatment of disease, a person having ordinary skill in the art would have to perform multiple further in vivo experiments, in human clinical trials, or in animal models that are predictive of cancer prevention of the broadly recited diseases with a reasonable expectation of success. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the method with a reasonable expectation of successfully treating and preventing the disclosed diseases and conditions. In view of the lack of predictability of the art to which the invention pertains, the lack of guidance and direction provided by applicant, and the absence of appropriate working examples commensurate with the scope of the claims, undue experimentation would be required to use the claimed invention . Claim Rejections - 35 USC § 102 07-07-aia AIA 07-07 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 – 07-08-aia AIA (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. 07-12-aia AIA (a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention. 07-15 AIA Claim s 1-15 are rejected under 35 U.S.C. 102( a)(2) and (a)(1 ) as being anticipated by Tuna (US2019/0202920A1, published 07/04/2019, effectively filed 07/19/2016) . The disclosure of Tuna is directed to specific binding members which bind human EGFR, and comprises anEGFR antigen-binding site located in the CH3 domain of the specific binding member ([0002], Lines 1-6). Tuna discloses the “specific binding members” of the disclosure are antigen-binding Fc fragments or “Fcabs” (e.g. Fig. 1 and [0070]). Regarding claim 1 , pertaining to an EGFR Fcab-drug conjugate comprising the formula Fcab-(Linker) m -(Drug) n , wherein m is an integer from 1-5 and n is an integer from 1-10, Tuna discloses a specific binding member comprising an EGFR antigen-binding site located in the CH3 domain (Pg. 67, claim 1), wherein the specific binding member is conjugated to an immune system modulator, cytotoxic molecule, or radioisotope (Pg. 68, claim 39) and that the therapeutic agent is conjugated by means of a linker ([0116], Lines 1-3). The Fcab of Tuna comprises m=1 and n=1. Regarding claim 2 , wherein the EGFR Fcab is selected from the group consisting of Fcabs having the amino acid sequences as set forth in SEQ ID NOs: 1-6, Tuna discloses the Fcab of the disclosure “FS1-60” set forth in SEQ ID NO:6, identical to instant SEQ ID NO: 4. The alignment is shown below: PNG media_image1.png 828 646 media_image1.png Greyscale Regarding claim 3 , pertaining to an EGFR Fcab-label conjugate comprising the formula Fcab-(Linker) m -(Label) n , wherein m is an integer from 1-5 and n is an integer from 1-10, Tuna discloses a specific binding member comprising an EGFR antigen-binding site located in the CH3 domain (Pg. 67, claim 1), wherein the specific binding member is conjugated to a detectable label (Pg. 68, claim 39) and that the detectable label is conjugated by means of a linker ([0116], Lines 1-3). The Fcab of Tuna comprises m=1 and n=1. Regarding claims 4 and 5 , pertaining to a pharmaceutical preparation comprising at least one EGFR Fcab-drug conjugate according to claim 1 (claim 4) and wherein the pharmaceutical preparation further comprises excipients and or adjuvants (claim 5), Tuna discloses a pharmaceutical composition comprising a specific binding member and a pharmaceutically acceptable excipient (Pg. 68, Claim 46). Regarding claim 6 , pertaining to a pharmaceutical preparation comprising at least one EGFR Fcab-drug conjugate and at least one further medicament active compound, Tuna discloses at least two treatment modalities that meet this limitation: (1) combined administration of an anti-EGFR Fcab and anti-HGF antibody ficlatuzumab (“FI”), the combination treatment is identified as FI+FSI-60 (Fig. 11A) and (2) a bispecific construct comprising the anti-EGFR Fcab co-expressed with the binding region of ficlatuzumab, the combined treatment identified as FI/FS1-60 mAb 2 (Fig. 11A, Table 11, and Example 17, Pg. 20). Both of these treatment preparations read on the limitation of “at least one further medicament active compound” and were provided to mice in a pharmaceutical preparation on treatment days. Regarding claim 7, pertaining to a process for the preparation of a pharmaceutical preparation characterized in that an EGFR Fcab conjugate is brought into a suitable dosage from together with a solid liquid, or semi-liquid excipient or adjuvant, this limitation is intrinsically met by Tuna who discloses the mice dosages were administered at 60 mg/kg in a PBS vehicle ([0216], Lines 16-21), indicating a preparation brought into a suitable dosage in the PBS liquid. Regarding claim 8 , pertaining to a diagnostic composition comprising at least one EGFR Fcab-label conjugate according to claim 3, Tuna discloses covalently linking a diagnostic agent to the binding member of the disclosure ([0119], Lines 1-5) and a pharmaceutical composition comprising a specific binding member and a pharmaceutically acceptable excipient (Pg. 68, Claim 46). Regarding claims 9-12 , pertaining to a method for treatment of physiological and/or pathophysiological states (claim 9) or treatment of a hyperproliferative disease or disorder (claim 10) comprising administering to a subject in need thereof an effective amount of a least one EGFR Fcab-drug conjugate according to claim 1, and wherein the hyperproliferative disease or disorder is cancer (claim 11), the cancer is an EGFR-positive cancer (claim 12), Tuna discloses a method of treating cancer in a patient wherein cells of said cancer express EGFR, and wherein the method comprises administering to the patient a therapeutically effective amount of a specific binding member of the disclosure (Pg. 68, claim 52). Regarding claims 13-14 , and wherein the cancer is selected from the lists of claims 13 and 14, Tuna discloses the use of the treatment method for multiple cancers including breast cancer, gastric cancer, colorectal cancer, ovarian cancer and pancreatic cancer (Pg. 68, claim 53). Regarding claim 15 , pertaining to a set consisting of separate packs of an effective amount of at least of EGFR Fcab-drug conjugate according to claim 1, and an effective amount of a further medicament active compound, Tuna discloses dosing with combination therapy FI+FS1-60 and FI/FS1-60 twice weekly (regimen shown Fig. 11), which reads on the claim limitations because it requires a “set” of separate doses used for each treatment ([0216], Lines 1-15). Conclusion No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROL ANN CHASE whose telephone number is (571)270-0934. The examiner can normally be reached Monday-Friday 9:00am-6:00pm. 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. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached at 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. 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. /CAROL ANN CHASE/Examiner, Art Unit 1646 /HONG SANG/Primary Examiner, Art Unit 1646 Application/Control Number: 18/561,506 Page 2 Art Unit: 1646 Application/Control Number: 18/561,506 Page 3 Art Unit: 1646 Application/Control Number: 18/561,506 Page 4 Art Unit: 1646 Application/Control Number: 18/561,506 Page 5 Art Unit: 1646 Application/Control Number: 18/561,506 Page 6 Art Unit: 1646 Application/Control Number: 18/561,506 Page 7 Art Unit: 1646 Application/Control Number: 18/561,506 Page 8 Art Unit: 1646 Application/Control Number: 18/561,506 Page 9 Art Unit: 1646 Application/Control Number: 18/561,506 Page 10 Art Unit: 1646 Application/Control Number: 18/561,506 Page 11 Art Unit: 1646 Application/Control Number: 18/561,506 Page 12 Art Unit: 1646
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