DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed February 12, 2026 is pending.
Claims 1-15 are pending.
Claims 1 and 8 are independent claims.
Election/Restriction
Applicant’s election with traverse to Invention I (claims 1-9, and 15, drawn to a modified T cell; a population of modified T cells; and a method for generating modified T cells in vitro, classified in A61K 35/17) and election without traverse to the species; (a) of a single anti-CD28 CAR comprising: (1) an antigen binding moiety comprising an anti-CD28 antibody comprising a VH CDR1, CDR2 and CDR3 consisting of the amino acid sequences of SEQ ID NO: 8, 9 and 10, and a VL CDR1, CDR2 and CDR3 of the amino acid sequences of SEQ ID NO: 11, 12 and 13; (2) an endodomain comprising a CD28 co-stimulatory domain and a CD3zeta intracellular signaling domain; and (3) a CD8 transmembrane domain; (b) a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas-based RNA-guided DNA endonuclease as the single method of disrupting the endogenous CD28-encoding gene; and (c) at least 25%, at least 50%, or at least 70% of the modified T cells of the population express the CAR on their surface as the single population of modified T cells in the reply filed on February 12, 2026 is acknowledged.
The traversal is on the ground(s) that the two groups of subject matter are not distinct as the methods of Group II explicitly rely on the modified T cells of Group I, and therefore Group II poses no additional search burden for the Office.
This is not found persuasive because, as noted in the restriction requirement mailed 12/12/2025, Inventions I and II are related as product and process of use. The inventions can be shown to be distinct if either or both of the following can be shown: (1) the process for using the product as claimed can be practiced with another materially different product or (2) the product as claimed can be used in a materially different process of using that product. See MPEP § 806.05(h).
In the instant case the method for treating, delaying the progression of, and/or otherwise ameliorating a symptom of a disorder in a subject in need thereof of invention II can be done with another materially different product than the modified T cells of invention I, such as, a small molecule or an antibody.
Given that Inventions I and II are independent or distinct, there would be a serious search and/or examination burden if restriction were not required. Therefore, the requirement mailed 12/12/2025 is still deemed proper and is therefore maintained.
Claims 10-14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 02/12/2026.
Claims 1-9 and 15 are currently under consideration.
Priority
The instant application is a CIP of PCT/EP2021/082713 filed 11/23/2021 and claims foreign priority to EP20209327.4 filed 11/23/2020.
A certified translated copy of EP20209327.4 has not been filed. Therefore, it is not clear if the foreign priority documents have adequate support for the instant claims.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 15 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claims do not fall within at least one of the four categories of patent eligible subject matter because claim 15 is directed to the “use” of the modified T cell according of claim 1 for selective depletion of CD28+ cells in a sample in vitro.
"Use" claims are non-statutory under 35 U.S.C. 101 because the claimed recitation of a use, without setting forth any steps involved in the process, results in an improper definition of a process, i.e., results in a claim which is not a proper process claim under 35 U.S.C. 101. See for example Ex parte Dunki , 153 USPQ 678 (Bd. App. 1967) and Clinical Products, Ltd v. Brenner, 255 F. Supp. 131, 149 USPQ 475 (D.D.C. 1966). See MPEP 2173.05(q).
Canceling claim 15 or amending claim 15 to be directed to statutory subject matter would obviate this part of the rejection.
For the purpose of applying prior art, claim 15 is being read as the modified T cell according of claim 1.
Claim Rejections - 35 USC § 112
Indefinite language
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-6 and 15 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 2-6 recite the terms “preferably,” “more preferable” and/or “even more preferable.” The recitation of the term “preferably,” “more preferable” and/or “even more preferable” in the claims renders the claims indefinite because it is unclear whether the limitation(s) following the phrases are part of the claimed invention. See MPEP § 2173.05(d).
Amending the claims to delete the “preferably,” “more preferable” and/or “even more preferable” clauses would obviate this part of the rejection.
For the purpose of applying prior art, the “preferably,” “more preferable” and/or “even more preferable” clauses have not been considered.
