DETAILED ACTION
This Action is in response to the communication filed on 01/02/2026.
Claims 1, 5-10, 21-32 are pending.
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 .
Election/Restrictions
It is noted that species election requirement was mailed on 10/02/205 and to which Applicant responded to on 01/02/2026, traversing the species election requirement asserting that there would not be a serious search burden. Upon completing a search of the elected species (SEQ ID NO 6), it was discovered that there was no prior art teaching the elected sequence. Accordingly, the search continued to the next species and no prior art was found for any of the claimed sequences (SEQ ID NOs: 1-7). Therefore, Applicant’s arguments are moot as all of the claimed species have been searched, and the species election requirement is hereby withdrawn.
Claims 1, 5-10, 21-32 are examined herein.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 5-10, 21-26 are rejected under 35 U.S.C. 103 as being unpatentable over Chmielewski et al. (“Chmielewski”; Cancer Res. 2011, 71(17)5697-5706; of record) and Bamford et al. (Journal of Immunology (1998); 160(9): 4418-4426; of record) in view of Sadelain et al. (Cancer Discovery (2013) vol. 3, no. 4, 388-398; of record).
Claims 1 and 26 have been amended to require that the transmembrane domain is from CD8 and to further require a plurality of intracellular signaling domains of CD28 and CD3-zeta. It is noted that all claims depend from either claim 1 or 26. Furthermore, claim 23 has been amended to remove the requirements for the transmembrane and intracellular signaling domains requirements and claim 24 has been amended to require that the one or more copies of the response element comprises a plurality of the indicated response elements. Claims 27-32 have been amended to require specific sequences (i.e., SEQ ID NOs).
It is noted that claims 1, 5-10, 21-26 as amended are subject to rejection based on the teachings of Chmielewski, Bamford, and Sadelain, which were cited in the rejection under 35 USC 103 in the previous office action. The rejection of the instant claims are a modification of the previous rejection, modified to address the amended claims which includes limitations present in the previous claims
As previously indicated, the Chmielewski and Bamford references render obvious the claimed genetically engineered effector cell comprising a single construct that includes in operative association (i) a modular sensing element, (ii) one or more copies of a response element, and (iii) a modular effector element, as previously set forth, wherein the signal peptide is non-natural to the therapeutic polypeptide, ) or that the signal peptide is of Interleukin-6 (IL-6) or Interleukin-2 (IL-2), the specific teachings of the Chmielewski and Bamford references are provided in previous office actions and incorporated by reference.
Chmielewski does not teach that the modular sensing element that encodes the CAR comprises a plurality intracellular signaling domains that include intracellular signaling domains of CD28 and CD3-zeta (or CD28, CD3-zeta, and 4-1BB); nor does Chmielewski teach that the transmembrane domain comprises a transmembrane domain of CD8.
However, the prior art teaches that modular sensing elements comprising a CAR having an extracellular antigen binding domain operably linked to a transmembrane domain comprising the transmembrane domain of CD8, and a plurality of intracellular domains that include intracellular signaling domains of CD28, CD3-zeta, and 4-1BB, was known prior to the effective filing date of the instant claims. For instance, Sadelain et al., “The Basic Principles of Chimeric Antigen Receptor Design”, is a review article that teaches the state of the art of Chimeric Antigen Receptor (CAR) design, as of its publication date (2013). Sadelain teaches three generations of CARs including (i) a first generation that included a CAR with a CD8-derived transmembrane domain and a CD3-zeta derived intracellular signaling domain, (ii) a second generation that included a CAR having a CD-28-derived transmembrane/intracellular signaling domain as well as a CD3-zeta-derived intracellular signaling domain, and (iii) a third generation CAR comprising a CD-28-derived transmembrane/intracellular signaling domain, as well as a CD3-zeta-derived intracellular signaling domain and a 4-1BB intracellular signaling domain (e.g., see Figure 1, Figure 2, etc.). Sadelain’s Table 1 also teaches many different specific CARs including scFv-CD8-CD3-ζ, scFv-CD28-CD3-ζ, scFv-CD28-41BB-CD3-ζ, IL-13- CD28-4-1BB-CD3-ζ. Accordingly, it was well known in the prior art that CARs comprised three basic elements: an extracellular antigen binding domain, a transmembrane domain, and an intracellular signaling domain, and Sadelain teaches that there was a multitude of different CARs comprising different extracellular antigen binding domains, transmembrane domains (including CD8- and CD28-derived transmembrane domains), and different intracellular signaling domains (including CD28-, CD3-ζ-, and 4-1BB-derived intracellular signaling domains).
