DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed on July 17, 2025 is acknowledged.
Claims 2, 3, and 8-11 are canceled.
Claims 1, 4-7, and 12-20 are pending and currently under investigation.
Examiner notes, on the record, that the Applicant has traversed all rejections under 35 USC § 112(a) Enablement and 103 set forth in the Office Action mailed on April 18, 2025. See the Remarks filed July 17, 2025, pages 6-9.
The Applicant has also requested in the Remarks filed July 17, 2025 that the nonstatutory double patenting rejections (NSDP) over the claims of co-pending Application Nos. 18/478,247, 18/547,748, 18/719,814 set forth in the Office Action mailed on April 18, 2025 be held in abeyance until the claims are otherwise allowable. It is also noted that the Applicant failed to respond to the 9 other NSDP rejections. See page 9 of the Remarks.
Thus, in view of this response, all of the NSDP rejections are maintained for the reasons of record.
In view of the applicant’s amendment filed on July 17, 2025, the rejections under 35 USC § 112(d) and 112(a) Enablement set forth in the Office Action mailed on April 18, 2025 have been obviated and are therefore withdrawn.
It is noted that the Examiner brought to the attention of the Applicant’s Attorney of record, Brian Giles, on July 13, 2025 that neither a marked up or substitute Specification was filed with the Applicant’s response filed July 17, 2025 which notes the enclosure of such (see the Amendments to the Specification file July 17, 2025). In response, the Attorney of record filed the marked up or substitute Specification on August 13, 2025.
Thus, the objections to the specification set forth in the Office Action mailed on April 18, 2025 have been obviated and are therefore withdrawn in view of the amended Specification filed on August 13, 2025.
In view of the applicant’s amendment filed on July 17, 2025, the rejections under 35 USC § 103 to claims 1, 4-7, and 13-16 set forth in the Office Action mailed on April 18, 2025 are withdrawn.
The following objections and rejections are set forth.
Priority
Applicant’s claim for domestic benefit to provisional US application 62/888,055 filed on August 16, 2019 is acknowledged. Claims 1, 4-7, and 12-20 are being examined with an effective filing date of August 16, 2019.
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.
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.
This is a New Ground of Rejection necessitated by applicant's amendment. Claims 1, 4-7, and 13-16 are rejected under 35 U.S.C. 103 as being unpatentable over Riley et al. 2019 (US20190022199A1, an IDS reference filed May 2, 2022) in view of Dranoff 2017 (WO2017149515, an IDS reference filed May 2, 2022), Diehl et al. 2013 (WO2013006505, an IDS reference filed May 2, 2022), Ju et al. 2016 (J Immunol. 197(12), 4613-4625 a reference of record), and Meyer and Negrin 2019 (WO2019157158, an IDS reference filed May 2, 2022).
The teachings of Riley et al. are outlined in the rejection under 35 U.S.C. 103 in the Office Action mailed on April 18, 2025.
The reference teachings differ from this instant invention by not teaching that the alloreactive/ autoreactive lymphocytes express CD83 or that the Treg cells are genetically modified to express the instantly claimed anti-CD83 chimeric antigen receptor (CAR) polypeptide, wherein in the CAR’s antigen binding domain is a single-chain variable fragment (scFv) of an anti-CD83 antibody comprising VH-CDRs1-3 and VL-CDRs1-3 amino acid sequences of SEQ ID NOs: 1-6, respectively. The reference teachings further differ from the instant invention by not teaching HLA mismatched donor cells.
The teachings of Dranoff, Diehl et al., Ju et al., and Meyer and Negrin are outlined in the rejection under 35 U.S.C. 103 in the Office Action mailed on April 18, 2025.
Dranoff further teaches that the antigen-binding domain of a CAR can comprise an scFv (e.g. see page 22, line 10) and that an scFv refers to a fusion protein comprising the VH and VL domains of a parent antibody, and wherein the scFv retains the specificity of the intact parent antibody from which it is derived (e.g. see page 23, lines 12-17).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Riley et al. to incorporate the teachings of Dranoff, Diehl et al., Ju et al., and Meyer and Negrin to include that the alloreactive/autoreactive lymphocytes express CD83; that the Tregs that are genetically modified to express the instantly claimed anti-CD83 CAR polypeptide; and that the donor cells are not HLA matched to the subject.
