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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4/22/2026 has been entered.
Claims status
Claims 3, 10 is/are cancelled. Claims 1, 11, 13-15, 17-19, 21-24, 26-28 is/are currently pending with claims 11, 13-15, 17, 18, 21-24, 26-28 is/are withdrawn. Claims 1, 19 is/are under examination.
Claim Rejections - 35 USC § 112(b) – Withdrawn
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.
Rejection of Claims 1, 3, 10 and 19 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in light of claim amendments or cancellations.
Claim Rejections - 35 USC § 112(d) - Moot
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Rejection of Claim 3 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends is moot due to claim cancellation.
Claim Rejections - 35 USC § 112(a) - Withdrawn
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.
Rejection of Claim 1, 3,10 and 19 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 light of claim amendments or cancellations.
Claim Rejections - 35 USC § 103 – New, necessitated by claim amendments
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Rejection of Claim(s) 1, 3, 19 under 35 U.S.C. 103 as being unpatentable over Oda et al (WO 2018/170475 A1, Sep 20, 2018; ref of record) in view of Hartmut (US7642046, Jan 5, 2010; ref of record) is withdrawn in light of amendment to claim 1 and cancellation of claim 3.
Rejection of Claim(s) 10 under 35 U.S.C. 103 as being unpatentable over Oda and Hartmut as applied to claim 1 above and further in view of Yu et al (US 2018/0118838 A1, May , 2018; ref of record) as evidenced by O’Neill et al (Protein-Specific Signal Peptides for Mammalian Vector Engineering. ACS Synth. Biol. 2023, 12, 2339−2352) is moot in light of claim cancellation.
Claim(s) 1 and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Oda et al (WO 2018/170475 A1, Sep 20, 2018; ref of record) in view of Hartmut (US7642046, Jan 5, 2010; ref of record) and Yu et al (US 2018/0118838 A1, May , 2018; ref of record) as evidenced by O’Neill et al (ACS Synth. Biol. 2023, 12, 2339−2352; ref of record).
Regarding claim 1, Oda teaches a cell comprising a CAR or TCR (=claimed a) and Immunomodulatory fusion proteins (IFPs) such as FLBR fusion proteins (=claimed b in part; page 11, para 4-6; page 4, para 2; page 26, last para).
Regarding IFPs, Oda teaches that these fusion proteins comprise an extracellular domain from a molecule that ordinarily, e.g., in its natural setting, is capable of delivering a negative or a inhibitory signal to the T-cell when bounds to its ligand, and an intracellular domain that ordinarily delivers a positive/stimulatory signal to the T-cell (page 36-37, bridging para). This configuration effectively converts a negative/inhibitory signal into a positive/stimulatory signal (page 40, para 1). Examples of extracellular domain from a negative/inhibitory molecule are provided, such as Fas extracellular domain (page 40-41, bridging para; page 42; page 44; page 50; Example 11, 22 for IFPs comprising Fas extracellular domain). Examples of intracellular domain from a positive/stimulatory molecule are provided, such as CD40 intracellular domain (page 59).
Thus, Oda teaches FLBR fusion proteins comprising Fas extracellular domain and CD40 intracellular domain (Page 4, lines 20-25; Page 28-29, bridging para; Page 31-lines 8-15; page 49-50 bridging para; page 59-lines 20-25).
Oda tests and shows that various IFPs increase CAR-T-cell proliferation, survival and function in vitro and in vivo, such as CD200R-CD28 (Example 3, 4, 5, 8, 14, 15, 16, 17, 18, 19), CD200R-4-1BB (Example 7), SIRPa-C28 (Example 9), PD-1-CD28 (Example 10), Fas-CD28 (Example 11, 22), LAG3-CD28 (Example 12), TIM3-CD28 (Example 13), Fas-4-1BB (Example 23-26).
Regarding claim 19, Oda teaches pharmaceutical compositions comprising the cells disclosed (page 12-lines 5-7; page 81:line 1-10).
