DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-3, 7, and 9-21, of record 1/15/2026, are pending and subject to prosecution. Claims 1, 3, 11, and 13-20 are amended. Claims 4-6 are cancelled.
Status of Prior Rejections/Response to Arguments
RE: Objection to the drawings:
The submission of replacement drawings is effective to obviate the objection. The objection is withdrawn.
RE: Objection to the specification:
The amendment to the specification is effective to obviate the objection. The objection is withdrawn.
RE: Objection to claims 14-16:
The amendment to claims 14-16 is effective to obviate the objection. The objection is withdrawn.
RE: Rejection of claims 13-18 under 35 U.S.C. 101:
The amendment to claims 13-18 to require a method of treating a patient is effective to obviate the rejection. The rejection is withdrawn.
RE: Rejection of claims 13-21 under 35 U.S.C. 112(b):
The amendments to claims 13-18 to require a method of treating a patient and to correct antecedent basis are effective to obviate the rejection. The rejection is withdrawn.
RE: Rejection of claims 1-3, 7, 9-14, and 17-18 under 35 U.S.C. 103 over Gill et al. (US 20180244748 A1) in view of Goodridge et al. (Traffic, 2012) and Chang et al. (Trends in Molecular Medicine, 2017):
RE: Rejection of claims 1-3, 7, and 9-18 under 35 U.S.C. 103 over Gill et al. (US 20180244748 A1) in view of Goodridge et al. (Traffic, 2012) and Chang et al. (Trends in Molecular Medicine, 2017), further in view of Blaeschke et al. (Cancer Immunology, Immunotherapy, 2018):
RE: Rejection of claims 1-3, 7, 9-14, and 17-20 under 35 U.S.C. 103 over Gill et al. (US 20180244748 A1) in view of Goodridge et al. (Traffic, 2012) and Chang et al. (Trends in Molecular Medicine, 2017), further in view of Wilson et al. (US 20180133252 A9):
The amendment to claim 1 to require SEQ ID NO 3 is effective to obviate the rejections. The rejections are withdrawn.
RE: Rejection of claims 1-7, 9-14, and 17-18 under 35 U.S.C. 103 over Gill et al. (US 20180244748 A1) in view of Goodridge et al. (Traffic, 2012) and Chang et al. (Trends in Molecular Medicine, 2017), further in view of Yokota et al. (Gene, 2001):
The applicant asserts that the “reverse Dectin-1” of the instant application differs from native Dectin-1 at the level of primary amino acid sequence orientation rather than at the level of membrane topology or domain positioning (Applicant Remarks, page 10-11). The applicant asserts that the prior art references do not teach or suggest that the amino acid sequence must or should be reversed when incorporated into a CAR and that the transmembrane domain sequence disclosed by Yokota et al. is longer than that of instant SEQ ID NO 3, now required by the independent claim (Applicant Remarks, page 11-13). The applicant asserts unexpected results in the form of enhanced cytokine secretion, reduced exhaustion potential, increased cell expansion, and distinct antitumor activity (Applicant Remarks, page 12).
The applicant’s arguments have been considered but are not found persuasive.
The image below is adapted from Goodridge et al. (fig. 2). For the sake of simplification, the dectin-1 intracellular signaling domain is indicated as ABCD, with D being the most N-terminal amino acid and A being the most C-terminal amino acid. The applicant’s argument appears to hinge on the idea that one of ordinary skill would assume that a dectin-1 domain sequence, when inserted into a CAR, should be inserted in the same relative position to the cell membrane as in the native protein. However, in the native protein, signaling propagation occurs in a C-terminal to N-terminal direction, as dectin-1 is
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a type II transmembrane protein with its C-terminus located extracellularly.
The native dectin-1 protein is expressed as N-term…DCBA…C-term, which corresponds to [C-term]-[extracellular domain]-[TM]-[ABCD]-[N-term]. CARs are constructed as type I membrane proteins, with their N-termini located extracellularly and their C-termini located intracellularly (See Chang et al., fig. 1), however. In order for the dectin-1 domain to have the same orientation relative to its putative intracellular interacting partners and to propagate signals in the same manner, the CAR would need to be expressed as N-term…ABCD…C-term or [N-term]-[extracellular domain]-[TM]-[ABCD]-[C-term]. Reversing the amino acid sequence of the dectin-1 domain relative to the native protein would be required to ensure recapitulation of native signaling activity and interaction with partners in a CAR, a deduction that would be fully within the power of the ordinary artisan who is capable of designing and constructing cellular receptors, and reversing the sequence of the dectin-1 intracellular domain (taught by Yokota et al., fig. 1) would yield a sequence comprising that of instant SEQ ID NO 3. While the sequence taught by Yokota et al. is longer than that of instant SEQ ID NO 3, the claims feature “comprising” language. Because “comprising” is open-ended or inclusive transitional phrase and does not exclude additional unrecited elements, the sequence of Yokota et al., when reversed, encompasses and therefore reads on the limitation requiring SEQ ID NO 3. See MPEP 2111.03(I).
