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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 20 April 2026 has been entered.
Status of the Claims
Applicant’s submission filed 20 April 2026 has been entered. Claims 1, 4, 11, 22-23, 25, 27, 34-35, 43-44, and 46-49 are pending. Claims 1, 11, 25, and 46-47 have been amended. Therefore, prosecution on the merits continues for claims 1, 4, 11, 22-23, 25, 27, 34-35, 43-44, and 46-49. All arguments have been fully considered with the status of each prior ground of rejection set forth below.
However, it is of note that the amendment to the claims filed on 20 April 2026 does not comply with the requirements of 37 CFR 1.121(c) because claim 43 maintains underlined text from previous amendments. Amendments to the claims filed on or after July 30, 2003 must comply with 37 CFR 1.121(c) which states (emphasis added):
(c) Claims. Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).
(1) Claim listing. All of the claims presented in a claim listing shall be presented in ascending numerical order. Consecutive claims having the same status of “canceled” or “not entered” may be aggregated into one statement (e.g., Claims 1–5 (canceled)). The claim listing shall commence on a separate sheet of the amendment document and the sheet(s) that contain the text of any part of the claims shall not contain any other part of the amendment.
(2) When claim text with markings is required. All claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of “currently amended,” and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived. Only claims having the status of “currently amended,” or “withdrawn” if also being amended, shall include markings. If a withdrawn claim is currently amended, its status in the claim listing may be identified as “withdrawn—currently amended.”
(3) When claim text in clean version is required. The text of all pending claims not being currently amended shall be presented in the claim listing in clean version, i.e., without any markings in the presentation of text. The presentation of a clean version of any claim having the status of “original,” “withdrawn” or “previously presented” will constitute an assertion that it has not been changed relative to the immediate prior version, except to omit markings that may have been present in the immediate prior version of the claims of the status of “withdrawn” or “previously presented.” Any claim added by amendment must be indicated with the status of “new” and presented in clean version, i.e., without any underlining.
(4) When claim text shall not be presented; canceling a claim.
(i) No claim text shall be presented for any claim in the claim listing with the status of “canceled” or “not entered.”
(ii) Cancellation of a claim shall be effected by an instruction to cancel a particular claim number. Identifying the status of a claim in the claim listing as “canceled” will constitute an instruction to cancel the claim.
(5) Reinstatement of previously canceled claim. A claim which was previously canceled may be reinstated only by adding the claim as a “new” claim with a new claim number.
As noted above, the amendment under consideration herein fails to comply with 37 CFR 1.121 because instant claim 43 contains underlined text in Line 8 while having the status identifier of “previously presented”, which requires a clean version of the claim. Thus, the amendment could be considered non-responsive. However, in the interest of compact prosecution the amendment at issue will not be considered non-responsive. The Examiner notes that any future responses failing to comply with 37 CFR 1.121 will be held non-responsive, and will not be considered.
Status of Prior Rejections/Response to Arguments
RE: Objection to the Specification
The substitute Specification filed 20 April 2026 is acknowledged and entered into the application file. With that, Applicant’s amendment to the tables within Pages 27-28, 79, and 81-82 of the disclosure filed 20 April 2026 obviates those objections of record. However, Applicant has failed to amend the hyperlinks disclosed on Pages 46, 53, and 58 to the top-level domain.
Therefore, the objections are withdrawn with regards to the tables, and maintained for the inclusion of hyperlinks or otherwise browser-executable code.
RE: Rejection of claims 1, 4, 11, 22, 34-35, and 43-44 under 35 USC 103 over Klebanoff in view of Bramson et al
Applicant's arguments filed 20 April 2026 have been fully considered but they are not persuasive.
Applicant has traversed the rejection, asserting in Page 7 of the Remarks filed 20 April 2026 that the ordinary artisan would not have arrived to the presently claimed dominant negative Fas comprising an endodomain from CD40 given the disclosures of Klebanoff and Bramson et al. More specifically, Applicant asserts that Klebanoff fails to teach the replacement of the intracellular domain of dominant negative Fas, and Bramson et al fail to teach the specific combination of a dominant negative Fas having a CD40 endodomain. In response, the Examiner respectfully submits that Klebanoff discloses a complete deletion of the death domain comprised within the intracellular domain of the dominant negative Fas polypeptide, and that the dominant negative Fas polypeptide can comprise a heterologous signal peptide. See, for example, Paragraphs [0101]-[0105], [0102], [0111] of Klebanoff. With that, Bramson et al disclose a dominant negative Fas molecule that comprises a CD40 endodomain, as the removal of the cytoplasmic region of Fas results in a dominant negative receptor. See, for example, Paragraphs [0007] and [0195] of Bramson et al. Therefore, the ordinary artisan would have reasonably arrived at the presently claimed dominant negative Fas comprising an endodomain from CD40, as a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, even nonpreferred embodiments. See MPEP § 2123: Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989); Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005).
