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 November 26, 2025 is pending.
Claims 1-28 and 30-41 are canceled.
Claims 29 and 42-47 are pending.
Claims 29 and 47 are independent claims.
Election/Restriction
Applicant’s election without traverse of Group II (claims 29 and 42-47 drawn to methods of treating cancer, a plasma cell disorder, or an autoimmune disease in a subject in need thereof); and the species of an autoimmune disease and systemic lupus erythematosus (SLE) in the reply filed on November 26, 2025 is acknowledged.
Claims 29 and 42-47 are currently under consideration as they read on the elected invention.
Priority
The instant Application is a CON of 16/476,588 (PAT 11,578,115) filed 07/09/2019 which is a 371 of PCT/US18/13213 filed 01/10/2018 which claims benefit to 62/584,060 filed 11/09/2017, 62/580,243 filed 11/01/2017, 62/472,275 filed 03/16/2017, and 62/444,605 filed 01/10/2017.
However, the provisional applications 62/444,605 (filed 01/10/2017) and 62/472,275 (filed 03/16/2017) upon which priorities are claimed fail to provide adequate support under 35 U.S.C. 112(a) for claims 29 and 42-47 of this application.
Specifically, insufficient support was identified for the limitation of “a method of treating an autoimmune disease in a subject” in these two provisional applications. Consequently, the claims have been accorded the priority of the filing date of the provisional application 62/580,243 on November 1, 2017.
Additionally, none of the priority documents provide adequate support under 35 U.S.C. 112(a) for claims 44 and 47 of this application.
Specifically, insufficient support was identified for the limitation of “wherein the lymphodepletion does not comprise administering fludarabine to the subject” in the priority documents. Consequently, claims 44 and 47 have been accorded the filing date of November 23, 2022.
Should Applicant disagree with the Examiner’s factual determination above, it is incumbent upon Applicant to provide a showing that specifically supports the instant claim limitations.
Nucleotide and/or Amino Acid Sequence Disclosures
It is noted that the Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. The Incorporation by Reference paragraph to the sequence listing recites the wrong file name. The paragraph should recite: “The contents of the electronic sequence listing (M105370010US04-SEQ-ARM.xml; Size: 58,957 bytes; and Date of Creation: November 23, 2022) is herein incorporated by reference in its entirety.”
Specification
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: in claim 44 the limitation “wherein the lymphodepletion does not comprise administering fludarabine to the subject” in lines 1 and 2 is not recited in the instant specification.
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 29 and 42-47 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 29 and 47 recite the limitation “a T cell intracellular signaling domain comprising a mutation of a tyrosine residue in an immunoreceptor tyrosine based activation motif (ITAM) II” in lines 8-9 and 10-11, respectively. The phrase “mutation of a tyrosine residue in an immunoreceptor tyrosine based activation motif (ITAM) II” has insufficient antecedent basis because it is unclear if the “T cell intracellular signaling domain” comprises an ITAM II that comprises a tyrosine that can be mutated.
Amending the claims to recite “a T cell intracellular signaling domain, wherein the T cell intracellular signaling domain comprises an immunoreceptor tyrosine based activation motif (ITAM) II, and wherein the ITAM II comprises a mutation in a tyrosine residue” would obviate this part of the rejection.
Claim 46 recites the limitation “wherein the target-binding comprises a CD19-binding sequence” in lines 1 and 2. There is insufficient antecedent basis for the phrase “the target-binding” because claim 46 depends on claim 29 which recites “a target-binding sequence” not just “a target-binding.” Amending claim 46 to recite “wherein the target-binding sequence comprises a CD19-binding sequence” 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 29 and 42-47 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 a methods of treating an autoimmune disease in a subject in need thereof, the method comprising administering a cell comprising a chimeric antigen receptor (CAR) polypeptide comprising: (a) an extracellular domain comprising a target-binding sequence; (b) a transmembrane domain; (c) a co-stimulatory domain; and (d) a T cell intracellular signaling domain comprising a mutation of a tyrosine residue in an immunoreceptor tyrosine based activation motif (ITAM) II.
The Applicant has disclosed a single CAR that comprises tyrosine mutations in its ITAM II: anti-BCMA CAR-mutITAM2 (SEQ ID NO: 36) (e.g. see [00327]). In anti-BCMA CAR-mutITAM2, the ITAM II comprises tyrosine to phenylalanine mutations at Y440 and Y452 of SEQ ID NO: 36 (e.g. see [00327]). It is noted that the Applicant has disclosed two scFv, a BCMA scFv (e.g. see [00289]) and a CD37 scFv (e.g. see [00293] and [00297]), which can theoretically be used as the target-binding sequence and combined with a T cell intracellular signaling domain comprising the mutITAM2 sequence.
