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 .
A request for continued examination under 37 CFR 1.114 was filed in this application after appeal to the Patent Trial and Appeal Board, but prior to a decision on the appeal. 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examination under 37 CFR 1.114 and the fee set forth in 37 CFR 1.17(e) has been timely paid, the appeal has been withdrawn pursuant to 37 CFR 1.114 and prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant’s submission filed on 07-22-26 has been entered.
Claims 1, 113, 118-119, 121, 127, 129-130, 141, 160, and 162-164 are pending.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Rejection Maintained
Claims 1, 113, 118-119, 121, 127, 129-130, 141, 160, and 162-164 remain rejected under 35 U.S.C. 103 as being unpatentable over Zah et al. 2016 (Cancer immunology research, 4(6), 498-508.; of record), and in view of Chen et al. 2018 (Leukemia, 32(2), 402- 412.; IDS), Ma et al. 2018 (US 2018/0162939 A1; of record), Gogishvili et al. 2017 (Blood, 130(26), 2838-2847.; IDS), and Ali et al. 2016 (Blood, 128(13), 1688-1700.; IDS) for the reasons of record (Final mailed 09/15/2025) and for the reasons set forth herein.
Applicants argue that the claims are not obvious because “The Office’s obviousness rationale is predicated on Zah’s framework for designing bispecific tandem CARs.” For example, in formulating the CD19/CD20 bi-specific CAR, Zah teaches that the size and rigidity of CAR molecules can be calibrated to match the specific antigens targets. Thus, applicants argue, the structure of the CAR is dependent on the specific antigen targeted. Applicants further note that Zah teaches that optimal OR-gate CAR structure can be deduced from known structural requirements for single-input CARs. In contrast, applicants state that the Office has failed to provide evidence of “established derived structural preferences” as Zah has done for CD19 and CD20. And, that this information from Zah cannot be extrapolated (contextually) to the claimed BCMA/CS1 CAR construct because “known spacer-length preferences exist for both single-input BCMA CARs and single-input CARS”. Applicants individually address Ali et al and Ma et al., and Gogishvili et al. (Remarks, pages 7-8) as not teaching a comparative, multi-spacer analysis to establish whether a short, medium, or longer spacer is preferred for either BCMA or CS1 single-input CARs.
These arguments have been considered but are not found persuasive. The obviousness rationale may well rely upon Zah’s framework, but consideration of “established derived structural preferences” is not a requirement when setting forth the combination of the references as obvious. On the one hand, this setting of a rigid structural preference is not an explicit teaching in Zah. On the other hand, applicant’s own specification appears to suggest that [0015] that there is some flexibility when constructing the bispecific CAR – “It is contemplated that in some embodiments, the CS1 binding region is membrane proximal, meaning its amino acid sequence is closer to the amino acid sequence of the transmembrane domain than the amino acid sequence of the BCMA binding region, which would then be considered membrane distal. In other embodiments, the BCMA-binding region is membrane proximal and the CS1-binding region is membrane distal.”. Also, Zah recognizes (page 506, 1st column, last para) that some experimentation or trial and error may be required: “To achieve the optimal conjugation distance between a T cell and its target, the receptor needs to be adjusted to match the size of the target antigen, resulting in the need for a shorter CAR when targeting antigens with extensive extracellular domains and vice versa.”. However, the latter is only a “hypothsis” that is consistent with their observations and they add, “quantitative imaging studies would be required to confirm its accuracy”. Thus, one of ordinary skill in the art would have appreciated that the exchange of CD19/CD20 with BCMA/CS1 antigen binding domains would not necessarily be one of “plug and play” configuration.
Moreover, all of the parts were known in the prior art. “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.” In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929). Further the Supreme Court, in KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007) stated, “Neither the enactment of §103 nor the analysis in Graham disturbed this Court’s earlier instructions concerning the need for caution in granting a patent based on the combination of elements found in the prior art. For over a half century, the Court has held that a “patent for a combination which only unites old elements with no change in their respective functions . . . obviously withdraws what is already known into the field of its monopoly and diminishes the resources available to skillful men.” Great Atlantic & Pacific Tea Co. v. Supermarket Equipment Corp., 340 U. S. 147, 152 (1950). This is a principal reason for declining to allow patents for what is obvious. The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.”.
Applicants further argue (page 9) that experimental evidence from the present application demonstrates why “efficacy” cannot be predicted from any straightforward application of Zah’s rationale.
For example, the inventors observed that a single-input (c11D5.3) BCMA CAR performs best with a long (229 aa) extracellular spacer, consistent with BCMA's very short (36 aa) ectodomain requiring greater extension to properly engage its antigen. The data show that, if one were properly to apply Zah's methodology, the single-input BCMA structural preference would point squarely toward a long spacer for the membrane-proximal BCMA scFv in any tandem CAR. Applicants argue that this is directly contradictory to the claimed configuration, which employs a short spacer of less than 20 amino acids. The Office's combination relies on transplanting Zah's CD19/CD20 TanCAR architecture - with its short IgG4 hinge-only spacer for the membrane-proximal scFv - into a BCMA/CS1 context and asserting that the combination of a short hinge and the (G4S)4 linker is an obvious choice. Yet Zah's core teaching is that the structure of the CAR is dependent on the specific antigens targeted, and that the optimal bi-specific structure is deduced from known structural requirements for single-input CARs.
This argument has been considered but is not found persuasive because there is no explicit evidence, that if one were to “properly” apply Zah's methodology, the single-input BCMA structural preference would point squarely toward a long spacer for the membrane-proximal BCMA scFv in any tandem CAR. This is a conjecture because applicants are relying upon their own data and are attesting that one would necessarily apply this exact data when practicing the methodology of Zah. However, it is well-established that a determination of obviousness based on teachings from multiple references does not require an actual, physical substitution of elements." In re Mouttet, 686 F.3d 1322, 1332, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012) (citing In re Etter, 756 F.2d 852, 859, 225 USPQ 1, 6 (Fed. Cir. 1985) (en banc)) ("Etter's assertions that Azure cannot be incorporated in Ambrosio are basically irrelevant, the criterion being not whether the references could be physically combined but whether the claimed inventions are rendered obvious by the teachings of the prior art as a whole."). See also In re Keller, 642 F.2d 413, 425, 208 USPQ 871, 881 (CCPA 1981) ("The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference.... Rather, the test is what the combined teachings of those references would have suggested to those of ordinary skill in the art.").
Pages 10-12 continue to summarize the work of applicant in comparison to the teachings of Zah with similar arguments as set forth above. For example, applicants argue (page 11) that as established in Sections 1 and 2, there is no empirically derived structural preferences in the cited art for either the anti-BCMA scFv or the anti-CS1 scFv. Or, on page 12, applicant reiterate that the present application provides the first experimental evidence of a structural preference for the single-input BCMA CAR- and that preference is for a longer spacer, not a short one. These arguments have already been considered but are not found persuasive for the reasons of record and for the reasons set forth above.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GARY B NICKOL, Ph.D. whose telephone number is (571)272-0835. The examiner can normally be reached M-F 9AM-5:30PM.
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/GARY B NICKOL/Primary Examiner, Art Unit 1643
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