Given the well-known problems with graft versus host disease (GVHD) or graft rejection following transplantation, Treg cells serve to ameliorate, inhibit, or reduce an adverse responses by the donor transplant against the recipient (e.g. see Riley et al. [0167]). A transplant, treated in order to activate transplant T cells, can be contacted with Tregs in order to reduce, inhibit, or eliminate the activity of the T cells that were activated by the treatment (e.g. see Riley et al. [0170]).
However, while contacting alloreactive T cells non-specifically with Treg cells is effective at reducing the risk of GVHD, a more targeted approach that enhances the immunosuppressive effect of the Tregs is desirable. As such, given the known importance of CD83 in immune function and its specific expression on alloreactive/autoreactive lymphocytes (e.g. see Diehl et al. [0269]; and Ju et al. pages 4621 and 4623), a targeted approach based on CD83 expression is of interest.
CD83 is a well-conserved type-1 membrane protein of the Ig superfamily found primarily on the surface of mature dendritic cells (DCs) (e.g. see Diehl et al. [0269]). Interestingly, CD4+ and CD8+ T cells upregulate surface CD83 expression transiently in response to stimulation, while CD83 is neither present nor expressed to any great extent on unactivated human natural Treg (e.g. see Ju et al. page 4623, left and right columns). This suggests that CD83 targeting immunotherapies, such as an anti-CD83 mAb, could encourage Treg alloimmune regulation after transplantation (e.g. see Ju et al. page 4623, right column).
As an alternative to mAb-based immunotherapy, approaches aimed at generating cells that express chimeric antigen receptors (CARs) is also advantageous given a CAR’s ability to facilitate a rapid and sustained immune response (e.g. see Dranoff page 1, lines 17-20). Dranoff discloses the design of cells, such as regulatory T cells, that express CARs that may target CD83 (e.g. see Dranoff page 2, lines 21-23; page 14, lines 8-10; and page 3, lines 1-3). These CARs comprise at least an extracellular antigen binding domain, a transmembrane domain, and a cytoplasmic signaling domain (also referred to as an intracellular signaling domain). Dranoff teaches that the antigen binding domain may comprise an scFv which is a fusion protein comprising a VH and VL domain of a parent antibody and retains the antigen specificity of the intact parent antibody from which it is derived (e.g. see Dranoff see page 22, line 10 and page 23, lines 12-17).
Given that the surface expression of CD83 is upregulated on activated T cells and it is not present or expressed to any great extent on Treg; it would have been obvious to a skilled artisan to implicate CD83 as an immunotherapeutic target to improve Treg alloimmune regulation after transplantation in Riley et al.’s methods of generating a general immunosuppressive effect by broadly inhibiting alloreactive T cells in a donor transplant. Specifically, it would have been obvious to a skilled artisan to modify Riley et al.’s methods for inhibiting alloreactive T cells and generating an immunosuppressive effect in a mammal having an alloresponse or autoimmune response by administering Treg and instead administer a genetically modified anti-CD83 CAR Treg which would, as a skilled artisan would have reasonably predicted, selectively target CD83-expressing alloreactive/autoreactive T cells to invoke a rapid, specific, and sustained immunosuppressive response, while avoiding a more general immunosuppressive effect. A skilled artisan would reasonably recognize that this would presumably improve Riley et al.’s method of generating an immunosuppressive effect by specifically suppressing alloreactive T cells while avoiding the beneficial Treg population in a donor transplant with a reasonable expectation of success.
Furthermore, regarding the structure of the antigen-binding domain of the CAR, given that a CAR may comprise an scFv which comprises the VH and VL domains of a parent antibody and retains the parent antibody’s antigen specificity, it would have been obvious to a skilled artisan to have selected the anti-CD83 60B10 antibody disclosed by Diehl et al. as the parent antibody from which the scFv is derived with a reasonable expectation of success. The 60B10 antibody comprises the instantly claimed CDRs and VH and VL regions (e.g. see instant SEQ ID NOs: 1-6, 19, and 20 and the sequence alignments below).