When given the broadest reasonable interpretation in light of specification, the CARs of the instant invention are defined broadly to be any CAR molecule that comprises a T cell intracellular signaling domain comprising a mutation of a tyrosine residue in an ITAM II.
It is noted that the broadest claim (claim 29) does not indicate any specific structure for the genus of CARs comprising a T cell intracellular signaling domain comprising a mutation of a tyrosine residue in an ITAM II as claimed.
None of the dependent claims rectify this deficiency.
Dependent claim 46 and independent claim 47 limit the genus of CARs to those that target CD19 but still fail to indicate any specific structure.
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 CD19) 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 antibody 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 CARs comprising a T cell intracellular signaling domain comprising a mutation of a tyrosine residue in an ITAM II and subgenera that target CD19 that encompasses those that comprise antigen binding domains derived from antibodies, namely an scFv comprising the CDRs or VH and VL domains of a parent antibody.
As noted above, the specification only discloses a single CAR that comprises tyrosine mutations in its ITAM II: anti-BCMA CAR-mutITAM2 (SEQ ID NO: 36). However, the Applicant has disclosed two scFv, a BCMA scFv (e.g. see [00289]) and a CD37 scFv (e.g. see [00293] and [00297]), which can theoretically be used as the target-binding sequence and combined with a T cell intracellular signaling domain comprising the mutITAM2 sequence.
Nonetheless, such a disclosure does not serve to provide sufficient written description of the claimed genus of CARs comprising a T cell intracellular signaling domain comprising a mutation of a tyrosine residue in an ITAM II or subgenera that target CD19. Further, the disclosure does not identify any specific structural features or combination of features which give rise to the function of binding to desired target or CD19. Additionally, there does not appear to be any reasonable shared structure present in the genus of recited CARs which gives rise to their functional activity. Ultimately, identifying an CAR simply on the basis of what it binds rather than by identifying the sequence/structure, namely the CDRs, of the CAR in question is generally insufficient to provide written description of the CAR in question.
There is insufficient written description for the breadth of CARs comprising a T cell intracellular signaling domain comprising a mutation of a tyrosine residue in an ITAM II as currently claimed, which are distinct and diverse and do not share a common structure that contributes to a common ability to bind to a desired target, including CD19.
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 CARs comprising a T cell intracellular signaling domain comprising a mutation of a tyrosine residue in an ITAM II encompassed by the claims at the time the instant application was filed.
Enablement
Claims 29 and 42-45 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating an autoimmune disease in a subject in need thereof by administering a cell comprising an anti-CD19 CAR that comprises a T cell intracellular signaling domain comprising a mutation of a tyrosine residue in an ITAM II; does not reasonably provide enablement for a method of treating an autoimmune disease in a subject in need thereof by administering a cell comprising any CAR that comprises a T cell intracellular signaling domain comprising a mutation of a tyrosine residue in an ITAM II. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The factors considered in determining whether a disclosure would require undue experimentation include:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP § 2164.01.
Nature of the invention/Breadth of the claims
Independent claim 1 is drawn to a method of treating an autoimmune disease in a subject in need thereof, the method comprising administering a cell comprising a chimeric antigen receptor (CAR) polypeptide comprising: (a) an extracellular domain comprising a target-binding sequence; (b) a transmembrane domain; (c) a co-stimulatory domain; and (d) a T cell intracellular signaling domain comprising a mutation of a tyrosine residue in an immunoreceptor tyrosine based activation motif (ITAM) II.
Dependent claim 42 and independent claim 47 limit the autoimmune disease to systemic lupus erythematosus (SLE).
Dependent claim 46 and independent claim 47 limit the CAR to an anti-CD19 CAR.