Regarding the assertion of unexpected results, in order for a showing of unexpected results to overcome a finding of obviousness, the evidence must be commensurate with the claims. See MPEP 716.02(d). In the example provided, CARs with CD19- or HER2-targeting scFvs, a CD8α hinge, CD3 signaling domain, and 4-1BB or dectin-1 intracellular costimulatory domains were compared (¶0134 and 0140). The scope of the instant claims is considerably broader than the tested dectin-1-derived CARs, and insufficient data is provided for one of ordinary skill in the art to be able to extrapolate the results of the disclosure to the genus of species encompassed by the claims. Further, comparison to only one other costimulatory domain does not enable evaluation of whether the results are genuinely unexpected.
The rejection is maintained in modified form to address amended limitations.
Maintained Rejections
Claim Interpretation
Claim 1 is interpreted as requiring the dectin-1 costimulatory domain to comprise any contiguous amino acid sequence within instant SEQ ID NO 3 that is capable of functioning in signaling.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 7, 9-14, and 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Gill et al. (US 20180244748 A1), of record, in view of Goodridge et al. (Traffic, 2012), of record, Chang et al. (Trends in Molecular Medicine, 2017), of record, and Yokota et al. (Gene, 2001), of record.
Regarding claims 1-2: Gill et al. teach immune cells expressing CARs for use in cancer therapy (See Abstract). The CAR comprises an antigen binding domain (which reads on “extracellular domain”), transmembrane domain, and an intracellular domain comprising a stimulatory and/or co-stimulatory molecule (which read on “costimulatory signaling domain”) (See ¶0005 and fig. 1). The antigen binding domain can target CD19 or HER2 and can comprise an scFv (See ¶0023, 0026, 0134-0135, 0216-0217, 0235). The CAR intracellular domain and/or transmembrane domain can comprise the transmembrane and/or intracellular domain of dectin-1 (See ¶0023, 0064-0067, 0229, and 0353-0354 and fig. 1B and 10). Gill et al. do not expressly teach the costimulatory domain as comprising a reverse dectin-1 sequence.
Goodridge et al. teach that dectin-1 is oriented in the cell membrane with its C-terminus extending extracellularly and its N-terminus internal to the cell (See fig. 2).
Chang et al. teach that CARs are constructed with N-terminal extracellular antigen binding domains and C-terminal co-stimulatory/activation domains (See fig. 1).
Yokota et al. teach that the human dectin-1 cytoplasmic domain comprises the sequence MEYHPDLENLDEDGYTQLHFDSQSNTRIAVVSEKGSCAASPPW (See fig. 1). The inverse of this sequence is comprised by instant SEQ ID NO 3 (See alignment below).
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It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the CAR of Gill et al. to comprise a dectin-1 intracellular domain wherein the sequence is reversed as compared to the native protein (which would read on “reverse dectin-1”). One would be motivated to make this modification because Goodridge et al. and Chang et al. teach that CARs are typically oriented in an opposite manner compared to dectin-1 relative to the intracellular and extracellular spaces, which suggests that, when expressed as part of a CAR, the dectin-1 intracellular domain sequence would need to be reversed in order to retain native functionality and interaction with binding partners in the signal transduction process. The sequence of Yokota et al., when reversed for integration into a CAR, would read on a CAR comprising the sequence of instant SEQ ID NO 3. There would be a reasonable expectation of success in making this modification because a reversed dectin-1 sequence could be readily cloned into a CAR expression construct.
Regarding claim 3: Following the discussion of claims 1-2, 7, 9-13, and 17-18, Gill et al. teach a CAR comprising a CD19 scFv, CD8 hinge, and dectin-1 intracellular domains (See fig. 10A) but do not expressly teach a CD3ζ signaling domain.
However, Gill et al. teach that the intracellular domain of the CAR can comprise dual signaling domains or can include any portion of one or more co-stimulatory molecules (See ¶0151 and 0228-0229). It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to further modify the CAR of Gill et al., modified by Goodridge et al. and Chang et al., to comprise a CD3ζ signaling domain. One would be motivated to make this modification because Gill et al. teach that co-stimulatory molecules such as CD3ζ can be used to modulate the initial stimulus (See ¶0151). There would be a reasonable expectation of success in making this modification because Gill et al. teach that the CAR can comprise more than one co-stimulatory or signaling domains (See ¶0151 and 0228-0229).
Regarding claim 7: Following the discussion of claims 1-2, Gill et al. teach that the CAR can be expressed via a lentiviral vector (See ¶0064, 0242, 0244, 0247, and 0321).
Regarding claims 9-13 and 17-18: Following the discussion of claims 1-2, Gill et al. teach that cells comprising the CARs can be included in a pharmaceutical composition with a pharmaceutically acceptable carrier for treating solid tumors and/or hematological tumors (which reads on “[u]se… in preparation of an antitumor drug”) (See Abstract and ¶0291-0292 and 0299). The types of cancer that can be treated include breast cancer, ovarian cancer, non-Hodgkin’s lymphoma, chronic myelogenous leukemia (which reads on “myelogenous leukemia”), and acute lymphocytic leukemia (which reads on “lymphoblastic leukemia”) (See ¶0146 and 0301). Gill et al. teach the CARs as expressed in a monocyte, macrophage, or dendritic cell but not expressly a T cell (See ¶0005 and 0210).
