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 the Claims
Applicant’s submission filed 16 October 2025 has been entered. Claims 1, 4, 11, 22-23, 25, 27, 34-35, 43-44, and 46-49 are pending. Claims 1, 4, 11, 22-23, 25, 27, 43, and 46 have been amended, while claims 5-6 have been cancelled without prejudice or disclaimer. 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.
Status of Prior Rejections/Response to Arguments
RE: Nucleotide and/or amino acid disclosure
The substitute Specification and replacement drawing sheets filed 16 October 2025 are acknowledged and entered into the application file.
With that, Applicant’s amendments to each of the drawings and Specification adding both sequence identifiers and an incorporation by reference paragraph obviate the objections of record.
Therefore, the objections are withdrawn.
RE: Objection to the Specification
The substitute Specification filed 16 October 2025 is acknowledged and entered into the application file.
With that, Applicant’s amendment to the title and removal of the referenced colors in regards to
Figure 2 on Page 80 obviate the objections of record pertaining to those items. 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 title and references to colors, and maintained for the inclusion of hyperlinks or otherwise browser-executable code.
RE: Objection to claims 4-6, 11, 22-23, 25, 27, 43, and 46
The cancellation of claims 5-6 render the objections of record moot for those claims. For the remaining claims, Applicant’s amendments to each of claims 4, 11, 22-23, 25, 27, 43, and 46 obviate the current objections of record.
Therefore, the objections are withdrawn.
RE: Rejection of claim 11 under 35 USC 112(b)
Applicant’s amendment to instant claim 11 clarifies the claim scope, thus obviating the rejection of record.
Therefore, the rejection is withdrawn.
RE: Rejection of claims 1, 4, 11, 22, 34-35, and 43-44 under 35 USC 102(a)(2) over Klebanoff
Applicant has amended independent claims 1 and 43 to require the nucleic acid sequence which encodes dominant negative Fas to comprise an endodomain of CD40, which is a new limitation that was not previously presented within the claims. This thereby obviates the rejection of record.
Therefore, the rejection is withdrawn.
RE: Rejection of claims 1, 4-6, 11, 22, 34-35, and 43-44 under 35 USC 103 over Klebanoff in view of Bramson et al
The cancellation of claims 5-6 renders the rejection moot for those claims. For the remaining claims, Applicant's arguments filed 16 October 2025 have been fully considered but they are not persuasive.
Applicant has traversed the rejection asserting in Pages 8-9 of the Remarks filed 16 October 2025 that Bramson et al do not teach a costimulatory CD40 domain in a dominant negative Fas molecule. In response, the Examiner respectfully submits that Bramson et al do disclose a dominant negative Fas (dnFas) molecule that comprises a CD40 endodomain, as Bramson et al disclose that 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.
Applicant has further traversed the rejection, asserting in Page 9 of the Remarks filed 16 October 2025 that the combination of Klebanoff and Bramson et al fail to teach the co-expression of dnFas together with FasL. With that, Applicant asserts that the co-expression of dnFas and FasL has distinct advantages. In response, the Examiner respectfully submits that at least independent claims 1 and 43 do not require the co-expression of dnFas and FasL, as those are only disclosed within options (b) and (c) of instant claim 1 wherein the claim is directed to options (a), (b), or (c). Likewise, instant claim 43 lists “a nucleic acid sequence encoding FasL” as an optional limitation. In regards to the purported advantages of the co-expression of dnFas and FasL, the Examiner respectfully submits that Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references.
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 Jarjour et al
Applicant has amended independent claims 1 and 43 to require the nucleic acid sequence which encodes dominant negative Fas to comprise an endodomain of CD40, which is a new limitation that was not previously presented within the claims. This thereby obviates the rejection of record.
Therefore, the rejection is withdrawn.
RE: Rejection of claims 1, 4, 11, 22, 25, 27, 34-35, 43-44, and 46-49 under 35 USC 103 over Klebanoff in view of Kessler et al
Applicant has amended independent claims 1, 43, and 46 to require the nucleic acid sequence which encodes dominant negative Fas to comprise an endodomain of CD40, which is a new limitation that was not previously presented within the claims. This thereby partly obviates the rejection of record.
However, Applicant has not amended independent claim 25 to require the engineered cell to express a dominant negative Fas that comprises a CD40 endodomain. Instead, Applicant has traversed the rejection, asserting in Page 10 of the Remarks filed 16 October 2025 that Kessler et al do not relate to T cells or CAR-T cells, rather disclosing pharmaceutical compositions comprising an adenoviral vector comprising Fas or FasL. With that, Applicant further asserts that Kessler et al do not teach the co-expression of Fas and FasL to give a cell a competitive advantage. In response, the Examiner respectfully submits that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Kessler et al is a secondary reference relied upon to teach the transduction of cells with a vector comprising nucleic acids encoding proteins that are deleterious to cancer cells, including FasL.
Therefore, the rejection is withdrawn for claims 1, 4, 11, 22, 34-35, 43-44, and 46, and maintained for claims 25, 27, and 47-49.
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 16 October 2025. 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.
In addition, the table header of “SEQ ID NO.” within Table 1 on Page 27 of the instant Specification filed 16 October 2025 is not comprised within its own section, thus the “Protein” heading reads as “Protein No.” and the “SEQ ID NO.” heading reads as “SEQ ID”.
