DETAILED ACTION
Claims 1-14 are pending in the instant application and being examined on the merit.
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 .
Claim Objections
Claims 5 and 8 are objected to because of the following informalities:
“to a quell cytokine storm” should read “to quell a cytokine storm” in claim 5;
“macrophates” should read “macrophages” in claim 5;
“wherein the CAR polypeptide cotransmembrane domain…” should read “wherein the CAR polypeptide comprises a cotransmembrane domain…” in claim 8.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claim 7 is 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.
Instant claim 7 recites the limitation "the macrophage activated syndrome" in the preamble of the claim (line 1). There is insufficient antecedent basis for this limitation in the claim, thus, the metes and bounds of the claim are unclear.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 9-11 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or it may be satisfied by the disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
Scope of the claims
Instant claims 9-11 are drawn to a method for treating ischemic stroke or acute coronary syndrome in a subject, the method comprising administering to the subject an effective amount of a regulatory T (Treg) cell, wherein (i) the Treg cell is genetically modified to express a chimeric antigen receptor (CAR) polypeptide comprising a CD83 antigen binding domain; OR (ii) wherein the Treg is co-administered with an immune effector cell genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain, wherein the CAR polypeptide comprises a cotransmembrane domain, an intracellular signaling domain, and a co-stimulatory signaling region, wherein the CD83 antigen binding domain is a single-chain variable fragment (scFv) of an antibody that specifically binds CD83 comprising mixing and matching the recited heavy and light chain CDR sequences; or different combination of VH or VL sequences.
Instant claimed methods requires a CAR comprising a scFv on the combination of CDRH1, CDRH2, and CDRH3 sequences of the variable heavy (VH) and the combination of CDRL1, CDRL2, and CDRL3 sequences of the variable light (VL) domain, wherein,
the CDRH1 sequence comprises the amino acid sequences SEQ ID NOs:1, 7, or 13;
the CDRH2 sequence comprises the amino acid sequences SEQ ID NOs:2, 8, or 14;
the CDRH3 sequence comprises the amino acid sequences SEQ ID NOs:3, 9, or 15;
the CDRL1 sequence comprises the amino acid sequences SEQ ID NOs:4, 10, or 16;
the CDRL2 sequence comprises the amino acid sequences SEQ ID NOs:5, 11, or 17;
the CDRL3 sequence comprises the amino acid sequences SEQ ID NOs:6, 12, or 18.
This results in a total of 729 distinct and structurally defined antibody embodiments covered by the instant claims. One of ordinary skill in the art would understand that proper pairing of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequences are required to form a proper antigen binding domain to bind to a specific antigen. Additionally, the instant disclosure does not test mixing and exchange of the antibody CDR regions of separate antibody CDRH1-H3 (amino acid sequences described above) and CDRL1-L3 (amino acid sequences described above) present in the CARs that possess the recited function of binding CD83. Instant claims 10 and 11, which are dependent on instant claim 9, incorporate the entire scope of instant claim 9, and the added limitation disclosed in these claims do not cure the underlying lack of support for the unexemplified structural species.
State of the Relevant Art
At the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). Almagro et al (Front. Immunol, 2018, 8:1751, Pages 1-19) also taught that while affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule”, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al (Antibodies, 2019 8(4):55, Pages 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of CDR-H3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
In addition to changes within the CDR altering target binding, alterations to the CDR have been shown to dramatically alter antibody secretion. Hasegawa et al. (mAbs, 2017, 9(5): 854-873) taught a pair of human IgG clones with a single amino acid substitution in the variable region was sufficient to alter the efficiency of immunoglobulin biosynthesis (page 866, last sentence left column). Hasegawa taught the two mAbs differed only by one amino acid in the LC's CDR1 and that despite the near-identity of their primary sequences, the parental mAb secreted copious amounts of IgG to the culture media, while the variant mAb induced RB phenotypes extensively and secreted 20-fold less IgG (page 866, right column, first paragraph). Importantly, the two model IgGs were by no means abnormal or defective as mAbs, but demonstrated a profound impact of a single amino acid substitution on immunoglobulin biosynthesis (page 866, right column, first paragraph).
At the time of filing the instant application, Li teaches that CD83, a member of the immunoglobulin superfamily, is an informative dendritic cell (DC) maturation marker and has been used in clinical trials of solid organ transplant rejection (page 2, left column, §CD83 Structure and Expression; page 4, left column, §CD83 as a DC Activation Marker and Viral Infection Target; Li et al, “CD83: Activation Marker for Antigen Presenting Cells and Its Therapeutic Potential”, June 7 2019, Frontiers in Immunology, 10(1312):1-9; hereinafter Li). Li also teaches that anti-CD83 specific antibodies with the ability to deplete CD83+ cells have shown efficacy in the treatment of pre-clinical models of GVHD without significantly affecting viral or tumor specific memory T-cell responses (page 1, last paragraph – page 2, first paragraph; Table 1). Furthermore, Li teaches that antibody targeting of CD83 offers the possibility of specifically depleting activated APC capable of stimulating allogenic T-cells while retaining non-activated APC that impart tolerance and memory T-cells crucial for protective immunity against infection and tumors (pages 4-5, §Antibody Targeting of CD83+ Cells for Treatment of GVHD). Li concludes that the translation of therapeutics targeting CD83 hold great promise as more selective strategies for achieving immunosuppression without significantly compromising protective immunity and have the potential to supersede the broad immunosuppressive drugs currently used to treat inflammatory diseases in the clinic (page 6, right column, §Concluding Remarks).
Shrestha teaches that targeting CD83 with a monoclonal antibody reduces xenogeneic GVHD in mice without impairing GVL or T cell responses against pathogenic viruses; however, the immune suppressive effect by the antibody is temporary and dependent on NK cell–mediated, antibody-dependent cellular cytotoxicity (ADCC). Therefore, Shrestha produced human CD83-targeted CAR T cells and determined its preclinical efficacy for GVHD prevention and treatment (page 4652, right column, second paragraph – page 4653, right column, first paragraph; Shrestha et al, “Human CD38-targeted chimeric antigen receptor T cells prevent and treat graft-versus-host disease”, May 21 2020, J. Clin. Invest., 130(9):4652-4662; hereinafter Shrestha). Shrestha discloses that CD83 CAR T cells provide a platform to eliminate alloreactive T cells without the need for broadly suppressive, nonselective calcineurin inhibitors or glucocorticoids, preserve donor antiviral immunity against CMV, EBV, and influenza, and have the potential to concurrently prevent GVHD as well as actively target life-threatening AML relapse. Thus, the CD83 CAR T cell carries high likelihood to reduce transplant-related mortality and improve outcomes after allogenic hematopoietic cell transplantation (allo-HCT) (page 4660, left column, third paragraph).