Claim 3 recites “wherein the CAR further comprises an endodomain comprising one or more T-cell-stimulatory molecules; wherein the T-cell-stimulatory molecule is preferably a signaling domain from a T-cell-co-stimulatory receptor, an immunoreceptor tyrosine-based activation motif (ITAM), and/or a Toll/interleukin-1 receptor (TIR) domain; wherein preferably (i) the T-cell-co-stimulatory receptor is selected from: CD28, ICOS (CD278), CD27, 4-1BB (CD137, TNFRSF9), OX40 (CD134), CD27, IL-2Rp, IL-15R-a, CD40L(CD154) and/or MyD88; and/or (ii) the ITAM is selected from: CD3-zeta (CD3𝞯, DAP12, Fc-epsilon receptor 1 gamma chain, CD3-gamma, CD3-delta, CD3-epsilon, and CD79A (antigen receptor complex-associated protein alpha chain); and/or (iii) the TIR domain is the TIR domain of Toll-like receptor 2 (TRL2)” in lines 1-13.
The recitation of “the T-cell-stimulatory molecule” in line 3 means that there is only one T-cell-stimulatory molecule. However the recitation of “one or more” in line 2 means that there can be more than one T-cell-stimulatory molecule. The recitation of a plural T-cell-stimulatory molecules followed by a singular T-cell-stimulatory molecule renders the claim indefinite because it is unclear how many T-cell-stimulatory molecules the CAR should comprise.
Furthermore, the recitation of “the/a/an T-cell-co-stimulatory receptor/immunoreceptor tyrosine-based activation motif (ITAM)/Toll/interleukin-1 receptor (TIR) domain” means that there is only one T-cell-co-stimulatory receptor, immunoreceptor tyrosine-based activation motif (ITAM), or Toll/interleukin-1 receptor (TIR) domain. However the recitation of “and/or” means that there can be more than one T-cell-co-stimulatory receptor, immunoreceptor tyrosine-based activation motif (ITAM), or Toll/interleukin-1 receptor (TIR) domain. The recitation of a plural T-cell-co-stimulatory receptors, immunoreceptor tyrosine-based activation motifs (ITAMs), or Toll/interleukin-1 receptor (TIR) domains followed by a singular T-cell-co-stimulatory receptor, immunoreceptor tyrosine-based activation motif (ITAM), or Toll/interleukin-1 receptor (TIR) domain renders the claim indefinite because it is unclear how many T-cell-co-stimulatory receptors, immunoreceptor tyrosine-based activation motifs (ITAMs), or Toll/interleukin-1 receptor (TIR) domains the CAR should comprise.
Amending claim 3 to recite “wherein the CAR further comprises an endodomain comprising a T-cell-stimulatory molecule; wherein the T-cell-stimulatory molecule is preferably a signaling domain from a T-cell-co-stimulatory receptor, an immunoreceptor tyrosine-based activation motif (ITAM), or a Toll/interleukin-1 receptor (TIR) domain; wherein preferably (i) the T-cell-co-stimulatory receptor is selected from: CD28, ICOS (CD278), CD27, 4-1BB (CD137, TNFRSF9), OX40 (CD134), CD27, IL-2Rp, IL-15R-a, CD40L(CD154) or MyD88; (ii) the ITAM is selected from: CD3-zeta (CD3𝞯, DAP12, Fc-epsilon receptor 1 gamma chain, CD3-gamma, CD3-delta, CD3-epsilon, or CD79A (antigen receptor complex-associated protein alpha chain); or (iii) the TIR domain is the TIR domain of Toll-like receptor 2 (TRL2)” would obviate this part of the rejection.
Claim 5 recites “comprises or consists of” in line 3. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 5 recites the broad recitation “comprises” and the claim also recites “consists of” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Amending claim to delete either “comprises” or “consists of” would obviate this part of the rejection.
Claim 15 is directed to the “use” of the modified T cell according of claim 1 for selective depletion of CD28+ cells in a sample in vitro. Attempts to claim a process without setting forth any steps involved in the process generally raises an issue of indefiniteness under 35 U.S.C. 112(b). For example, a claim which read: "[a] process for using monoclonal antibodies of claim 4 to isolate and purify human fibroblast interferon" was held to be indefinite because it merely recites a use without any active, positive steps delimiting how this use is actually practiced. Ex parte Erlich, 3 USPQ2d 1011 (Bd. Pat. App. & Inter. 1986). See MPEP 2173.05(q).
