Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Election/Restrictions
2. Applicant’s election with traverse of Group III, claims 221-224, in the reply filed on 20 November 2025 is acknowledged. Applicant’s election with traverse of A6 comprising: (i) a heavy chain of SEQ ID NO:226 which comprises: a CDR1 of SEQ ID NO:132, a CDR2 of SEQ ID NO:133, a CDR3 of SEQ ID NO: 134; and (ii) a light chain of SEQ ID NO: 224 which comprises: a CDR1 of SEQ ID NO:135, a CDR2 of SEQ ID NO:136, a CDR3 of SEQ ID NO:137 as the species of FGFR4-binding protein is also acknowledged. Applicant’s arguments as they pertain to the restriction requirement and election of species are persuasive, and therefore the restriction requirement of 02 October 2025 is hereby withdrawn.
Status of Application, Amendments, and/or Claims
3. The Response filed on 20 November 2025 has been entered in full. Claims 215-234 have been cancelled, and claims 235-254 have been added. Therefore, claims 235-254 are pending and claims the subject of this Office Action.
Information Disclosure Statement
4. The information disclosure statements (IDS) submitted on 20 March 2023, 03 October 2023 and 25 September 2024 have been considered by the examiner.
Specification
Nucleotide and/or Amino Acid Sequence Disclosures
5. 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’s electronic filing system (see Section I.1 of the Legal Framework for EFS-Web or Patent Center (https://www.uspto.gov/patents-application- process/filing-online/legal-framework-efs-web), 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 EFS-Web or Patent Center 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 EFS-Web or Patent Center 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:
The file size is incorrect (See image below for correct file name and size).
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55
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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), with the file size in bytes;
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specifically, Applicant must provide:
a substitute specification which has the appropriate statement with the file name, file creation date and file size (in bytes).
Claim Rejections - 35 USC § 112
6. 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.
7. Claim 253 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.
8. Claim 253 recites the limitation "the CAR of claim 51". There is insufficient antecedent basis for this limitation in the claim. While claim 51 does recite a CAR, the claim is drawn to a cell which comprises a CAR.
Claim Rejections - 35 USC § 112, 1st Paragraph
9. 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.
10. Claims 235-254 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
11. The claims are drawn quite broadly to a chimeric antigen receptor (CAR) comprising: (a) an antigen binding region which specifically binds an IgIII membrane-proximal domain of a human fibroblast growth factor receptor 4 (FGFR4) protein, comprising: (i) a complementarity determining region 1 of a heavy chain variable region (H-CDR1) comprising the amino acid sequence set forth in SEQ ID NO: 132 with zero, one, two, or three amino acid additions, deletions, or substitutions, (ii) an H-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:133 with zero, one, two, or three amino acid additions, deletions, or substitutions, (iii) an H-CDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs:74, 98, 110, 134 and 146 with zero, one, two, or three amino acid additions, deletions, or substitutions, (iv) a complementarity determining region 1 of a light chain variable region (L-CDR1) comprising the amino acid sequence set forth in SEQ ID NO:135 with zero, one, two, or three amino acid additions, deletions, or substitutions, (v) an L-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:136 with zero, one, two, or three amino acid additions, deletions, or substitutions, (vi) an L-CDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs:77, 101 and 137 with zero, one, two, or three amino acid additions, deletions, or substitutions; (b) a transmembrane domain; and (c) an intracellular signaling domain. The claims also recite wherein: (i) the light chain variable region comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs:174,194 and 224; and (ii) the heavy chain variable region comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs:176, 196, 206, 226 and 236, or wherein the antigen binding region comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs:09-22. The claims also recite nucleic acids encoding said CAR, cells and compositions thereof comprising the CAR, and a method of treatment utilizing said cell. Thus the claims are drawn to a large genus of CARs comprising antigen binding regions that have additions, deletions or substitutions within the CDRs.