Furthermore, at the time of filing, Seldon teaches proteins that bind to CD83 and uses thereof in therapy, prophylaxis, diagnosis, and prognosis (Seldon et al, US9,840,559 B2, Priority to February 1, 2013; hereinafter Seldon). Seldon discloses utilizing light chain shuffling for affinity maturation to improve the strength of the antigen-antibody interaction as a strategy for enhancing functionality (page 40, column 51, Example 6; Table 5). These antibodies are all comprised of 3 distinct VH CDR sequences that pair with light chains that comprise distinct VL CDR sequences to form an antigen binding site that binds to CD83 (pages 20-21, Table “Sequence Listing”; page 26, column 23, lines 4-16; Table 5; FIG. 6A-6C). Seldon further discloses that an affinity-matured variant of 3C12.WT, referred to as 3C12.C, had the highest observed affinity for CD83 (KD=6.1x10-9M), including the best off-rate, and demonstrated superior binding to KM-H2 cells relative to the parent wild-type antibody (page 40, column 51, Example 6; Table 5; Fig. 7A and 7B). This demonstrates that the process of CDR exchange resulted in measurable difference in binding properties. Furthermore, without performing the mutagenesis and binding studies, a skilled artisan cannot predict the 6 CDR sequences that forms a proper antigen binding domain to bind to CD83.
Summary of Species Disclosed in the original specification
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
However, the instant specification does no disclose any species of the anti-CD83 scFv, wherein the scFvs comprise specific combinations of the CDRH1-H and CDRL1-L3 sequences that fall within the scope of instant claim 9. As noted above, the art generally accepted that the combination of the CDRs within the VH and VL pair of an antibody are essential for binding specificity. But the specification does not describe what residues within the CDRs confer the binding activity claimed, and the claim language permits changes in the VH and VL that contain the CDRs. Accordingly, the skilled artisan would not be able to discern a structure or function correlation for the CAR polypeptides that comprise the CD83 antigen binding domain..
Given the lack of shared structural properties of the CDR regions, and the fact that there are no species that were described in the specification, Applicant was not in possession of the invention as claimed.
Instant claims 10 and 11 directly cover the genus disclosed in instant claim 9. Instant claim 10 recites amino acid sequences that comprise the VH domain of the anti-CD83 scFv, and instant claim 11 recites amino acid sequences that comprise the VL domain of the anti-CD83 scFv. However, since the Applicant has not provided the necessary functional written description to establish that the structural species are capable of performing the recited functions of binding to CD83, claims 10 and 11 are rejected.
Conclusion
The instant specification and the state of the art does not teach a representative species of antibodies of CD83 antigen binding domain that would permit a skilled artisan to determine the structure activity relationship between antibody CDR residues and recited function of binding to CD83. Given the lack of shared structural properties that provide the claimed binding activity, and the fact that there were no species described to represent the broad genus, one of skill in the art would reasonably conclude that Applicant was not in possession of the required genus of CDR substitutions of the scFv comprising the CAR polypeptide at the time of filing.
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 1-2 and 8-14 are rejected under 35 U.S.C. 103 as being unpatentable over Davila (Davila and Betts, US20200108098 A1, Priority to February 23, 2018, Published on 4/9/2020, IDS entered on 11/30/2023; hereinafter Davila), and further in view of Sakai (Sakai et al, “Regulatory T Cells: Pathophysiological Roles and Clinical Applications”, July 26 2019, Keio J Med, 69(1):1-15, IDS entered on 11/30/2023; hereinafter Sakai).
Regarding instant claims 1-2 and 8-14, Davila teaches a method of treating autoimmunity or preventing Graft-Versus-Host Disease (GVHD) in a subject comprising administering to the subject an effective amount of a regulatory T cell genetically modified with a disclosed anti-CD83 CAR (page 37, ¶ [0007]), wherein the disclosed CAR-modified regulatory T cells may be administered either alone, or as a pharmaceutical composition in combination with other components such as IL-2 (page 85, ¶ [0198]). Davila also teaches that the disclosed CAR is generally made up of three domains: an ectodomain, a transmembrane domain, and an endodomain, wherein (i) the ectodomain comprises the CD83-binding region and is responsible for antigen recognition with an optional signal peptide (SP); (ii) the transmembrane domain (TD) connects the ectodomain to the endodomain; and (iii) the endodomain is the business end of the CAR that transmits an activation signal to the immune effector cell after antigen recognition wherein the endodomain can contain an intracellular signaling domain (ISD) and optionally a co-stimulatory signaling region (CSR) (page 50, ¶ [0142]; pages 44-45 , ¶ [0080]; Fig. 1A). Davila also discloses that the anti-CD83 scFv can comprise a variable heavy (VH) domain having CDR1, CDR2 and CDR3 sequences and a variable light (VL) domain having CDR1, CDR2 and CDR3 sequences, wherein the CDR1 sequence of the VH domain comprises the amino acid sequence GFSITTGGYWWT (SEQ ID NO:1), CDR2 sequence of the VH domain comprises the amino acid sequence GYIFSSGNTNYNPSIKS (SEQ ID NO:2), CDR3 sequence of the VH domain comprises the amino acid sequence CARAYGKLGFDY (SEQ ID NO:3), CDR1 sequence of the VL comprises the amino acid sequence TLSSQHSTYTIG (SEQ ID NO:4), CDR2 sequence of the VL domain comprises the amino acid sequence VNSDGSHSKGD (SEQ ID NO:5), and CDR3 sequence of the VL domain comprises the amino acid sequence GSSDSSGYV (SEQ ID NO:6) (pages 38-39, ¶ [0017]-[0019]). SEQ ID NOs:1-6 of Davila is identical to instant SEQ ID NOs:1-6 of the instant application. Davila further teaches that the anti-CD83 scFv VH domain comprises the amino acid sequence SEQ ID NO:19 (page 39, ¶ [0022]) and the VL domain comprises the amino acid sequence SEQ ID NO:20 (page 39, ¶ [0023]). Davila also discloses that the anti-CD83 scFv comprises the amino acid sequence SEQ ID NO:57 (page 43, ¶ [0060]). Finally, Davila teaches that the costimulatory molecule is 4-1BB (CD137) (page 51, ¶ [0168]), and the intracellular signaling domain is derived from CD3 zeta (page 51, ¶ [0166]).
However, Davila does not teach a method of treating ischemic stroke in a subject that involves administering to the subject an effective amount of a regulatory T cell genetically modified with a disclosed anti-CD83 CAR-T cells.
The deficiency is resolved by Sakai.