This applies to the instant case where claims 15 claim “use of the modified T cell” without reciting any steps involved in said use.
Canceling claim 15 or amending claims 15 to recites “A method for…” would obviate this part of the rejection.
Written Description
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 1-9 and 15 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 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.
The instant claims are drawn to (1) a modified T cell, comprising (a) a disrupted endogenous CD28-encoding gene; and (b) a polynucleotide encoding a chimeric antigen receptor (CAR), wherein the CAR comprises in its ectodomain at least one antigen binding moiety that is capable of specific binding to the extracellular portion of CD28 and (2) a method for generating modified T cells in vitro, comprising (a) disrupting the endogenous CD28-encoding gene in T cells; and (b) introducing into said T cells a polynucleotide encoding a chimeric antigen receptor (CAR), wherein the CAR comprises in its ectodomain at least one antigen binding moiety that is capable of specific binding to the extracellular portion of CD28.
The Applicant has disclosed 20 anti-CD28 CAR constructs (CD28_CAR_1-20) which comprise one of five anti-CD28 scFv antigen binding fragments (TGN1412, CD28.3, Cl1B4, cl83, or Fengfeng) (e.g. see Tables 1 and 2). TGN1412 is a well-known humanized CD28-binding full-length monoclonal antibody which has previously been reported to not only specifically bind CD28, but to also acting as a strong agonist ("superagonist") of CD28, i.e., that is capable of activating T cells, in particular regulatory T cells, without the need of simultaneous T cell receptor (TCR)-mediated co-stimulation (e.g. see Example 3 on page 64, lines 24-31).
The Applicant discloses that the inventors assessed whether CAR T cells containing a scFv derived from TGN1412 (CD28_CAR_1, CD28_CAR_2, CD28_CAR_11 and CD28_CAR_12 (Table 1) having a scFv containing the same heavy and light chain variable domains (VH and VL domains) as the full- length TGN1412 antibody would exert any particular effects on wild-type (and thus predominantly CD28-expressing) T cells, as compared to: (i) CAR T cells containing a scFv which also specifically binds CD28, but which has no known (super-)agonistic activity (CD28_CAR_14 having the same VH and VL domains as the full-length monoclonal antibody "CD28.3"; (ii) CAR T cells containing a CD19-binding scFv ("CD19_CAR"); or (iii) untransduced T cells (= T cells not transduced with a CAR encoding gene) (e.g. see Example 3 spanning page 64, line 33 – page 65, line 6).
The Applicant discloses that no increased IFNy levels were detected in the wild-type T cells 24 hours after co-culture with either of the different CAR T cells or the untransduced T cells (e.g. see Example 3 on page 65, lines 25-28). The Applicant also discloses that CAR T cells bearing a TGN1412 scFv provided stronger improvement in survival as compared to CAR T cells bearing a CD28.3 scFv (e.g. see page 70, lines 18-20).
When given the broadest reasonable interpretation in light of specification, the anti-CD28 CARs of the instant invention are defined broadly to be any CAR that comprises any ectodomain comprising at least one of any antigen binding moiety that is capable of specific binding to the extracellular portion of CD28.
It is noted that the broadest claims (claims 1 and 8) do not indicate sufficient structure for the genus of anti-CD28 CARs.
Dependent claim 2 recites sufficient structure for the anti-CD28 CARs but the structure is recited in a “preferably” clause which, as noted above in the rejection under U.S.C. 112(b), means that it is unclear whether or not this structure is actually a part of the invention or merely exemplary.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by 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 genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3). In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
It is well known that antigen binding domains of CARs fall in three general categories, either single chain variable fragments (scFvs) derived from antibodies, Fab’s selected from libraries, or natural ligands that engage their cognate receptor (e.g. see Sadelain et al. Cancer Discov. 2013;3(4):388–398, page 389, left column, second paragraph under “CAR TARGETING”). Successful examples in each of these categories have been reported. scFvs derived from murine immunoglobulins are commonly used, as they are easily derived from well-characterized monoclonal antibodies. They, however, may prove to be more immunogenic than Fab’s derived from human libraries or invariant human ligands (e.g. see Sadelain et al. Cancer Discov. 2013;3(4):388–398, page 389, left column, second paragraph under “CAR TARGETING”).
