DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/8/26 has been entered.
New claim 37 has been added. Claims 1, 3-4, 6-8, 21-22, and 24-37 are currently pending in this application. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . An action on the merits follows.
Those sections of Title 35, US code, not included in this action can be found in a previous office action.
Claim Rejections - 35 USC § 112
The rejection of claims 1, 3-4, 6, 8, 21-22, and 27-36 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn in view of applicant’s amendments to the claims.
Claims 28-36 are newly 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn in view of applicant’s amendments to the claims.
Claim 28 recites, “wherein the ligand domain consists of the alpha 1 domain, and optionally the alpha 2 domain, and the beta 1 domain, and optionally the beta 2 domain of a HLA class II molecule”. As written, it is unclear whether the beta 1 domain is optional or required. The prior use of the term “optionally” makes the subsequent recitation of “and the beta 1 domain” confusing since it is not clear where the “optionally” is only intended to refer to the alpha 2 domain or both the alpha 2 and beta 1 domain. Thus, the metes and bounds of this claim cannot be determined. Claim 29-36 depends on claim 28 and thus are included in this rejection.
If applicant intends the non-optional inclusion of the beta1 domain it is suggested that applicant amend claim 28 to recite that the ligand domain consists of the alpha 1 domain, the beta 1 domain, and optionally the alpha 2 domain, and/or the beta 2 domain of a HLA class II molecule.
Claim Rejections - 35 USC § 103
Amended and new claims 1, 3-4, 6-8, 21-22, and 24-37 remain or are newly rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent 6,056,952 (2000), hereafter referred to as Rosenberg, in view of WO 02/074331 (9/26/02), hereafter referred to as Screaton et al., and Fleury et al. (1995) J. Exp. Med., Vol. 182, 733-741. Applicant’s amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons set forth in detail below.
The applicant reiterates their arguments that the references, particularly Rosenberg and Screaton, teach different approaches whose teachings cannot be combined. The applicant reiterates that Rosenberg does not make obvious that cells of the recipient patient can attack cells expressing the claimed fusion proteins, and that Rosenberg et al. does not teach to include a mutation in the MHC I or II domains of the fusion protein to reduce or abolish binding to patient CD8+ or CD4+ T cells. The applicant further reiterates arguments that neither Screaton nor Fleury remedy the alleged deficiencies of Rosenberg because Screaton teaches to mutate a full length MHC I in transplanted cells to hinder the binding of CD8+ T cells to the transplanted cells, and does not teach an artificial fusion protein as claimed. The applicant argues that Screaton does not teach that the patient T cells are affected by the mutated MHC and thus teaches a different modes of action for introducing the mutations that cannot be combined with Rosenberg’s fusion proteins. Finally, the applicant argues that Fleury et al. also does not teach that mutations in MHC class II domains can be used to inactive T cells which bind to the immune cells expressing a fusion protein comprising an MHC class II domain.
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). In addition, 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). Obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In the instant rejection, Rosenberg was cited for teaching a variety of major histocompatibility complex (MHC) based chimeric receptor (MHC-CAR) useful in targeting autoreactive immune cells for treating autoimmune diseases (Rosenberg et al., abstract). Rosenberg teaches MHC-CAR comprising one or more MHC polypeptides or an extracellular domain thereof and one or more cell signaling domains, where the signaling domains comprise a cytoplasmic signaling domain such as CD3ζ and at least one co-stimulatory domain, such as a co-stimulatory domain from 4-1BB or CD28 (Rosenberg et al., paragraph 46). Rosenberg further teaches that the MHC-CAR may also comprise an antigenic peptide from an autoantigen or a foreign antigen