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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 09/26/2025 has been entered.
Response to Arguments
Applicant's arguments filed 09/26/2025 have been fully considered but they are not persuasive. Arguments pertaining to any remaining rejections are addressed in this Office Action.
Status of the Claims & Amendments
This action is in response to papers filed 09/26/2025 in which claims 1, 11, and 13 were amended, claims 3 - 4, 6 - 7, and 10 were canceled, and no new claims were added. All of the amendments have been thoroughly reviewed and entered.
Applicant has amended claim 1 to overcome the 35 USC § 103 rejection; the 35 USC § 103 rejections of claim 1 and dependent claims have not been overcome. Applicant' s arguments, see Pgs. 6 - 9, filed 09/26/2025, with respect to the 35 USC § 103 rejections have been fully considered but are not persuasive for the reasons discussed in this office action.
Any rejection or objection not reiterated herein has been overcome by amendment.
Election/Restrictions
Applicant’s election without traverse of Group I (i.e., claims 1-33, and 38 drawn to cells and a kit) in the reply filed on June 6, 2024, was previously acknowledged. With the cancellation of claims 2 - 10, the election of claims 1, 11-22, 25, 27-33, and 38 stands. Additionally, Applicant’s election without traverse of Species: tumor antigen (claim 19), CD 19 (claims 21 and 22), and CAR (claim 25), was previously acknowledged and stands.
Claims 23 - 24, 26, and 34 – 37 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected groups, there being no allowable generic or linking claim.
Accordingly, claims 1, 11-22, 25, 27-33, and 38 are currently under consideration.
Information Disclosure Statement
The information disclosure statements (IDS) filed 8 Feb 2022, 19 Sept 2022, 7 Aug 2023, and the Third-Party submission filed 17 May 2022 have been considered.
Claim Interpretation
Regarding claim 1, the term, “ an antimorphic mutation” with respect to Fas is being interpreted as a Fas polypeptide that interacts with a wild-type Fas polypeptide, but blocks its signal transduction to downstream molecules and is the same as “dominant negative” (bridging Pgs. 24-25, specification).
Regarding the sequences disclosed, the following relationship between sequences is understood. Differences highlighted in bold:
1 50
US-17-214-436-12 MLGIWTLLPLVLTSVARLSSKSVNAQVTDINSKGLELRKTVTTVETQNLE
US-17-214-436-14 MLGIWTLLPLVLTSVARLSSKSVNAQVTDINSKGLELRKTVTTVETQNLE
US-17-214-436-10 MLGIWTLLPLVLTSVARLSSKSVNAQVTDINSKGLELRKTVTTVETQNLE
51 100
US-17-214-436-12 GLHHDGQFCHKPCPPGERKARDCTVNGDEPDCVPCQEGKEYTDKAHFSSK
US-17-214-436-14 GLHHDGQFCHKPCPPGERKARDCTVNGDEPDCVPCQEGKEYTDKAHFSSK
US-17-214-436-10 GLHHDGQFCHKPCPPGERKARDCTVNGDEPDCVPCQEGKEYTDKAHFSSK
101 150
US-17-214-436-12 CRRCRLCDEGHGLEVEINCTRTQNTKCRCKPNFFCNSTVCEHCDPCTKCE
US-17-214-436-14 CRRCRLCDEGHGLEVEINCTRTQNTKCRCKPNFFCNSTVCEHCDPCTKCE
US-17-214-436-10 CRRCRLCDEGHGLEVEINCTRTQNTKCRCKPNFFCNSTVCEHCDPCTKCE
151 200
US-17-214-436-12 HGIIKECTLTSNTKCKEEGSRSNLGWLCLLLLPIPLIVWVKRKEVQKTCR
US-17-214-436-14 HGIIKECTLTSNTKCKEEGSRSNLGWLCLLLLPIPLIVWVKRKEVQKTCR
US-17-214-436-10 HGIIKECTLTSNTKCKEEGSRSNLGWLCLLLLPIPLIVWVKRKEVQKTCR
201 250
US-17-214-436-12 KHRKENQGSHESPTLNPETVAINLSDVDLLKDITSDSENSNFRNEIQSLV
US-17-214-436-14 KHRKENQGSHESPTLNPETVAINLSDVDLSKYITTIAGVMTLSQVKGFVR
US-17-214-436-10 KHRKENQGSHESPTLNPETVAINLSDVDLSKYITTIAGVMTLSQVKGFVR
251 300
US-17-214-436-12 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
US-17-214-436-14 KNGVNEAKIVEIKNDNVQDTAEQKVQLLRNWHQLHGKKEAYDTLIKDLKK
US-17-214-436-10 KNGVNEAKIDEIKNDNVQDTAEQKVQLLRNWHQLHGKKEAYDTLIKDLKK
301 335
US-17-214-436-12 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
US-17-214-436-14 ANLCTLAEKIQTIILKDITSDSENSNFRNEIQSLV
US-17-214-436-10 ANLCTLAEKIQTIILKDITSDSENSNFRNEIQSLV
Claim Rejections - 35 USC § 112
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.