Oda does not teach a FLBR with the claimed sequence of SEQ ID NO: 41 which is a 246 amino acid polypeptide sequence that comprises a well-known signal peptide sequence (residues 1-19=instant SEQ ID No: 43) followed by Fas extracellular domain and transmembrane domains (residues 20-184=instant SEQ ID No: 49) followed by CD40 intracellular domain (residues 185-246=instant SEQ ID No: 4).
However, Oda teaches a FLBR with Fas extracellular domain and a CD40 intracellular domain, as well as teaches the sequence of Fas ectodomain in SEQ 186 (=100% identical to the ectodomain residues 26-173 of instant SEQ ID NO: 49; see alignment in IDS 2/9/2023 cited as “DATABASE genetic sequence [Online] 15 November 2018 (2018-11-15), "Human FAStm-41BB fusion construct SEQ: 186," Retrieved from EBI accession no. GSP:BFR47856 Database accession no. BFR47856 abstract, XP055816915, 1 page”).
Furthermore, the sequence of CD40 endodomain and the alternative signal peptide sequence such as in the claimed SEQ ID NO:41 was known in the art.
Hartmut teaches SEQ ID NO:1 as the sequence for CD40 intracellular domain (=100% identical to instant SEQ ID NO: 4; see alignment below and ref of record; Figure 3A).
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Yu teaches SEQ ID NO: 43 as one of alternative signal peptides that could be used to direct expression of fusion receptors to the cell membrane (=100% identical to residues 1-19 of instant SEQ ID NO: 41; see alignment below and in PTO-892; [0269-0273]).
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Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the sequences taught by Yu (for signal peptide), Oda (for Fas ectodomain and transmembrane domain) and Hartmut (for CD40 endodomain) to generate the Fas-CD40 of SEQ ID NO: 41. An artisan would be motivated to use Hartmut’s CD40 endodomain sequence to generate Oda’s FLBR with CD40 endodomain (i.e. Fas-CD40) because Oda does not disclose this known sequence. An artisan would be motivated to substitute the Fas signal peptide of Oda with the well-known alternative signal peptide of Yu because these are alternatives known to perform the same function (see MPEP 2144.06). Both Oda’s and Yu’s signal peptide perform the function of allowing membrane translocation of fusion receptor proteins. Further, O’Neill evidences that Yu’s signal peptide is a well-known industry standard (Table 1 designates Yu’s sequence as “C” which the legend describes as “industrially relevant standard reference signal peptide”). An artisan would reasonably expect to generate a FLBR with CD40 endodomain because Oda teaches the general structure of FLBR comprising Fas ectodomain and a TNFRSF endodomains such as from CD28 or CD40 (Figure 11, 23, Example 11) and Hartmut teaches the sequence of CD40 endodomain and Yu teaches the sequence of the signal peptide that would be used to generate a Fas-CD40 (SEQ ID NO: 41). An artisan would reasonably expect to generate a Fas-CD40 with a sequence of SEQ ID No: 41 as claimed because the sequences that comprise SEQ ID No: 41 were taught by Yu, Oda and Hartmut which an ordinary artisan could combine using standard molecular biology techniques such as used by Oda to generate their fusion proteins (see at least Example 11).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Response to Arguments
Applicant’s arguments with respect to the U.S.C. 103 rejection of claim(s) have been considered but are moot because the new ground of rejection necessitated by claim amendments.
Arguments relevant to instant U.S.C. 103 rejection of claim(s) 1, 19 are discussed below.
Applicants point to a para from the response to arguments presented in OA dated 12/23/2025 wherein it was noted that that the arguments presented were not commensurate in scope with the claims. Applicant appear to argue that since the claims are now limited to a CAR/TCR comprising T-cell that comprises the FLBR with the specific sequence of SEQ ID No: 41, therefore the claims are non-obvious over the prior art in view of example 4, 5 and Figures 17-21.
This is not persuasive because in response to Applicants arguments regarding unexpected and/or superiors results presented in remarks filed 10/30/2025, the only issue raise was not that the arguments presented were not commensurate in scope with the claims. Critically, arguments pertaining to unexpected and superior results rendering the claims non-obvious were unpersuasive.
