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 .
Status of Application, Amendments and/or Claims
The amendment of 21 November 2025 has been entered in full. Claims 1, 4, 8, 11, 13, 14, 16, and 21 are amended. Claims 2, 3, 5-7, 9, 10, 12, 15, 17, 18, 24, and 30-37 are cancelled.
Claims 16, 19-23, 25-29, 38, and 39 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03 July 2025.
Claims 1, 4, 8, 11, 13, and 14 are under consideration in the instant application.
Withdrawn Objections and/or Rejections
1. The Sequence Listing Requirement deficiency set forth at pages 3-4 of the previous Office Action of 22 August 2025 is withdrawn in view of Applicant’s amendment to the instant specification (21 November 2025).
2. The objections to the specification as set forth at page 5 of the previous Office Action of 22 August 2025 are withdrawn in view of the amended specification (21 November 2025).
3. The objections of claims 8 and 13 as set forth at page 5 of the previous Office Action of 22 August 2025 are withdrawn in view of the amended claims (21 November 2025).
4. The rejections of claims 4 and 11 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph as set forth at page 6 of the previous Office Action of 22 August 2025 are withdrawn in view of the amended claims (21 November 2025).
5. The rejection of claim 13 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112 (pre-AIA ), 4th paragraph as set forth at pages 6-9 of the previous Office Action of 22 August 2025 is withdrawn in view of the amended claim and Applicant’s persuasive argument (21 November 2025).
6. The rejection of claim 13 under 35 U.S.C. 102(a)(1) as being anticipated by Wang et al. (US 2018/0208671; 26 July 2018) as set forth at pages 16-18 of the previous Office Action of 22 August 2025 is withdrawn in view of the amended claim (21 November 2025).
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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.
7. Claims 1, 4, 8, 11, 13, and 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 a polypeptide comprising
(i) an extracellular domain comprising the amino acid sequence of SEQ ID NO: 9;
(ii) a transmembrane domain,
(iii) a hinge or stalk region, wherein the hinge or stalk region is a linker, a human immunoglobulin (Ig) hinge; or a CD8a hinge, and
(iv) an intracellular signaling domain,
does not reasonably provide enablement for a polypeptide comprising:
(i) an extracellular domain comprising an amino acid sequence having at least 70% identity to SEQ ID NO: 9;
(ii) a transmembrane domain; and
(iii) an intracellular signaling domain,
wherein the polypeptide does not comprise a CD27 stalk or hinge domain.
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 use the invention commensurate in scope with these claims. The basis for this rejection is set forth at pages 9-16 of the previous Office Action of 22 August 2025.
(i) At the middle of page 9 of the Response of 21 November 2025, Applicant argues that amended claim 1 does not require any function of the claimed polynucleotide [polypeptide] and it is improper to import claim limitations (e.g. functional limitations) from the specification into the claims, so polypeptide function should not be considered when determining enablement (citing MPEP 2111.01(II)). Applicant asserts that the skilled person would readily know how to make and use the polypeptide of the amended claims. Applicant states that, for example, the skilled person would have been able to identify any peptide having at least 70% identity to SEQ ID NO: 9 (using computer sequence alignment algorithms). Applicant also contends that the skilled person could have been able to generate a polynucleotide encoding a polypeptide, as claimed, that comprises a peptide having at least 70% sequence identity to SEQ ID NO: 9 using known molecule biology techniques. At the top of page 10 of the Response, Applicant submits that the skilled person also would have been able make a polypeptide with an extracellular domain having at least 70% identity to SEQ ID NO: 9, a transmembrane domain, and an intracellular signaling domain that does not have a CD27 hinge or transmembrane domain. Applicant argues that this could have been accomplished as described above and by simply not including a CD27 hinge or transmembrane domain in the polypeptide (e.g., not including nucleotides encoding a CD27 hinge or transmembrane domain in a polynucleotide used to express the polypeptide).
Applicant’s arguments have been fully considered but are not found to be persuasive. The Examiner acknowledges that although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. However, Applicant is reminded that the requirement of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph is that the specification describes how to make and use the claimed invention. Proper detailed analysis of the Wands factors for the two issues raised by the Examiner (i.e., variants of the CD70-binding domain of SEQ ID NO: 9 and polypeptides lacking a CD27 stalk or hinge domain) was provided in the previous Office Action, which Applicant has not specifically addressed. The rejection is maintained for reasons previously made of record and reiterated herein below for convenience, in light of the amended claims.
(i) The specification of the instant application teaches chimeric antigen receptors (CARs) comprising an extracellular target binding domain comprising a polypeptide that binds CD70, a transmembrane domain, and an intracellular signaling domain (page 1, lines 22-30; page 9, lines 12-14). The specification discloses that the polypeptide that binds CD70 comprises a CD70-binding domain of CD27 (page10, lines 6-10). The specification indicates that the CD70-binding domain in CD27 comprises a peptide comprising the amino acid sequence of TRPHCESCRHCN (SEQ ID NO: 9) that is located in the extracellular domain of CD27 (page 10, lines 22-24). The specification teaches that extracellular targeting binding domain of the CAR comprises a polypeptide comprising an amino acid sequence that is at least 70% identical, at least 80%, at least 90%, or at least 95% identical to the amino acid sequence of SEQ ID NO: 9 (page 10, lines 24-34).