that mimics an autoantigen in eliciting autoimmune responses (Rosenberg et al., paragraph 46). Rosenberg also teaches nucleic acids encoding the MHC-CAR, vectors carrying such, and genetically engineered immune cells such as T cell and natural killer (NK) cells expressing the MHC-CAR (Rosenberg et al., paragraph 46). Rosenberg et al. teaches the MHC-CAR can be a single fusion polypeptide containing the MHC moiety, the antigenic peptide, and the at least one cell signaling moiety where the single fusion polypeptide may form complexes with endogenous cell membrane proteins such as β-microglobulin when expressed in a suitable immune cell, or that the MHC-CAR may be a multi-chain protein complex (Rosenberg et al., paragraphs 49-50). Rosenberg also teaches that the MHC-CAR may further comprise a hinge domain or peptide linker adjacent to the MHC moiety and between the MHC moiety and other components such as the transmembrane domain (Rosenberg, paragraphs 50, and 100). Rosenberg et al. teaches the use of a number of transmembrane domains including the transmembrane domains of MHC Class I HLA-A3, or the MHC class II HLA-DR*1501 or DRA*0101 transmembrane domains (Rosenberg, paragraph 95). Rosenberg also teaches hinge sequences which are 10-75 amino acids in length, and peptide linker sequences which are 13 or 15 amino acids in length (Rosenberg, paragraph 85-89, and 100). In particular, Rosenberg teaches hinge sequences derived from MHC Class I or II molecules, immunoglobulin hinge regions such as IgG1 hinge, and CD8alpha hinge regions. Note that immunoglobulin hinge regions such as IgG1 comprises disulphide motifs capable of dimerization with other disulphide motifs. Rosenberg teaches that the MHC moiety can be MHC class I or MHC class II and when an MHC class II molecule is used for constructing a MHC-CAR, the MHC moiety may include two subunits capable of forming a heterodimer, one including the α-chain or an extracellular portion thereof such as α1, α2, or both, the other including the b-chain or an extracellular portion thereof such as β1, β2, or both (Rosenberg et al., paragraph 55). Thus, Rosenberg teaches the presence of dimerization domains either as part of the hinge region- in the form of IgG1 hinge- or as part of the MHC class I or class II chains. Rosenberg also teaches that in cases where only the region that interacts with other cell types is used (i.e., α1 and β1), specific amino acid modifications may be required to enhance the folding of the mini-MHC (Rosenberg, paragraph 55). In one embodiment, Rosenberg discloses a fusion protein comprising MHC-DRA*1010, a hinge region, a transmembrane region, and CD3 zeta signaling domain (Rosenberg, paragraph 111). Rosenberg teaches that MHC class I molecules are heterodimers which are formed from the dimerization of the MHC class I alpha chain and beta-2-microglobulin, and that MHC class II is a heterodimer formed from the dimerization of the MHC class II alpha chain and the MHC class II beta chain (Rosenberg et al. paragraph 54). As such, both the MHC class I alpha and beta-2 microglobulin protein comprises dimerization domains which are capable of dimerization with each other to form MHC class I heterodimers, and both the MHC class II alpha and beta chains comprise dimerization domains, which are capable of dimerization with each other to form the MHC class II heterodimers. Figures 3, 4 5, 6, 7, 8, and 10 provides numerous examples of both single chain and multichain MHC class I-CAR and MHC-class II CAR. Note that in some of the embodiments, each chain of the MHC-CAR comprises one or more signaling domains (Figures 5 and 6). Applicant is correct that Rosenberg does not teach to mutate the MHC class I or class II domain to reduce or prevent binding to CD8 or CD4 respectively on a T cell. However, it is noted that Rosenberg teach all the physical limitations of the MHC-CAR fusion proteins recited in the instant claims with the exception of the inclusion of a mutation in either the MHC class I or class II domain capable of reducing or preventing binding to CD8 or CD4 respectively. Further, as discussed in the previous office action, the teachings of Rosenberg are not read in a vacuum, but rather in view of the teachings of the secondary references.