Applicant has further traversed the rejection, asserting in Pages 7-10 of the Remarks filed 20 April 2026 that cells expressing a dominant negative Fas comprising a CD40 endodomain (dnFas-CD40) have an unexpected superiority in proliferation, cytotoxic activity, and survival in the presence of FasL when compared to cells expressing dnFas-41BB or dnFas-BAFFR – which are taught by Bramson et al. Applicant supports these assertions with Example 4 and Figures 17-20 of WO 2021/205176 A1, which is the international phase of co-pending US Application No. 17/915637. In response, the Examiner respectfully reminds Applicant that, in submitting evidence asserted to establish unobvious results, there is a burden on Applicant to indicate how the examples asserted to represent the claimed invention are considered to relate to the examples intended to represent the prior art and, particularly, to indicate how those latter examples do represent the closest prior art. The evidence relied upon should also be reasonably commensurate in scope with the subject matter claimed and illustrate the claimed subject matter relative to the prior art subject matter. See MPEP § 2145. It should also be established that the differences in the results are in fact unexpected and unobvious and of both statistical and practical significance. See MPEP § 716.02(b). In the instant case, the Examiner notes that the evidence relied upon is not commensurate in scope with the pending claims. More specifically, the instant claims require any cell (claims 25, 47) that has been engineered to express, in part, any nucleic acid sequence of interest (NOI) (claim 1), or a NOI that is either a CAR, a transgenic TCR, or a NOI which inhibits expression of an endogenous TCR (claims 43, 46). On the contrary, the cells of the referenced example are PBMCs that comprise a second generation anti-CD19 CAR. As the instant claims are broader than the referenced example, the cells relied upon as evidence are not of the same scope as the pending claims.
Therefore, the rejection is maintained and amended to encompass the claims as currently written.
RE: Rejection of claims 1, 4, 11, 22-23, 34-35, and 43-44 under 35 USC 103 over Klebanoff in view of Bramson et al and Jarjour et al
Applicant's arguments filed 20 April 2026 have been fully considered but they are not persuasive.
Applicant has traversed the rejection, citing the same assertions presented within Pages 7-10 of the Remarks filed 20 April 2026 in the discussion of the 35 USC 103 rejection over Klebanoff in view of Bramson et al. In response, the Examiner respectfully directs Applicant to the discussion of the 35 USC 103 rejection over Klebanoff in view of Bramson et al above.
Therefore, the rejection is maintained and amended to encompass the claims as currently written.
RE: Rejection of claims 1, 4, 11, 22, 34-35, 43-44, and 46 under 35 USC 103 over Klebanoff in view of Bramson et al and Kessler et al
Applicant has amended instant claim 44 to no longer require the kit to comprise a second vector comprising a nucleic acid sequence encoding FasL. As this broadens the scope of the instant claim, the claim is now covered within the rejection of Klebanoff in view of Bramson et al.
Therefore, the rejection is withdrawn.
RE: Rejection of claims 25, 27, and 47-49 under 35 USC 103 over Klebanoff in view of Kessler et al
Applicant has amended independent claim 25 to require the engineered cell to express a dominant negative Fas that comprises a CD40 endodomain, which is a new limitation that was not previously presented within the claim. This thereby obviates the rejection of record.
Therefore, the rejection is withdrawn.
New/Maintained Grounds of Rejection
Specification
The disclosure remains objected to because it contains an embedded hyperlink and/or other form of browser-executable code in Pages 46, 53, and 58 of the instant Specification filed 20 April 2026. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. It is of note that the top-level domain in the instant case would be “cbs.dtu.dk”.
Appropriate correction is required.
Claim Objections
Claim 46 is objected to because of the following informalities:
Regarding claim 46: The instant claim is objected to for being directed to “[a] kit of vectors” when only a single vector is required.