Sakai teaches that for clinical applications such as the suppression of both autoimmune diseases and the rejection of transplanted organs, methods to generate stabilized antigen-specific Tregs are required. In addition to conventional Tregs, Sakai teaches that tissue Tregs exhibit tissue-specific functions that contribute to the maintenance of tissue homeostasis and repair, and discloses that brain Tregs accumulate in the brain during the chronic phase of ischemic brain injury. Sakai also teaches established methods for the generation of stable antigen-specific Tregs to suppress GVHD, and the potential role of brain Tregs in neuronal recovery after an ischemic brain injury (e.g. ischemic stroke), wherein the increased number of brain Tregs by chemokines or serotonin may promote neuronal recovery (page 1, abstract; page 10, left column, first paragraph). In the case of ischemic stroke, Sakai teaches that inflammation occurs both in humans and in mouse models, and it is suggested that neuroinflammation is an attractive treatment target for reducing brain damage. Sakai also discloses that Sakai and others have identified a massive accumulation of lymphoid cells, including Tregs, in the chronic phase, more than 2 weeks after stroke onset, wherein Tregs account for approximately half of CD4+ T cells localized inside and around the cerebral infarction lesion in close proximity to scar-forming astrocytes and surviving neuronal cells (page 7, §Tregs in Ischemic Brain Injury; Fig. 5). Furthermore, Sakai teaches that although it has not yet been demonstrated that Tregs accumulate in the brains of ischemic stroke patients, selective serotonin reuptake inhibitors (SSRI) are known to ameliorate neurological symptoms after stroke onset, therefore suggesting that it is highly likely that brain Tregs work on neural repair in human stroke patients (page 9, §Clinical Implications of Tregs for Central Nervous System Diseases).
Regarding instant claim 1, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the method of treating autoimmunity or preventing Graft-Versus-Host Disease (GVHD) in a subject comprising administering to the subject an effective amount of a regulatory T cell genetically modified with anti-CD83 CAR as taught by Davila to include treating ischemic stroke as taught by Sakai. This is obvious because, Davila teaches a method of treating autoimmunity or preventing Graft-Versus-Host Disease (GVHD) in a subject that involves administering to the subject an effective amount of a regulatory T cell genetically modified with a disclosed anti-CD83 CAR-T cells, and Sakai teaches the therapeutic use of Tregs to suppress GVHD and promote neuronal recovery after an ischemic stroke. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method for treating ischemic stroke in a subject, the instant method of treating ischemic stroke comprising administering to the subject an effective amount of a Treg cell, wherein the Treg cell is genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain.
Regarding instant claim 2, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the method of treating ischemic stroke in a subject comprising administering to the subject an effective amount of a regulatory T cell genetically modified with anti-CD83 CAR as taught by the combined teachings of Davila and Sakai to further include co-administering to the subject an effective amount of IL-2 as taught by Davila. This is obvious because, the combined teachings of Davila and Sakai teach a method of treating ischemic stroke in a subject comprising administering to the subject an effective amount of a regulatory T cell genetically modified with anti-CD83 CAR, and Davila teaches that the disclosed CAR-modified regulatory T cells may be administered either alone, or in combination with other components such as IL-2. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating ischemic stroke comprising administering to the subject an effective amount of a Treg cell wherein the Treg cell is genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain and further comprise co-administering to the subject an effective amount of IL-2.
Regarding instant claims 8-14, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the method of treating ischemic stroke in a subject comprising administering to the subject an effective amount of a regulatory T cell genetically modified with anti-CD83 CAR as taught by the combined teachings of Davila and Sakai to further include that the disclosed CAR is generally made up of three domains: an ectodomain, a transmembrane domain, and an endodomain, wherein (i) the ectodomain comprises an anti-CD83 scFv comprising the amino acid sequence SEQ ID NO:57, wherein the anti-CD83 scFv comprises a VH domain comprising the amino acid sequence SEQ ID NO:19, and a VL domain comprising the amino acid sequence SEQ ID NO:20, wherein the VH domain comprises CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences SEQ ID NOs:1-3, respectively, and the VL domain comprises CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences SEQ ID NOs: 4-6, respectively; (ii) the endodomain comprises an ISD and a CSR, wherein the ISD is derived from CD3 zeta and the CSR is 4-1BB as taught by Davila. This is obvious because, the combined teachings of Davila and Sakai teach a method of treating ischemic stroke in a subject comprising administering to the subject an effective amount of a regulatory T cell genetically modified with anti-CD83 CAR, and Davila teaches that the disclosed CAR is generally made up of three domains: an ectodomain, a transmembrane domain, and an endodomain, wherein (i) the ectodomain comprises the anti-CD83 scFv that binds to CD83 comprising the amino acid sequence SEQ ID NO:57, wherein the VH domain comprises the amino acid sequence SEQ ID NO:19, and the VL domain comprises the amino acid sequence SEQ ID NO:20, wherein the CDR1 sequence of the VH domain comprises the amino acid sequence GFSITTGGYWWT (SEQ ID NO:1), CDR2 sequence of the VH domain comprises the amino acid sequence GYIFSSGNTNYNPSIKS (SEQ ID NO:2), CDR3 sequence of the VH domain comprises the amino acid sequence CARAYGKLGFDY (SEQ ID NO:3), CDR1 sequence of the VL comprises the amino acid sequence TLSSQHSTYTIG (SEQ ID NO:4), CDR2 sequence of the VL domain comprises the amino acid sequence VNSDGSHSKGD (SEQ ID NO:5), and CDR3 sequence of the VL domain comprises the amino acid sequence GSSDSSGYV (SEQ ID NO:6); (ii) the transmembrane domain connects the ectodomain to the endodomain; and (iii) the endodomain comprises an intracellular signaling domain derived from CD3 zeta and optionally a co-stimulatory signaling region wherein the costimulatory molecule is 4-1BB (CD137). Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating ischemic stroke comprising administering to the subject an effective amount of a Treg cell, wherein the Treg cell is genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain, wherein the instant CAR polypeptide comprises a cotransmembrane domain, an intracellular signaling domain comprising a CD3 zeta signaling domain, and a co-stimulatory signaling region comprising 4-1BB, wherein the CD83 antigen binding domain is a scFv of an antibody that specifically binds CD83 wherein the anti-CD83 scFv comprises a VH domain having CDR1, CDR2, and CDR3 comprising amino acid sequences instant SEQ ID NOs:1-3, respectively, and a VL domain having CDR1, CDR2, and CDR3 comprising amino acid sequences instant SEQ ID NOs:4-6, respectively.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Davila (Davila and Betts, US20200108098 A1, Priority to February 23, 2018, Published on 4/9/2020, IDS entered on 11/30/2023; hereinafter Davila), and Sakai (Sakai et al, “Regulatory T Cells: Pathophysiological Roles and Clinical Applications”, July 26 2019, Keio J Med, 69(1):1-15, IDS entered on 11/30/2023; hereinafter Sakai) as applied to claim 1 above, and further in view of Johnston (Johnston et al, WO2019241549A1, Priority to June 15, 2019; hereinafter Johnston).
Regarding instant claim 3, the combined teachings of Davila and Sakai are discussed above.
However, the combined teachings of Davila and Sakai do not teach a method of treating ischemic stroke comprising administering to the subject an effective amount of a Treg cell in combination with an effective amount of IL-2, wherein the Treg cell is genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain, wherein the Treg cell is genetically modified to secrete IL-2.
The deficiency is resolved by Johnston.