Claims 1, 11-22, 25, 27-33, and 38 are rejected 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.
Claim 1 recites the limitation "the" in wherein the Fas polypeptide... There is insufficient antecedent basis for this limitation in the claim.
One would not know which Fas polypeptide is being referred to in the wherein clause because (b) recites two Fas polypeptides. See recitation of (b): a Fas polypeptide comprising an antimorphic mutation that acts antagonistically to a wild type Fas polypeptide…Therefore, the Fas polypeptide that comprises the amino acid sequence set forth in SEQ ID NO: 12 or SEQ ID NO: 14, as recited in the wherein clause could be referring to the antimorphic Fas or the wild-type Fas. As such, the limitation in the wherein clause is indefinite.
Those claims identified in the statement of rejection but not explicitly referenced in the rejection are also rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
Examiner Note
Below rejections are based on the same references as previous OAs. However, different embodiments presented in the reference are focused on.
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.
Claim(s) 1, 11-22, 25, 27-29, 32-33, and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Pule (GB1810070.1, corresponding to US 20210363217 with a priority filing date: 06/19/2018) in view of Wang (Wang, L., et al. The Fas–FADD death domain complex structure reveals the basis of DISC assembly and disease mutations. Nat Struct Mol Biol 17, 1324–1329 (2010)).
Regarding claim 1, Pule teaches a cell which comprises:
(i) an engineered intracellular binding polypeptide which is capable of modulating an
intracellular signalling pathway; and
(ii) a chimeric antigen receptor (CAR) or a transgenic T cell receptor (TCR) (Pg. 2, 2nd para).
Pule’s recitation (ii) reads on instant claim 1(a) and Pule recitation (i) broadly reads on instant claim 1(b). Specifically, Pule teaches an embodiment wherein the engineered intracellular binding polypeptide:
(i) reduces or prevents an interaction between its target polypeptide and a second
polypeptide;
(ii) sequesters and/or facilitates degradation of its target polypeptide; or
(iii) activates its target polypeptide (Pule claim 12).
The intracellular signalling pathway in Pule’s claim 1 is an apoptosis, self-renewal, cell survival or cell activation pathway (claim 15). Pule further teaches that various modifications and variations of the described methods and system of the invention will be apparent to those skilled in the art (lines 11-12, Pg. 47).
See comparison of Pule’s invention with instant claim 1:
Pule (GB1810070.1) pg. 2 recitation
Instant Claim 1 recitation
Thus, in a first aspect the present invention provides a cell which comprises:
(i) an engineered intracellular binding polypeptide which is capable of modulating an intracellular signalling pathway; and
(ii) a chimeric antigen receptor (CAR) or a transgenic T cell receptor (TCR).
A cell comprising:
(a) an antigen-recognizing receptor that binds to an antigen, and
(b) a Fas polypeptide comprising an antimorphic mutation that acts antagonistically to a wild type Fas polypeptide wherein the Fas polypeptide comprises the amino acid sequence set forth in SEQ ID NO:12 or SEQ ID NO: 14.
Pule does not name the intracellular binding polypeptide a Fas polypeptide comprising an antimorphic mutation of Fas, but Pule teaches the intracellular binding polypeptide functions by inhibiting /reducing the activity of the pro-apoptotic protein Fas (lines 16-20, Pg. 10); i.e., acts antagonistically to a wild type Fas polypeptide, as recited in the amendment. See following recitation from Pule bridging pgs. 1 and 2:
Thus, the intracellular binding polypeptide may improve the ability of the engineered immune cell to function in a hostile microenvironment by reducing its susceptibility to apoptosis, increasing the level of self-renewal and/or cell survival and/or increasing levels of cell activation (e.g. following antigen binding to a CAR or transgenic TCR).