With that, the instant claim is further objected to for reciting “a first vector” when a second vector is no longer required. Instead, the claim should read as “a .
Appropriate correction is required.
Claim Interpretation
Under the broadest reasonable interpretation of each claim, all of the “optional” limitations are not required.
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 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.
Claims 1, 4, 11, 22, 25, 27, 34-35, 43-44, and 46-49 are rejected under 35 U.S.C. 103 as being unpatentable over Klebanoff (US 2021/0214415 A1, of record) in view of Bramson et al (US 2022/0348936 A1, of record).
Klebanoff is considered prior art under 35 USC 102(a)(2), with an effective filing date of 30 September 2018. Bramson et al is also considered prior art under 35 USC 102(a)(2), with an effective filing date of 16 September 2019.
Regarding claims 1, 22, 25, 27, 43-44, and 47: Klebanoff discloses methods and compositions for enhancing the immune response toward cancers and pathogens, wherein the methods and compositions comprise cells that comprise an antigen-recognizing receptor (e.g., a chimeric antigen receptor (CAR) or a T cell receptor (TCR)) and a dominant negative Fas polypeptide (Abstract).
As such, Klebanoff discloses transducing the cells with a retroviral vector comprising a first polynucleotide encoding a CAR and a second polynucleotide encoding dominant negative Fas (Paragraphs [0048], [0167], [0176], [0181]-[0184]). Klebanoff further discloses that the transduced cells are then exposed to recombinant FasL molecules oligomerized through a leucine zipper domain (Iz-FasL) to mimic the function of membrane-bound FasL (Paragraphs [0038]-[0040], [0256], [0287]-[0288], [0298], [0301]-[0302]; Figures 2B, 3C, 6B, 9-11).
Klebanoff further discloses that, in certain embodiments, the dominant negative Fas polypeptide comprises a partial or complete deletion of the death domain comprised within the intracellular domain (Paragraphs [0101]-[0105]). Klebanoff further discloses that the dominant negative Fas polypeptide can comprise a heterologous signal peptide (Paragraphs [0102], [0111]).
Klebanoff does not disclose that the dominant negative Fas polypeptide comprises the Fas extracellular domain and an endodomain from CD40, as required by instant claims 1, 25, and 43.
Bramson et al, however, disclose chimeric costimulatory receptor (CCR) molecules having an extracellular domain of a Tumor Necrosis Factor Superfamily member, a transmembrane domain and a cytosolic costimulatory signaling domain from a Tumor Necrosis Factor Receptor Superfamily member (Abstract).
As such, Bramson et al disclose CCR molecules comprising a Fas extracellular domain and a CD40 cytosolic domain (Paragraphs [0007]-[0010], [0120]-[0121], [0123], [0131]).
Bramson et al further disclose that the CCR molecules are expressed within T cells that further express a CAR or TCR (Paragraphs [0016]-[0018]). Bramson et al further disclose that the transduced T cells are cultured with FasL (Paragraphs [0083], [0203]-[0206]).
Therefore, it would have been prima facie obvious to have modified the method of Klebanoff such that the dominant negative Fas polypeptide is a chimera comprising the cytosolic domain – or endodomain – of CD40, as detailed in Bramson et al. One of ordinary skill before the effective filing date of the invention would have been motivated to utilize a chimera comprising a Fas extracellular domain and CD40 endodomain, as it allows for the replacement of the cell death signal with a costimulatory signal that enhances T cell survival (Bramson et al: Paragraph [0195]), and would have had a reasonable expectation of success since the disclosures of both Klebanoff and Bramson et al are concerned with the transduction of cells with a dominant negative Fas molecule and contacting of the cells with FasL. See MPEP § 2143(I)(G).
Consequently, Klebanoff as modified by Bramson et al render obvious a method of transducing cells with a retroviral vector comprising a first polynucleotide encoding a CAR (claims 22, 27) and a second polynucleotide encoding dominant negative Fas comprising a Fas extracellular domain and CD40 endodomain (claims 43-44). Klebanoff further discloses that the transduced cells are then exposed to Iz-FasL. This therefore renders obvious the methods of instant claims 1 and 47 and cell of instant claim 25.
Regarding claim 4: Following the discussion of claim 1, Klebanoff further discloses that the dominant negative Fas comprises a modification in the cytoplasmic death domain such that it does not bind a Fas-associated protein with death domain (FADD) polypeptide (Paragraphs [0101]-[0103]). This therefore reads on the method of the instant claim.