VH alignment (CDRs are bolded and underlined):
Query Match 100.0%; Score 648; Length 120;
Best Local Similarity 100.0%;
Matches 120; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLKESGPGLVKPSQSLSLTCSVTGFSITTGGYWWTWIRQFPGQKLEWMGYIFSSGNTN 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLKESGPGLVKPSQSLSLTCSVTGFSITTGGYWWTWIRQFPGQKLEWMGYIFSSGNTN 60
Qy 61 YNPSIKSRISITRDTSKNQFFLQLNSVTTEGDTARYYCARAYGKLGFDYWGQGTLVTVSS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 YNPSIKSRISITRDTSKNQFFLQLNSVTTEGDTARYYCARAYGKLGFDYWGQGTLVTVSS 120
VL alignment (CDRs are bolded and underlined):
Query Match 100.0%; Score 587; Length 111;
Best Local Similarity 100.0%;
Matches 111; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QPVLTQSPSASASLGNSVKITCTLSSQHSTYTIGWYQQHPDKAPKYVMYVNSDGSHSKGD 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QPVLTQSPSASASLGNSVKITCTLSSQHSTYTIGWYQQHPDKAPKYVMYVNSDGSHSKGD 60
Qy 61 GIPDRFSGSSSGAHRYLSISNIQPEDEADYFCGSSDSSGYVFGSGTQLTVL 111
|||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GIPDRFSGSSSGAHRYLSISNIQPEDEADYFCGSSDSSGYVFGSGTQLTVL 111
Finally, regarding the claim limitation “wherein the subject is the recipient of transplant donor cells that are not HLA matched to the subject,” it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified Riley et al.’s method to include donor cells that are not HLA matched to the subject.
Given that HLA is implicated in GVHD (e.g. see Meyer and Negrin [0066]), it would have been obvious to a skilled artisan to include HLA mismatched donor cells in Riley et al.’s methods in order to increase the pool of donors available to the recipient with a reasonable expectation of success.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Applicant’s arguments have been fully considered but have not been found persuasive.
The Applicant argues that:
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Regarding the cited references, the Applicant argues that:
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Applicant further argues that Dranoff teaches the use of CAR-T cells that dually bind to a tumor antigen and to a B-cell antigen (e.g. CD83). The purpose of the anti-CD83 CAR in this CAR-T cell is to use B cell-binding as a source of additional stimulation for the CAR-T cell to increase proliferation and persistence. Therefore, the CD83 CAR is only useful in the teachings of Dranoff in a CAR-T cells dually expressing a second CAR, e.g. that binds a tumor antigen. More significantly, nothing in Dranoff suggests that the CD83 CAR would have any benefit on a Treg's immunosuppressive effects. Also, since very little is known about the effects of CARs in Tregs, the person of ordinary skill in the art would not reasonably assume that a CD83 CAR would stimulate a Treg in the same way Dranoff demonstrated for CAR-T cells. Rather, there is little in Dranoff to predict the possible effects that an activated CD83 CAR would have on a Treg.
The Applicant also states that:
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The Applicant finally argues that, since Tregs are immunosuppressive, the person of ordinary skill in the art would reasonably presume that the Treg would suppress the donor cells that are not HLA matched, which Applicant surprisingly showed was not the case. Moreover, since little is known about the effects of CARs in Tregs, there was no way to predict from the cited references that the CD83 CAR would enhance the immunosuppressive effects of the Treg. These were unexpected results and therefore non-obvious.
This is not found persuasive for the following reasons:
It is noted that in considering the disclosure of a reference, it is proper to take into account not only specific teaching of the reference but also the inferences which one skilled in the art would be reasonably be expected to draw therefrom. In re Preda, 401 F.2d 825, 159 USPQ 342, 344 (CCPA 1968). See MPEP 2144.01.
Furthermore, specific statements in the references themselves which would spell out the claimed invention are not necessary to show obviousness, since questions of obviousness involves not only what references expressly teach, but what they would collectively suggest to one of ordinary skill in the art.