Johnston teaches that Treg therapy could provide general immunosuppression to suppress diseases such as GVHD (page 4, ¶ [006]), and successful immunosuppressive therapy with Treg cells requires persistence and suppressive function (pages 10-11, ¶ [045]). Johnston also discloses that Treg stability is maintained when there is increased IL-2 signaling particularly via activating STAT5 (pages 10-11, ¶ [045]). To produce chimeric-antigen-receptor regulatory T cells (CAR-Tregs) with a persistent Treg phenotype, Johnston discloses various embodiments of vectors in which the IL-2 pathway signaling is controlled to increase the persistence CAR-Tregs in a patient being treated for diseases such as GVHD (page 1, abstract, page 12, ¶ [050]). Furthermore, Johnston teaches that the CAR-Treg secretes IL-2 although it is lower when compared to a CD4+ cell (page 32, ¶ [125]).
Regarding instant claim 3, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the method of treating ischemic stroke in a subject comprising administering to the subject an effective amount of a regulatory T cell genetically modified with anti-CD83 CAR wherein the method further comprises co-administering to the subject an effective amount of IL-2 as taught by the combined teachings of Davila and Sakai to comprise the vector that controls IL-2 signaling to maintain stability of the Treg as well as secrete IL-2 as taught by Johnston. This is obvious because, the combined teachings of Davila and Sakai teach a method of treating ischemic stroke in a subject comprising administering to the subject an effective amount of a regulatory T cell genetically modified with anti-CD83 CAR wherein the CAR-modified regulatory T cells may be administered in combination with IL-2, and Johnston teaches producing CAR-Tregs with a persistent Treg phenotype using vectors that control IL-2 signaling to maintain stability of the CAR-Tregs, wherein the CAR-Treg secretes IL-2. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating ischemic stroke comprising administering to the subject an effective amount of a Treg cell in combination with an effective amount of IL-2, wherein the Treg cell is genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain and wherein the instant Treg cell is genetically modified to secrete IL-2.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Davila (Davila and Betts, US20200108098 A1, Priority to February 23, 2018, Published on 4/9/2020, IDS entered on 11/30/2023; hereinafter Davila), and Sakai (Sakai et al, “Regulatory T Cells: Pathophysiological Roles and Clinical Applications”, July 26 2019, Keio J Med, 69(1):1-15, IDS entered on 11/30/2023; hereinafter Sakai) as applied to claim 1 above, and further in view of Eskandari (Eskandari et al, “Regulatory T cells engineered with TC signaling-responsive IL-2 nanogels suppress alloimmunity in sites of antigen encounter”, November 11 2020, Science Translational Medicine, 12(569):1-15; hereinafter Eskandari).
Regarding instant claim 4, the combined teachings of Davila and Sakai are discussed above.
However, the combined teachings of Davila and Sakai do not teach a method of treating ischemic stroke comprising administering to the subject an effective amount of a Treg cell in combination with an effective amount of IL-2, wherein the Treg cell is genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain, wherein the Treg cell is coated with a cell-bound matrix containing IL-2.
The deficiency is resolved by Eskandari.
Eskandari teaches that because Treg homeostasis is known to require continuous T cell receptor (TCR) ligation and exogenous IL-2, some studies have explored the use of low-dose IL-2 injections to increase endogenous Treg responses. However, Eskandari teaches that systemic IL-2 immunotherapy can lead to the activation of cytotoxic T lymphocytes and natural killer cells, causing adverse therapeutic outcomes. Therefore, Eskandari teaches protein nanogels (NGs) synthesized with cleavable bis(N-hydroxysuccinimide) cross-linkers and IL-2/Fc fusion (IL-2) proteins to form particles that release IL-2 under reducing conditions, as found at the surface of T cells receiving stimulation through the TCR, wherein the NGs will autostimulate Tregs with IL-2 in response to TCR-dependent activation, and thus activate these cells in sites of antigen encounter (page 1, Abstract). Furthermore, Eskandari discloses that Tregs surface-conjugated with IL-2 NGs were found to have preferential, allograft-protective effects relative to unmodified Tregs or Tregs stimulated with systemic IL-2, and murine and human NG–modified Tregs carrying an IL-2 cargo perform better than conventional Tregs in suppressing alloimmunity in murine and humanized mouse allotransplantation models (page 5, §NG-engineered Tregs suppress in vivo alloimmunity better than conventional Tregs – page 9, §NG-engineered Tregs prolong murine allograft survival better than conventional Tregs; FIGs. 3 and 4).
Regarding instant claim 4, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the method of treating ischemic stroke in a subject comprising administering to the subject an effective amount of a regulatory T cell genetically modified with anti-CD83 CAR as taught by the combined teachings of Davila and Sakai to comprise that the Treg cell comprises a protein nanogel containing IL-2 as taught by Eskandari. This is obvious because, the combined teachings of Davila and Sakai teach a method of treating ischemic stroke in a subject comprising administering to the subject an effective amount of a regulatory T cell genetically modified with anti-CD83 CAR wherein the CAR-modified regulatory T cells may be administered in combination with IL-2, Eskandari teaches protein nanogels containing IL-2 proteins for improved function of the Tregs as well as better suppression of alloimmunity, wherein the NGs autostimulate Tregs with IL-2 in response to TCR-dependent activation, thus activating these cells in sites of antigen encounter, and the instant specification discloses that the cell-bound matrix is a nanogel (page 2, second paragraph). Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating ischemic stroke comprising administering to the subject an effective amount of a Treg cell in combination with an effective amount of IL-2, wherein the Treg cell is genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain and wherein the Treg cell is coated with a cell-bound matrix containing IL-2.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Davila (Davila and Betts, US20200108098 A1, Priority to February 23, 2018, Published on 4/9/2020, IDS entered on 11/30/2023; hereinafter Davila), and Sakai (Sakai et al, “Regulatory T Cells: Pathophysiological Roles and Clinical Applications”, July 26 2019, Keio J Med, 69(1):1-15, IDS entered on 11/30/2023; hereinafter Sakai) as applied to claim 1 above, and further in view of Tsurikisawa (Tsurikisawa et al, “An increase of CD83+ dendritic cells ex vivo correlates with increased regulatory T cells in patients with active eosinophilic granulomatosis and polyangiitis”, August 31 2014, BMC Immunology, 15(32):1-12; hereinafter Tsurikisawa).
Regarding instant claim 6, the combined teachings of Davila and Sakai are discussed above.
However, the combined teachings of Davila and Sakai do not teach method of treating ischemic stroke comprising administering to the subject an effective amount of a Treg cell in combination with an effective amount of IL-2, wherein the Treg cell is genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain, wherein the subject has vasculitis.
The deficiency is resolved by Tsurikisawa.