State of the prior art/Predictability of the art
Müller et al. 2024 (N Engl J Med. 390:687-700) teach that targeting B cells in autoimmune disease has long been limited to antibodies that either deplete B cells (e.g., through binding the B-cell–specific surface molecule CD20) or inhibit their activation (e.g., through binding B-cell activating factor) (e.g. see page 688, left column, first paragraph). Although antibody-based B-cell targeting certainly improved treatment of autoimmune disease, achieving long-lasting drug-free remission has proven elusive. CAR T cells could potentially achieve this goal by deep depletion of B cells through the targeting of the surface molecule CD19, which is expressed on a wide spectrum of B cells and plasmablasts. Several cases and one small case series have suggested the feasibility and short-term efficacy of CD19 CAR T-cell therapy in autoimmune disease (e.g. see page 688, left column, first paragraph).
Thus, Müller et al. teach that CD19 CAR T-cell transfer appeared to be feasible, safe, and efficacious in three different autoimmune diseases, including severe SLE, idiopathic inflammatory myositis, and systemic sclerosis (e.g. see Abstract, conclusions).
Müller et al. teach that despite differences in disease entities and previous treatments, the dynamics of CAR T-cell expansion and of B-cell ablation were highly consistent among patients (e.g. see page 695, right column, first paragraph under “Discussion”). CD19 CAR T cells at least appear to be able to achieve sustained disease- and drug-free remission (e.g. see page 698, right column, second paragraph).
Wang et al. 2025 (Medicine. 104: 47, 1-7) teach that CAR-T cell therapy has demonstrated promising efficacy and safety in the treatment of refractory autoimmune diseases, with CD19, BCMA, and CD20 as primary targets (e.g. see conclusion). With the continuous advancement of CAR-T cell technology, other surface antigens on B cells, such as CD22, CD70, CD33, and BAFF, are also being gradually developed as new therapeutic targets (e.g. see page 5, right column, second paragraph; and page 6, left column, first and second paragraphs). However, challenges remain, including immune-related toxicity, limited long-term follow-up, and the risk of antigen escape (e.g. see conclusion).
Thus, the prior art teaches that CAR T cells targeting CD19, BCMA, and CD20 are effective for treating autoimmune disease and CAR T cells targeting CD22, CD70, CD33, and BAFF show potential. However, the art very clearly teaches that the CAR cannot target any antigen.
Working examples/Guidance in the specification
The Applicant does not disclose any examples for treating an autoimmune disease with a CAR that comprises a T cell intracellular signaling domain comprising a mutation of a tyrosine residue in an ITAM II. The only examples of using any CAR were for treating multiple myeloma or B-cell malignancies (e.g. see examples).
Amount of experimentation necessary
The instant specification does not disclose any examples for treating an autoimmune disease with a CAR that comprises a T cell intracellular signaling domain comprising a mutation of a tyrosine residue in an ITAM II. The only examples of using any CAR were for treating multiple myeloma or B-cell malignancies.
Thus, there is insufficient objective evidence that the disclosed methods of treating multiple myeloma or a B-cell malignancy using a CAR that comprises a T cell intracellular signaling domain comprising a mutation of a tyrosine residue in an ITAM II can be extrapolated to provide guidance and direction for how to make and/or use any CAR comprising a mutation of a tyrosine residue in an ITAM II for treating an autoimmune disease, including SLE.
Thus, based on the content of the disclosure in view of the prior art which teaches that CAR T cells targeting primarily CD19, BCMA, and CD20 are effective for treating autoimmune disease, a skilled artisan, through extensive trial-and-error experimentation, would have to make a CAR for any target that comprises a T cell intracellular signaling domain comprising a mutation of a tyrosine residue in an ITAM II; and then use CAR for treating an autoimmune disease with a reasonable expectation of success. This quantity of experimentation goes beyond what is considered “a reasonable degree of experimentation” and constitutes undue further experimentation in order to enable the method for the breadth of what is claimed.
Thus, the specification does not enable one of ordinary skill in the art to make and/or use what is claimed and therefore claims 29 and 42-45 are rejected under 35 U.S.C. 112(a), enablement.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 29, 42, and 46 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Radic 2020 (US20200085871A1).
Given that the instant claims are recorded with the priority date of the filing date of the provisional application 62/580,243 on November 1, 2017 for the reasons stated above. Radic claims priority to US provisional application 62/472,709 filed 03/17/2017 and is therefore deemed to be a prior art under 35 USC 102(a)(2).
Radic teach a method of treating an autoimmune disease in a subject, the method comprising: administering a plurality of engineered cytotoxic T cells to the subject, wherein each of the plurality of engineered cytotoxic T cells comprise a recombinant vector that expresses a chimeric antigen receptor, depleting the number of antibody-producing cells in the subject, improving one or more clinical manifestations of the autoimmune disease in the subject, and treating the autoimmune disease in the subject (e.g. see claim 1). Radic also teach that the autoimmune disease is Systemic Lupus Erythematosus (SLE) (e.g. see claim 2) and that the chimeric antigen receptor (CAR) comprises anti-CD19 binding domain (e.g. see claim 8).