In response to applicant's argument that there was no way to predict from the cited references that the CD83 CAR would enhance the immunosuppressive effects of the Treg and this was an unexpected result and therefore non-obvious, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In this case, contrary to the applicant’s statement that the cited references appear to teach that: 1) Tregs are immunosuppressive, 2) CD83 CARs can enhance CAR-T cells, and 3) CD83 is involved in autoimmune disease and GVHD and arguments that the reference teachings are not sufficient to lead one of ordinary skill in the art to produce an anti-CD83 CAR-Treg for use suppressing alloreactive or autoreactive lymphocytes in a subject that is the recipient of transplant donor cells that are not HLA matched to the subject with a reasonable expectation of success, note that Riley et al. teach a method of ameliorating, inhibiting, or reducing an adverse response by the donor transplant against the recipient (such as GVHD or graft rejection) by contacting alloreactive T cells with Tregs in order to exact an immunosuppressive effect on the alloreactive T cells. While the Examiner acknowledges that Riley et al. do not teach that the Treg expresses an anti-CD83 CAR, a skilled artisan, with the goal of improving Riley et al.’s method, would have considered a more a targeted anti-CD83 CAR-Treg-based approach in view of the cited secondary references in order to selectively suppress alloreactive T cells while avoiding beneficial Treg cells and broad immunosuppression with a reasonable expectation of success for the reasons outlined in the rejection under 35 U.S.C 103 above.
To summarize, CD83 is neither present nor expressed to any great extent on unactivated human natural Treg while CD4+ and CD8+ T cells upregulate surface CD83 expression transiently in response to stimulation (e.g. see Ju et al. page 4623, left and right columns). This suggests that CD83 targeting immunotherapies, such as an anti-CD83 mAb, could encourage Treg alloimmune regulation after transplantation (e.g. see Ju et al. page 4623, right column).
An alternative to mAb-based immunotherapy is the CAR-based approach. Cells expressing CARs are advantageous because they invoke a target-specific, rapid, and sustained immune response (e.g. see Dranoff page 1, lines 17-20). CARs comprise an antigen binding domain which may comprise an scFv comprising the VH and VL domains of a parent antibody while retaining the parent antibody’s antigen specificity (e.g. see Dranoff see page 22, line 10 and page 23, lines 12-17).
As such the instantly claimed method of suppressing alloreactive or autoreactive lymphocytes with an anti-CD83 CAR Treg in a subject that is the recipient of transplant donor cells that are not HLA matched to the subject would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. A person having ordinary skill in the art would have recognized that Riley et al.’s Treg cells could be genetically modified to express an anti-CD83 CAR in which the antigen binding site comprises an scFv comprising the CDRs of the parent 60B10 antibody disclosed by Diehl et al. with predictable success. The motivation to do this lies in the fact that the surface expression of CD83 is upregulated on activated T cells while it is not present or expressed to any great extent on Treg. Thus, a skilled artisan with the goal of improving Riley et al.’s broadly immunosuppressive method, would select CD83 as an immunotherapeutic target for CAR-Treg-based inhibition of alloreactive T cells. The anti-CD83 CAR-modified Treg cells will specifically bind to and suppress CD83-expressing alloreactive/autoreactive T cells while avoiding indiscriminate interaction with beneficial Tregs, thereby enhancing the immunosuppressive effect on the transplant donor cells with a reasonable expectation of success.
It is noted that all that is required is a reasonable expectation of success, not absolute predictability of success. See In re O’Farrell, 853 F.2d 894,903 (Fed. Cir. 1988).
Regarding the Applicant’s arguments that that none references reasonably predict that Tregs genetically modified to express an anti-CD83 CAR will have enhanced immunosuppression of alloreactive T cells, the properties of a compound cannot be separated from the compound, see In re Papesch, 315 F.2d 381,391 (CCPA 1963) (“a compound and all its properties are inseparable). Thus, in the absence of evidence to the contrary and in view of the prior art teachings, the anti-CD83 CAR Treg cells would inherently have the property of enhanced immunosuppression of alloreactive T cells relative to the unmodified Treg cells.
Furthermore, the object of CAR-T-based technology is to specifically bind and activate the T-cell in which the CAR is expressed toward a precise target. As the Applicant states Tregs are immunosuppressive and therefore, a person of ordinary skill in the art would reasonably presume that the inherent and underlying immunosuppressive properties of the Treg cell would be activated upon target binding by the CAR. Therefore, in the absence of evidence to the contrary, a skilled artisan would reasonably predict that genetically modifying a Treg cell to express an anti-CD83 CAR would allow for a more targeted and specific immunosuppressive effect on CD83-expressing cells, such as alloreactive T cells, and avoid indiscriminate immunosuppressive activity on non-CD83 expressing cells, such as Treg cells, thereby enhancing immunosuppression.