Regarding CARs comprising antibody-derived antigen binding domains, artisans are well aware that knowledge of a given antigen (for instance CD28) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. (J. Mol. Biol., 2003, 334:103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document).
As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen, as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data, such as that of Edwards et al., indicating the diversity of sequences in a population of antibodies that bind to a given antigen, no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen.
It should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antigen binding molecule to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway Jr et al., Immunology, 3rd Edition, 1997 Garland Publishing Inc., pages 3:1-3:11.see entire selection).
Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
This applies to the instant invention which is drawn to a genus of the anti-CD28 CAR T cells.
As noted above, the Applicant has disclosed 20 anti-CD28 CAR constructs which comprise one of five anti-CD28 scFv antigen binding fragments (TGN1412, CD28.3, Cl1B4, cl83, or Fengfeng). Such a disclosure does not serve to provide sufficient written description of the claimed genus of anti-CD28 CAR T cells.
The disclosure does not identify sufficient structural features or combination of features which give rise to the function of CD28 binding. Additionally, there does not appear to be any reasonable shared structure present in the genus of recited anti-CD28 CAR T cells which gives rise to their functional activity. Ultimately, identifying a CAR T cell simply on the basis of binding to CD28 rather than by identifying the sequence/structure, namely a complete set of six CDRs, of the anti-CD28 CAR T cells in question is generally insufficient to provide written description.
The claims are drawn to a broad genus of anti-CD28 CAR T cells which are functionally defined by their ability to bind to CD28 without reciting a corresponding structure expected to correlate with this ability as supported by Applicant’s disclosure. Thus, there is insufficient written description for the breadth of anti-CD28 CAR T cells as currently claimed, which are distinct and diverse and do not share a common structure that contributes to a common ability to bind to CD28.
Therefore, in view of the breadth of the claims and the limited disclosure, artisans would reasonably conclude that applicant was not in possession of the full breadth of anti-CD28 CAR T cells as encompassed by the claims at the time the instant application was filed.
Amending the claims to recite the amino acid sequences of the full set of six CDRs of TGN1412, CD28.3, Cl1B4, cl83, or Fengfeng, as is done in instant claim 2, and not in a “preferably” clause, would obviate this part of the rejection.
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 1-9 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Gomes-Silva et al. 2017 (Blood. 130 (3): 285–296, an IDS reference filed 07/19/2023) in view of Bahlis et al. 2007 (Blood. 109 (11): 5002–5010, an IDS reference filed 07/19/2023).
Independent claim 1 is drawn to a modified T cell, comprising (a) a disrupted endogenous CD28-encoding gene; and (b) a polynucleotide encoding a chimeric antigen receptor (CAR), wherein the CAR comprises in its ectodomain at least one antigen binding moiety that is capable of specific binding to the extracellular portion of CD28.
Dependent claim 2 limits the antigen binding moiety that is capable of specific binding to the extracellular portion of CD28 to an anti-CD28 antibody.
Dependent claim 3 limits the CAR to that which further comprises an endodomain comprising one or more T-cell-stimulatory molecules.
Dependent claim 4 limits the CAR of claim 3 to that wherein the endodomain of the CAR comprises a CD28 signaling domain and a CD3-zeta (CD3𝞯) signaling domain.
Dependent claim 5 limits the CAR to that which further comprises a transmembrane domain.
Dependent claim 6 limits the disruption of the endogenous CD28-encoding gene to that which is due to one or more nucleotide base insertions and/or deletions ('InDels') resulting from non-homologous end joining (NHEJ) DNA repair of DNA double-strand breaks (DSBs).
Dependent claim 7 is drawn to a population of modified T cells, comprising the modified T cell of claim 1, wherein at least 25%, at least 50%, or at least 70% of the modified T cells of the population express the CAR on their surface.
Dependent claim 8 is drawn to a method for generating modified T cells in vitro, comprising (a) disrupting the endogenous CD28-encoding gene in T cells; and (b) introducing into said T cells a polynucleotide encoding a chimeric antigen receptor (CAR), wherein the CAR comprises in its ectodomain at least one antigen binding moiety that is capable of specific binding to the extracellular portion of CD28.
Dependent claim 9 is drawn to modified T cells obtained by the method of claim 8.