Thus, Pule teaches an invention that provides a solution to modulate the ability of engineered immune cells to function efficiently in adoptive immunotherapy of cancer by allowing the cell that comprises the engineered polypeptide to reduce its susceptibility to apoptosis (lines 6-7 and 19-24 on Pg. 1 and lines bridging pgs. 1 - 2).
Regarding the limitation wherein the Fas polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 12 or SEQ ID NO: 14 of claim 1, Pule teaches that the Fas protein is human Fas (SEQ ID NO: 7, Uniprot accession number P25445, lines 20-21, Pg. 11). Pule further teaches the sequence of the cytoplasmic domain of Fas (SEQ ID NO: 8). See sequence below of Fas with the sequence of the intracellular (cytoplasmic) domain underlined, both as disclosed by Pule (SEQ ID NO: 7 and 8 respectively):
MLGIWTLLPLVLTSVARLSSKSVNAQVTDINSKGLELRKTVTTVETQNLEGLHHDGQFCHKPCPPGERKARDCTVNGDEPDCVPCQEGKEYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCKPNFFCNSTVCEHCDPCTKCEHGIIKECTLTSNTKCKEEGSRSNLGWLCLLLLPIPLIVWVKRKEVQKTCRKHRKENQGSHESPTLNPETVAINLSDVDLSKYITTIAGVMTLSQVKGFVRKNGVNEAKIDEIKNDNVQDTAEQKVQLLRNWHQLHGKKEAYDTLIKDLKKANLCTLAEKIQTIILKDITSDSENSNFRNEIQSLV. This sequence is the same as instant SEQ ID NO: 10 disclosed; i.e., wild-type Fas.
Regarding claim 11, Pule further teaches that the intracellular binding polypeptide enhances cell persistence of the immunoresponsive cell (improve the ability of engineered immune cells to proliferate, survive and/or engraft in a microenvironment; lines 20-23, Pg. 1).
Regarding claim 12, Pule further teaches that the antigen-recognizing receptor is expressed from a vector (lines 1-2, Pg. 31).
Regarding claim 13, Pule further teaches that the exogenous intracellular binding polypeptide is expressed from a vector (lines 24-27, Pg. 37).
Regarding claim 14, Pule further teaches that the cell is an immunoresponsive cell (cytolytic immune Cell, lines 11-12, Pg. 44).
Regarding claims 15 and 16, Pule further teaches that the cell is a cell of the lymphoid lineage like Natural Killer (NK) cell (NK cells, belonging to the group of innate lymphoid cells, lines 19 - 24, Pg. 29).
Regarding claim 17, Pule further teaches that the cell is a T cell (lines 15-16, Pg. 44).
Regarding claim 18, Pule further teaches that the T cell of claim 17 is a cytotoxic T lymphocyte (CTL) cell (Cytolytic T cells (TC cells, or CTLs), line 7, Pg. 29).
Regarding claims 19 and 20, Pule further teaches that the antigen is a tumor antigen (tumour associated antigens (TAA), Table 1 and lines 14-16, Pg. 31).
Regarding claim 21, Pule further teaches that the tumor antigen is selected from a group of antigens that includes CD19 (Table 1, Pg. 31).
Regarding claim 22, Pule further teaches that the antigen is CD19 (Table 1, Pg. 31).
Regarding claim 25, Pule further teaches that the antigen-recognizing receptor is a chimeric antigen receptor (CAR) (lines 24-27, Pg. 37).
Regarding claim 27, Pule further teaches that the CAR comprises an extracellular antigen-binding domain, a transmembrane domain, and an intracellular signaling domain (lines 12-13, Pg. 30).
Regarding claim 28, Pule further teaches that the intracellular signaling domain further comprises at least one co-stimulatory signaling region (comprise additional co-stimulatory signaling, lines 12-13, Pg. 33).
Regarding claim 29, Pule further teaches that the at least one co-stimulatory signaling region comprises a CD28 polypeptide (lines 12-13, Pg. 33).
Regarding claim 32, Pule further teaches a composition comprising an effective amount of a cell of claim 1 (a pharmaceutical composition comprising an engineered cell, lines 5-6, Pg. 38).
Regarding claim 33, Pule further teaches that the composition further comprises a pharmaceutically acceptable excipient (lines 13-14, Pg. 38).