MPEP 716.02 guides that “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected”. See In re Corkill, 771 F.2d 1496, 226 USPQ 1005 (Fed. Cir. 1985). In Corkhill, the claimed combination showed an additive result when a diminished result would have been expected.” See also Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). However, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage.
In the instant case, the prior art taught fusion proteins comprising a Fas ectodomain fused to endodomains from proteins expected to increase T-cell proliferation in response to Fas ligand, reciting a list of 39 alternatives out of which CD28 and 4-1BB were tested and shown to function as expected (Oda, page 30-31 bridging para; see section Immunomodulatory Fusion proteins: Intracellular component on page 58; Example 11, 23). An ordinary artisan is motivated to test other combinations already identified in the hopes to find an endodomain that results in higher proliferation than the endodomains tested by Oda. This is largely a difference in degree and not kind. See In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art."). Critically, Applicant do not provide any evidence that the expectation in the art was that the an ordinary artisan motivated to test the other alternatives taught, including CD40, would expect the alternatively taught endodomains to perform poorly or all equally well such that identification of one or more endodomains that performs better is unexpected. Furthermore, the data presented shows that several endodomains tested performed better than a comparator, not just CD40. On page 44, the specification states “The proliferation fold difference compared to the day 0 analysis (Figure 19) showed that expression of Fas-CD27, Fas-CD40, Fas-BCMA and Fas-Fn14 induces greater proliferation of transduced PBMCs than expression of Fas-41 BB and FasΔDD.” and “As shown in Figure 20, cells expressing Fas- CD40 showed a significantly higher release of interferon gamma than cells expressing FasΔDD. An increase in IFNy release was observed for cells expressing the Fas-CD40 FLBR even in the absence of exposure to immobilised FasL. Cells expressing the FLBRs Fas-CD27, Fas-CD40, Fas-BCMA and Fas-Fn14 also showed a higher interferon gamma release (pg/ml) when incubated with immobilised Fas ligand when compared to that of the FasΔDD construct.” On page 45, the specification states “GD2 CAR-T cells co-expressing Fas-XEDAR, Fas-CD40, Fas-BCMA and Fas-Fn14 (Figure 21 E, F, H and I) significantly outperformed control GD2 CAR-T cells and GD2 CAR- T cells co-expressing FasΔDD, Fas-41BB and Fas-CD27 (Figure 21 B, C, D and G) when measuring their ability to maintain cytotoxicity and expansion after repeated encounters with GD2-positive SupT1 tumour cells during in vitro sequential co-culture killing assays. Both control GD2 CAR-T cells and GD2 CAR-T cells co-expressing FasΔDD, Fas-41BB or Fas- CD27 started failing to clear the targets by the 5th re-stimulation, losing their ability to expand and eliminate GD2-positive tumour cells. In contrast, GD2 CAR-T cells co-expressing Fas- XEDAR, Fas-CD40, Fas-BCMA and Fas-Fn14 continued responding to antigen stimulation for much longer and were consequently superior at clearing target cells.” No statistical comparison is shown that Fas-CD40 is superior to other endodomains in any of these parameters (Figures 19-21) while Oda taught several of these other endodomains such that it appears that the present specification tests endodomains taught by Oda, using methods known in the art, to identify several endodomains that function better than a comparator.
“When evidence has been presented to rebut an obviousness rejection, it should not be evaluated simply for its "knockdown" value. Rather, all evidence must be reweighed to determine whether the claims are nonobvious” (MPEP 2145). In the instant case, identifying CD40 as an endodomain that results in increased proliferation and thus cytotoxicity does not overcome the obviousness of the instant invention since the art provided ample teachings and suggestions regarding using CD40 endodomains in Fas-fusion receptors to increase T-cell proliferation and activity. An artisan in the field of CAR-T cell remains motivated to increase CAR-T cell proliferation and cytotoxicity to improve its therapeutic efficacy.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATASHA DHAR whose telephone number is (571)272-1680. The examiner can normally be reached M-F 8am-4pm (EST).
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/MATASHA DHAR/Examiner, Art Unit 1632
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