Furthermore, contrary to the Applicants assertion that the following are unexpected discoveries: 1) CD83 is differentially expressed on alloreactive T cells; 2) a Treg engineered to express an anti-CD83 CAR can selectively target alloreactive T cells that cause GVHD while sparing GVL; and 3) the anti-CD83 CAR significantly enhances the immunosuppressive activity of the Treg against alloreactive cells; it is noted that Ju et al. teach that this differential expression. Specifically, CD83 is upregulated on the surface of stimulated (or activated) T cells while CD83 is neither present nor expressed to any great extent on unactivated human natural Treg (e.g. see Ju et al. page 4623, left and right columns).
Regarding the recited properties of the anti-CD83 CAR, the properties of a compound cannot be separated from the compound, see In re Papesch, 315 F.2d 381,391 (CCPA 1963) (“a compound and all its properties are inseparable). Thus, the anti-CD83 CAR Treg cells would inherently have the property of selectively targeting alloreactive T cells that cause GVHD while sparing GVL and enhanced immunosuppressive activity against alloreactive cells. Nonetheless, see paragraph above addressing these inherent properties.
While Example 2 in the specification, as cited by the Applicant, shows that the claimed anti-CD83 CAR-Tregs have significantly higher alloreactivity suppression of entirely HLA-mismatched dendritic, T cells, and Tregs compared to mock Tregs; the Examiner disagrees that this property is not taught or suggested in the cited references. It is noted that the property of enhanced alloreactivity suppression is inherent to the anti-CD83 CAR-Tregs given that CD83 is upregulated on the surface of stimulated (or activated) T cells while CD83 is neither present nor expressed to any great extent on unactivated human natural Treg (e.g. see Ju et al. page 4623, left and right columns). Thus, an anti-CD83 CAR Treg would selectively suppress those CD83-expressing alloreactive T cells while the mock Treg would display a more general and non-specific immunosuppressive effect. The anti-CD83 CAR Treg serves to direct the inherently immunosuppressive Treg specifically to alloreactive T cells because the alloreactive T cells express CD83.
In response to applicant's argument that the references fail to show certain features of the invention (i.e., sparing GVL), it is noted that the feature of “sparing GVL,” upon which applicant relies, is not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Furthermore, beyond page 1 of the specification, which only briefly mentions GVL, the specification is silent on GVL and certainly does not show any evidence of “sparing GVL.”
Finally, Riley et al. is cited as the primary reference because they teach a method of suppressing alloreactive T cells with Treg cells. The Examiner has acknowledged the deficiencies of Riley et al.’s teachings above and has cited the secondary references, Dranoff, Diehl et al., Ju et al., and Meyer and Negrin to overcome them. The rationale for combining these references is outlined above.
The Applicant summarizes the reference teachings by stating that they appear to individually teach that: 1) Tregs are immunosuppressive, 2) CD83 CARs can enhance CAR-T cells, and 3) CD83 is involved in autoimmune disease and GVHD. However, 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).
Furthermore, in response to applicant's argument that these teachings are not sufficient to lead one of ordinary skill in the art to produce an anti-CD83 CAR-Treg for use suppressing alloreactive or autoreactive lymphocytes in a subject that is the recipient of transplant donor cells that are not HLA matched to the subject with a reasonable expectation of success, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim limitations regarding intended use.
Dranoff is cited as a secondary reference to demonstrate CAR structure, particularly that the antigen-binding site can be an scFv of a parent antibody that has the desired antigen specificity, and that CAR-T cell technology is an alternative targeted immunotherapy to mAb-based approaches. CAR-T cell- and mAb-based approaches have distinct mechanisms of action and immunological activity. While mAb interact with an antigen through its Fab domain and engage effector molecules to induce an immunological response through its Fc domain, a CAR T-cell will bind a target through its antigen-binding domain and trigger a series of intracellular signaling events that lead to T cell activation. CAR T cells are advantageous because of their rapid and sustained immune response (e.g. see Dranoff page 1, lines 17-20).