Tsurikisawa teaches that eosinophilic granulomatosis with polyangiitis (EGPA) is classified as a vasculitis of arteries that are small or medium in diameter (page 1, right column, first paragraph). Tsurikisawa also teaches that in patients with EGPA, the percentage of CD83+ dendritic cells (DCs) was higher in patients with EGPA in remission than in relapse and correlated with the percentage of Treg cells. Tsurikisawa also discloses that according to previous reports, CD83+ DCs were found to suppress the immune response by inducing Treg, wherein mature DCs expressing CD83+ at remission, which were present in higher numbers after treatment with corticosteroids, immunosuppressants, and IVIG, induce the differentiation of both iTreg cells and nTreg cells (page 5, left column, second paragraph). Therefore, Tsurikisawa concludes that CD83+ DCs are related to EGPA disease activity, wherein an increase in the number of CD83+ DCs generated from monocytes may induce differentiation of iTreg and nTreg cells, subsequently leading to remission in patients in EGPA by suppressing inflammation and disease activity (page 1, Abstract; pages 6-7, §Conclusion).
Regarding instant claim 6, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the method of treating ischemic stroke in a subject comprising administering to the subject an effective amount of a regulatory T cell genetically modified with anti-CD83 CAR wherein the method further comprises co-administering to the subject an effective amount of IL-2 as taught by the combined teachings of Davila and Sakai to include that the subject has vasculitis as taught by Tsurikisawa. This is obvious because, the combined teachings of Davila and Sakai teach a method of treating ischemic stroke in a subject comprising administering to the subject an effective amount of a regulatory T cell genetically modified with anti-CD83 CAR wherein the CAR-modified regulatory T cells may be administered in combination with IL-2, and Tsurikisawa teaches that the percentage of CD83+ DCs was higher in patients with EGPA, classified as a vasculitis of arteries that are small or medium in diameter, inducing differentiation of iTreg and nTreg cells, thereby suppressing inflammation and disease activity. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating ischemic stroke comprising administering to the subject an effective amount of a Treg cell in combination with an effective amount of IL-2, wherein the Treg cell is genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain and wherein the subject has vasculitis.
Claims 5 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Davila (Davila and Betts, US20200108098 A1, Priority to February 23, 2018, Published on 4/9/2020, IDS entered on 11/30/2023; hereinafter Davila) and further in view of Sumegi (Sumegi et al, “Gene expression profiling of peripheral blood mononuclear cells from children with active hemophagocytic lymphohistiocytosis”, April 14, 2011, Blood 117(15):e151-e160, IDS entered on 11/30/2023; hereinafter Sumegi).
Regarding instant claims 5 and 7, the teachings of Davila are discussed above. Davila also discloses a method of suppressing alloreactive donor cells in a subject receiving transplant donor cells, the method comprising administering to the subject an effective amount of a first immune effector cell genetically modified to express a first CAR polypeptide, comprising a CD83 antigen binding domain, a transmembrane domain, an intracellular signaling domain, and a co-stimulatory signaling region, thereby suppressing alloreactive donor cells in the subject (page 37, ¶ [0008]).
However, the Davila does not teach a method of treating a subject with macrophage activated syndrome, the method comprising administering to the subject an effective amount of an immune effector cell genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain to target CD83+ activated macrophages and monocytes to quell a cytokine storm, wherein the macrophage activated syndrome comprises hemophagocytic lymphohistiocytosis.
The deficiency is resolved by Sumegi.
Sumegi teaches that familial hemophagocytic lymphohistiocytosis (FHL) is a rare, genetically heterogeneous autosomal recessive immune disorder that results when the critical regulatory pathways that mediate immune defense mechanisms and the natural termination of immune/inflammatory responses are disrupted or overwhelmed (page e151, abstract). Sumegi also teaches that some of the clinical and laboratory characteristics of FHL are also observed in severe sepsis and related syndromes, including macrophage activation syndrome (page e151, column 2, first paragraph). Sumegi discloses that TREM1 (triggering receptor expressed on myeloid cells-1), which amplifies acute inflammatory responses by enhancing degranulation and secretion of proinflammatory mediators, and genes in the TREM1 signaling pathway (e.g. CD83) were found to be up-regulated in FHL patients (page e157, column 1, fourth paragraph; Figure 4C; supplemental Table 3). Moreover, Sumegi discloses that the “cytokine storm” has been considered as a hallmark of the immunologic phenotype of FHL, wherein the gene expression data suggest that the underlying mechanism of FHL includes an imbalance of cytokine homeostasis that shows massive up-regulation (>50-fold) of genes encoding proinflammatory proteins, and a moderate (0.58- to 10-fold) increase in the expression of genes coding for anti-inflammatory proteins, which has been a pattern that has also been observed in GVHD (page e158, column 1, fourth paragraph).
Regarding instant claims 5 and 7, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the method of preventing GVHD comprising administering to a subject an effective amount of a first immune effector cell genetically modified to express a first CAR polypeptide, wherein the CAR polypeptide comprises a CD83 antigen binding domain as taught by Davila and modify it to include treating a subject with FHL (also known as familial HLH) as taught by Sumegi. This is obvious because, Davila teaches a method of preventing GVHD comprising administering to a subject an effective amount of a first immune effector cell genetically modified to express a first CAR polypeptide, wherein the CAR polypeptide comprises a CD83 antigen binding domain, and Sumegi teaches that FHL patients have upregulated genes in the TREM1 signaling pathway (e.g. CD83), and the cytokine storm, which is considered as a hallmark of the immunologic phenotype of FHL, displays a pattern that is also observed in GVHD patients. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating a subject with macrophage activated syndrome, the method comprising administering to the subject an effective amount of an immune effector cell genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain to target CD83+ activated macrophages and monocytes to quell a cytokine storm, wherein the instant macrophage activated syndrome comprises hemophagocytic lymphohistiocytosis.
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.
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Claims 1 and 8-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-15, and 17 of copending Application No. 18/041,542 (US20230321239 A1; hereinafter ‘542) in view of Davila (Davila and Betts, US20200108098 A1, Priority to February 23, 2018, Published on 4/9/2020, IDS entered on 11/30/2023; hereinafter Davila), Sakai (Sakai et al, “Regulatory T Cells: Pathophysiological Roles and Clinical Applications”, July 26 2019, Keio J Med, 69(1):1-15, IDS entered on 11/30/2023; hereinafter Sakai) and Zhao (Zhao et al, “Alloimmune Response Results in Expansion of Autoreactive Donor CD4+ T cells in Transplants that can Mediate Chronic Graft-versus-Host Disease”, January 15 2011, The Journal of Immunology, 186(2):856-868; hereinafter Zhao). This is a provisional nonstatutory double patenting rejection.