Dependent claim 15 is drawn to the use of the modified T cell according of claim 1 for selective depletion of CD28+ cells in a sample in vitro.
Gomes-Silva et al. teach that although CD7 is an attractive therapeutic target for T-cell malignancies, effector T cells modified with CD7-specific CARs fail to substantially downregulate CD7 expression, resulting in extensive fratricide and precluding T-cell expansion (e.g. see page 294, paragraph spanning left and right columns). Regarding claims 1 and 8, Gomes-Silva et al. further teach that targeted genomic disruption of the CD7 gene renders CD7 CAR T cells resistant to fratricide, permitting robust expansion without compromising T-cell antigen recognition through their native or chimeric receptors. CD7KO CD7 CAR T cells eliminated malignant T-cell lines and primary tumor cells and protected mice against systemic leukemia progression in a xenograft model (e.g. see page 294, paragraph spanning left and right columns). Gomes-Silva et al. also teach that their genetic editing approach may enable the generation of CAR T cells to be redirected to other T-lineage antigens to broaden the range of targetable tumors (e.g. see page 295, right column, third paragraph).
Further regarding claim 1 and regarding claims 2-4 and 8, Gomes-Silva et al. also teach that a CD7-specific single-chain variable fragment of CD7-specific antibody were cloned into a second-generation backbone CAR containing a IgG1 Fc as a spacer region, a CD28 transmembrane domain and CD28 and CD3z endodomains (e.g. see page 286, left column, third paragraph; and Figure 1A).
Regarding claim 6, Gomes-Silva et al. also teach that the CD7 gene was disrupted using the CRISPR/Cas9 system (e.g. see page 288, paragraph spanning left and right columns).
Regarding claims 7, 9, and 15, Gomes-Silva et al. also teach that their method allowed for them to consistently obtain a T-cell product containing >80% CD7-knockout (CD7KO)CD7 CAR T cells (e.g. see paragraph spanning pages 288 and 289 and Figure2D).
Degrading claim 8, teach a method of generating the CD7KO CD7 CAR T cells in vitro by disrupting the endogenous CD7-encoding gene in T cells and transducing the T cells with a CD7 CAR-encoding gammaretroviral vector (e.g. see page 286, left column, paragraphs 3 and 4; and the paragraphs spanning pages 287-291).
Gomes-Silva et al. do not teach CD28 instead of CD7. Specifically, Gomes-Silva et al. do not teach that the CAR T cell targets CD28 or that the CD28 gene is disrupted in the CAR T cell instead of CD7.
Bahlis et al. teach that CD28 has a restricted lineage expression, found predominantly on T cells but also on normal plasma cells, primary myeloma isolates, and myeloma cell lines at levels comparable with T cells (e.g. see page 5002, paragraph spanning left and right columns). Bahlis et al. also teach that CD28 expression on myeloma cells correlates with poor prognosis and disease progression and delivers both antiproliferative and prosurvival signals (e.g. see page 5008, left column, third paragraph). Bahlis et al. also teach that identifying CD28 and bone marrow APCs as potential contributors to the pathogenesis of MM raises the possibility of targeting them therapeutically, such as strategies for direct targeting/blocking of CD28 (e.g. see page 5009, paragraph spanning the left and right columns).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Gomes-Silva et al. to incorporate the teachings of Bahlis et al. to include that the CAR T cell targets CD28 and that the CD28 gene is disrupted in the CAR T cell instead of CD7. This is because CD28 appears to be a good target for treating multiple myeloma but CD28 is still expressed on T cells (Bahlis et al.).
Given that CD28 appears to be a good target for treating multiple myeloma because of its expression on myeloma cells correlates with poor prognosis and disease progression while also delivering both antiproliferative and prosurvival signals; it would have been obvious to a skilled artisan, with the goal of treating multiple myeloma, to modify the anti-CD7-CAR T cell taught by Gomes-Silva et al. to instead target CD28 with a reasonable expectation of success.
Furthermore, given that endogenous CD7 expression was knocked out by genomic disruption in the anti-CD7-CAR T cell taught by Gomes-Silva et al. in order to eliminate fratricide; it would have been obvious to a skilled artisan to also knock out endogenous CD28 expression in the anti-CD28 CAR T cells taught by Gomes-Silva et al. in view of Bahlis et al. Given that CD28 is well known to be expressed on T cells, a skilled artisan would have reasonably expected that knocking out endogenous CD28 expression in these anti-CD28 CAR T cells would render them resistant to fratricide.