Therefore, the phrase “an extracellular domain comprising an amino acid sequence having at least 70% identity to SEQ ID NO: 9” recited in instant claim 1 is broadly interpreted by the Examiner as reading upon variants, fragments, and/or derivatives of SEQ ID NO: 9 (that have at least 70% identity thereto). However, the specification does not teach any variants of the amino acid sequence of SEQ ID NO: 9. The CD70-binding domain of CD27 (SEQ ID NO: 9) is only 12 amino acids in length and the specification does not disclose which residues can be substituted or deleted.
The problem of predicting protein and DNA structure from sequence data and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein and DNA is extremely complex. While it is known that many amino acid substitutions are generally possible in any given protein the positions within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of success are limited. Certain positions in the sequence are critical to the protein's structure/function relationship, e.g. such as various sites or regions directly involved in binding, activity and in providing the correct three-dimensional spatial orientation of binding and active sites. These or other regions may also be critical determinants of antigenicity. These regions can tolerate only relatively conservative substitutions or no substitutions (see Wells, 1990, Biochemistry 29:8509-8517; Ngo et al., 1994, The Protein Folding Problem and Tertiary Structure Prediction, pp. 492-495).
However, Applicant has provided little or no guidance beyond the mere presentation of sequence data to enable one of ordinary skill in the art to determine, without undue experimentation, the positions in the CD70-binding domain of CD27 (SEQ ID NO: 9) which are tolerant to change (e.g. such as by amino acid substitutions or deletions), and the nature and extent of changes that can be made in these positions. Even if an active or binding site were identified in the specification, they may not be sufficient, as the ordinary artisan would immediately recognize that an active or binding site must assume the proper three-dimensional configuration to be active, which conformation is dependent upon surrounding residues; therefore substitution of non-essential residues can often destroy activity. The art recognizes that function cannot be predicted from structure alone (Bork, 2000, Genome Research 10:398-400; Skolnick et al., 2000, Trends in Biotech. 18(1):34-39, especially p. 36 at Box 2; Doerks et al., 1998, Trends in Genetics 14:248-250; Smith et al., 1997, Nature Biotechnology 15:1222-1223; Brenner, 1999, Trends in Genetics 15:132-133; Bork et al., 1996, Trends in Genetics 12:425-427). See also Tokuriki et al. (Current Opinion in Structural Biology 19: 596-604, 2009), who teach that mutations are generally destabilizing. For instance, Tokuriki et al. teach at page 596, right column, last paragraph, that “as mutations accumulate, protein fitness declines exponentially...or even more than exponentially...So by the time an average protein accumulates, on average, five mutations, its fitness will decline to <20%.” Further, at page 598, left column, last paragraph, Tokuriki et al. note that 50% of mutations are destabilizing, and >15% of mutations are highly destabilizing, and of the about 5% of mutations that are stabilizing values...many of these mutations result in inactive protein. Indeed, Tokuriki et al. conclude that “a more comprehensive understanding of how mutations affect protein fitness within living cells is needed, including their combined effects on function, thermodynamic and kinetic stability, and clearance through aggregation and degradation” (see page 602, left column, 2nd paragraph). Fenton et al. (Medicinal Chemistry Research 29:1133-1146, 2020) also state that while it is well known that most substitutions at conserved amino acid positions (which they call “toggle” switches) abolish function, it is also true that substitutions at nonconserved positions (which they call “rheostat” positions) are equally capable of affecting protein function. They conclude that substitutions at rheostat positions have highly unpredictable outcomes on the activities and specificities of protein-based drugs. Bhattacharya et al. (PLoS ONE 12(3): e0171355, 2017) state that the range of possible effects of even single nucleotide variations at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge (p. 18). Furthermore, when multiple mutations are introduced, there is even less predictability. For evidence thereof, see Guo et al. (PNAS USA 101(25):9205-10, 2004), who state that the effects of mutations on protein function are largely additive (page 9207, left column, full paragraph 2). Fenton et al. supra, also acknowledge this (see abstract). There is little to no guidance in the specification indicating which amino acids are considered essential in the amino acid sequence of SEQ ID NO: 9 for the binding of CD27 to CD70 (other than the full-length sequence of SEQ ID NO: 9).