Regarding instant claims 1 and 8-14, claims 1, 8-9, 15, and 17 of ‘542 teach a method of inhibiting autoreactive lymphocytes in a subject, the method comprising administering to the subject an effective amount of regulatory T cells genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain, a transmembrane domain, an intracellular signaling domain comprising a CD3 zeta signaling domain, and a costimulatory signaling region consisting of 4-1BB, thereby inhibiting autoreactive lymphocytes in the subject, wherein the CD83 antigen binding domain is a scFv of an antibody that specifically binds CD83. Claims 10 and 11 of ‘542 teach that the anti-CD83 scFv comprises a variable heavy (VH) domain having heavy chain (HC) CDR1, CDR2, and CDR3 regions comprising the amino acid sequences SEQ ID NOs:1, 2, and 3, respectively, and a variable light (VL) domain having light chain (LC) CDR1, CDR2, and CDR3 regions comprising the amino acid sequences SEQ ID NOs:4, 5, and 6, respectively. The amino acid sequences SEQ ID NOs:1-6 are identical to instant SEQ ID NOs:1-6 recited in instant claim 9. Claims 12 and 13 of ‘542 also teaches that the anti-CD83 scFv comprises a VH comprising the amino acid sequence of SEQ ID NO:19 and a VL comprising the amino acid sequence of SEQ ID NO:20. SEQ ID NOs:19-20 are identical to instant SEQ ID NOs:19-20 recited in instant claims 10-11. Furthermore, claim 14 of ‘542 teach that the anti-CD83 scFv comprises the amino acid sequence SEQ ID NO:57, which is identical to instant SEQ ID NO:57 recited in instant claim 12.
However, ‘542 does not teach a method for treating ischemic stroke in a subject comprising administering to the subject an effective amount of a Treg cell, wherein the Treg cell is genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain.
The deficiency is resolved by Davila, Sakai and Zhao.
The combined teachings of Davila and Sakai are discussed above.
Zhao teaches that chronic graft-versus-host disease (cGVHD) is a multisystem chronic alloimmune and autoimmune disorder that occurs after allogeneic hematopoietic cell transplantation (HCT), wherein autoreactive donor-type CD4+ T cells contribute to the pathogenesis of cGVHD (page 856, left column, first paragraph – page 857, left column, first paragraph).
Regarding instant claims 1, 8, and 13-14, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the method of inhibiting autoreactive lymphocytes in a subject, the method comprising administering to the subject an effective amount of regulatory T cells genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain, a transmembrane domain, an intracellular signaling domain, and a costimulatory signaling region as taught by ‘542 to comprise treating ischemic stroke as taught by the combined teachings of Davila, Sakai and Zhao. This is obvious because, ‘542 teaches a method of inhibiting autoreactive lymphocytes in a subject, the method comprising administering to the subject an effective amount of regulatory T cells genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain, a transmembrane domain, an intracellular signaling domain comprising a CD3 zeta signaling domain, and a costimulatory signaling region consisting of 4-1BB, thereby inhibiting autoreactive lymphocytes in the subject, wherein the CD83 antigen binding domain is a scFv of an antibody that specifically binds CD83, the combined teachings of Davila and Sakai teach a method of treating ischemic stroke in a subject comprising administering to the subject an effective amount of a regulatory T cell genetically modified with anti-CD83 CAR, and Zhao teaches that autoreactive donor-type CD4+ T cells contribute to the pathogenesis of cGVHD. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating ischemic stroke comprising administering to the subject an effective amount of a Treg cell, wherein the Treg cell is genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain wherein the CD83 antigen binding domain is a scFv of an antibody that specifically binds CD83, a cotransmembrane domain, an intracellular signaling domain comprising a CD3 zeta signaling domain, and a costimulatory signaling region consisting of 4-1BB.
Regarding instant claims 9-12, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the method of treating ischemic stroke in a subject comprising administering to the subject an effective amount of a regulatory T cell genetically modified with anti-CD83 CAR as taught by the combined teachings of ‘542, Davila, Sakai, and Zhao to further include that the anti-CD83 scFv comprises the amino acid sequence SEQ ID NO:57, wherein the anti-CD83 scFv comprises a VH domain comprising the amino acid sequence SEQ ID NO:19, and a VL domain comprising the amino acid sequence SEQ ID NO:20, wherein the VH domain comprises CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences SEQ ID NOs:1-3, respectively, and the VL domain comprises CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences SEQ ID NOs: 4-6, respectively as taught by ‘542. This is obvious because, the combined teachings of ‘542, Davila, Sakai, and Zhao teach a method of treating ischemic stroke in a subject comprising administering to the subject an effective amount of a regulatory T cell genetically modified with anti-CD83 CAR, and ‘542 teaches that the anti-CD83 scFv that binds to CD83 comprises the amino acid sequence SEQ ID NO:57, wherein the VH domain comprises the amino acid sequence SEQ ID NO:19, and the VL domain comprises the amino acid sequence SEQ ID NO:20, wherein the CDR1 sequence of the VH domain comprises the amino acid sequence SEQ ID NO:1, CDR2 sequence of the VH domain comprises the amino acid sequence SEQ ID NO:2, CDR3 sequence of the VH domain comprises the amino acid sequence SEQ ID NO:3, CDR1 sequence of the VL comprises the amino acid sequence SEQ ID NO:4, CDR2 sequence of the VL domain comprises the amino acid sequence SEQ ID NO:5, and CDR3 sequence of the VL domain comprises the amino acid sequence SEQ ID NO:6. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating ischemic stroke comprising administering to the subject an effective amount of a Treg cell, wherein the Treg cell is genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain, wherein the instant anti-CD83 scFv comprises a VH domain having CDR1, CDR2, and CDR3 comprising amino acid sequences instant SEQ ID NOs:1-3, respectively, and a VL domain having CDR1, CDR2, and CDR3 comprising amino acid sequences instant SEQ ID NOs:4-6, respectively.
Claims 1 and 8-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 12-13, 15, and 19-20 of copending Application No. 17/635,119 (US20220289862 A1; hereinafter ‘119) in view of Davila (Davila and Betts, US20200108098 A1, Priority to February 23, 2018, Published on 4/9/2020, IDS entered on 11/30/2023; hereinafter Davila), Sakai (Sakai et al, “Regulatory T Cells: Pathophysiological Roles and Clinical Applications”, July 26 2019, Keio J Med, 69(1):1-15, IDS entered on 11/30/2023; hereinafter Sakai) and Zhao (Zhao et al, “Alloimmune Response Results in Expansion of Autoreactive Donor CD4+ T cells in Transplants that can Mediate Chronic Graft-versus-Host Disease”, January 15 2011, The Journal of Immunology, 186(2):856-868; hereinafter Zhao). This is a provisional nonstatutory double patenting rejection.