12. The specification discloses a number of FGFR4 binders that are defined by particular amino acid sequences for the heavy and light chain variable regions and CDRs (See Tables 3-5), as wells as the amino acid sequences for the CARs comprising said FGFR4 binders. For example a CAR comprising the FGFR4 binder A6 which comprises: (i) a heavy chain variable region of SEQ ID NO:226 which comprises: a CDR1 of SEQ ID NO:132, a CDR2 of SEQ ID NO:133, a CDR3 of SEQ ID NO: 134; and (ii) a light chain variable region of SEQ ID NO: 224 which comprises: a CDR1 of SEQ ID NO:135, a CDR2 of SEQ ID NO:136, a CDR3 of SEQ ID NO:137, is disclosed as binding to Rh30 cells (human alveolar rhabdomyosarcoma cell line known to express FGFR4), and was shown to demonstrate cytotoxic activity on said cells (See Example 4 and Example 6 at pp. 133-135). However, the specification does not provide sufficient written description as to the structural features of the claimed genus of FGFR4 binders or CARs comprising them that are encompassed by the claims which have variations within the CDRs, that have the same binding specificity and functional activity.
13. A "representative number of species" means that the species, which are adequately described, are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen [us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004)("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)(Claims directed to PTFE dental floss with a friction-enhancing coating were not supported by a disclosure of a microcrystalline wax coating where there was no evidence in the disclosure or anywhere else in the record showing applicant conveyed that any other coating was suitable for a PTFE dental floss.).
14. It is well known that minor structural differences even among structurally related compounds can result in substantially different biology, expression and activities. Based on the instant disclosure, one skilled in the art would not know which residues in the CDRs are critical for binding. In the instant case, there is insufficient guidance based on the reliance of disclosure FGFR4 binders having a heavy chain variable region comprising CDRs having an H-CDR1 of SEQ ID NO: 132, a H-CDR2 of SEQ ID NO: 133, and a H-CDR3 of SEQ ID NO: 74, 98, 110, 134 or 146, and a light chain variable region comprising CDRs having L-CDR1 of SEQ ID NO: 135, a L-CDR2 of SEQ ID NO: 136, and a L-CDR3 of SEQ ID NO: 77, SEQ ID NO: 101 or SEQ ID NO: 137, to direct a person of skill in the art to select or to predict particular residues within the CDRs as essential for binding FGFR4.
15. It is well established in the art that the amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff, et al. (PNAS, 1982. Vol. 79, page 1979). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. MacCallum, et al. (J. Mol. Biol., 262:732-745) analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right column) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left column). De Pascalis, et al. (Journal of Immunology, 2002. 169:3076-3084) demonstrate that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential for preserving the structural integrity of the antigen binding site (see page 3079, right column). Although abbreviated CDR residues were used in the constructs, some residues in all 6 CDRs were used for the constructs (see page 3080, left column).
16. The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site is underscored by Casset, et al. (Biochemical and Biophysical Research Communications, 2003. 307:198-205) which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (see entire document). Casset, et al. also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (page 199, left column) and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3 (see page 202, left column). Chen, et al. (Journal of Molecular Biology, 1999. 293:865-881) describe high affinity variant antibodies binding to VEGF wherein the results show that the antigen binding site is almost entirely composed of residues from heavy chain CDRs, CDR-H1, H2, H3 (page 866). Wu, et al. (Journal of Molecular Biology, 1999. 294:151-162) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left column) but certain residues have been identified as important for maintaining conformation.
17. In the absence of sufficient direction and guidance, the disclosure of a single species of antibody does not provide sufficient written description for the entire genus of immunoglobulin molecules encompassed by the claims in view of the evidence cited supra.
18. For inventions in an unpredictable art, adequate written description of a genus, which embraces widely variant species, cannot be achieved by disclosing only one or two species within the genus. See, e.g., Eli Lilly. Description of a representative number of species does not require the description to be of such specificity that it would provide individual support for each species that the genus embraces. If a representative number of adequately described species are not disclosed for a genus, the claim to that genus must be rejected as lacking adequate written description under 35 U.S.C. 112, first paragraph.
19. Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “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). As discussed above, the skilled artisan cannot envision the detailed structure of the encompassed genus of antibodies, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. 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. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
20. One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
21. Therefore, only CARs comprising FGFR4 binders having a heavy chain variable region comprising CDRs having an H-CDR1 of SEQ ID NO: 132, a H-CDR2 of SEQ ID NO: 133, and a H-CDR3 of SEQ ID NO: 74, 98, 110, 134 or 146, and a light chain variable region comprising CDRs having L-CDR1 of SEQ ID NO: 135, a L-CDR2 of SEQ ID NO: 136, and a L-CDR3 of SEQ ID NO: 77, SEQ ID NO: 101 or SEQ ID NO: 137, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph. 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).
Claim Rejections - 35 USC § 112 (Scope of Enablement)
22. 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.
23. Claim 254 is 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 methods of treating a cancer that expresses FGFR4, or inhibiting the growth of an FGFR4-expressing tumor in a patient in need thereof, does not reasonably provide enablement for methods of treating, inhibiting or ameliorating every type of cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
24. Factors to be considered in determining whether a disclosure enables one skilled in the art to make and use the claimed invention in its full scope without resorting to undue experimentation include: (1) the quantity of experimentation necessary; (2) the amount of direction or guidance presented; (3) the presence or absence of working examples; (4) the nature or complexity of the invention; (5) the state of the prior art; (6) the relative skill of those in the art; (7) the predictability or unpredictability of the art; and (8) the breadth of the claims. See In re Wands, 8 USPQ2d. 1400 (Fed. Cir. 1988).
25. In the instant case, the claims are broadly drawn to methods of treating, inhibiting or ameliorating cancer comprising administering an engineered cell comprising the claimed CAR. Thus the claims encompass complex and unpredictable subject matter, involving the effects of complex biological molecules on diseased physiological states. As was found in Ex parte Hitzeman, 9 USPQ2d 1821 (BPAI 1987), a single embodiment may provide broad enablement in cases involving predictable factors such as mechanical or electrical elements, but more will be required in cases that involve unpredictable factors such as most chemical reactions and physiological activity. This invention is in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology”, Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001). See also In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970); Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 927 F.2d 1200, 1212, 18 USPQ2d 1016, 1026 (Fed. Cir.), cert, denied, 502 U.S. 856 (1991).
26. The specification provides detailed guidance regarding a CAR comprising the FGFR4 binder A6, for example, which comprises: (i) a heavy chain variable region of SEQ ID NO:226 which comprises: a CDR1 of SEQ ID NO:132, a CDR2 of SEQ ID NO:133, a CDR3 of SEQ ID NO: 134; and (ii) a light chain variable region of SEQ ID NO: 224 which comprises: a CDR1 of SEQ ID NO:135, a CDR2 of SEQ ID NO:136, a CDR3 of SEQ ID NO:137, is disclosed as binding to Rh30 cells (human alveolar rhabdomyosarcoma cell line known to express FGFR4), and was shown to demonstrate cytotoxic activity on said cells (See Example 4 and Example 6 at pp. 133-135). However, the data presented in the Specification does not provide any guidance on the treatment of a cancer or tumor that does not express FGFR4. Therefore, while administration of an engineered cell comprising a CAR comprising the FGFR4 binder A6, for example, would be expected to treat cancers characterized by the expression of FGFR4, one skilled in the art would not predict that it would treat every type of cancer. There are no working examples provided in the instant application which demonstrate the treatment, inhibition or amelioration of a cancer that does not express FGFR4.
27. Thus, in view of the breadth of the claims, the lack of guidance, and the lack of working examples, the instant specification is not found to be enabling for a method of treating, inhibiting or ameliorating every type of cancer comprising administration of an engineered cell expressing the claimed CARs. It would require undue experimentation and making a substantial inventive contribution for the skilled artisan to discover how to make and/or use the claimed invention in its full scope.
Summary
28. No claim is allowed.
Advisory Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jon M. Lockard whose telephone number is (571) 272-2717. The examiner can normally be reached on Monday through Friday, 8:00 AM to 4:30 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached on (571) 272-2911. The fax number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JON M LOCKARD/Examiner, Art Unit 1647 January 8, 2026