The amount of experimentation required to generate variants of the CD70-binding domain of CD27 (SEQ ID NO: 9) would not have been routine, much less could one of ordinary skill in the art predict that any one or combination of all the variants or fragments encompassed by the instant claims would result in a domain of CD27 that still binds CD70. Because of this lack of guidance in the instant specification, the extended experimentation that would be required to determine which amino acid sequence modifications would be acceptable to retain occluding structural and functional activity, and the fact that the relationship between the sequence of a protein/peptide and its tertiary structure (i.e. its activity) are not well understood and are not predictable, it would require an undue amount of experimentation for one of skill in the art to arrive at the large number of variants of the extracellular domain of CD27 with at least 70% sequence identity to SEQ ID NO: 9. Applicant has not provided sufficient guidance to enable one of ordinary skill in the art to make and use the genus of variants of the CD70-binding domain of CD27 (SEQ ID NO: 9) in the claims in a manner reasonably correlated with the scope of the claims. The scope of the claims must bear a reasonable correlation with the scope of enablement. See In re Fisher, 166 USPQ 19 24 (CCPA 1970).
Due to the large quantity of experimentation necessary to generate an extracellular domain comprising all possible variants of the extracellular domain of CD27 with at least 70% sequence identity to SEQ ID NO: 9 and screen such for the desired functional activity; the lack of direction/guidance presented in the specification regarding the same; the absence of working examples directed to the same; the complex nature of the invention; the state of the prior art which establishes the unpredictability of the effects of mutation on protein structure and function; and the breadth of the claims, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention.
(ii) Regarding the phrase “wherein the polypeptide does not comprise a CD27 stalk or hinge domain” as recite in instant claim 1, the specification does not teach any methods or working examples that indicate CAR polypeptides that lack a CD27 stalk or hinge domain are functional and still bind CD70. It is noted that the claims do not require that the polypeptide comprises any stalk or hinge domain. The limited guidance in the specification regarding CAR polypeptide constructs lacking a stalk or hinge domain is not adequate and is merely an invitation for the skilled artisan to use the current invention as a starting point for further experimentation.
Relevant literature teaches that a hinge domain is a structure between the targeting moiety (i.e., extracellular target binding domain) and the T cell plasma membrane (Qin et al., J Hematol Oncol 10: 68, 2017; page 1, bottom of column 2). Qin et al. disclose that the incorporation of a hinge into CAR constructs can substantially increase the CAR T cell percentage during the in vitro culture period and enhance the invasiveness of T cells (page 2, column 2, 1st full paragraph; Figure 1A). Qin et al. suggest that a hinge may reduce steric inhibitory effects between the scFv and its epitope; or, improve the flexibility of the scFv (page 9, column 1). The post-filing date art of Leick et al. (Cancer Cell 40: 494-508, 2022; with two instant inventors as authors) even teaches that a CD27-based CAR to target CD70 that has a deleted hinge domain is not functional (page 497, middle of column 2; Figure S4A; page 502, bottom of column 1).
Therefore, in view of the teachings of the state of the art, one skilled in the art would not expect a CAR polypeptide comprising an extracellular binding domain comprising a CD70-binding domain of CD27 (SEQ ID NO: 9), but does not comprise a (CD27) stalk or hinge domain, to be functional. Applicant is reminded that 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. See In re Vickers, 141 F.2d 522, 526-27, 61 USPQ 122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA 1971); In re Soll, 97 F.2d 623, 634, 38 USPQ 189, 191 (CCPA 1938; In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970); In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991).
Due to the large quantity of experimentation necessary to generate a CAR polypeptide that does not comprise a CD27 stalk or hinge domain (or that does not specifically require any stalk or hinge domain) and screen the same for activity; the lack of direction/guidance presented in the specification regarding the same; the absence of working examples directed to same; the complex nature of the invention; and the state of the art which establishes that a CD27-based CAR to target CD70 that has a deleted hinge domain is not functional (see Leick et al.); and the unpredictability of the functional effects of removing a stalk or hinge region from a CAR polypeptide, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention.
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.
8. Claims 1, 4, 8, 11, 13 and 14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 7, 9, 12, 13, 15, 17, 19 of copending Application No. 18/856,583. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims recite a polypeptide comprising
(i) an extracellular target binding domain comprising a CD70-binding domain of CD27;
(ii) a transmembrane domain; and
(iii) an intracellular signaling domain,
wherein the CAR does not comprise a CD27 stalk or hinge domain.
The basis for this rejection is set forth at pages 18-21 of the previous Office Action of 22 August 2025.
(i) At the bottom of page 10 through the top of page 11 of the Response of 21 November 2025, Applicant indicates that this application has a patent term filing date of September 16, 2020, which is earlier than the patent term filing date of the ‘583 application, which is April 13, 2023. Applicant believes that all other rejections and objections have been addressed by the amendment and request that the provisional double patenting rejection be withdrawn.
Applicant’s arguments have been fully considered but are not found to be persuasive. The rejection is maintained and held in abeyance until all other issues are resolved (see maintained rejection under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, above). However, Applicant is encouraged to submit a terminal disclaimer at Applicant's earliest convenience.
Conclusion
No claims are allowable.
THIS ACTION IS MADE FINAL. 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.
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BEB
Art Unit 1647
09 March 2026
/BRIDGET E BUNNER/ Primary Examiner, Art Unit 1647