Given the teachings of Gomes-Silva et al. in view of Bahlis et al.; a skilled artisan would have reasonable expected that a CD28KO CD28 CAR T would be able to specifically target and kill CD28-expressing myeloma cells while also remaining resistant to fratricide.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 1 and 2 are rejected under 35 U.S.C. 103 as being unpatentable over Gomes-Silva et al. 2017 (Blood. 130 (3): 285–296, an IDS reference filed 07/19/2023) in view of Bahlis et al. 2007 (Blood. 109 (11): 5002–5010, an IDS reference filed 07/19/2023), as applied to claim 1, respectively, and further in view of Georges et al. 2020 (US20200199234A1).
It is noted that dependent claim 2 has already been rejected under 35 U.S.C. 103 above because the CDRs recited in the claim are recited in a “preferably” clause have not been considered for the purposes of applying prior art for the reasons set forth in the rejection under 35 U.S.C. 122(b) above.
However, if the CDRs are considered a part of the invention, then they can still be rejected under 35 U.S.C. 103 for the reasons outlined below.
Dependent claim 2 limits the antigen binding moiety that is capable of specific binding to the extracellular portion of CD28 to an anti-CD28 antibody, preferably an anti-CD28 single-chain variable fragment (scFv); wherein preferably the anti-CD28 antibody or anti-CD28 scFv comprises: a VH CDR1, CDR2 and CDR3 consisting of the amino acid sequences of SEQ ID NO: 8, 9 and 10, and a VL CDR1, CDR2 and CDR3 of the amino acid sequences of SEQ ID NO: 11, 12 and 13.
The combined teachings of Gomes-Silva et al. in view of Bahlis et al. pertaining to claim 1 and the rationale for combining them is outlined in the 103 rejection above.
The combined reference teachings differ from the instant invention by not teaching that the anti-CD28 antibody or anti-CD28 scFv comprises: a VH CDR1, CDR2 and CDR3 consisting of the amino acid sequences of SEQ ID NO: 8, 9 and 10, and a VL CDR1, CDR2 and CDR3 of the amino acid sequences of SEQ ID NO: 11, 12 and 13.
Georges et al. teach an anti-CD28 antibody comprising the CDRs recited in claim 2 (e.g. see the VH (SEQ ID NO: 26) and VL (SEQ ID NO: 27) amino acid sequences for CD28(SA) in table B on page 66 and sequence alignments below). Georges et al. also teach that the CD28(SA) antibody is a superagonist that has a very strong affinity for CD28 in the range of 1-2 nM with a binding half-life of about 32 minutes (e.g. see [0903]).
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Alignment of Georges et al.’s SEQ ID NO: 26 and fused instant SEQ ID NOs: 8-10:
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Alignment of Georges et al.’s SEQ ID NO: 27 and fused instant SEQ ID NOs: 11-13:
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combined teachings of Gomes-Silva et al. in view of Bahlis et al. as applied to claim 1, and to incorporate the teachings of Georges et al. to include that the anti-CD28 antibody or anti-CD28 scFv comprises: a VH CDR1, CDR2 and CDR3 consisting of the amino acid sequences of SEQ ID NO: 8, 9 and 10, and a VL CDR1, CDR2 and CDR3 of the amino acid sequences of SEQ ID NO: 11, 12 and 13.
Given that the CD28KO CD28 CAR T cells taught by Gomes-Silva et al. in view of Bahlis et al. comprise an antigen-binding domain comprising an anti-CD28 scFv antibody; it would have been obvious to a skilled artisan to select the CD28(SA) antibody as taught by Georges et al. as the source of the CDRs for the anti-CD28 scFv antibody in the CD28KO CD28 CAR T cells taught by Gomes-Silva et al. in view of Bahlis et al. with a reasonable expectation of success. The CD28(SA) antibody taught by Georges et al. has very strong affinity for CD28 and, therefore, a skilled artisan would reasonably choose to use it as a template for an anti-CD28 binding domain of a CAR T cell.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
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/GRACE H LUNDE/Examiner, Art Unit 1641 /MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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