Regarding instant claims 1 and 8-14, claims 1, 13, and 15, of ‘119 teach a method of suppressing autoreactive lymphocytes in a subject, the method comprising administering to the subject an effective amount of regulatory T cells to suppress CD83-expressing autoreactive lymphocytes, wherein the Treg cell is genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain, a transmembrane domain, an intracellular signaling domain comprising a CD3 zeta signaling domain, and a costimulatory signaling region consisting of 4-1BB, thereby suppressing autoreactive lymphocytes in the subject, wherein (i) the CD83 antigen binding domain is a scFv of an antibody that specifically binds CD83; (ii) the anti-CD83 scFv comprises a variable heavy (VH) domain having heavy chain CDR1, CDR2, and CDR3 regions comprising the amino acid sequences SEQ ID NOs:1, 2, and 3, respectively, and a variable light (VL) domain having light chain CDR1, CDR2, and CDR3 regions comprising the amino acid sequences SEQ ID NOs:4, 5, and 6, respectively; and (iii) the subject is the recipient of transplant donor cells that are not HLA matched to the subject. The amino acid sequences SEQ ID NOs:1-6 are identical to instant SEQ ID NOs:1-6 recited in instant claim 9. Claim 12 of ‘119 also teaches that the anti-CD83 scFv comprises the amino acid sequence SEQ ID NO:57, which is identical to instant SEQ ID NO:57 recited in instant claim 12. Furthermore, claims 19-20 of ‘119 teach that the anti-CD83 scFv comprises a VH comprising the amino acid sequence of SEQ ID NO:19 and a VL comprising the amino acid sequence of SEQ ID NO:20 or a VH comprising the amino acid sequence of SEQ ID NO:48 and a VL comprising the amino acid sequence of SEQ ID NO:54. SEQ ID NOs:19-20, 48 and 54 are identical to instant SEQ ID NOs:19-20, 48 and 54 recited in instant claims 10-11.
However, ‘119 does not teach a method for treating ischemic stroke in a subject comprising administering to the subject an effective amount of a Treg cell, wherein the Treg cell is genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain.
The deficiency is resolved by Davila, Sakai and Zhao.
The combined teachings of Davila, Sakai, and Zhao are discussed above. Davila also teaches a method of preventing rejection of “off-the-shelf” therapeutic immune effector cells, such as CAR-T cells, in a subject that involves administering to the subject an effective amount of a regulatory T cell genetically modified with a disclosed anti-CD83 CAR-T cells, wherein the transplant donor cells, such as off-the-shelf CAR-T cells, are not HLA matched to the subject (page 37, ¶ [0009]-[0010]).
Regarding instant claims 1, 8-9, and 13-14, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the method of suppressing autoreactive lymphocytes in a subject, the method comprising administering to the subject an effective amount of regulatory T cells to suppress CD83-expressing autoreactive lymphocytes, wherein the Treg cell is genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain, a transmembrane domain, an intracellular signaling domain, and a costimulatory signaling region, thereby suppressing autoreactive lymphocytes in the subject, wherein (i) the CD83 antigen binding domain is a scFv of an antibody that specifically binds CD83 comprising a VH domain comprising CDR1, CDR2, and CDR3 regions comprising the amino acid sequences SEQ ID NOs:1, 2, and 3, respectively, and a VL domain comprising CDR1, CDR2, and CDR3 regions comprising the amino acid sequences SEQ ID NOs:4, 5, and 6, respectively; and (ii) the subject is the recipient of transplant donor cells that are not HLA matched to the subject as taught by ‘119 to comprise treating ischemic stroke as taught by the combined teachings of Davila, Sakai and Zhao. This is obvious because, ‘119 teaches a method of suppressing autoreactive lymphocytes in a subject, the method comprising administering to the subject an effective amount of regulatory T cells to suppress CD83-expressing autoreactive lymphocytes, wherein the Treg cell is genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain, a transmembrane domain, an intracellular signaling domain comprising a CD3 zeta signaling domain, and a costimulatory signaling region consisting of 4-1BB, thereby suppressing autoreactive lymphocytes in the subject, wherein (i) the CD83 antigen binding domain is a scFv of an antibody that specifically binds CD83; (ii) the anti-CD83 scFv comprises a variable heavy (VH) domain having heavy chain CDR1, CDR2, and CDR3 regions comprising the amino acid sequences SEQ ID NOs:1, 2, and 3, respectively, and a variable light (VL) domain having light chain CDR1, CDR2, and CDR3 regions comprising the amino acid sequences SEQ ID NOs:4, 5, and 6, respectively; and (iii) the subject is the recipient of transplant donor cells that are not HLA matched to the subject, the combined teachings of Davila and Sakai teach a method of treating ischemic stroke in a subject comprising administering to the subject an effective amount of a regulatory T cell genetically modified with anti-CD83 CAR, Davila teaches a method of preventing rejection of “off-the-shelf” therapeutic immune effector cells, such as CAR-T cells, in a subject that involves administering to the subject an effective amount of a regulatory T cell genetically modified with a disclosed anti-CD83 CAR-T cells, wherein the transplant donor cells, such as off-the-shelf CAR-T cells, are not HLA matched to the subject, and Zhao teaches that autoreactive donor-type CD4+ T cells contribute to the pathogenesis of cGVHD. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating ischemic stroke comprising administering to the subject an effective amount of a Treg cell, wherein the Treg cell is genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain wherein the CD83 antigen binding domain is a scFv of an antibody that specifically binds CD83, a cotransmembrane domain, an intracellular signaling domain comprising a CD3 zeta signaling domain, and a costimulatory signaling region consisting of 4-1BB, wherein the instant anti-CD83 scFv comprises a VH domain having CDR1, CDR2, and CDR3 comprising amino acid sequences instant SEQ ID NOs:1-3, respectively, and a VL domain having CDR1, CDR2, and CDR3 comprising amino acid sequences instant SEQ ID NOs:4-6, respectively.
Regarding instant claims 10-12, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the method of treating ischemic stroke in a subject comprising administering to the subject an effective amount of a regulatory T cell genetically modified with anti-CD83 CAR as taught by the combined teachings of ‘119, Davila, Sakai, and Zhao to further include that the anti-CD83 scFv comprises the amino acid sequence SEQ ID NO:57, wherein the anti-CD83 scFv comprises a VH domain comprising the amino acid sequence SEQ ID NO:19 , and a VL domain comprising the amino acid sequence SEQ ID NO:20, or a VH domain comprising the amino acid sequence SEQ ID NO:48 , and a VL domain comprising the amino acid sequence SEQ ID NO:54 as taught by ‘119. This is obvious because, the combined teachings of ‘119, Davila, Sakai, and Zhao teach a method of treating ischemic stroke comprising administering to the subject an effective amount of a Treg cell, wherein the Treg cell is genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain wherein the CD83 antigen binding domain is a scFv of an antibody that specifically binds CD83, a cotransmembrane domain, an intracellular signaling domain, and a costimulatory signaling region, wherein the instant anti-CD83 scFv comprises a VH domain having CDR1, CDR2, and CDR3 comprising amino acid sequences instant SEQ ID NOs:1-3, respectively, and a VL domain having CDR1, CDR2, and CDR3 comprising amino acid sequences instant SEQ ID NOs:4-6, respectively, and ‘119 teaches that the anti-CD83 scFv that binds to CD83 comprises the amino acid sequence SEQ ID NO:57, wherein the VH domain comprises the amino acid sequence SEQ ID NO:19, and the VL domain comprises the amino acid sequence SEQ ID NO:20 or the VH domain comprises the amino acid sequence SEQ ID NO:48, and the VL domain comprises the amino acid sequence SEQ ID NO:54. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating ischemic stroke comprising administering to the subject an effective amount of a Treg cell, wherein the Treg cell is genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain wherein the CD83 antigen binding domain is a scFv of an antibody that specifically binds CD83 comprising a VH domain having CDR1, CDR2, and CDR3 comprising amino acid sequences instant SEQ ID NOs:1-3, respectively, and a VL domain having CDR1, CDR2, and CDR3 comprising amino acid sequences instant SEQ ID NOs:4-6, respectively, a cotransmembrane domain, an intracellular signaling domain, and a costimulatory signaling region, wherein the instant anti-CD83 scFv comprises the amino acid sequence instant SEQ ID NO:57, wherein the VH domain comprises amino acid sequence instant SEQ ID NO:19, and the VL domain comprises amino acid sequence instant SEQ ID NO:20 or wherein the VH domain comprises amino acid sequence instant SEQ ID NO:48, and the VL domain comprises amino acid sequence instant SEQ ID NO:54.
