DETAILED ACTION
Applicant’s amendment and response received on 12/15/25 has been entered. Claims 2, 5, 9-20, and 23 have been canceled, and new claims 27-36 have been added. Claims 1, 3-4, 6-8, 21-22, and 27-36 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 Objections
The objection to previously pending claims 1-26 lack the appropriate indefinite article “A” (for independent claims) or the definite article “The” (for dependent claims) at the start of each claim, is withdrawn in view of either the cancellation of or the amendments to the claims.
Claim Rejections - 35 USC § 112
The rejection of previously pending claims 3-5, 7, 10-13, and 15-21 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn over canceled claims 5, 10-13, and 15-20, further withdrawn over amended claims 3-4 in view of applicant’s amendments to the claims, and maintained over claim 7. However, in view of applicant’s amendments to claim 1 and the addition of new claims 28-36, the following grounds of rejection have been necessitated.
Claim 7 remains, and amended or new claims 1, 3-4, 6, 8, 21-22, and 27-36 are now 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. Applicant’s arguments concerning claim 7 have been fully considered but have not been found persuasive. These arguments will be addressed below following the statement of new grounds of rejection.
Claim 1 and new claim 28 both recite in part, “wherein the ligand domain is a cognate antigen against which an undesired immune response is directed, for a T-cell receptor and/or for a B-cell receptor,”. The phrase “, for a T-cell receptor and/or a B-cell receptor” renders the claims indefinite as the use of the commas surrounding this phrase and the use of the word “for” are confusing because it unclear whether the undesired immune response to the cognate antigen is “for” i.e. affects or is directed to the T-cell receptor or the B-cell receptor, or whether the undesired immune response is caused by an activity of the T-cell receptor or B-cell receptor upon binding to the cognate antigen. As such, the metes and bounds of claims 1 and 28, both independent claims, cannot be determined. Claims 3-4, 6, 8, 21-22, 27, and 29-36 depend on either claim 1 or claim 28 and thus are included in this action.
If applicant intends that the undesired immune response is caused by the T-cell receptor or the B-cell receptor upon binding to the cognate antigen, rather than affecting a T-cell receptor or the B-cell receptor, it is suggested that applicant amended this section of claim 1 and claim 28 to recite, “wherein the ligand domain is a cognate antigen against which an undesired immune response is directed by a T-cell receptor and/or a B-cell receptor,”.
In addition, claim 1 as amended now recites, “wherein the ligand domain contains at least one mutation effective to reduce or abolish binding to the immune cell which expresses the fusion protein of a CD8 molecule expressed on a CD8+ T cell”. As written, this wherein clause is confusing as it appears to state that the mutation reduces or abolishes the binding of the ligand domain “to the immune cell which expresses the fusion protein of a CD8 molecule”. Claim 1 does not provide proper antecedent basis for “the fusion protein of a CD8 molecule”, or to “the immune cell which expresses the fusion protein of CD8 molecule”. As such, the metes and bounds of this limitation and the claim as whole cannot be determined.
Claim 7 continues to recite, and new claim 33 now recites the limitation, “wherein the dimerization domains only dimerize to heterodimers”. The applicant argues that this language is no confusing because it is understood as “dimerizing different monomers to heterodimers”. It is noted that this part of the explanation only further confuses the issue as it appears that applicant is saying that they mean to claim that different monomers dimerize to heterodimers such as the dimerization of a monomer to an already existing heterodimer. However, applicant’s subsequent explanation contradicts this interpretation as the applicant then states that the specification discloses exemplary dimerization domains and, “the effect of the formation of heterodimers by such a dimerization is that dimerization of two differing monomers occurs in a controlled manner…”. From this statement it appears that applicant intends the claim to actually recite that the dimerization domains only dimerize to form heterodimers. However, due to the contradiction in applicant’s explanation and the continuing lack of clarity in the language present in the claims, the rejection over claim 7, and now new claim 33, is maintained.
It is suggested that if the second of the interpretation presented above is in fact the intended interpretation that applicant claims 7 and 33 to recite, “wherein the dimerization domains only dimerize to form heterodimers”.
Amended claim 21 is now further indefinite based on applicant’s amendments to both claim 21 and claim 1 upon which it depends indirectly through claim 4. Claim 1 as amended recites that the ligand domain “consists of” particular components of HLA Class I. Claim 21, however, now recite that the ligand domain “comprises” and additional element which is a heavy chain of HLA class I. The use of the language “consists of” in claim 1 is considered closed language such that adding additional elements to the ligand is precluded. As such, the recitation in claim 21 which uses open language “comprises” and then recitation an additional element not recited in claim 1 conflicts with the limitations of claim 1 essentially claiming a broad limitation after an earlier narrow limitation. This conflict renders the claim indefinite such that the metes and bounds of the claims cannot be determined.
It is suggested that if applicant wishes to include the additional element of the heavy chain in the ligand domain that applicant amend claim 1 to use the open language, “wherein the ligand domain comprises an alpha I domain…..”.
Claim Rejections - 35 USC § 102
The rejection of claims 1-9, and 12-26 under 35 U.S.C. 102(a)(1) as being anticipated by U.S. Patent 6,056,952 (2000), hereafter referred to as Rosenberg is withdrawn over canceled claims 2, 5, 9, 12-20, and 23, and further withdrawn over claims 1, 3-4, 6-8, 21-22 and 24-26 in view of applicant’s amendment to independent claim 1 which now recites that the ligand domain contains at least one mutation effective to reduce or abolish binding to the immune cell which expresses the fusion protein of a CD8 molecule expressed on a CD8+ T cell.
Claim Rejections - 35 USC § 103
The rejection of previously pending claims 1 and 10-11 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, is now maintained or newly applied to amended and new claims 1, 3-4, 6-8, 21-22, and 27-36. Note that claims 10-11, previously rejected, have been canceled. 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 argues that the references, particularly Rosenberg and Screaton teach different approaches whose teachings cannot be combined without hindsight reasoning. The applicant further argues 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 then argues 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 argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Further, 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, 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 with CD4 or CD8 co-stimulation. It is also noted 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. It is also noted that while Screaton et al. does not teach specific mutations of the Class II extracellular domain, 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 T cells up to and including the death of the autoreactive T cells, and 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). 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, it is maintained that 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, based motivation to modify MHC class I or MHC class II to prevent CD8 or CD4 binding respectively in order to improve the therapeutic targeting and killing of autoreactive T cells as taught by Screaton et al., and 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 is maintained that 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.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication 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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