Dranoff also happens to suggest an anti-CD83 CAR Treg cell which the Applicant argues is only useful in the teachings of Dranoff in a CAR-T cell dually expressing a second CAR for a tumor antigen and that nothing in Dranoff suggests that the CD83 CAR would have any benefit on a Treg's immunosuppressive effects. Furthermore, the Applicant’s argument that since very little is known about the effects of CARs in Tregs, the person of ordinary skill in the art would not reasonably assume that a CD83 CAR would stimulate a Treg in the same way Dranoff demonstrated for CAR-T cells and that there is little in Dranoff to predict the possible effects that an activated CD83 CAR would have on a Treg. The Examiner respectfully disagrees, in the absence of evidence to the contrary, a skilled artisan would reasonably predict that an anti-CD83 CAR Treg cell would have enhanced immunosuppressive properties toward CD83-expressing alloreactive T cells because as it is known to a skilled artisan the object of CAR-T-based technology is to specifically bind and activate the T-cell in which the CAR is expressed toward a precise target. As the Applicant states Tregs are immunosuppressive, therefore, a person of ordinary skill in the art would reasonably presume that the inherent and underlying immunosuppressive of the Treg cell that is expressing the CAR would be activated upon target binding.
Diehl et al. is included as a secondary reference for their recitation of the instantly claimed CDRs and VH and VL domains (specifically SEQ ID NOs: 19 and 20) in the 60B10 antibody, which the Applicant acknowledged. Dranoff teaches, as stated above, that the antigen binding domain of a CAR may comprise scFv which comprises the VH and VL domains , and therefore the CDRs, of a parent antibody which binds the desired target. Thus it would be obvious to select an anti-CD83 antibody, including Diehl’s 60B10 antibody, to be applied in the CAR platform defined by Dranoff. Thus, Applicant’s argument that Diehl does not teach or suggest the use of this agonist antibody in a CAR is not persuasive.
Regarding the Applicant’s argument that there is no way to predict from Diehl or the other cited references the effect of the anti-CD83 antibody in a CAR, the Applicant states that it would predictably provide a completely different effect than the agonist antibody by itself (such as an antagonistic effect) since the CAR would be stimulating the Treg with its intracellular signaling domains. The Examiner agrees that the agonist anti-CD83 60B10 antibody taught by Diehl et al. would have distinct immunological properties to an anti-CD83 CAR Treg which incorporates the CDRs of the 60B10 antibody into the antigen-binding domain. The 60B10 antibody is a mAb and as stated above CAR-T cell- and mAb-based approaches have distinct mechanisms of action and immunological activity. Given a CAR T-cell will bind a target through its antigen-binding domain and trigger a series of intracellular signaling events that lead to T cell activation, in the absence of evidence to the contrary, a skilled artisan would reasonably predict that the anti-CD83 CAR Treg cell would display the inherent and underlying immunosuppressive properties of the Treg cell which is expressing the CAR upon CD83 binding.
Finally, Ju et al. is cited as a secondary reference because they teach the differential expression of CD83 on alloreactive T cells. While the Examiner agrees that Ju et al. do not teach or suggest engineering a Treg to express an anti-CD83 CAR or provide any expectation that doing so will increase the immunosuppressive effects of the Treg, their suggestion of anti-CD83 immunotherapy for alloimmune regulation provides the motivation needed for incorporating the teachings Dranoff and Diehl et al. in Riley et al.’s teachings. Given that CD83 is differentially expressed on activated T cells and not on Tregs, genetically modifying Riley et al.’s Treg to express Dranoff’s anti-CD83-Diehl-modified CAR, offers a targeted approach that a skilled artisan would reasonably presume would improve the immunosuppressive effect in patients receiving completely HLA mismatched transplant donor cells because it avoids broad immunosuppression and spares beneficial Tregs.
As such, the applicant’s arguments have not been found persuasive.
This is a New Ground of Rejection necessitated by applicant's amendment. Claims 17 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Riley et al. 2019 (US20190022199A1, an IDS reference filed May 2, 2022) in view of Dranoff 2017 (WO2017149515, an IDS reference filed May 2, 2022), Diehl et al. 2013 (WO2013006505, an IDS reference filed May 2, 2022), Ju et al. 2016 (J Immunol. 197(12), 4613-4625 a reference of record), and Meyer and Negrin 2019 (WO2019157158, an IDS reference filed May 2, 2022) as applied to claim 1 above, and further in view of Fesnak et al. 2016 (Nat Rev Cancer 16, 566–581 (2016), a reference of record).