Regarding claim 38, Pule further teaches a kit comprising a cell of claim 1 (lines 26-27, Pg. 34).
Pule does not teach or suggest that the antimorphic Fas polypeptide comprises SEQ ID NO:12 or SEQ ID NO: 14 as recited in claim 1 or how to arrive at such sequences.
However, before the effective filing date of instant application, Wang had taught several mutations within the Fas cytoplasmic (death domain) complex (title, abstract). Wang taught such mutations from autoimmune lymphoproliferative syndrome (ALPS) patients (abstract) and further tested some of these mutations for their function; i.e., abrogation of mutant Fas’s ability to signal apoptosis (Fas mutants engineered to disrupt the Fas–FADD complex also act as dominant negatives, D260V almost completely abrogated apoptosis; line 4 and lines 8-9 below Fig 4, left-side column, Pg. 1328).
e.g., the D260V modification in the cytoplasmic death domain prevents the binding between the dominant negative Fas polypeptide and a FADD polypeptide (Fas mutants engineered to disrupt the Fas–FADD complex also act as dominant negatives, D260V almost completely abrogated apoptosis; line 4 and line 8-9 below Fig 4, left-side column, Pg. 1328). Wang taught that the point mutations in human Fas are structure-based point mutations or mutations obtained from ALPS patients (Fig. 2b, and Fig. 2b legend). The location of the point mutation disclosed by Wang (line 8 below Fig 4, left-side column, Pg. 1328) is bolded in Pule’s sequence above. Wang further teaches the sequence of the death domain of Fas (Fig. 2b, and Fig. 2b legend). By alignment, this position of the sequence is identical to instant sequence. Wang further teaches that the dominant negative Fas polypeptide comprises a point mutation at position 260 of a human Fas consisting of the amino acid sequence set forth in instant SEQ ID NO: 10 (Fas mutants engineered to disrupt the Fas–FADD complex also act as dominant negatives, lines 4 and 8 below Fig 4, left-side column, Pg. 1328).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, seeking long-lived immunoresponsive cell in vivo for adoptive immunotherapy (a goal of Pule), to combine the teachings of Wang with the teachings of Pule because Wang provides the teachings to make an antimorphic mutant of Fas and Pule provides the motivation to seek out peptides that will abrogate Fas-mediated apoptotic signaling (among other teachings) in therapeutic approaches. It would have been prima facie obvious for the skilled artisan to follow the teachings of Wang and make modifications in the cytoplasmic domain of Fas because of the known benefit of such modifications taught by Wang. Thus, given the teachings of the cited references and the level of skill of the ordinary skilled artisan, one of ordinary skill in the art would have been motivated to modify the cytoplasmic domain of Pule as taught by Wang. One of ordinary skill in the art would have reasonable expectation of success because both references focus on the intracellular binding polypeptide of Fas as essential to making an antimorphic Fas. See MPEP 2143 I (G).
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[AltContent: rect]Thus, one of ordinary skill in the art seeking to modify human Fas, would take the sequence of human Fas taught by Pule (SEQ ID NO: 7 and 8 combined), and modify the amino acid at position 260 because Wang teaches that a D260V mutation at this position abrogates apoptosis. By alignment, it is seen that modifying a D to a V in combined SEQ ID NO: 7 and 8 of Pule one would obtain the sequence of SEQ ID NO: 14 as shown here:
In the alignment above, Qy is combination of SEQ ID NO: 7 and 8 of Pule) and Db is SEQ ID NO: 14 of the instant application the boxed region is the position indicated by Wang (D260V) as being responsible for abrogating apoptosis.
Thus, one would obtain the cell of claim 1, wherein the dominant negative Fas polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 14, as recited.
SEQ ID NO: 12 is not considered here because it has been recited as being optional; i.e., or.
Thus, Pule in view of Wang make obvious instant claims 1, 11-22, 25, 27-29, 32-33, and 38.
Claims 30 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Pule (GB1810070.1, filing date: 06/19/2018) and Wang (Wang, L., et al. The Fas–FADD death domain complex structure reveals the basis of DISC assembly and disease mutations. Nat Struct Mol Biol 17, 1324–1329 (2010)) as applied to claims 1, 11-22, 25, 27-29, 32-33, and 38 above, and in view of Adusumilli (US 20180273601, published 2018-09-27).
Regarding claims 30 and 31, the cell of claim 1 is discussed above.