However, Gill et al. teach that T cells can be engineered to express ant-CD19 CARs and demonstrate high patent response rates (See ¶0002), which suggests that the CARs taught could also be readily expressed in T cells for anti-cancer use. While Gill et al. teach that CAR-T cell efficacy may be limited in terms of infiltration ability (See ¶0002-0003), the disclosure of a preferred embodiment (monocytes, macrophages, or dendritic cells) does not teach away from non-preferred alternatives. See MPEP 2123(I-II).
Regarding claim 14: Following the discussion of claims 1-2, 9-13, and 17-18, Gill et al. teach that the CAR-expressing cell possesses targeted effector activity that can include cytokine secretion (which reads on “stimulate secretion of effector cytokine” (See ¶0010 and 0293).
Claims 1-3, 7, and 9-18 are rejected under 35 U.S.C. 103 as being unpatentable over Gill et al. (US 20180244748 A1), of record, in view of Goodridge et al. (Traffic, 2012), of record, Chang et al. (Trends in Molecular Medicine, 2017), of record, and Yokota et al. (Gene, 2001), of record, further in view of Blaeschke et al. (Cancer Immunology, Immunotherapy, 2018), of record.
The teachings of Gill et al., Goodridge et al., Chang et al., and Yokota et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claims 15-16: Following the discussion of claims 1-3, 7, 9-14, and 17-18, Gill et al., modified by Goodridge et al., Chang et al., and Yokota et al., render obvious a T cell comprising a CAR comprising a reverse dectin-1 intracellular co-stimulatory domain but do not expressly teach the t cell as having a central memory phenotype upon stimulation.
Blaeschke et al. teach the induction of a central memory phenotype in anti-CD19 CAR-T cells for increasing proliferation and persistence in T cell therapy (See Abstract). CD4+ and CD8+ cells were separated, activated, and transduced with a CAR, resulting in approximately half of the cells having a central memory phenotype (which reads on “upon being stimulated, display phenotype of a central memory T cell”) (See fig. 1 and 4B). The cells released IFN-γ, TNF-α, and IL-6 upon target recognition (See Abstract and fig. 6).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the CAR-T cell rendered obvious by Gill et al., modified by Goodridge et al., Chang et al., and Yokota et al., with the production method of Blaeschke et al. One would be motivated to make this modification because Blaeschke et al. teach that central memory T cells promote sustained proliferation and persistence (See Abstract). The modified cells would be similarly expected to produce the cytokines IFN-γ, TNF-α, and IL-6 as taught by Blaeschke et al., upon CD19 binding. Such a modification to induce a central memory phenotype could be readily made.
Claims 1-3, 7, 9-14, and 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Gill et al. (US 20180244748 A1), of record, in view of Goodridge et al. (Traffic, 2012), of record, Chang et al. (Trends in Molecular Medicine, 2017), of record, and Yokota et al. (Gene, 2001), of record, further in view of Wilson et al. (US 20180133252 A9), of record.
The teachings of Gill et al., Goodridge et al., Chang et al., and Yokota et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claims 19-20: Following the discussion of claims 1-3, 7, 9-14, and 17-18, Gill et al., modified by Goodridge et al., Chang et al., and Yokota et al., render obvious a CAR comprising a reverse dectin-1 intracellular co-stimulatory domain. Gill et al. teach that the CAR construct can be cloned into a plasmid but do not expressly teach synthesis of the receptor expression construct.
Wilson et al. teach methods of making and using CARs for immunotherapy (See Abstract). A CD8α hinge and transmembrane domain and CD3ζ intracellular signaling domain were subcloned from cDNA (which reads on “synthesizing a gene sequence”) and assembled using splicing by overlapping extension by PCR (which reads on “synthesizing primers according to a target” and “an overlapping PCR method”) (See ¶0174).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Gill et al., modified by Goodridge et al., Chang et al., and Yokota et al., to comprise the transgene synthesis methods taught by Wilson et al. One would be motivated to make this modification because Wilson et al. demonstrate that CAR-T cells having specific anti-cancer activity can be generated in such a manner (See ¶0186-0200). While Wilson et al. teach a transmembrane domain from CD8α, not dectin-1, or forward and reverse primers, one of ordinary skill in the art would understand that PCR approaches can readily be tailored to a sequence of interest, such as dectin-1, and that forward and reverse primers are both intrinsic to the process and easily designed. Combining the teachings of Gill et al., Goodridge et al., Chang et al., Yokota et al., and Wilson et al. for generating an expression construct for a CAR comprising a dectin-1 transmembrane domain would yield a reasonable expectation of success.
Allowable Subject Matter
Claim 21 is objected to as being dependent upon a rejected base claim but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter: instant SEQ ID NOs 7-10 appear to be free of the prior art.
Conclusion
THIS ACTION IS MADE FINAL. 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 or earlier communications from the examiner should be directed to JENNIFER S SPENCE, whose telephone number is 571-272-8590. The examiner can normally be reached M-F 8:30-5:30.
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/J.S.S./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633