Regarding claim 11: Following the discussion of claim 1, Klebanoff further discloses that Iz-FasL mimics the function of membrane-bound FasL (Paragraphs [0038]-[0040], [0256], [0287]-[0288], [0298], [0301]-[0302]; Figures 2B, 3C, 6B, 9-11). As membrane-bound FasL is synonymous with FasL expressed on the surface of a cell, this therefore reads on the method of the instant claim.
Regarding claims 34-35 and 48-49: Following the discussion of claims 1 and 25, Klebanoff further discloses that the transduced cells can be comprised within a pharmaceutical composition (claims 34, 48) and administered to a subject suffering from cancer (claims 35, 49) (Paragraphs [0196]-[0198], [0206]-[0212]). This therefore reads on the pharmaceutical compositions and methods of the instant claims.
Regarding claim 46: As aforementioned in the discussion of claim 44, Klebanoff as modified by Bramson et al render obvious a retroviral vector comprising a first polynucleotide encoding a CAR and a second polynucleotide encoding dominant negative Fas comprising a Fas extracellular domain and CD40 endodomain.
Klebanoff further discloses kits comprising the vectors (Paragraphs [0219]-[0220]). This therefore renders obvious the kit of the instant claim for the same reasons as discussed in the rejection of instant claim 44.
Claims 1, 4, 11, 22-23, 25, 27, 34-35, 43-44, and 46-49 are rejected under 35 U.S.C. 103 as being unpatentable over Klebanoff (US 2021/0214415 A1, of record) in view of Bramson et al (US 2022/0348936 A1, of record), and further in view of Jarjour et al (US 2019/0241910 A1, of record).
The discussion of Klebanoff as modified by Bramson et al regarding claim 1 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Klebanoff as modified by Bramson et al render obvious claims 1, 4, 11, 22, 25, 27, 34-35, 43-44, and 46-49. Jarjour et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2), with publication date of 08 August 2019.
Regarding claim 23: As aforementioned in the discussion of claim 1, Klebanoff as modified by Bramson et al render obvious a method of transducing cells with a retroviral vector comprising a first polynucleotide encoding a CAR and a second polynucleotide encoding dominant negative Fas comprising a CD40 endodomain.
The combination of Klebanoff and Bramson et al do not teach that the cells comprise a nucleotide of interest that inhibits expression of an endogenous TCR, as required by instant claim 23.
Jarjour et al, however, disclose compositions for adoptive immune effector cell therapies for treatment, prevention, or amelioration of numerous conditions including, but not limited to cancer (Abstract).
As such, Jarjour et al disclose that the immune effector cells comprise modified TCRα alleles – such that the modified TCRα is non-functional – and a nucleic acid comprising a polynucleotide encoding an immunosuppressive signal damper and an engineered antigen receptor inserted into the one or more modified TCRα alleles (Paragraphs [0017]-[0019]). Jarjour et al further disclose that the immunosuppressive signal comprises a Fas exodomain, a transmembrane domain, and a modified endodomain that is unable to transduce immunosuppressive signals to the cell, and that the engineered antigen receptor is a CAR (Paragraphs [0030]-[0033], [0068], [0075]-[0077]).
Therefore, it would have been prima facie obvious to have modified the method of Klebanoff in view of Bramson et al such that the transduced cells further comprise non-functional TCRα alleles, as detailed in Jarjour et al. One of ordinary skill before the effective filing date of the invention would have been motivated to remove any residual TCR expression that may interfere with CAR signaling in engineered T cells (Jarjour et al: Paragraph [0009]), and would have had a reasonable expectation of success since the disclosures of both Klebanoff and Jarjour et al are concerned with the transduction of cells with a vector comprising a Fas molecule which only comprises a Fas exodomain and a CAR. See MPEP § 2143(I)(G).
Consequently, Klebanoff as modified by Bramson et al and Jarjour et al render obvious the transduction of cells with a vector comprising a dominant negative Fas molecule comprising a CD40 endodomain and CAR such that the expression of TCRα is inhibited. This therefore renders obvious the method of instant claim 23.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA G WESTON whose telephone number is (571)272-0337. The examiner can normally be reached Monday-Thursday 8AM - 4PM (CT); Friday 8AM - 11AM (CT).
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/ALYSSA G WESTON/Examiner, Art Unit 1633
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