The combined teachings of Riley et al. in view of Dranoff, Diehl et al., Ju et al., and Meyer and Negrin pertaining to claim 1 and the rationale for combining them is outlined in the 103 rejection above.
Applicant arguments against combining these references to arrive that the instant invention and the Examiner’s response to these arguments are also outlined above.
The combined reference teachings differ from the instant invention only by not teaching that the method further comprises administering a checkpoint inhibitor or that the checkpoint inhibitor comprises an anti-PD-1 antibody, anti-PD-L1 antibody, anti-CTLA-4 antibody, or a combination thereof.
The teachings of Fesnak et al. are outlined in the rejection under 35 U.S.C. 103 in the Office Action mailed on April 18, 2025.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combined teachings of Riley et al. in view of Dranoff, Diehl et al., and Ju et al. and further in view of Fesnak et al.to include the administration of a checkpoint inhibitor comprising an anti-PD-1 antibody, anti-PD-L1 antibody, anti-CTLA-4 antibody, or a combination thereof.
Immune checkpoint blockade can enhance the efficacy of T cell therapies, such as CAR T cells, and many groups are now attempting to generate CAR T cells resistant to PD1–PD1 ligand 1 (PDL1) or cytotoxic T lymphocyte-associated antigen 4 (CTLA4)–CD80/CD86 signaling. For example, the addition of programmed cell death protein 1 (PD1; also known as PDCD1) monoclonal antibody has been shown to enhance the function of CAR T cells in preclinical models (e.g. see Fesnak et al. page 576, left column, under Avoiding tumour suppression and escape).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Riley et al.’s methods for inhibiting alloreactive T cells and for generating an immunosuppressive effect in a mammal having an alloresponse or autoimmune response comprising contacting alloreactive T cells with or administering to the mammal an effective amount of iTregs in view of Dranoff, Diehl et al., and Ju et al. to genetically modify the Treg cells to express Dranoff’s anti-CD83 CAR comprising an extracellular antigen binding domain as an scFv of Diehl et al.’s anti-CD83 antibody, 60B10, and apply them in the method to suppress CD83-expressing alloreactive or autoreactive lymphocytes, such as Diehl et al.’s DCs or Ju et al.’s activated T cells and further to include administering Fesnak et al.’s checkpoint inhibitors, such as anti-PD-1, PD-L1, and/or CTLA-4 antibodies with a reasonable expectation success.
Given the known advantages of using Tregs in conjunction with immunosuppressive drugs, such as checkpoint inhibitors, in transplantation to ameliorate the severity of the immune response following transplantation and for the treatment of host rejection to the donor tissue or graft versus host disease (e.g. see Riley et al. [0178]); it would have been obvious to a skilled artisan to experiment with using Fesnak et al.’s checkpoint inhibitors, including anti-PD-1, PD-L1, and/or CTLA-4 antibodies, in order to enhance the efficacy of Riley et al.’s T cell therapies with a reasonable expectation of success.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
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.
As noted above, the Applicant requested that the NSDP rejections over the claims in co-pending Application Nos. 18/478,247, 18/547,748, 18/719,814 as set forth in the Office Action mailed on April 18, 2025 be held in abeyance until the claims are otherwise allowable. It was also noted that the Applicant failed to respond to the 9 other NSDP rejections. Thus, all of the NSDP rejections set forth in the Office Action mailed on April 18, 2025 are maintained for the reasons of record.
It is noted that a Notice of Allowance was mailed for co-pending Application No. 16/969,056 (the ‘056 Application) on June 23, 2025. Thus, the NSDP rejections to claims 1, 4-7, and 12-20 over claims 1, 6-9, and 13-19 of the ‘056 Application are no longer provisional.
It is also noted that a new set of claims has been filed for co-pending Application No. 17/635,111 (the ‘111 Application). Thus, the NSDP rejection to claims 1, 4-7, and 12-20 over claims 4-7 of the ‘056 Application is updated to be a rejection over claims 1, 2, 5-12, 14, 15, and 17 the ‘056 Application.
Conclusion
No claim is allowed.
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 Grace H. Lunde whose telephone number is (703)756-1851. The examiner can normally be reached Monday - Thursday 5:00 a.m. - 3:00 p.m. (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached on (571) 272-0839. 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.
/GRACE H LUNDE/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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