Therefore, it would have been prima facie obvious to one or ordinary skill in the art prior to the time the claimed invention was filed to further modify the single construct comprising (i) a modular sensing element that encodes a CAR comprising an extracellular antigen binding domain operably linked to a transmembrane domain, and intracellular domains, (ii) at least one response element, and (iii) a modular effector element that encode a therapeutic polypeptide fused to a signal peptide that is non-natural to the therapeutic polypeptide, rendered obvious by the Chmielewski and Bamford, as previously set forth, by substituting the transmembrane domain with a CD8-derived transmembrane domain, and substituting the intracellular signaling domain with an intracellular signaling domain comprising a CD28-derived, a CD3-zeta-derived, and a4-1BB-derived intracellular signaling domain, with a reasonable expectation of success. That is, based on Sadelain, it would have been prima facie obvious to create a third generation CAR having a CD8-derived transmembrane, and an intracellular signaling domain comprising a CD28-derived intracellular signaling domain, a CD3-zeta-derived intracellular signaling domain, and a 4-1BB intracellular signaling domain, with a reasonable expectation of success. The fact that Sadelain teaches that a CD8-derived transmembrane domain can be successfully used as a transmembrane domain, and further teaches that a CD-28-derived, CD3-zeta-derived, and 4-1BB-derived intracellular signaling domain can be successfully used in CARs provides the basis for a reasonable expectation of success.
The combination of prior art cited above satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 USPQ2d 1385 (2007):
“Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) “Obvious to try” – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.”
In this case any or all of rationales (A)-(E) may apply. Therefore, the instant claims are unpatentable over Chmielewski, Bamford, and Sadelain.
Claim Objections
Claims 27-32 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. It is noted that a search of the required SEQ ID NOs did not identify any prior art for the sequences of SEQ ID NOs: 1-7.
Response to Arguments
With respect to the rejection under 35 USC 112(a) (Written Description) Applicant’s arguments have been fully considered and in view of the amendment to the claims are persuasive. The rejection has been withdrawn.
With respect to the rejection of claims under 35 USC 103 based on Chmielewski, Bamford, and Sadelain, applicant’s argue that none of the reference teach a plurality of intracellular signaling domains including CD28, 4-1BB, and CD3-zeta signaling domains.
In response, it is acknowledged that no single reference a plurality of intracellular signaling domains as is now required by the amended claims. However, the combination of all three references teaches all of the required limitations as indicated in the rejection.
Applicant also argues that one of ordinary skill in the art would not have a reasonable expectation of success of modifying the multiple constructs of Chmielewski to include a single construct comprising the exogenous polynucleotide sequence as claimed. Applicant contends that it is unclear from the record how the proposed modification to combine two constructs into a single construct would change the functioning of the modified T-cell and/or IL-12 and/or the ability to transfect, as compared to the two constructs in Chmielewski. Applicant submits that a living cell such as a T-cell is not a predictable system with changes in different variables impacting cell viability and ability to incorporate the single (large) construct rather than two (smaller) constructs. Applicant contends that a variety of factors would need to be considered and refers to paragraphs 0003, 0043, 0075, and 0083 of the specification. Applicant also refers to Regents of the Univ. of Cal. V. Broad Inst., Inc., 903 F.3d 1286 (Fed. Cir. 2018) which indicated the unpredictability of the living cell systems rendered applying CRISPR-Cas9 to a eukaryotic cell, rather than a prokaryotic cell, non-obvious), stating that similar to Regents of the Univ. of Cal. V. Broad, as the living cell system is unpredictable, one of ordinary skill in the art would not have a reasonable expectation of success to modify the multiple constructs of Chmielewski to incorporate onto a single construct comprising an exogenous polynucleotide sequence to form the genetically engineered effector cell as claimed.
In response, it is noted that the PTAB previously affirmed that combining the two construct system taught by Chmielewski into a single construct was obvious (see PTAB’s statement provided above). Furthermore, the is no evidence of record indicating that that there would be any undesirable change to the functioning of the modified T-cell and/or IL-12 and/or the ability to transfect, as compared to the two constructs in Chmielewski. Furthermore, there is no evidence of record indicating that combining the two constructs into a single construct would negatively impact cell viability or ability to incorporate the single (large) construct rather than two (smaller) constructs. Paragraphs 0003, 0043, 0075, and 0083 of the specification have been reviewed but do not provide evidence or reasoning why the two-construct system could successfully be combined into a single construct. Furthermore, the facts of the instant case are fundamentally different from the fact of Regents of the Univ. of Cal. V. Broad. For instance, in Regents of the Univ. of Cal. V. Broad, the issue was whether or not the results found in a prokaryotic cell would work in a eukaryotic cell, while in this case Chmielewski teaches using a two-vector system in a eukaryotic cell and the issue is whether or not modifying the two vector system into a single vector system would work in a eukaryotic cell.
Therefore, Applicant’s arguments are not persuasive.
It is noted that claims 27-32 are free of the prior art as the prior art does not teach any of SEQ ID NOs: 1-7; therefore, limiting the claims to require any of SEQ ID NOs: 1-7 would obviate all rejections and be allowable.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to J. E. Angell whose telephone number is (571)272-0756. The examiner can normally be reached Monday-Friday (8:30-5:00).
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J. E. Angell
Primary Examiner
Art Unit 1637
/J. E. ANGELL/ Primary Examiner, Art Unit 1637
Prosecution Insights