Pule does not teach or suggest that the cell further comprises a suicide gene and the suicide gene is inducible Caspase 9 Suicide gene.
However, Adusumilli teaches immune cells which (a) recombinantly express a chimeric antigen receptor (CAR), and a dominant negative form of an inhibitor of a cell mediated immune response of the immune cell, and (b) an exogenous dominant negative immune checkpoint polypeptide (paragraph (0014]) as a means of improved adoptive immunotherapy (paragraph [0218]). Adusumilli also teaches that further modifications can be introduced to the immune cells of the invention such as, the cells can be modified to address immunological complications and/or targeting by the CAR to healthy tissues that express the same target antigens as the tumor cells. For example, a suicide gene can be introduced into the cells to provide for depletion of the cells when desired (paragraph [0079]) and thus eliminate any undesired effects of an engineered adoptive immune cell. Adusumilli further teaches a specific embodiment wherein the suicide gene is an inducible Caspase 9 Suicide gene (last line of paragraph [0015]).
It would have been obvious to one of ordinary skill in the art, seeking long-lived immunoresponsive cell in vivo for adoptive immunotherapy (a goal of Pule), to combine the teachings of Adusumilli with the teachings of Pule because Adusumilli provide the teachings to deplete rogue immunoresponsive cells and Pule seek to use engineered immunoresponsive cells in therapeutic approaches. It would have been prima facie obvious for the skilled artisan to follow the teachings of Adusumilli and make further modifications in the immunoresponsive cell of Pule because of the known benefit of such modifications disclosed by Adusumilli. Thus, given the teachings of the cited references and the level of skill of the ordinary skilled artisan, one of ordinary skill in the art would have been motivated to combine prior art elements according to known methods to yield predictable results (introduce the suicide gene of Adusumilli into the engineered immunoresponsive cell of Pule). See MPEP 2143 I.(A) and (G).
Thus, Pule and Wang in view of Adusumilli make obvious instant claims 30 and 31.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Response to Arguments
Applicant’s arguments, see Pgs. 6 - 8, filed 9-26-2025, with respect to rejections under 35 USC § 103 have been fully considered but they are not persuasive for the reasons discussed below.
First, see Pg. 6, Applicant summarizes the USC § 103 rejection presented in the Final Office Action (FOA). Then, Applicant cites case law of Sandstrom v. Microsoft Corp., to argue that a skilled artisan not only could have made but would have been motivated to make the combinations or modifications of prior art to arrive at the claimed invention.
Next, see Pgs. 7-8, Applicants essentially assert that the Examiner has not established that one skilled in the art would have been motivated to arrive at the claimed subject matter based on the cited art, because:
1) the secondary reference of Wang teaches i) certain mutations of the Fas cytoplasmic domain from ALPS patients and the art shows that these mutations are responsible for pathogenic disease mechanisms associated with uncontrolled proliferation of lymphoid cells, ii) one of ordinary skill in the art would recognize that the abrogation of apoptosis, a hallmark of oncogenesis, would have an oncogenic effect if introduced into the cells of Pule, and iii) with such correlative observation between the mutations and their oncogenic potential, one of ordinary skill in the art would still have no motivation to combine the references as alleged by the Examiner.
2) Applicants proffer the reference of Villa-Morales et al (2014), [a] causative relationship between the occurrence of FAS mutations and cancer has been widely suggested in the literature. From this reference, Applicant conclude that the skilled in the art would not have been motivated to use any mutation of the cytoplasmic domain of Fas because said mutations could lead to uncontrolled proliferation and potentially cancer;
and
3) regarding the other secondary references of i) Tartaglia, Applicant argues, Tartaglia fails to disclose a dominant negative Fas (instead, it discusses a distinct protein, TNF-R1, that shares only 28% identity to Fas). Therefore, Applicant contends that there is no basis in Tartaglia to arrive at the claimed Fas polypeptide; ii) Adusumilli, Applicant argues, Adusumilli provides no suggestions relating to the use of Fas polypeptides comprising antimorphic mutations, it cannot cure the deficiencies of the remaining references.