Furthermore, the tables on Pages 79 and 81 of the instant Specification filed 16 October 2025 comprise shading. Shading is not allowed within the instant disclosure, as it sharply reduces the reproduction quality. See Patent Rule 1.52.
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, 34-35, and 43-44 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, and 43-44: 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 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 modify 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 (claim 22) 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 reads on method part (a) of instant claim 1.
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: Following the discussion of claim 1, Klebanoff further discloses that the transduced cells can be comprised within a pharmaceutical composition (claim 34) and administered to a subject suffering from cancer (claim 35) (Paragraphs [0196]-[0198], [0206]-[0212]). This therefore reads on the pharmaceutical composition and method of the instant claims.
Claims 1, 4, 11, 22-23, 34-35, and 43-44 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, 34-35, and 43-44. Jarjour et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2), with an effective filing date of 11 March 2016.
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 modify 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.
Claims 1, 4, 11, 22, 34-35, 43-44, and 46 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 Kessler et al (US 2006/0257369 A1, of record).
The discussion of Klebanoff as modified by Bramson et al regarding claims 43-44 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, 34-35, and 43-44. Kessler et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2), with an effective filing date of 14 November 2003.
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 (Paragraph [0028]).
Klebanoff further discloses that the cells transduced by the vector 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 the transduced cells can be comprised within a pharmaceutical composition and administered to a subject suffering from cancer.
Although the transduced cells are contacted with FasL, Klebanoff as modified by Bramson et al do not teach that the cells are engineered to express FasL, as required by instant claim 46.
Kessler et al, however, disclose methods for treating cancer in humans (Abstract). As such, Kessler et al disclose the transduction of cells with a vector comprising nucleic acid sequences encoding proteins that are deleterious to cancer cells, including Fas, Fas ligand (FasL), which are known in the art (Paragraphs [0037], [0048], [0055], [0058).
Therefore, it would have been prima facie obvious to modify the method of Klebanoff in view of Bramson et al such that the cells are further transduced with a vector comprising a nucleic acid encoding FasL, as detailed in Kessler et al, instead of just being contacted with FasL. One of ordinary skill before the effective filing date would have been motivated to generate a cell expressing Fas and FasL proteins that are known in the art to be deleterious to cancer cells, and would have had a reasonable expectation of success since both Klebanoff and Kessler et al are concerned with formation of pharmaceutical compositions comprising transduced cells for the treatment of cancer. See MPEP § 2143(I)(A) and (G).
Consequently, Klebanoff as modified by Bramson et al and Kessler et al render obvious a kit of vectors, wherein a first vector comprises a nucleic acid encoding a CAR and a nucleic acid encoding dominant negative Fas comprising a CD40 endodomain, and a second vector comprises a nucleic acid encoding FasL. This therefore renders obvious the kit of vectors of the instant claim.
Claims 25, 27, and 47-49 are rejected under 35 U.S.C. 103 as being unpatentable over Klebanoff (US 2021/0214415 A1, of record) in view of Kessler et al (US 2006/0257369 A1, of record).
Klebanoff is considered prior art under 35 USC 102(a)(2), with an effective filing date of 30 September 2018. Kessler et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2), with an effective filing date of 14 November 2003.
Regarding claims 25, 27, and 47: Klebanoff discloses a method of transducing 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 the transduced cells can be comprised within a pharmaceutical composition and administered to a subject suffering from cancer.
Although the transduced cells are contacted with FasL, Klebanoff does not disclose that the cells are engineered to express FasL, as required by instant claim 25.
Kessler et al, however, disclose methods for treating cancer in humans (Abstract). As such, Kessler et al disclose the transduction of cells with a vector comprising nucleic acid sequences encoding proteins that are deleterious to cancer cells, including Fas, Fas ligand (FasL), which are known in the art (Paragraphs [0037], [0048], [0055], [0058).
Therefore, it would have been prima facie obvious to modify the method of Klebanoff such that the cells are further transduced with a vector comprising a nucleic acid encoding FasL, as detailed in Kessler et al, instead of just being contacted with FasL. One of ordinary skill before the effective filing date would have been motivated to generate a cell expressing Fas and FasL proteins that are known in the art to be deleterious to cancer cells, and would have had a reasonable expectation of success since both Klebanoff and Kessler et al are concerned with formation of pharmaceutical compositions comprising transduced cells for the treatment of cancer. See MPEP § 2143(I)(A) and (G).
Consequently, Klebanoff as modified by Kessler et al render obvious a method of transducing cells with vectors, wherein a first vector comprises a nucleic acid encoding a CAR (claim 27) and a nucleic acid encoding dominant negative Fas, and a second vector encoding FasL. This therefore reads on the cell of instant claim 25 and method of instant claim 47.
Regarding claims 48-49: Following the discussion of claim 25, Klebanoff further discloses that the transduced cells can be comprised within a pharmaceutical composition and administered to a subject suffering from cancer (Paragraphs [0196]-[0198], [0206]-[0212]). This therefore reads on the pharmaceutical composition of instant claim 48 and treatment method of instant claim 49.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 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).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Babic can be reached at (571) 272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALYSSA G WESTON/Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633