Radic also teach that the conserved tyrosine residues in two of the three ITAMs, including ITAM2, from the CD3ζ (zeta) signaling domain were mutated to alanine residues, which reduce the activation of CAR-T cells, and thus decreases exhaustion leading to an increased persistence of the engineered T cells in vivo (e.g. see [0539]).
As such, claims 29, 42, and 46 are anticipated by Radic.
Claim Rejections - 35 USC § 103
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 43 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Radic 2020 (US20200085871A1, a 102(a)(2) reference with an effective filing date of 03/17/2017) in view of Enblad et al. 2015 (Hum. Gene Ther. 26(8), 498-505).
The teachings of Radic are outlined in the 102 rejection above
Radic does not teach that lymphodepletion is performed on the subject prior to administering the cell; or wherein the lymphodepletion comprises administering cyclophosphamide or Bendamustine to the subject.
Enblad et al. teach that CAR T-cell therapy has limited effect if the patients do not receive preconditioning therapy (e.g. see page 502, right column, first paragraph). Preconditioning chemotherapy is often given to patients receiving immunotherapy to decrease Tregs and MDSCs that may otherwise hinder the intended immune activation. The most commonly used protocol uses fludarabine and cyclophosphamide before infusion of CAR T-cells (e.g. see page 502, right column, first paragraph).
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 Radic to incorporate the teachings of Enblad et al. to include that that lymphodepletion is performed on the subject prior to administering the cell and wherein the lymphodepletion comprises administering cyclophosphamide or Bendamustine to the subject.
Given that the effects of CAR T-cell therapy are limited if the patients do not receive preconditioning therapy in order to decrease Tregs and MDSCs that may otherwise hinder the intended immune activation and that the most common preconditioning protocol uses fludarabine and cyclophosphamide before infusion of CAR T-cells; it would have been obvious to a skilled artisan, with the goal of improving Radic’s method of treating an autoimmune disease with a CAR that comprises a modified ITAM, to have experimented with preconditioning the subjects with fludarabine and cyclophosphamide in order to decrease Tregs and MDSCs that may otherwise hinder the intended immune activation by the CAR T cells with a reasonable expectation of success.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 44 and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Radic 2020 (US20200085871A1, a 102(a)(2) reference with an effective filing date of 03/17/2017) in view of Enblad et al. 2015 (Hum. Gene Ther. 26(8), 498-505) and Maziarz et al. 2022 (Transplant. Cell. Ther. 28(11), 723-726).
The teachings of Radic are outlined in the 102 rejection above
Radic does not teach performing lymphodepletion on the subject, wherein the lymphodepletion does not comprise administering fludarabine to the subject.
The teachings of Enblad et al. are outlined in the 103 rejection above.
Maziarz et al. teach that host immune depletion has been recognized as a necessary step for successful adoptive immune cell transfer in both the autologous and allogeneic settings (e.g. see Abstract). The chemotherapy agent fludarabine as an immune suppressive agent has a central role in multiple conditioning regimens for both transplantation and immune effector cell therapies. With the recent and sudden recognition of an imminent worldwide fludarabine shortage, novel approaches to overcome supply chain disruption are needed, including exploration of alternative therapies (e.g. see Abstract).
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 Radic to incorporate the teachings of Enblad et al. and Maziarz et al. to include that that lymphodepletion is performed on the subject prior to administering the cell and wherein the lymphodepletion does not comprise administering fludarabine to the subject.
Given that the effects of CAR T-cell therapy are limited if the patients do not receive preconditioning therapy in order to decrease Tregs and MDSCs that may otherwise hinder the intended immune activation and the recent and sudden recognition of an imminent worldwide fludarabine shortage; it would have been obvious to a skilled artisan, with the goal of improving Radic’s method of treating an autoimmune disease with a CAR that comprises a modified ITAM and preserving the dwindling fludarabine, to have experimented with preconditioning subjects for lymphodepletion with an agent other than fludarabine in order to decrease Tregs and MDSCs that may otherwise hinder the intended immune activation by the CAR T cells with a reasonable expectation of success.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed
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/GRACE H LUNDE/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641