The rejection of record acknowledged that Rosenberg differs from the instant claims by not teaching to use MHC class I or MHC class II ligand domains with particular point mutations. Screaton et al. was cited to supplement Rosenberg et al. by teaching that autoimmune therapy which targets autoreactive T cells can be improved by using MHC class I molecules comprising mutations that decrease or prevent CD8 binding on CD8+ T cells or by using MHC class II molecules comprising mutations that decrease or prevent CD4 binding on CD4+ T cells, as stimulation of TCR without CD4 or CD8 binding can inhibit the autoreactive T cells and lead to autoreactive T cell death (Screaton et al., page 3). This specific teaching by Screaton et al. contradicts applicant contention that Screaton only teaches passive effects on the autoreactive T cells. On the contrary, Screaton teaches that mutation preventing binding of the MHC with CD4 or CD8 can lead to the death of the autoreactive T cell due to stimulation without CD4 or CD8 co-stimulation. It is also reiterated that the claims under examination are exclusively product claims, not methods of killing T or B cells using any particular mechanism. The applicant is also reminded that the fact that the inventor may have recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Screaton provides substantial motivation to introduce mutations, including specific mutations in the Class I alpha 3 domain at preferably in any amino acid between residues 220-250, and more specifically at residue 227 (Screaton et al., page 6), by teaching benefits to incorporating the mutations into an MHC class I extracellular domain. Further, Screaton et al. is not required to teach the same structure as claimed. Applicant’s argument that Screaton et al. does not teach MHC class I or II fusion proteins as claimed with intracellular signaling components as claimed is not persuasive as Rosenberg et al., the primary reference, already teaches immune cells expressing fusion proteins with the same structures as claimed, including the intracellular domains as claimed. As noted above, the only difference between the fusion proteins of Rosenberg et al. and the instant claimed fusion proteins in that Rosenberg et al. does not teach to further include the mutations to reduce CD4 or CD8 binding. Screaton et al. provides substantial motivation to make these kinds of mutations in MHC class I and MHC class II molecules in order to prevent unwanted activity by autoreactive T cells up to and including the death of the autoreactive T cells. Note as well that Rosenberg, as noted above, teaches that the MHC-CAR may also comprise an antigenic peptide from an autoantigen or a foreign antigen that mimics an autoantigen in eliciting autoimmune responses Thus, in fact, both Rosenberg et al. and Screaton et al. teach a goal of reducing/preventing unwanted activity by autoreactive cells including T cells. As such, the skilled artisan reading Screaton et al. would have been amply motivated to modify the MHC fusion proteins taught by Rosenberg et al. to contain the mutations taught by Screaton et al. in order to maximize the ability of cells expressing the MHC fusion proteins to prevent unwanted autoreactive T cell activity both by preventing co-stimulatory molecule co-activation of the autoreactive TCR and by triggering activation of the immune cell expressing the MHC fusion protein leading ultimately in both cases to the death of the autoreactive T cell.
Regarding specific mutations of the Class II extracellular domain, while Screaton et al. does teach that mutations which can inhibit the binding of MHC to either CD4 or CD8 on an autoreactive T cell will have the benefit or preventing unwanted activity by the autoreactive T cells up to and including the death of the autoreactive T cells, Fleury et al. was cited to further supplements Rosenberg et al. and Screaton et al. by teaching specific mutation to the Class II beta chain at position 137 which abrogates CD4 binding (Fleury et al., page 738). The applicant argues that Fleury’s teaching are not applicable because Fleury et al. does not teach fusion proteins as claimed or teach to introduce mutations preventing CD4 binding into fusion proteins as claimed. Applicant’s arguments are not found persuasive as Rosenberg et al., discussed in detail above, has been cited as the primary reference for the teaching the fusion proteins as claimed, and Screaton et al., also discussed above, has been cited for providing the requisite motivation to introduce mutations into MHC class I and MHC class II to inhibit binding to CD8 and CD4 respectively in order to prevent unwanted activity by autoreactive T cells. The teachings of Fleury et al. provide specific mutations to MHC class II which inhibit binding to CD4. Therefore, it is maintained that based on the specific teachings provided by Screaton et al. to introduce mutations into the MHC class I extracellular ligand binding domain in cells for transplant to prevent autoreactive T cell effector function and to inhibit or even kill the autoreactive T cells, the skilled artisan would have found ample motivation to introduce mutations into the MHC class I domains or MHC class II domains of the MHC/CAR fusion protein taught by Rosenberg et al. with a reasonable expectation of success.
Therefore, it is maintained that based on the motivation to modify MHC class I or MHC class II to prevent CD8 or CD4 binding respectively in order to unwanted autoreactive T cell activity as taught by Screaton et al., the specific mutations for inhibiting CD8 binding by mutation of residue 227 of MHC class I alpha as taught by Screaton et al. or inhibition of CD4 binding by mutation of residue 137 of MHC class II beta by Fleury et al., it would have been prima facie obvious to the skilled artisan at the time of filing to introduce the MHC class I alpha mutation of residue 227 or the MHC class II beta mutation of residue 137 into the MHC-CAR useful for autoimmune therapy taught by Rosenberg et al. with a reasonable expectation of success.
No claims are allowed.
Any inquiry concerning this communication from the examiner should be directed to Anne Marie S. Wehbé, Ph.D., whose telephone number is (571) 272-0737. If the examiner is not available, the examiner’s supervisor, Maria Leavitt, can be reached at (571) 272-1085. For all official communications, the technology center fax number is (571) 273-8300. Please note that all official communications and responses sent by fax must be directed to the technology center fax number. For informal, non-official communications only, the examiner’s direct fax number is (571) 273-0737. For any inquiry of a general nature, please call (571) 272-0547.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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