Applicants arguments are not persuasive because:
Regarding 1), Wang and the art teaches certain mutations of the Fas cytoplasmic domain are associated with uncontrolled proliferation of lymphoid cells, The skilled artisan knows that association is not causation. Further, the mutations associated with uncontrolled proliferation of lymphoid cells are not the same mutations as discussed by Wang. Specifically, with respect to instant mutation, Wang on pg. 1328, left column, last para, recite:
As previously described (Martin DA, et al., Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4552-7. doi: 10.1073/pnas.96.8.4552), the ALPS-associated mutants A257D, D260Y and D260V almost completely abrogated apoptosis induced by either cross-linked anti-Fas antibody or FasL oligomerized through a leucine zipper tail (FasL-LZ) (Fig. 4c).
Abrogation of apoptosis is what a skilled artisan is seeking when adopting a dominant negative or antimorphic Fas polypeptide to enhance the cell persistence, prevent activation induced cell death, prevent FasL-induced cell death, and/or improving the anti-tumor effect of an immunoresponsive cell.
Regarding 2), art post Villa-Morales et al (2014) shows that mutations in cytoplasmic domain of Fas were continued to be used to prevent premature apoptosis in engineered immune cells. For e.g., Shannon Oda (Cheating death: a Fas-41BB immunomodulatory fusion protein obviates a death signal to enhance T cell function and adoptive therapy targeting leukemia and solid tumors, J IMMUNOL, vol. 200, 1 May 2018 (2018-05-01)) in abstract, discuss: efficacy of T cell immunotherapy is dampened by limited costimulation as well as increased inhibitory and death signals in the TME. In a model of leukemia, Fas-4-1BB-transduced T cells eradicated otherwise lethal disease and exhibited increased persistence. Fas-4-1BB is Fas protein mutated in its cytoplasmic domain (where the death domain resides).
Thus, not all mutations in the cytoplasmic domain are considered equal. Therefore, not all mutations are causative with respect to cancer.
Regarding 3), in response to applicant's arguments against the references individually, 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).
Specifically, i) Applicant has cancelled claims 6 – 7. Therefore the argument regarding Tartaglia is moot; ii) Applicant has not discussed Adusumilli’s deficiency with respect to suicide genes, as this was the limitation that Adusumilli was relied upon for. Applicant’s argument with respect to Adusumilli not teaching Fas, is moot. It was known before the effective filing date of instant application to include a suicide switch as a fail-safe mechanism in gene therapy. See Quay (WO 2018063985 A1) that modifies immune cells for gene therapy of cancer. The modified cells also comprise a safety switch chosen from death gene switches, fluorescein isothiocyanate (FITC)-based switches, and peptide neo-epitope (PE)-based switches, where the death gene switch is a human herpes simplex virus thymidine kinase type 1 gene (HSVtk), inducible caspase 9 (iCaspase9), or Fas-associated protein with death domain (FADD) (pg. 3, lines 19 – 23). In the instant case, and as suggested by primary and secondary references, the Fas cytoplasmic domain is modified. Therefore, FADD would not be a choice of suicide gene. One of skill in the art would pick any other gene disclosed by the reference, as a suicide gene of choice.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 11-22, 25, 27-33, and 38 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1- 96 of copending Application No. US 17/858,320, corresponding to US 20230058774 (referred to as ‘320) for reasons of record set forth in the office action of 03-26-2024, reiterated below.
. Although the claims at issue are not identical, they are not patentably distinct from each other because claims of the aforementioned co-pending application are also drawn to a dominant negative Fas polypeptide comprising a first modification in the cytoplasmic death domain. Any additional limitations of the ‘320 claims are encompassed by the open claim language “comprising” found in the instant claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Applicant’s Remarks
Applicant's arguments filed 9-26-2025 have been fully considered but they are not persuasive because applicant did not address the merits of the provisional rejection.
It is noted that the response states that they will address the rejection at such time as the claims are otherwise considered allowable.
Relevant Prior Art
Shannon (WO 2018/170475 Al , of record as 3rd party IDS submission) teach immunomodulatory fusion proteins containing an extracellular binding domain and an intracellular signaling domain, wherein binding of a target can generate a modulatory signal in a host cell, such as a T cell (abstract). On pg. 8, last para, an embodiment is presented wherein the extracellular component comprises an extracellular portion of a CD95 (Fas) and the intracellular portion is another protein. On pg. 41, Shannon disclose: For example, dominant negative fusion proteins are included within the scope of the disclosure. Example 25 shows immunotherapy with T cells expressing Fas-4-1BB fusion proteins improve survival.
Conclusion
No claims are allowed.
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/SHABANA S MEYERING/Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635