Claims 1, 8-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-8, and 11-12 of U.S. Patent No. 12,492,254B2 (hereinafter ‘254) in view of Davila (Davila and Betts, US20200108098 A1, Priority to February 23, 2018, Published on 4/9/2020, IDS entered on 11/30/2023; hereinafter Davila), Sakai (Sakai et al, “Regulatory T Cells: Pathophysiological Roles and Clinical Applications”, July 26 2019, Keio J Med, 69(1):1-15, IDS entered on 11/30/2023; hereinafter Sakai) and Zhao (Zhao et al, “Alloimmune Response Results in Expansion of Autoreactive Donor CD4+ T cells in Transplants that can Mediate Chronic Graft-versus-Host Disease”, January 15 2011, The Journal of Immunology, 186(2):856-868; hereinafter Zhao)
Regarding instant claims 1 and 8-14, claims 1-3, 5, and 11-12 of ‘254 teach a method of suppressing alloreactive donor cells in a subject receiving transplant donor cells, the method comprising administering to the subject an effective amount of regulatory T cells genetically modified to express a CAR polypeptide, thereby suppressing alloreactive donor cells in the subject, wherein the CAR polypeptide comprises a CD83 antigen binding domain, a transmembrane domain, an intracellular signaling domain comprising a CD3 zeta signaling domain, and a costimulatory signaling region consisting of 4-1BB, wherein the CD83 antigen binding domain is a scFv comprising the amino acid sequence SEQ ID NO:59 wherein the variable heavy (VH) domain comprises the amino acid sequence SEQ ID NO:48 and the variable light (VL) domain comprises the amino acid sequence SEQ ID NO:54. The amino acid sequences SEQ ID NOs:48, 54, and 59 are identical to instant SEQ ID NOs:48, 54, and 59 recited in instant claims 10-12. Claims 6-8 of ‘254 teach an isolated nucleic acid sequence encoding the CAR polypeptide (claim 6), a vector comprising the isolated nucleic acid encoding the CAR polypeptide (claim 7), and a cell comprising the vector comprising the isolated nucleic acid encoding the CAR polypeptide (claim 8).
However, ‘254 does not teach a method for treating ischemic stroke in a subject comprising administering to the subject an effective amount of a Treg cell, wherein the Treg cell is genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain.
The deficiency is resolved by Davila, Sakai and Zhao.
The combined teachings of Davila, Sakai, and Zhao are discussed above. Zhao further teaches that After allogenic HCT, alloreactive donor T cells are activated by interaction with host APCs presenting alloantigens, wherein the activated alloreactive T cells interact with donor B cells that present both allo- and autoantigens, including non-polymorphic Ags from both donor and host. Furthermore, Zhao teaches that thereafter, the activated donor B cells subsequently activate and expand the autoreactive donor CD4+ T cells in transplants that contribute to the development of autoimmune-like manifestations in the recipients (page 865, left column, last paragraph – right column, first paragraph).
Regarding instant claims 1, 8-14, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the method of suppressing alloreactive donor cells in a subject receiving transplant donor cells, the method comprising administering to the subject an effective amount of regulatory T cells genetically modified to express a CAR polypeptide, thereby suppressing alloreactive donor cells in the subject, wherein the CAR polypeptide comprises a CD83 antigen binding domain, a transmembrane domain, an intracellular signaling domain, and a costimulatory signaling region, wherein the CD83 antigen binding domain is a scFv comprising the amino acid sequence SEQ ID NO:59 wherein the variable heavy (VH) domain comprises the amino acid sequence SEQ ID NO:48 and the variable light (VL) domain comprises the amino acid sequence SEQ ID NO:54 as taught by ‘254 to comprise treating ischemic stroke as taught by the combined teachings of Davila, Sakai and Zhao. This is obvious because, ‘254 teaches a method of suppressing alloreactive donor cells in a subject receiving transplant donor cells, the method comprising administering to the subject an effective amount of regulatory T cells genetically modified to express a CAR polypeptide, thereby suppressing alloreactive donor cells in the subject, wherein the CAR polypeptide comprises a CD83 antigen binding domain, a transmembrane domain, an intracellular signaling domain comprising a CD3 zeta signaling domain, and a costimulatory signaling region consisting of 4-1BB, wherein the CD83 antigen binding domain is a scFv comprising the amino acid sequence SEQ ID NO:59 wherein the variable heavy (VH) domain comprises the amino acid sequence SEQ ID NO:48 and the variable light (VL) domain comprises the amino acid sequence SEQ ID NO:54, the combined teachings of Davila and Sakai teach a method of treating ischemic stroke in a subject comprising administering to the subject an effective amount of a regulatory T cell genetically modified with anti-CD83 CAR, and Zhao teaches that after allogenic HCT, alloreactive donor T cells are activated by interaction with host APCs presenting alloantigens, wherein the activated alloreactive T cells interact with donor B cells that present both allo- and autoantigens, wherein thereafter, the activated donor B cells subsequently activate and expand the autoreactive donor CD4+ T cells in transplants that contribute to the development of autoimmune-like manifestations in recipients. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating ischemic stroke comprising administering to the subject an effective amount of a Treg cell, wherein the Treg cell is genetically modified to express a CAR polypeptide comprising a CD83 antigen binding domain wherein the CD83 antigen binding domain is a scFv of an antibody that specifically binds CD83, a cotransmembrane domain, an intracellular signaling domain comprising a CD3 zeta signaling domain, and a costimulatory signaling region consisting of 4-1BB, wherein the instant anti-CD83 scFv comprises the amino acid sequence instant SEQ ID NO:59, wherein the VH domain comprises amino acid sequence instant SEQ ID NO:48, and the VL domain comprises amino acid sequence instant SEQ ID NO:54.
Regarding claims 6-8 of ‘254, the CAR polypeptide comprising a CD83 antigen binding domain of the instant application that is administered is obvious over the claimed polynucleotide encoding the CAR polypeptide, because the specification of ‘254 discloses that the polynucleotides and polynucleotide vectors encoding the disclosed CD83-specific CARs allow expression of the CD83-specific CARs in the disclosed immune effector cells.
Conclusion
No claims are allowed.
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/J.H./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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